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THE
VETERINARY
CLINICS OF
NORTH
AMERICA
SMALL ANIMAL PRACTICE
Vaccines and Vaccinations
RICHARD B. FORD, DVM, MS, GUEST EDITOR
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VOLUME 31 NUMBER 3
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THE VETERINARY CLINICS OF NORTH AMERICA:
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May 2001
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VACCINES AND VACCINATIONS
GUEST EDITOR
RICHARD B. FORD, DVM, MS, Diplomate, American College of Veterinary Internal
Medicine; Professor, Department of Clinical Sciences, College of Veterinary Medicine,
North Carolina State University, Raleigh, North Carolina
CONTRIBUTORS
DEBORAH J. BRIGGS, MS, PhD, Rabies Laboratory, Kansas State University, College of
Veterinary Medicine, Manhattan, Kansas
M. GAYNE FEARNEYHOUGH, BS, DVM, Prior Director, Oral Rabies Vaccination
Program, Texas Department of Health, Zoonosis Control Division, Austin, Texas
from 1993-2000. Currently in private veterinary practice, San Antonio, Texas and
Director of AeroVace Co., a company for the aerial delivery of wildlife vaccine.
DUANE FLEMMING, DVM, JD, Diplomate, American College of Veterinary
Ophthalmologists; Contra Costa Animal Eye Clinic, Pleasant Hill, California
RICHARD B. FORD, DVM, MS, Diplomate, American College of Veterinary Internal
Medicine; Professor, Department of Medicine, North Carolina State University,
College of Veterinary Medicine, Raleigh, North Carolina
CRAIG E. GREENE, DVM, MS, Professor, Department of Small Animal Medicine,
College of Veterinary Medicine, University of Georgia, Athens, Georgia
DAVID R. HUSTEAD, DVM, International Technical Director, Fort Dodge Animal
Health, Overland Park, Kansas
E. KATHRYN MEYER, VMD, Veterinary Behavior Clinic, Potomac, Maryland; Former
Coordinator, United States Pharmacopeia Veterinary Practitioners' Reporting
Program, United States Pharmacopeia, Rockville, Maryland
GREGORY K. OGILVIE, DVM, Diplomate, American College of Veterinary Internal
Medicine; Professor of Oncology and Internal Medicine, Animal Cancer Center,
College of Veterinary Medicine, Department of Clinical Sciences, Veterinary Teaching
Hospital, Colorado State University, Fort Collins, Colorado
JAMES RICHARDS, DVM, Director, Cornell Feline Health Center, College of Veterinary
Medicine, Cornell University, Ithaca, New York
ILONA RODAN, DVM, Diplomate, American Board of Veterinary Practitioners;
Director, Cat Care Clinic, Madison, Wisconsin
iii
RONALD D. SCHULTZ, PhD, Professor, Department of Pathobiological Sciences, School
of Veterinary Medicine, University of Wisconsin-Madison, Madison, Wisconsin
KRISTEN SCHWEITZER, BS, Rabies Laborat0,!l' Kansas State University, College of
Veterinary Medicine, Manhattan, Kansas
...
KENT R. VAN KAMPEN, DVM, PhD, The Van Kampen Group, Inc., Hoover, Alabama
iv
CONTRfBUTORS
VACCINES AND VACCINATIONS
CONTENTS
Preface
Richard B. Ford
Vaccines and Vaccinations: The Strategic Issues
Richard B. Ford
The rapid proliferation of companion animal vaccines, advances
in diagnostic and vaccine technology, and concerns over vaccine
safety are clearly among the most important issues practicing
veterinarians face as we enter the 21st century. Although many
would argue that these are already issues, the future promises to
be especially challenging as the vaccines we currently use and
the protocols we recommend undergo unprecedented review.
Feline Vaccination Guidelines
James Richards and TIona Rodan
The 1998 Report of the American Association of Feline Practitioners
and Academy of Feline Medicine Advisory Panel on Feline Vaccines
was developed to help veterinary practitioners formulate vaccina-
tion protocols for cats. The current panel report updates informa-
tion, addresses questions, and speaks to concerns raised by the
1998 report. In addition it reviews vaccine licensing, labeling, and
liability issues and suggests ways to successfully incorporate
vaccination protocol changes into a private practice setting.
Canine Vaccination
Craig E. Greene, Ronald D. Schultz, and Richard B. Ford
New technologies for vaccine development and infectious disease
diagnosis are likely to be introduced in the near future. With this
VETERINARY CLINICS OF NORTII AMERICA:

VOLUME 31 NUMBER 3 MAY 2001
xi
439
455
473
v
new technology comes the opportunity to vaccinate companion
animals against even more infectious agents than is currentlx
practiced in the United States. As we look forward, it
-becomes
particularly important to review current vaccination standards
applied to dogs with respect to current knowledge of duration of
immunity, awareness of incidence, iWd likelihood of injurious
or even fatal adverse events associated with vaccination, and
individual risk factors that dictate which vaccines are most appro-
priate at which stage of life.
Vaccine-Associated Adverse Events
E. Kathryn Meyer
Although vaccination plays a vital role in maintaining animal
health, there are risks associated with this medical procedure.
Veterinarians are beginning to reexamine dogmatic vaccine proto-
cols and consider both risks and benefits of vaccination, with
special emphasis on adverse event information generated by prac-
titioner experience. The current status of postmarketing surveil-
lance for commercially available veterinary vaccines is presented,
along with a discussion of the strengths and limitations of surveil-
lance programs. An overview of adverse events commonly re-
ported by veterinarians is included, along with practical informa-
tion on how veterinarians can share their observations and learn
about adverse events reported by their colleagues.
The Potential for Liability in the Use a n ~ Misuse of
Veterinary Vaccines
Duane Flemming
The lack of specific rules regarding the use of animal vaccines by
veterinarians leaves them vulnerable to legal action for negligence
or breach of warranty. A veterinarian's liability may depend on
the answers to the questions asked in this article. The answers
ultimately depend on the specific circumstances of the case. Al-
though no one can ensure that he or she is never going to be
sued, veterinarians can go a long way in defending themselves
against these kinds of allegations by conforming to the standards
of practice as they apply to the care and use of vaccines; by
adhering closely to the doctrines of informed consent; and by not
providing undue warranty to the vaccine product he or she sells.
Recent Advances in the Treatment of Vaccine-Associated
Sarcomas
Gregory K. Ogilvie
This article reviews the background information about vaccine-
associated sarcomas followed by diagnostic procedures essential
to understand how to determine the extent of the primary and
metastatic tumor as well as to understand the general health of
493
515
525
vi CONTENTS
the patient. It also addresses the importance of understanding the
nonmedical needs of the client who is faced with this perplexing
problem.
Recombinant Vaccine Technology in Veterinary
Medicine
Kent R. Van Kampen
Recombinant technology is relatively new to veterinary medicine.
It combines safety, purity, potency, and efficacy in the vaccine. Its
positive features include not exposing the vaccinate to the patho-
gen, the lack of need for adjuvants, and stability that allows
some vaccine to remain viable at ambient temperatures. These
recombinants can receive multiple genetic inserts and present an
opportunity to have multiple combination vaccines for use in
animals. Licensed recombinant vaccines in veterinary medicine
include those protecting against Lyme disease, pseudorabies, ra-
bies, canine distemper, Newcastle disease, and a strain of avian
influenza.
What You Can and Cannot Learn From Reading a
Vaccine Label
David R. Hustead
Although most veterinarians look at vaccine labels each day, they
rarely see them. When practitioners sense a need to read labels,
they find that the labeling answers some of their basic questions
but that these labels often fail to address many relevant issues. In
addition, veterinarians find that the issues addressed are often
presented simplistically and that the labels are sometimes just
wrong. This article addresses what practitioners need to do to
better understand the products most of them use on a daily basis.
Rabies Postexposure Prophylaxis: Human and Domestic
Animal Considerations
M. Gayne Fearneyhough
The emphasis on rabies control and prevention in the United
States seems to be a function of our perception of proximity of
the threat. Wildlife rabies epizootics within a state may be of little
concern to the uninformed urban dweller. Additionally, many
parts of the western United States are free of terrestrial rabies;
were it not for the presence of bat rabies, people in those areas
would likely interpret rabies control as a minor public health
concern. It is essential that federal, state, and local public health
programs emphasize the importance of rabies control through
activities that include rabies education, sponsorship of legislated
requirements for domestic animal vaccination, support for local
animal control programs, and the promotion of recommendations
CONTENTS
535
539
557
vii
that encourage the appropriate use of postexposure prophylaxis.
We are almost guaranteed that rabies is going to remain a majQr
public health issue well into the next century because of ex-
panding wildlife rabies epizootics, identification of new rabies
viral variants with increased public fl'ealth concern, emotional and
legal concerns associated with rabilili exposure, and increasing
national cost associated with rabies control and prevention. Nev-
ertheless, the development of new laboratory technology that
allows an understanding of the epidemiologic nature of the rabies
virus based on an evolving genetic history and the interrelation-
ship with wildlife reservoirs should allow access to valuable tools
for rabies control. When combined with programs using new
developments in oral rabies vaccine that can immunize whole
populations of wildlife reservoirs, that technology offers encour-
agement in our effort to control one of the diseases of antiquity.
Importation of Dogs and Cats to Rabies-Free Areas of
the World
Deborah J. Briggs and Kristen Schweitzer
Public pressure from a very mobile society has caused the govern-
ments of many rabies-free areas to reevaluate lengthy quarantine
systems. In some areas a policy of vaccination, certification, and
rabies antibody testing have been implemented to reduce the
length of time a dog or cat must spend in quarantine. This has
caused an increasing need for pet owners and veterinarians to
understand quarantine regulations and shipping methods.
Index
573
585
Subscription Information Inside back cover
viii
CONTENTS
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ENDOSCOPY
Lynda Melendez, DVM, MS, Guest Editor
September 2001
ENDOCRINOLOGY
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Robert Kemppainen, DVM, PhD, Guest Editors
November 2001
CRITICAL CARE: C ARDIOVASCULAR Focus
Nishi Dhupa, BVM, MRCVS, Guest Editor
RECENT ISSUES
Mars:h 2001
C LINICAL THERIOGENOLOGY
Autumn P. Davidson, DVM, Guest Editor
January 2001
LAMENESS
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November 2000
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Philip Padrid, RN, DVM, Guest Editor
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VACCINES AND VACCINATIONS
PREFACE
RICHARD B. FORD, DVM, MS,
DIPLOMATE ACVIM
Guest Editor
By its very nature, the concept of change is a bitter pill ... after all, change
not only defies tradition, it challenges intellect and fosters uncertainty. Perhaps
it should be no surpirse that recent presentations and publications suggesting
dogs and cats receive fewer vaccines, and do so less often, have provoked
significant controversy, concern, and even confusion among companion animal
practitioners.
So why change? Vaccination is what we do well, and its what many veteri-
narians do most! Historically speaking, vaccination is a service that veterinary
medicine has provided to pets for well over 50 years ... and with exceptional
results. What better health value is there, in fact, than a vaccine capable of
preventing infection by highly contagious, virulent organisms such as rabies
virus, feline panleukopenia virus, or canine parvovirus? That dogs and cats
derive substantial health benefits from vaccination programs is unquestioned.
But, is there a "down-side" to vaccination? Have we, in fact, reached a point of
diminishing returns with respect to vaccination?
In this issue of The Veterinary Clinics of North America: Small Animal Practice,
we have attempted to address the controversies and the concerns over recom-
mended changes in vaccination protocols for dogs and cats. The reader must
understand that this publication is neither the final word on companion animal
vaccination nor is it intended to represent national vaccination standards. In-
stead, it is a compilation of articles that specifically target the foremost vaccina-
tion issues of importance to practicing veterinarians. Objectively, the articles
published in this issue will enable practitioners to make an informed decision
regarding which vaccines to use and how often to administer them.
In separate articles, an in-depth review of key controversies is presented
followed by two articles outlining the most current vaccination guidelines for
dogs and for cats. Supporting references are included. These three articles set
the stage for the papers that follow. A review of the table of contents will reveal
that some of the most contentious issues surrounding the vaccine controversy
are addressed: vaccine-associated adverse events (i.e., adverse reactions), use of
adjuvanted vaccine in cats, feline vaccine-associated fibrosarcoma, and new
xi
vaccine technology (recombinant vaccines). Of significant importance to veteri-
narians are the legal issues surrounding decisions to vaccinate in a 1l\anner not
specifically recommended on the manufacturers' label (package insert). Two
articles, one on interpreting the vaccine label and another that specifically ad-
dresses practitioner liability related to vlft:cination are included. Finally, two
highly informative articles on rabies imm4Pization, postexposure immunopro-
phylaxis and the latest update on importation of dogs and cats to rabies-free
areas of the world, are presented.
Back, then, to the original question. Are we, in fact, vaccinating dogs and
cats with too many vaccines, too often? In the absence of national vaccination
standards and routine monitoring, only the individual practitioner can answer
this question. Vaccination is a medical procedure that mandates clinical assess-
ment of the patient's health status and risk of exposure to infectious disease
when deciding which vaccine(s) to administer and when. All of us who have
contributed to this issue hope that the information provided will represent a
compelling starting point for at least reviewing vaccination protocols in place
within individual practices.
As the editor of this issue, I want to extend my sincere thanks to each of
the contributing authors who have willingly shared much of their valuable time
and expertise in preparing manuscripts on what must be considered one of the
most important topics facing companion animal medicine today. In addition, I
want to acknowledge Mr. John VassaUo, editor of The Veterinary Clincis of North
America: Small Animal Practice, for his suggestions, his patience, and his assis-
tance in completing this issue.
Professor of Medicine
North Carolina State University
College of Veterinary Medicine
Raleigh, NC 27606
xii
RICHARD B. FORD, DVM, MS, DIPLOMATE ACVIM
Guest Editor
PREFACE
VACCINES AND VACCINATIONS 0195--5616/ 01 $15.00 + .00
VACCINES AND VACCINATIONS
The Strategic Issues
Richard B. Ford, DVM, MS
The rapid proliferation of companion animal vaccines, advances in
diagnostic and vaccine technology, and concerns over vaccine safety are
clearly among the most important issues practicing veterinarians face as
we enter the twenty-first century. Although many would argue that
these are already issues, the future promises to be especially challenging
as the vaccines we currently use and the protocols we recommend
undergo unprecedented review.
Over the course of many years, veterinary medicine has done an
excellent job of educating pet owners on the importance of vaccinating
adult dogs and cats annually. There is absolutely no debate over the
health benefits that millions of animals have derived from widespread
availability of low-cost and highly effective vaccines. Nevertheless, a
growing awareness of vaccine-associated fibrosarcomas in cats and a
plausible relation between vaccination and immune-mediated disease
(e.g., hemolytic anemia, thrombocytopenia, polyarthritis) have motivated
pet owners and veterinarians to question the risk versus benefit associ-
ated with annual vaccination of adult dogs and cats. In 1998, the Ameri-
can Association of Feline Practitioners published the report of an advi-
sory panel on feline vaccines/ in which it was recommended that adult
cats be vaccinated every 3 years rather than annually against just one
antigen: feline parvovirus (panleukopenia). Reaction to this report was
profound. Veterinarians throughout North America voiced strong con-
From the Department of Clinical Sciences, College of Veterinary Medicine, North Carolina
State University, Raleigh, North Carolina
VETERINARY CLINICS OF NORTH AMERICA: SMALL ANIMAL PRACTICE
VOLUME 31 NUMBER 3 MAY 2001 439
440 FORD
'.
,
....
cems that anything other than annual vaccination of adult cats was
inappropriate, irrational, and quite detrimental. Now, approxi-
mately 3 years later, the "every 3 years" recommendation for feline
parvovirus remains in place and has, in been extended to include
feline herpesvirus-1 and feline calicivirus.
22
,24 Indeed, change is happening.
It is important to note, however, that the strategic issues sur-
rounding vaccination protocols are by no means limited to whether or
not a particular vaccine should be administered at intervals of 1 or 3
years. There are many other reasons why companion animal prac-
titioners should be compelled to review which vaccines are recom-
mended and how protocols are assigned to individual patients. For
example, what is the realistic risk of exposure considering the environ-
ment in which an individual animal lives? What is the realistic risk of
infection based on the patient's age? Are we overvaccinating our pa-
tients? What is the justification for incorporating new vaccines into
the practice? Should antibody titers be performed in lieu of annual
vaccination? Does the practice, in fact, have a unified vaccination policy?
To assume that all dogs and cats in the practice should be vaccinated
every year with every licensed vaccine is wrong. Vaccination is a medical
procedure, and it is the clinician's obligation to assess an individual
patient's health status in relation to age, living environment, and risk of
exposure and infection when making such medical decisions.
All this considered, are we vaccinating individual patients too often
with too many vaccines? Most authors would agree that the answer to
this question is "yes." The reader is reminded, however, despite all
the controversy, there are many strategic issues behind these public
proclamations of overvaccination that justify the need to challenge the
vaccination paradigms we have lived with for the past 50 or more years.
The discussion that follows addresses a number of the primary concerns
that, in effect, are promoting a comprehensive review of companion
animal vaccination protocols. These issues are likely to take on even
more importance in the future as new vaccines continue to be introduced
and as more veterinarians take time to report adverse events associated
with vaccination.
ANNUAL VACCINATION
In 1989, the American Veterinary Medical Association (AVMA)
Council on Biologic and Therapeutic Agents published immunization
guidelines for dogs and cats.2 In its report, booster vaccinations for all
canine and feline vaccines were recommended annually (vaccines for
canine Lyme disease, canine corona virus, canine giardiasis, feline infec-
VACClNES AND VACClNATIONS 441
tious peritonitis, feline Bordetella bronchiseptica, feline giardiasis, and fe-
line Microsporum canis were not available at the time these recommenda-
tions were made). As recently as 1996, a survey of vaccination practices
conducted in veterinary schools throughout North American indicated
that annual revaccination of adult dogs and cats was routinely per-
formed.
19
It is reasonable to assume that most practitioners currently
recommend annual booster vaccinations to their companion animal cli-
entele.
Nevertheless, recent publications
4
17, 18, 20, 21, 25 and the 2000 Report of
the American Association of Feline Practitioners and Academy of Feline
Medicine Advisory Panel on Feline Vaccines
22
suggest that conventional
guidelines fail to address realistic duration of immunity (001) for at
least some of the vaccines licensed for cats. At issue is the fact that a
protective immune response is likely to persist for several years after
vaccination and, in fact, routine administration of annual booster vac-
cines to dogs and cats is not necessary. Despite the absence of published
001 studies, a growing body of data supports recommendations for
booster vaccination that include administering core vaccines (e.g., feline
panleukopenia, herpesvirus-I, calicivirus, canine distemper, canine par-
vovirus, rabies) at 3-year (or longer) intervals in adult animals. In fact,
some licensed vaccines (e.g., B. bronchiseptica, leptospirosis, feline chla-
mydia) may not consistently provide a I-year duration of immunity and
thus are justifiably administered to "at-risk" patients every 6 months,
despite a product label (insert) that stipulates "annual booster recom-
mended."17. 21
Companion animal vaccination guidelines are currently undergOing
critical scrutiny by representatives from private practice, industry, and
academia. Despite widespread recommendations for annual revaccina-
tion, information available today suggests that current vaccination prac-
tices in North America do not necessarily correspond with the body of
knowledge pertaining to 001 derived from licensed vaccines. As a direct
result, companion animal practitioners should expect significant changes
in the current standard of practice pertaining to the administration of
vaccines to dogs and cats.
Among the most significant changes anticipated in the future is the
recommendation to discontinue routine administration of annual booster
vaccinations to adult dogs (distemper virus and parvovirus) and cats
(parvovirus [panleukopenia], feline herpesvirus-I, and calicivirus). The
incidence of canine distemper, canine parvovirus, and feline panleuko-
penia among vaccinated adult (> 1 year of age) animals is virtually zero.
Furthermore, protection derived from vaccination against 'these viruses
seems to be sustained for periods as long as 5 or 6 years.
5
10. 23. 24 Future
"
442 FORD
vaccination standards for adult dogs and cats seem likely to center
around conservative booster intervals e,very 3 years for selected vaccines.
Vaccines intended to proted a g a i n ~ t diseases such as B. bronchisep-
tica, canine parainfluenza virus, and feline leukemia virus (FeLV) are not
known to provide protection against challenge for more than 1 year.
Annual boosters are likely to continue to be recommended for those
animals considered at risk of exposure to diseases caused by these
organisms. Although annual boosters are still recommended, the actual
risk:benefit ratio derived from FeLV and feline infectious peritonitis
virus vaccination simply does not seem to justify the number of cats
receiving annual vaccines.
TITERS VERSUS ANNUAL VACCINATION
What is the feasibility of performing annual antibody titers in pa-
tients rather than subjecting them to annual booster vaccination?
Despite the fact that a number of laboratories offer selected canine
and feline antibody titers to veterinarians, there are a number of signifi-
cant factors that, in this author's opinion, do not justify offering this
service to clientele on a routine basis. In addition to the fact that antibody
concentration does not necessarily correlate with protection against dis-
ease, there are other compelling reasons behind the fact that widespread
acceptance and use of antibody determinations is not likely to happen
in clinical practice. First, standardized methods for determining antibody
concentration in serum for the various vaccine antigens have not been
achieved. The risk lies in the fact that a single serum sample divided
three times and sent to three different laboratories is quite likely to yield
three different titers, and quite possibly three different interpretations.
What may be deemed "protective" by one laboratory could well be
labeled "susceptible" by another. Furthermore, it is important to note
that a vaccinated dog or cat that does not have a significant concentra-
tion of antibody may, in fact, have excellent immunity. A "negative"
antibody titer does not necessarily correlate with susceptibility to infec-
tion. Likewise, the presence of antibody, even at high levels, does not
guarantee immunity subsequent to exposure.
7
15. 17
It should also be noted that over the next 5 to 10 years recombinant
(genetically engineered) vaccines are likely to become the predominant
technology used by manufacturers in the production of companion
animal biologics. Although measurable antibody titers are expected to
be associated with some of these products, others are not likely to
produce antibody that is measurable in vitro. The ability of recombinant
vaccines to provoke immunity through cell-mediated immune (eMI)
mechanisms further complicates in vivo assay of immune responses,
VACCINES AND VACCINATIONS 443
because measuring CMI responses is complex and availability is quite
limited.
SELECTION OF ANTIGENS
Not only is it perceived that veterinarians are vaccinating too often,
but it has been suggested that pets are inoculated with vaccines con-
taining an excessive combination of antigens. There is no immunologic
evidence to support the hypothesis that the immune system of dogs and
cats is being "overwhelmed" by the frequent administration of various
vaccines. In fact, the real issue at hand for the future is to determine
which vaccines are, in fact, indicated and which are not. Surveys of
companion animal practitioners and veterinary teaching hospitals on
vaccination protocols indicate that there is considerable diversity of
opinion withiri the profession on which vaccines should and should not
be administered.
In the future, vaccination protocols for dogs and cats are likely
to center on recommendations for administering so-called "core" and
"noncore" vaccines. Core vaccines are those recommended for adminis-
tration to every dog and cat presented to the practice. Recommendations
for designating a particular vaccine as core are determined by (1) sever-
ity of disease, (2) transmissibility to other animals, and (3) the potential
for a particular infection to be zoonotic. Conversely, noncore vaccines
would be recommended to clientele when a known or likely risk is
anticipated or when an animal's lifestyle represents a reasonable risk
after exposure to an infectious agent. Examples include FeLV, feline
infectious peritonitis virus, and canine Lyme disease vaccine.
Another issue pertaining to the selection of vaccines is the adminis-
tration of modified-live virus (MLV) versus killed virus vaccine. Al-
though recommendations against administration of multivalent MLV
vaccines were made 10 years ago,26 most veterinarians continue to ad-
minister MLV biologics. This is certainly justified, as these products do
provide a superior sustained immune response. Furthermore, there are
no data demonstrating that there are significant advantages in using
killed virus vaccines as compared with MLV vaccines. The suggestion
that MLV vaccines pose an unreasonable safety risk is largely anecdotal
and without scientific merit. Unfortunately, killed virus vaccines have
generally not proved to be suitable alternatives.
Selection of Antigens in the Shelter Environment
Selecting core versus noncore antigens is somewhat more complex
when applied to an animal shelter environment. As veterinarians who
444 FORD
practice shelter medicine can attest, there are no standatdized formulae
for immunization success within anim'l,ls shelters considering the innu-
merable variables in the equation, including shelter finances, "kill versus
nonkill" policy, staff experience and mow ledge base with infectious
disease (from cleaning to screening), census, concurrent illnesses, hold-
ing times, season of the year, construction, and air exchange, just to
name a few.
In developing a vaccination program for an animal shelter, a few
assumptions must be taken into consideration:
Assume infectious disease exposure has already occurred or is
going to occur.
Assume that puppies and kittens are at considerably more risk
than adult dogs and cats.
Assume that healthy-appearing infected adults are the critical
reservoir of infection for puppies and kittens.
Assume that vaccination does not preclude the development of
clinical disease.
Assume that routine cleaning and routine use of isolation facilities
are not likely to prevent disease outbreaks.
There are three approaches to managing infectious disease in shel-
ters.
Darwinian Approach
Do not screen and do not vaccinate any animals, ever. Those that
survive are the fittest-they win. Although that is the most economical
approach, the downside is the risk of rampant infectious diseases among
susceptible animals, especially the young, living in the shelter.
Filtered Approach
Using skilled personnel trained to recognize sick animals, simply
screen and remove (or euthanatize) those animals that are obviously
sick. It is a daily (at least) job, and it obviously does nothing to prevent
those who are about to become sick from spreading their illness.
Unlimited Funds Approach
Vaccinate every animal on admission to the facility, hold them in
isolation for 14 days, and ensure they are examined and monitored by a
veterinarian. Those that survive the quarantine period are escorted to
the main facility, where they enter environmentally controlled housing,
VACCINES AND VACCINATIONS 445
get two square meals a day, and have unlimited access to a graduate
student doing animal-bond research.
It is not likely that anyone of these approaches is going to effec-
tively eliminate or even contain infectious disease outbreaks in a shelter.
Vaccination is simply not the cornerstone of infectious disease control
within a shelter environment. Facility construction, especially the ability
to isolate, the ability to move air, and the ability to clean effectively,
become especially critical factors. TIUs is not to suggest that vaccination
has no role whatsoever in shelter medicine, however. Personal experi-
ence suggests that routine inoculation of dogs and cats with core vac-
cines (as defined previously) is indicated at the time the animal enters
the facility. The benefit of administering noncore vaccines (such as canine
corona virus and FeLV) to shelter animals does not seem to justify the
cost.
VACCINE SAFETY
Among the most important issues facing practitioners today is that
of vaccine safety. For most vaccines currently on the market, it must still
be assumed that the benefits of vaccination, when performed in accor-
dance with currently published standards, far outweigh the risk of
vaccine-induced illness or disease. Recent reports have raised serious
concerns within the profession over the relation between vaccination
and delayed adverse events, specifically vaccine-associated fibrosarcoma
in cats
6
, 11, 12. 16 and immune-mediated disease in dogs.
S
' 13 Determining
which vaccines pose a risk to which animals, and when, simply cannot
be determined with the information available today. It is still the prac-
titioner who assumes responsibility not only for recommending a partic-
ular vaccination protocol but for any consequences that might arise as a
result of administering a vaccine (see section on liability).
Concern over the risks associated with the use of attenuated (MLV)
vaccines, disease caused by residual virulence, and disease attributed to
contamination during manufacture has sustained the market for inacti-
vated products. There are significant advantages associated with using
attenuated vaccines, including rapid onset, sustained protection, the
ability to stirnulate CMI, and the ability to immunize by way of natural
routes, which argue against the decision to offer only killed vaccines to
companion animal patients.
Adverse Event
Information on the behavior of individual vaccines used under
typical field conditions is maintained by the manufacturers and reported
446 FORD
,'"
to the US Department of Agriculture Center for Veterihary Biologics.
27
Such postmarketing surveillance also ;;erves as an alert system for the
rapid detection of vaccine-related events that seem to be unusual in
nature or frequency. The single most significant factor that serves to
compromise the effectiveness of the postmarketing surveillance program
is the lack of adverse event reporting by practitioners. In many instances,
not even deaths associated with vaccine administration are consistently
reported.
An adverse event is any undesirable occurrence after the use of an
irnmunobiologic product, including illness or reaction, whether or not
the product caused the event. Anecdotal surveys suggest that adverse
event reports from veterinarians dramatically underrepresent the num-
ber of reactions observed and regarded to be vaccine associated. Despite
efforts to categorize adverse events based on type, there are still no
uniform standards used by practitioners or manufacturers to classify
frequency and type of event. The US Department of Agriculture has
developed adverse event reporting guidelines that practitioners should
use when addressing known or suspected adverse events associated
with administration of any vaccine. Reporting criteria to include when
reporting a vaccine-associated adverse event include:
Patient information
Patient signalment (age, breed, sex)
Pertinent history
Case identification number (if applicable)
Adverse event
Description of the event (e.g., onset of signs after inoculation,
clinical signs/ lesions)
Supporting laboratory data, including normal and abnormal
findings (if applicable)
Date of inoculation
Date signs were first noticed
Outcome
List of all irnmunobiologic products administered" that might
be associated with the adverse event, including:
Product brand name
Serial or lot number
Product code number
Administration information (each vaccine administered), includ-
ing:
Dose
Route
' For combination products, list the product code and serial number of each vial as
well as the product code of the combination package.
VACCINES AND VACCINATIONS 447
Site
Needle size
Administration of concurrent (nonbiologic) drugs
Date vaccine was reconstituted
Personal information
Name, address, and telephone number of veterinarian
Name, address, and telephone number of owner/ agent
Although only a few reports specifically address various causes of
adverse events, reactions have been attributed to preservatives, purity,
contamination, virulence of attenuated agents, adjuvant, route of admin-
istration, concurrent administration of other vaccines, and ordinal num-
ber of the vaccine administration (most immediate reactions occur subse-
quent to administration of the first vaccine dose as opposed to the
second or third vaccine dose in: a series). Neither the cause nor the exact
frequency of delayed reactions such as tumor formation or immune-
mediated disease is known.
Reporting of adverse events remains the responsibility of the prac-
titioner who administers the vaccine and observes the reaction. Reports
should be made directly to the vaccine manufacturer, usually to the
technical service section.
Feline Vaccine-Associated Fibrosarcoma
Over the past decade, the cause-and-effect relation between vaccina-
tion and fibrosarcoma in cats has been central to the concerns of veteri-
narians and pet owners with regard to vaccine-induced disease. Esti-
mates of tumor prevalence range from 1 in 10,000 to 1 in 1000 cats
vaccinated and are most frequently reported to be associated with the
administration of FeLV and killed rabies vaccinesY' 12. 16 Tumors are
aggressive and have a high rate of recurrence. Although the etiopatho-
genesis is not completely understood, there is compelling evidence to
support a relation between postvaccination inflammation and tumor
formation. Of particular concern is the role that adjuvants such as
aluminum hydroxide, a common component of killed vaccines used in
human beings and animals, seem to take in mediating the inflammatory
response that culminates in tumor development.
Veterinarians are encouraged to follow the research reports and
recommendations of the AVMA Feline Vaccine-Associated Sarcoma Task
Force when developing vaccination recommendations for cats. Until a
definitive statement can be made about the adjuvant-inflammation-
tumor relation, it is this author's recommendation that veterinarians
restrict administration of feline vaccines to nonadjuvanted biologics
448 FORD
..
.
when feasible. When it is the decision .of the practice to proceed with
the use of adjuvanted vaccine in cats, .it is recommended that every
effort be made to conduct a thorough risk assessment so as to offer the
client and the patient the most effective but safest level of protection.
Multidose Vials
Veterinarians are advised to administer vaccine from single-dose
vials only. Administering vaccine from a multidose, or TANK, vial
(typically 10 doses per vial) containing killed virus carries the risk of
delivering significantly different concentrations of adjuvant to each pa-
tient. Depending on the thoroughness with which the multi dose vaccine
is mixed before each dose is administered, the adjuvant concentration in
the doses withdrawn can be highly variable.
LIABILITY
Discussions with vaccine manufacturers, practicing veterinarians,
attorneys, and representatives from the AVMA Liability Trust suggest
that there is considerable confusion among practicing veterinarians over
the use of vaccines in a manner not specifically recommended by the
manufacturer (as published in the package insert) and the liability as-
sumed when a vaccine causes, or is presumed to cause, a serious or
expensive injury to the patient.
It has been found that vaccination protocols for companion animals
vary considerably throughout North America. Furthermore, it is the
veterinarian who, after assessing the various risk factors unique to the
individual patient, makes recommendations as to which type of vaccine
and which choice of antigen are to be administered as well as which
product is to be used, when, and how often. Veterinarians are not
obligated to follow the recommendation outlined in the package insert
for a specific product (see the article on vaccination liability in this
issue). Discretion in the administration of vaccines is acceptable as long
as it meets the provision defined as the "standard of practice." The
standard of practice for administering vaccines is to recommend the
most appropriate antigens (vaccines) at the most appropriate stages of
life and to use the most efficacious but safest products available.
RISK ASSESSMENT
Providing effective imrnunoprophylaxis does not require that all
dogs and cats presented for vaccination be inoculated with each of the
VACCINES AND VACCINATIONS 449
antigens for which a vaccine is currently licensed. Intrinsic and extrinsic
factors related to the individual patient as well as factors unique to the
infectious agent should be taken into consideration when establishing
recominendations and assigning a vaccination protocol to an individual
animal.
Core vaccines are recommended for administration to all dogs and
cats seen by the practice. Recommendations for determining which
antigens are deemed "core" should be based on whether (1) the conse-
quences of infection are particularly severe (e.g., canine parvovirus,
feline panleukopenia), (2) the infection is zoonotic and potentially puts
human health at risk (e.g., rabies), and (3) the disease is prevalent and
easily transmitted such that it poses a significant risk to the population
at large (e.g., feline herpesvirus and calicivirus). The decision to vacci-
nate with a noncore vaccine should be based on the clinician's assess-
ment of the individual animal's risk profile and take into consideration
information about the patient, the patient's environment, and the infec-
tious agent.
Host Factors
Suboptimal response to vaccination is possible among animals that
are malnourished, have concurrent infection or illness, or are receiving
regular doses of immune-suppressive drugs. Additional intrinsic factors
considered to influence the outcome of infection include heritable resis-
tance (and possible susceptibility) factors as well as stress. Age at the
time of exposure is an important independent variable in assessing an
individual's risk. Although no age group can be considered entirely free
of risk, kittens and puppies less than 6 months of age are generally
regarded as being more susceptible to infection than adults after expo-
sure and thus represent the primary target population for vaccination.
The presence of maternal antibody is an intrinsic host factor known to
protect a kitten after exposure to an infectious agent; however, interfer-
ence with vaccine antigen by maternal antibody is the single most
common cause of vaccination failure. Failure to vaccinate a puppy or
kitten at an age when maternal antibody has declined sufficiently in-
creases an animal's risk of infection after exposure.
Environmental Factors
Population density and opportunity for exposure to other animals
are among the most critical issues affecting an individual animal's risk
of exposure to an infectious agent. Puppies and kittens living in cluster
450 FORD
"
populations are at substantially higher risk of infection than are those
living in one- or two-pet households. Ftl.rthermore, the introduction of
new animals into a household or c l u s t ~ poses a potential risk to the
entire population. Geographic distribution of various infectious agents
may represent significantly different exposure risk in different parts of
North America and should be considered when determining which
noncore vaccines would be most appropriate.
In multiple-animal households, sustained high ambient tempera-
tures and humidity, in addition to a housing environment with fewer
than 12 air exchanges per hour, increase the risk of an animal's exposure
to respiratory pathogens. In kennels, a single puppy with parvovirus
puts all other non vaccinated puppies at risk for as long as 1 month
because of the long survival time of the virus in the environment.
Agent Factors
Independent agent-associated variables such as virulence, dose, and
mutation do influence the outcome of infection but are difficult to
objectively assess in the clinical setting. In the domain of risk assessment,
it is the interaction between the agent and the host that dictates the
outcome after exposure and infection. The severity of an infection, partic-
ularly a viral infection, is highly variable within a population of animals
with similar exposure to the same agent. Clinical illness with the exact
same pathogen may range from inapparent or mild to severe acute
illness to chronic or latent infection.
RECOMBINANT VACCINE TECHNOLOGY
Recombinant vaccines are among the newest products in the rapidly
emerging biotechnology/ vaccine market. The technologic advance be-
hind these products is their ability to isolate and splice (or recombine)
gene-sized fragments of DNA from one organism and to transfer them
to another organism by way of a vector virus or plasmid DNA. It has
already been demonstrated that the hybrid organism resulting from the
in vitro exchange of genetic material has tremendous potential to deliver
safe and immunogenic DNA into the host animal and, as such, repre-
sents a truly new generation of vaccine development for the veterinary
profession. The recombinant vaccines currently being introduced into
companion animal practice seem to provide an exceptionally safe prod-
uct, although efficacy and duration of immunity still have to be estab-
lished for each product. Nucleic acid or "naked" DNA vaccines have
been developed, and some have already been shown to be effective
against certain companion animal diseases. The DNA vaccines are com-
VACCINES AND VACCINATIONS 451
pletely unique in that only DNA is inoculated; it subsequently transfects
host cells to produce vaccine antigen.
The technology behind recombinant vaccines is quite sophisticated
and has quickly moved routine vaccination of dogs and cats from the
level of the whole organism to the subcellular level. The practice of
administering attenuated live agents or whole killed products is likely
to change in the near future. I , 3, 10, 14 As we enter the twenty-first century,
it is anticipated that even newer technologies will be introduced, giving
rise to veterinary-label vaccines that are safer, have exceptional efficacy,
and have a duration of immunity that persists for several years if not
for the life of the patient. Veterinarians are encouraged to become famil-
iar with recombinant vaccines so as to understand the basic technology
behind their development and .to become familiar with the potential
advantages and disadvantages of each new product as it is introduced.
Then, the clinician, considering conventional and recombinant vaccines,
should be able to administer the most appropriate product only as often
as necessary to prevent significant disease.
OVER-THE-COUNTER SALES OF VACCINES
It could be argued that over-the-counter sales of vaccines for com-
panion animals is an insignificant issue that has little impact on an
individual practice. Medical and ethical considerations justify discourag-
ing this practice, however. The number of vaccines available in the
companion animal market is overwhelming. Although many of the
products available are sold under the label of major biologic manufactur-
ers, many other products are not. This raises important questions regard-
ing safety and efficacy studies of at least some of products on the market.
Rabies vaccines can be, and are, sold to nonveterinarians through catalog
sales (Omaha Vaccine Company, Omaha, NE) in 23 states. In effect,
rabies vaccine can be sold' and administered by nonveterinarians
throughout the United States. The implications are not insignificant
when, for example, a dog or cat vaccinated by a nonveterinarian bites a
person or if the nonveterinarian owner elects to administer rabies vac-
cine to a pet that is a wolf-dog hybrid, regardless of prevailing laws
prohibiting such practice.
Although vaccination protocols among individual veterinary prac-
tices do vary, the protocol recommended by at least some companies
offering catalog sales of vaccine is, quite simply, wrong. Advising cus-
tomers to administer vaccine to puppies at 5 weeks, then at 6 weeks,
and then every 2 weeks until they reach 18 weeks of age is simply not
in accordance with the standard of practice in the United States. There
is no rationale behind the recommendation to vaccinate puppies or
452 FORD
. ~
kittens at intervals of less than 2 weeks. Nevertheless, the resources to
monitor and address these standards do..not exist, and the companies
that make these recommendations are JUlder no legal obligation to
change.
Nosodes
The fact that pet owners are concerned about vaccination recom-
mendations traditionally offered by veterinarians is apparent from the
proliferation of antivaccination web sites, in which animal owners,
breeders, and veterinarians offer alternative approaches, largely homeo-
pathic, to protecting pets against infectious diseases. Their concerns
center predominantly on "immune-system overload" and vaccine-in-
duced disease. One of the proposed alternative approaches to vaccina-
tion of dogs and cats involves the administration of nos ode vaccines.
Nosodes are products prepared from infected tissues, infected dis-
charges, or the actual pathogenic organism that causes the disease one
is attempting to immunize against. All nosodes are administered orally,
but according to various web site resources, they do not need to be
swallowed. What prevents the nos ode from actually infecting the animal
and causing illness is the fact that the final product undergoes what is
referred to as homeopathic dilution and "potentization." Apparently,
infectious material is subjected to multiple dilutions such that the quan-
tity of infectious material remaining is insignificant to cause disease or
is absent. Dosing recommendations seem to vary but generally entail
administering either a three-drop dose ("small animals") or a six-drop
dose ("large" animals) orally. A dose is given on 3 days of the first week
(of life?), once weekly for the next 3 weeks, once monthly for the next 6
months, and once every 6 months thereafter. To the author's knowledge,
only one controlled study on the efficacy of a canine parvovirus nosode
has been conducted. Subsequent to administration of the parvovirus
nosode, dogs were orally challenged with virulent parvovirus. Results
showed that 100% of the control dogs and 100% of the "vaccinates"
became infected with parvovirus (R.D. Schultz, personal communica-
tion, 2000).
References
1. Adams LG, Ford RB, Gershwin LJ, et al: Recombinant vaccine technology. Veterinary
exchange. Compend Contin Educ Pract Vet 19(suppl):5-16, 1997
2. American Veterinary Medical Association Council on Biologic and Therapeutic Agents:
Canine and feline immunization guidelines. JAVMA 195:314-317, 1989
3. Babiuk LA, Lewis }, Van Den Hurk S, et al: DNA immunization: Present and future.
Adv Vet Med 41:163-179, 1999
VACCINES AND VACCINATIONS 453
4. Bowlin CL: Proceedings from Perspectives on Vaccines in Feline Practice, Eighth
Annual Feline Practitioners Seminar, Columbus, OH, 1996
5. Burr H, Coyne M, Gay C, et aI: Duration of Imrrnrnity in Companion Animals
after Natural Infection and Vaccination. Research Report, Exton, PA, Pfizer Animal
Health. 1998
6. Burr H, Coyne M, Hall 1, et aI: Injection Site Sarcoma and the Vaccination of Cats.
Research Report, Exton, PA, Pfizer Animal Health, 2000
7. Dodds WJ: More bumps on the vaccine road. Adv Vet Med 41:715-732, 1999
8. Duval 0, Giger U: Vaccine-associated immune-mediated hemolytic anemia in the dog.
J Vet Intern Med 10:290--295, 1996
9. Elston T, Rodan I, Hemming 0, et al: 1998 Report of the American Association of
Feline Practitioners and Academy of Feline Medicine Advisory Panel on Feline Vaccine.
JAVMA 212:227-241,1998
10. Ford RB, Schultz RD: Vaccines and vaccinations: Issues for the twenty-first Century.
In Bonagura JD (ed): Current Veterinary Therapy XIII. Philadelphia, WE Saunders,
2000, pp 250--253
11. Hendrick MI, Goldschmidt MH: Do injection site reactions induce fibrosarcomas in
cats? JAVMA 199:968, 1991
12. Hendrick MI, Kass PH, McGill LD, et al: Postvaccinal sarcomas in cats. J Nat! Cancer
Inst 86:341-343, 1994a
13. Hogenesch H, Azcona-Olivera 1, Scott-Moncrieff C, et aI: Vaccine-,induced autoimmu-
nity in the dog. Adv Vet Med 41:733-747, 1999
14. Horzinek MC: Vaccination: A philosophical view. Adv Vet Med 41:1--<i, 1999
15. Hustead DR, Carpenter T, Sawyer 0 , et aI: Vaccination issues of concern to prac-
titioners. JAVMA 214:1000--1002, 1999
16. Kass PH, Barnes WG, Spangler WL, et al : Epidemiologic evidence for a causal relation
between vaccination and fibrosarcoma tumorigenesis in cats. JAVMA 203:396-405, 1993
17. Kruth SA, Ellis, JA: Vaccination of dogs and cats: General principles and duration of
immunity. Can Vet J 39:423-426, 1998
18. Larson RL, Bradley JS: Immunologic principles and immunization strategy. Compend
Contin Educ Pract Vet 18:963-971, 1996
19. Mansfield PO: Vaccination of dogs and cats in veterinary teaching hospitals in North
America. JAVMA 208:1242-1247, 1996
20. Paul MA, Wolf AM: Vaccinations: What's right? What's not? Proceedings of a Sympo-
sium held at the North American Veterinary Conference, Schering Plough, Orlando,
FL,1999
21. Phillips TR, Schultz RD: Canine and feline vaccines. In Kirk RW (ed): Current Veteri-
nary Therapy XI. Philadelphia, WE Saunders, 1992, pp 202-206
22. Richards 1, Rodan I, Elston T, et al: 2000 Report of the American Association of Feline
Practitioners and Academy of Feline Medicine Advisory Panel on Feline Vaccines,
AAFP / AFM, Nashville, TN, 2000
23. Schultz R: Current and future canine and feline vaccination programs. Vet Med
93:233-254, 1998
24. Scott FW, Geissinger eM: Long-term immunity in cats vaccinated with an inactivated
trivalent vaccine. Am J Vet Res 60:652--<i58, 1999
25. Smith CA: Are we vaccinating too much? JAVMA 207:421-425, 1995
26. Tlzard I: Risks associated with use of live vaccines. JAVMA 196:1851-1858, 1990
27. US Department of Agriculture Center for Veterinary Biologics: Animal Immunobiologic
Vigilance. Ames, lA, US Department of Agriculture Center for Veterinary Biologics,
1996
Address reprint requests to
Richard B. Ford, DVM, MS
College of Veterinary Medicine
North Carolina State University
4700 Hillsborough Street
Raleigh, NC 27606
e-mail: richard_ford@ncsu.edu
VACCINES AND VACCINATIONS 0195-5616/ 01 $15.00 + .00
FELINE VACCINATION
GUIDELINES
James Richards, DVM, and ilona Rodan, DVM
The 1998 Report of the American Association of Feline Practitioners and
Academy of Feline Medicine Advisory Panel on Feline Vaccines
14
was devel-
oped to help veterinary practitioners formulate vaccination protocols for
cats. The current panel report updates information, addresses questions,
and speaks to concerns raised by the 1998 report. In addition, it reviews
vaccine licensing, labeling, and liability issues and suggests ways to
successfully incorporate vaccination protocol changes into a private
practice setting. The material in the 1998 report is not fully reproduced
here, and readers are referred to the 1998 report for more detailed
information.
Vaccines play an important role in the control of infectious diseases.
Most vaccines do not induce complete protection from infection or
disease, however, nor do they induce the same degree of protection in
all animals. Factors that negatively affect an individual animal's ability
to respond to vaccination include maternal antibody interference, con-
genital or acquired immunodeficiencies, concurrent disease, inadequate
nutrition, immunosuppressive medication, and stress (e.g., overcrowd-
ing, poor sanitation).20 Every effort should be made to ensure that
Portions of this article were previously published in the 2000 Report of the American
Association of Feline Practitioners and Academy of Feline Medicine Advisory Panel on
Feline Vaccines, American Association of Feline Practitioners, Nashville, TN, 2000.
Written in collaboration with Thomas . Elston, DVM; Duane Flemming DVM, JD;
Richard Ford, DVM, MS; Steven Henry, DVM; David Hustead, DVM; Michael Lappin,
DVM, PhD; Michael Paul, DVM; David Rosen, DVM; Margie Scherk, DVM; Fred Scott,
DVM, PhD; and Link Welborn, DVM.
From the Cornell Feline Health Center, College of Veterinary Medicine, Cornell University,
Ithaca, New York UR); and Cat Care Clinic, Madison, Wisconsin (IR)
VETERINARY CLINICS OF NORTH AMERICA: SMALL ANIMAL PRACTICE
VOLUME 3} NUMBER 3 MAY 200}
455
456 RICHARDS & RODAN
.,.
patients are healthy before vaccination. Because vaccination alone does
not completely protect animals from infe.ction and disease, environmen-
tal conditions should be addressed and,..exposure to infectious agents
should be minimized.
The overall objectives of vaccination are to vaccinate the largest
possible number of individuals in the population at risk, vaccinate each
individual no more frequently than necessary, and vaccinate only against
infectious agents to which individuals have a realistic risk of exposure
and subsequent development of disease. Kittens younger than 16 weeks
of age are generally more susceptible to infection than are adult cats and
typically develop more severe disease. They represent the principal
target population for vaccination.
40
Maternal antibody interference is
the most common reason why some animals are not immuniZed after
vaccination, and it is also the reason why a series of vaccinations is
necessary for kittens younger than 12 weeks of age.
20
Vaccination needs
of adult cats should be assessed at least once yearly and, if necessary,
modified on the basis of an assessment of their risk.
VACCINE SELECTION AND ADMINISTRATION
It is recommended that administration sites for parenteral vaccine
be chosen in accordance with the guidelines established by the American
Association of Feline Practitioners and adopted by the Vaccine-Associ-
ated Feline Sarcoma Task Force (Table 1).46 Use of multiple-dose vials is
discouraged, because inadequate mixing may result in unequal distribu-
tion of antigen and adjuvant, possibly resulting in decreased efficacy or
an increased likelihood of adverse events; iatrogenic contamination is an
additional risk. The panel discourages the use of polyvalent vaccines
other than those containing combinations of feline panleukopenia virus,
feline herpesvirus-l (FHY-l), and feline calicivirus (FCV), exclusively.
This opinion is based on the belief that as the number of antigens in a
vaccine increases, so too does the probability of associated adverse
events. Additionally, use of polyvalent vaccines may force practitioners
to administer vaccine antigens not needed by the patient.
Feline Panleukopenia
Feline panleukopenia is caused by feline parvovirus (FPV). The
virus remains infectious for months to years in the environment and is
primarily spread via the fecal-oral route. Fomites (e.g., cages, food bowls,
litter boxes, health care workers) play an important role in the transmis-
sion of the organism. Clinical signs of infection include lethargy, an-
FELINE VACCINATION GUIDELINES 457
orexia, vomiting, diarrhea, fever, and profound panleukopenia; mortality
is highest in young susceptible catsY In utero infection with FPV is a
common cause of cerebellar hypoplasiaY
Va'ccination against FPV is highly recommended for all cats. Immu-
nity to feline panleukopenia is primarily through antibody response to
natural infection, vaccination, or passive transfer of maternal antibodies
from queen to kittens. Maternal antibody may interfere with immuniza-
tion when antibody titers are high during the neonatal period. Maternal
antibody titers generally wane sufficiently to allow immunization by 12
weeks of age.
47
Immunity conferred by feline panleukopenia vaccines is
considered to be excellent, and most vaccinated animals are completely
protected from infection and clinical disease. Serologic and challenge
exposure data indicate that a parenteral FPV vaccine induces immunity
that is sustained for at least 7 years.
4S
49 After the initial series of
vaccinations and revaccination 1 year later, cats should be vaccinated no
more frequently than once every 3 years.
Modified-live virus (MLV) vaccines and adjuvanted inactivated vi-
rus vaccines for parenteral administration as well as an MLV vaccine for
topical (intranasal) administration are available and effective. Experi-
mental studies have shown that intranasal administration of canine
parvovirus-2 vaccines to puppies is less effective than parenteral admin-
istration in overcoming maternal antibody interference (Ronald Schultz,
PhD, personal communication, 2000). The most likely reasons are that
fewer virus particles reach lymphoid tissue when the product is given
._ intranasally compared with parenteral administration and viral replica-
tion in lymphoid tissue is required for immunization with MLV parvovi-
rus vaccines. Although studies have not been performed in cats, the
same phenomenon may occur in this species. Caution is appropriate
when contemplating the use of intranasal FPV vaccines for primary
immunization of kittens, especially those residing in environments
where exposure to FPV is likely.
It has been found recently that some cats with panleukopenia-like
disease were infected with canine parvovirus-2b. Studies show that FPV
vaccines provide excellent protection not only from FPV but also from
canine parvovirus-2b; thus, canine parvovirus infection should not be
a concern for cats immunized as a result of vaccination with FPV
vaccines.
39
Serious adverse events associated with FPV vaccines are rare. Tumor
formation at the site of a topically administered vaccine has not been
reported. Vaccination of pregnant queens with modified-live FPV vac-
cines may possibly result in neurologic disease in developing fetuses
52
;
the same concern applies to kittens vaccinated at less than 4 weeks of
age. The use of MLV vaccines should be avoided in pregnant queens
and kittens less than 1 month of age.
52
62
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462 RICHARDS & RODAN

Feline Viral Rhinotracheitis and Feline Calicivirus
Infection ...
"
l'
Feline viral rhinotracheitis caused by FHV-1 and FeV infection
account for up to 90% of all cases of infectious upper respiratory tract
disease in catsY Both viruses are shed in ocular, nasal, and pharyngeal
secretions of infected catsY Organisms are transmitted from cat to cat
directly through sneezed macrodroplets or indirectly via contaminated
fomitesY The disease is self-limiting; however, infected cats may de-
velop chronic oculonasal disease. Latent infection is lifelong for cats
infected with FHV-1; reactivation can occur during periods of stress or
after corticosteroid administration. Some cats infected with FCV become
persistently infected and shed virus for prolonged periods (months to
years). Although rarely serious in adult cats, disease caused by these
viruses may be severe, and sometimes fatal, in kittens. Lameness and
chronic oral inflammatory syndromes have been linked to calicivirus
infection and vaccination with modified-live calicivirus vaccines.
3
7. 10. 11.
45. 57 Risk of exposure to either FHV-1 or FCV is high, because both
organisms are widespread in the feline population.
Vaccination against FHV-1 and FCV is highly recommended for all
cats. Immunity is through humoral and cell-mediated immune responses
to natural infection or vaccination or through passive transfer of mater-
nal antibodies from queen to kittens. Maternal antibody may interfere
with induction of a systemic immune response; however, by the time
that kittens are 12 weeks . of age, maternal antibody titers wane suffi-
ciently to allow parenteral immunization. Topically administered (intra-
nasal, conjunctival) vaccines are capable of inducing a local immune
response in the face of high maternal antibody titers.
27
Serologic and
challenge exposure data indicate that parenteral FHV-1 and FCV vac-
cines induce protection that lasts at least 3 years.
48
49 After the initial
series of vaccinations and revaccination 1 year later, cats should be
vaccinated once every 3 years.
. Regardless of the route of administration, FHV-1 and FCV vaccines
induce only relative but not complete protection. At best, these vaccines
induce an immune response that lessens the severity of disease; vacci-
nates are not immune to infection nor are they protected from all signs
of disease.
2o
Currently available FCV vaccines probably do not induce
protection from all isolates of the virus.
9
MLV and inactivated virus vaccines for parenteral administration
and MLV vaccines for topical (intranasal and conjunctival) administra-
tion are available. If a susceptible cat is born into or is entering an
environment in which viral upper respiratory tract disease is endemic
(e.g., some catteries, boarding facilities, shelters), the use of a topical
product may be advantageous. Administration of such products to kit-
tens as young as 10 to 14 days of age could be considered in these
FELINE VACCINATION GUIDELINES 463
situations; however, products that also contain modified-live FPV anti-
gens should not be administered to kittens younger than 4 weeks of
age.
62
Adverse events associated with vaccination against FHV-l and
FCV . include mild transient fever, sneezing, conjunctivitis, oculonasal
discharge, lameness, and, for parenteral products, pain at the injection
site.
9

11
Sneezing, conjunctivitis, oculonasal discharge, and ulceration of
the nasal philtrum are believed to occur more frequently with vaccines
licensed for topical use. Tumor formation at the site of a topically
administered vaccine has not been reported.
Rabies
Rabies is transmitted mainly through bite wounds of infected mam-
mals. More cats than dogs develop rabies in the United States
29
; although
they are relatively resistant to rabies, both species serve as potential
sources of infection for human beings.
21
, 29 Treatment is ineffective in cats
that develop clinical signs and should not be attempted because of the
high potential for zoonotic infection.
21
All instances of suspected or
known rabies virus infection must be reported to local health department
officials. Proper precautions and quarantine procedures as outlined by
local regulations and described in the Compendium of Animal Rabies
Prevention and Control, 2000
26
should be followed.
Although vaccine-associated sarcomas have been reported to de-
velop in association with administration of a variety of vaccines, current
data suggest that they are more frequently associated with administra-
tion of feline leukemia virus (FeLV) vaccines and adjuvanted raoies virus
vaccines.28 Inflammatory reactions are commonly observed at sites where
adjuvanted rabies virus vaccines have been administered, and concern
has arisen regarding the possible association between these reactions and
vaccine-associated sarcomas.
35
With the exception of a recently approved
canarypox virus-vectored recombinant feline rabies virus vaccine (Pure-
Vax Feline Rabies Vaccine; Merial Limited, Iselin, NJ), all rabies virus
vaccines currently on the market contain adjuvants. In rats, inflammation
induced by the recombinant product seems to be rninirnal,34 but whether
the use of this vaccine is associated with a reduced likelihood of vaccine-
associated sarcoma formation in cats is not yet known. The recombinant
product is currently licensed only for annual administration.
Rabies virus vaccination is highly recommended for all cats and is
required by law in some states and municipalities. Manufacturers are
required by the US Department of Agriculture to establish, by means
of experimental challenge exposure studies, the minimum duration of
immunity for the rabies virus vaccines that they sell, and products
approved for use every year or every 3 years are available. Statutes
governing the administration of rabies virus vaccines vary considerably
464 RICHARDS & RODAN
,
"
throughout the United States; veterinarians should com}:>ly with the
legal requirements of their area,
Feline Leukemia Virus Infection
FeLV infects domestic cats throughout the world, Transmission is
through transfer of virus in the saliva or nasal secretions resulting from
prolonged intimate contact (e,g" mutual grooming), biting, or sharing of
food and water utensils, The virus may also be transmitted by transfu-
sion of blood from an infected cat, in utero, or through the milk,33
Exposure to virus persisting in the environment on fomites or in aerosol-
ized secretions is not an efficient means of viral transmission, Clinical
signs of FeLV infection are primarily related to neoplasia, anemia, and
diseases resulting from immunosuppression,
Kittens are the most susceptible to infection; resistance increases
with maturity, Experimental data demonstrate that kittens younger than
16 weeks of age are most susceptible to infection, with cats older than
this being relatively resistant.
23
Cats at greatest risk include outdoor cats
(free-roaming pets, stray 'cats, and feral cats), Also at risk are cats
residing in open multiple-cat environments, cats living with FeLV-in-
fected cats, and cats reSiding in households with unknown FeLV status,
The decision to vaccinate an individual cat against FeLV infection
should be based on the cat's age and its risk of exposure, Vaccination
against FeLV is recommended for cats at risk of exposure (i,e" cats not
restricted to a closed, FeLV-negative, indoor environment), especially
those younger than 4 months of age, Vaccination is not recommended
for cats with minimal to no risk of exposure, especially those older than
4 months of age, The ability of a particular vaccine brand to induce an
immune response sufficient to resist persistent viremia varies from study
to study, 53 Because protection is not induced in all vaccinates, preventing
exposure to infected cats remains the single best way to prevent FeLV
infection, Vaccination against FeLV does not diminish the importance of
testing cats to identify those that are viremic, It is of critical importance
that viremic cats not be in contact with other cats, especially those
younger than 4 months of age, As a result, the FeLV infection status of all
cats should be determinedY Adverse events associated with vaccination
against FeLV include local swelling or pain, transient lethargy or fever,
and postvaccination granuloma formation, Although vaccine-associated
sarcomas have been reported to develop in association with administra-
tion of other vaccines, current data suggest that they are more frequently
associated with administration of FeLV vaccines and adjuvanted rabies
virus vaccines, 28 If vaccination is deemed appropriate, annual revaccina-
tion is recommended, Cats should be tested for FeLV infection before
initial vaccination and when there is a possibility that they have been
exposed to FeLV since they were vaccinated, The enzyme-linked immu-
FELINE VACCINATION GUIDELINES 465
nosorbent assay is the preferred screening test; the indirect immunofluo-
rescent assay is the preferred confirmatory testY Individuals confirmed
to be infected with FeLV need not receive FeLV vaccines, but they should
be segregated from uninfected cats.
Chlamydiosis
Chlamydia psittaci is a bacterial pathogen of the conjunctiva and
respiratory tract of cats. Transmission is through direct cat-to-cat contact;
fomite transmission is less likely, because the organism is unstable in
the environment. Serous conjunctivitis, which may initially affect only
one eye, is the most common clinical sign. Sneezing or nasal discharge
may develop, but if it does develop, it is usually mild. Clinical signs are
usually evident 5 to 10 days after infection and resolve with appropriate
antimicrobial treatment.1
8
Isolation rates have been reported to range
from approximately 1% for cats without signs of respiratory tract disease
to approximately 14% for cats with concurrent upper respiratory tract
disease. 56 The highest rates of infection are reported for cats between 5
weeks and 9 months of age.
61
Immunity conferred by C. psittaci vaccines
is similar to that conferred by FHV-1 and FCV vaccines in that vaccinates
are protected from severe clinical disease but not from infection.
20
The
frequency of adverse systemic events associated with C. psittaci vaccines
is higher than that associated with other commonly used vaccines;
reactions include lethargy, depression, anorexia, lameness, and fever 7
to 21 days after vaccination.
55
Because signs of disease associated with
C. psittaci infection are comparatively mild and respond favorably to
treatment, and because adverse events associated with the use of C.
psittaci vaccines are of greater concern than adverse events associated
with the use of many other products, routine vaccination against C.
psittaci infection is not recommended. Vaccination may be considered
for cats in multiple-cat environments, where infections associated with
clinical disease have been confirmed. If vaccination is deemed appro-
priate, annual revaccination is recommended.
Feline Infectious Peritonitis
Feline coronaviruses (FCoVs) vary considerably in pathogenic po-
tential and have historically been grouped into two biotypes: feline
enteric coronaviruses, which typically cause subclinical to mild enteric
infections, and feline infectious peritonitis (FIP) viruses, which cause FIP.
Currently, FIP viruses are believed to be generated as mutant variants in
feline enteric coronavirus-infected cats.
58

59
FCoVs are widespread ill
feline populations worldwide, with seropositivity rates highest in
crowded multiple-cat environmentsY Transmission of the virus is
466 RlCHARDS & RODAN
mainly via the fecal-oral route. In environments in which FCo V infection
is endemic (e.g., most multiple-cat eo.vironments), 35% to 70% of cats
are shedding FCoVs in the stool at auY given time. 16, 22 Most infected
cats remain healthy, although a few (usually between 1% and 5%)
ultimately develop FIP. Affected cats rarely survive regardless of treat-
ment.
43
Kittens are most often affected with FIP, but the disease report-
edly can develop in cats of all ages. A genetic predisposition has been
suggested, with higher disease incidence in certain lines. 15, 43
Considerable controversy surrounds the ability of the currently
available FIP vaccine (Primucell-FIP; Pfizer Animal Health, Exton, PA) to
prevent disease, Some studies demonstrate protection from disease
I9
, 24;
others show little benefit from vaccination,36, 51 Antibody-dependent
enhancement of disease in vaccinates has been demonstrated in experi-
mental challenge exposure studies,SO but it is uncertain whether anti-
body-dependent enhancement occurs in a natural setting. Discrepancies
between study results are probably attributable to differences in test
methodology (e,g., strain and dose of challenge virus, genetic predisposi-
tion of the test animals), Protection from disease has not been demon-
strated in animals vaccinated when younger than 16 weeks of age. Most
kittens born and reared in environments in which FCo V infection is
endemic are infected before reaching this age.
l
, 22 In these instances,
vaccination of infected cats has not proven beneficial, At this time, there
is no evidence that the vaccine induces clinically relevant protection,
and its use is not recommended.
Dermatophytosis
Dermatophytosis in cats is primarily caused by infection with Mi-
crosporum canis. A variety of clinical manifestations, including transitory
clinical disease and chronic infection with or without clinical signs,
have been reported. Although successful treatment of individual cats is
usually straightforward, elimination of endemic infection from multiple-
cat environments is expensive, labor-intensive, and time-consuming.
38
An M. canis vaccine (Fel-O-Vax MC-K; Fort Dodge Animal Health,
Overland Park, KS) is approved for use as an aid in the prevention and
treatment of clinical signs associated with M, canis infection, Vaccination
has not been demo!"lstrated to prevent infection or to eliminate M. canis
organisms from infected cats. As a result, routine vaccination against M.
canis infection is not recommended, At the time of this writing, the
product has not been independently evaluated for efficacy. Based on
studies conducted by the manufacturer, it is reasonable to consider
vaccination as adjunctive treatment for individual infected cats 4 months
of age or older to hasten resolution of clinical signs, If the vaccine
FELINE VACCINATION GUIDELINES 467
induces an immune response that accelerates lesion resolution, the num-
ber of infectious fungal spores produced by vaccinates may be reduced
as well; thus, it is reasonable to consider vaccination as one component
of a comprehensive treatment program in multiple-cat environments in
which M. canis infection is endemic. Nonetheless, the ability of this
product to hasten elimination of endemic infections from such environ-
ments has not been evaluated. The revaccination interval is not stipu-
l a t ~ d on the label. Major adverse events reportedly associated with the
use of this product are pain, temporary hair loss, and formation of sterile
abscesses or granulomas at the vaccine site.
38
Bordetel/a bronchiseptica Infection
Bordetella bronchiseptica is a small, aerobic, gram-negative coccobacil-
lus long recognized as a respiratory tract pathogen of several species of
animals. The natural route of transmission in cats is believed to be via
the aerosol or intranasal route.
8
Experimental challenge exposure studies
have shown that B. bronchiseptica can act as a primary pathogen in
cats; inoculation of specific-pathogen-free kittens results in self-limiting
disease characterized by variable degrees of fever, nasal or ocular dis-
charge, sneezing, induced or spontaneous coughing, pulmonary rales,
and submandibular lymphadenopathy.8 Bronchopneumonia associated
with naturally occurring B. bronchiseptica infection has been reported
in kittens and adult cats.60 Other factors, including nutritional status,
overcrowding, coinfection with other agents such as FeV or FHV-1, and
suboptimal hygiene, may influence the outcome of exposure.
41

54
Seroprevalence surveys suggest that exposure to the organism is
common, with infection rates varying from population to population.
The highest r'!tes of seropositivity (often over 80%) are found among
cats in rescue shelters and multiple-cat households, especially when
there is a history of respiratory tract disease. The lowest rates are found
among cats in households with few cats and no history of respiratory
tract disease.
4

37
Similarly, isolation rates vary. B. bronchiseptica was iso-
lated from the oropharynx in 19 of 614 (3.1%) asymptomatic cats and
from the distal trachea in 6 of 614 (1%) asymptomatic cats from shelters
in Lousiana. 25 In a recent survey of 740 cats in the United Kingdom,
none of the household cats were found to be infected, but 9% of cats
from breeding colonies and 19% of cats from rescue shelters were found
to be carrying the organism.
5
In the same survey, 9% of healthy cats and
14% of cats with respiratory tract disease tested positive for the organ-
ism. An additional finding was a strong positive association between
oropharyngeal isolation of B. bronchiseptica and residence in households
containing dogs with a recent history of respiratory tract disease.
468 RICHARDS & RODAN
Definitive diagnosis of disease associated with B. bronchiseptica infec-
tion may be difficult, in part, because signs of infection often mimic
those associated with FHV-l or FeV infection. Isolation of B. bronchisep-
tica from a cat with respiratory tract disease is supportive of the diagno-
sis, but carriage of the organism in asymptomatic cats 'precludes estab-
lishing a direct cause-and-effect relation. Resolution of disease with
appropriately chosen antimicrobial medication might suggest a causative
role for B. bronchiseptica, but the self-limiting nature of many cases of
viral upper respiratory tract disease prevents attributing disease resolu-
tion solely to antimicrobial treatment.
A vaccine (Protex-Bb; Intervet) to prevent disease caused by infec-
tion with B. bronchiseptica has recently been licensed. The product con-
tains a live reduced-virulence culture of B. bronchiseptica and is licensed
for administration via the intranasal route in cats 4 weeks of age and
older. Efficacy of the vaccine has not been independently evaluated;
however, in studies conducted by the manufacturer to gain vaccine
licensure, vaccinated 4-week-old specific-pathogen-free cats experienced
less severe signs of disease than did unvaccinated controls when exposed
to challenge 3 weeks after vaccination. Similar results were obtained
when 8-week-old kittens were exposed to challenge 72 hours after vacci-
nation. As of this writing, studies to evaluate the duration of protection
induced by the vaccine have not been completed and the revaccination
interval is not yet stipulated on the label. Routine use of this. vaccine is
not recommended. It is reasonable to consider vaccinating cats entering
or residing in multiple-cat environments (e.g., shelters, catteries, board-
ing facilities) where disease associated with B. bronchiseptica infection
has been confirmed. The ability of the product to reduce the prevalence
of infection or the severity of disease in such environments has not been
evaluated, however.
Giardiasis
Infection of cats with the protozoan CiardUi lamblia is associated
with acute or chronic gastrointestinal disease ranging in severity from
subclinical to severe.
32

64
Because infected cats shed cysts intermittently,
diagnosis of C. lamblia infection is often cumbersome and usually re-
quires multiple fecal examinations. Several methods of diagnosis are
available, including examination of a fecal smear, the zinc sulfate centrif-
ugation method, and use of an enzyme-linked immunosorbent assay to
test feces.64 There are currently no approved treatment methods for cats,
and although treatment commonly controls signs of disease, it is uncer-
tain that it clears infection.
63
Treatment effectiveness is highly variable,
and resistant organisms are commonly encounteredY 63 C. lamblia is
FELINE VACCINATION GUIDELINES 469
transmitted via the fecal-oral route; cysts may be ingested from contami-
nated water, from direct cat-to-cat transmission especially in crowded
environments (e.g., through mutual grooming), from exposure to con-
tarnfuated litter boxes, and from consuming prey.30 31 Giardiasis is a
recognized zoonotic disease, but the role of cats in transmission of the
organism is not well established.
2
6. 64
A vaccine has recently been licensed by the US Department of
Agriculture (Fel-O-Vax Giardia; Fort Dodge Animal Health) as an aid in
the prevention of disease associated with G. lamblia infection and reduc-
tion in the severity of shedding of cysts. This vaccine is composed of
quantified, homogenated, and chemically inactivated G. lamblia tropho-
zoites, and it contains an adjuvant commonly found in other feline
products from the manufacturer but different from the adjuvant in the
manufacturer's canine product. The vaccine is approved for use in cats
8 weeks of age and older. At the time of this writing, the vaccine has
not been independently evaluated for efficacy, but in studies conducted
by the manufacturer to gain vaccine licensure, vaccinates had a statisti-
cally significant reduction in severity of clinical signs (diarrhea), duration
of cyst shedding, and prevalence of infection (percentage of cats with
trophozoites at the end of the trial) compared with control animals.
Protection was demonstrated to persist for at least 1 year after vaccina-
tion.
Routine use of this vaccine is not recommended, but because vacci-
nates had less severe clinical disease and shed cysts for a shorter time,
it is reasonable to consider vaccination as part of a comprehensive
control program in environments where exposure to G. lamblia is clini-
cally significant. When parasite exposure is ongoing, revaccination at
annual intervals is recommended. Some vaccinates may shed cysts sub-
sequent to G. lamblia exposure; thus, proper hygiene and sanitation
practices should be implemented even with vaccinated cats. The ability
of this product to aid in hastening elimination of endemic infection from
multiple-cat environments has not been evaluated.
References
1. Addie DO, Jarrett 0: A study of naturally occurring feline coronavirus infections in
kittens. Vet Rec 130:133--137, 1992
2. Barr SC: Enteric protozoal infections. In "Greene CE (ed): Infectious Diseases of the
Dog and Cat, ed 2. Philadelphia, WB Saunders, 1998, pp 482-491
3. Bennett 0 , Gaskell RM, Mills A, et al: Detection of feline calicivirus antigens in the
joints of infected cats. Vet Rec 124:329-332, 1989
4. Bergman IE, Vemooij J, Zegers EM: Prevalence of antibodies against Bordetella bronchi-
septica in cats with a history of respiratory disease. Vet Q 19(suppl):S50--51, 1997
5. Binns SH, Dawson 5, Speakman AJ, et aI: Prevalence and risk factors for feline
Bordetella bronchiseptica infection. Vet Rec 144:575-580, 1999
(,t'
470 RICHARDS & RODAN
6. Bowman D: Feline giardiasis. CFHC Information Bulletin 13:1-3, 1994
7. Church R: Lameness in kittens after vaccinatiqn. Vet Rec 125:609, 1989
8. Coutts AJ, Dawson S, Binns S, et al: Studies on natural transmission of Bordetella '
bronchiseptica in cats. Vet Microbiol 48:19- 27, 1 ~
9. Dawson S, Gaskell RM: Problems with respiratory virus vaccination in cats. Compend
Contin Educ Pract Vet 15:1347-1354, 1993
10. Dawson S, Bennett 0, Carter SO, et al: Acute arthritis of cats associated with feline
calicivirus infection. Res Vet Sci 56:133-143, 1994
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Address reprint requests to
James Richards, DVM
Cornell Feline Health Center
College of Veterinary Medicine
Cornell University
PO Box 13
Ithaca, NY 14853
VACCINES AND VACCINATIONS 0195-5616/ 01 $15.00 + .00
CANINE VACCINATION
Craig E. Greene, DVM, MS, Ronald D. Schultz, P.hD,
and Richard B. Ford, DVM, MS
Despite the concerns over recommendations to reduce the frequency
and number of vaccines administered annually to dogs and cats, the
need for companion animal vaccines and vaccinations continues to be a
fundamental part of health management programs in the twenty-first
century. What is happening now, however, is an effort by aca-
demicians and practitioners to review companion animal vaccination
standards in the United States. The American Association of Feline
Practitioners and the Academy of Feline Medicine, in a consensus paper
compiled by a panel of experts, have already published the latest vacci-
nation recommendations for cats
27
(the reader is referred to the article
on feline vaccination in this issue).
What constitutes the ideal vaccination protocol goes beyond a docu-
ment of vaccine recommendations used at a veterinary teaching hospital
or compiled by a panel of academicians. Instead, a vaccination protocol
selected for use within a practice entails identifying preventable diseases
that pose a serious risk to the individual animal, and vaccinating that
animal at an early age, hopefully prior to exposure to the pathogen,
with a product that provides long term immunity and has minimal risk
of causing adverse reactions. There are currently a number of products
that meet these requirements.
What follows is an objective and clinically relevant review of the
canine vaccines licensed for use in North America today and a discus-
From the Department of Small Animal Medicine, College of Veterinary Medicine, Univer-
sity of Georgia, Athens, Georgia (CEG); Department of Pathobiological Sciences,
School of Veterinary Medicine, University of Wisconsin-Madison, Madison, Wisconsin
(RDS); and Department of Clinical Sciences, College of Veterinary Medicine, North
Carolina State University, Raleigh, North Carolina (RBF)
VETERINARY CLINICS OF NORTH AMERICA: SMALL ANlMAL PRACTICE
VOLUME 31 NUMBER 3 MAY 2001 473
474 GREENE et aJ
..
,
sion of the facts that have compelled so many authors to challenge
existing vaccination practices. This article is not intended to establish
new vaccination standards for dogs, n01,. should it be used as a template
for a national canine vaccination protocol. Nevertheless, change is in
the wind, and revised recommendations for canine vaccination can be
anticipated. The material presented in this article serves as a guide for
clinicians willing to consider proposed canine vaccination recommenda-
tions as they apply to individual patients. Table 1 represents a summary
of the information presented in this article.
WHY CHANGE?
Is it really necessary to revise vaccination recommendations for
dogs? Many would challenge that premise. After all, vaccination practice
over the last 20 years has, in fact, worked well; canine distemper,
canine parvovirus, and canine rabies are virtually nonexistent among
vaccinates. Yet, despite the obvious successes attributable to companion
animal vaccination, veterinarians must be willing to at least review, if
not revise, vaccination practice standards as new vaccines are introduced
and new vaccine technologies are developed. The objective, quite simply,
is to administer the most appropriate vaccine(s) at the most appropriate
stage of life and to do so with the best product(s) available. What should
not occur is complacency and regimentation with respect to selection
and administration of vaccines. Yet, that does happen.
The demand among veterinarians that vaccines be simple to admin-
ister and timesaving has led to the long-term and widespread use of
polyvalent vaccines. Twenty-five years ago, the most commonly used
polyvalent products contained three vaccines (distemper-hepatitis-lep-
tospirosis) . Today, products containing eight or more vaccines per dose
are routinely administered to dogs. Furthermore, polyvalent vaccines
are routinely administered annually with seemingly little regard for the
actual risk of infection. This is a disturbing trend. Annual administration
of polyvalent vaccine implies that each vaccine antigen, whether of
bacterial or viral origin, in each polyvalent product induces the same
degree of immunity for the same duration in every patient. Immunologi-
cally, this is irrational. Depending on the vaccine and based on the
results of controlled challenge studies, dogs derive protective immunity
that persists for as little as a few months to as long as 7 or more years.
2
,
4,7, 14, I B, 20. 25, 29. 30 Convenience rather than science seems to be the driving
force behind conventional recommendations listed on vaccine "labels"
(product inse;ts). Even the 1995 ruling by US Department of Agriculture
that manufacturers of new veterinary biologic agents must document
the duration of immunity listed on the label (this ruling does not apply
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480 GREENE et aJ
" ,I
to vaccines licensed before 1995) is not likely to change "annual booster"
recommendations stipulated by manufaGturers. It is important to under-
stand that manufacturers are not m a n d a ~ d to establish the full duration
of immunity but only to document what they claim. Studies to establish
the maximum duration of immunity that would meet USDA guidelines
are not economically feasible.
The recommendation that virtually all canine vaccines be adminis-
tered annually to adult dogs has been embraced by the veterinary
profession for many years. Interestingly, however, for most vaccines
administered to dogs today, there are no scientific studies at all establish-
ing a 12-month duration of immunity. Vaccine efficacy studies for most
vaccines in use today challenged vaccinates just 3 to 4 weeks after the
last inoculation. The paradigm that adult dogs and cats require annual
boosters for all the commonly administered vaccines is being challenged.
We simply cannot continue to arbitrarily administer vaccines without
regard for the number and type of vaccine antigens in the product and
without realistic consideration of the risk of infection facing the individ-
ual animal Y 15. 16, 22, 24
CANINE DISTEMPER
Modified live virus (MLV) vaccines have been most effective in
protecting dogs against canine distemper. Inactivated whole viral vac-
cines are not effective; however, a vectored recombinant vaccine is cur-
rently available. In puppies, distemper vaccination is performed at 3- to
4-week intervals, with the earliest inoculation being given when the
puppy is 6 to 8 weeks of age. Most distemper vaccines used in North
America today overcome maternal immunity by the time puppies are
12 weeks of age. Vaccination in puppies is usually continued until they
reach 16 weeks of age. Dogs older than 12 weeks of age at the time they
are presented for initial vaccination should receive at least two canine
distemper virus (CDV) inoculations 2 to 3 weeks apart. The minimum
duration of immunity, as determined by challenge, to attenuated (MLV)
CDV is at least 7 years for vaccines using the Rockport strain of CDV,
although that for vaccines using the Onderstepoort strain is at least 5
years.
2
,29
The recombinant CDV vaccine is a canary pox-vectored vaccine
that expresses distemper fusion and hemagglutinin glycoproteins.
23
Dogs
receiving this vaccine must receive at least two doses initially. The
reported duration of immunity is at least 12 months. Annual booster
vaccination is recommended when using this product.
A combined distemper-measles vaccine is still available. At a stage
of life when administration of MLV CDV vaccine is expected to fail,
measles vaccine is capable of causing a heterotypic immune response in
CANlNE VACCINATION 481
the presence of high concentrations of maternally derived distemper
antibody. Some veterinarians still recommend administration of a' CDV-
measles virus vaccine to puppies between 6 and 9 weeks of age. This
product should not be used in female puppies over 12 weeks of age,
because maternal antibodies to CDV and measles may develop. These
antibodies would be transferred to subsequent offspring at a level that
could interfere with both measles and CDV vaccination in the puppies.
Therefore, antibodies would interfere with the protective effects of the
MV-CDV vaccination and the heterotypic MV would not provide early
protection from CDV Administration of a combined MLV CDV-measles
virus vaccine should be limited to those puppies in which the nursing
status is unknown or that are likely to face CDV exposure as puppies.
Measles vaccine is not indicated in dogs over 16 weeks of age.
INFECTIOUS CANINE HEPATITIS (CANINE
ADENOVIRUS INFECTION)
Vaccination for canine adenovirus infection, the cause of infectious
canine hepatitis (ICH), is usually done in combination with that for
distemper and other diseases beginning when puppies are 6 to 8 weeks
of age. Attenuated (MLV) adenovirus vaccines are generally used in the
United States because of their ability to produce a superior immune
response, but inactivated products are still available in the U.S. and
marketed in many countries. Vaccination for ICH reduced the prevalence
of a disease that was once widespread. Outbreaks or isolated cases still
occur when vaccination of puppies is delayed or incomplete. Shedding
of modified viruses and high stability outside the host have been respon-
sible for inadvertent immunization of many dogs. Vaccines for ICH
contain either a killed homologous canine adenovirus-l (CAV-l) or a
closely related respiratory isolate, MLV canine 'adenovirus-2 (CAV-2).
The former is generally shed in the urine, and the latter is shed in upper
respiratory secretions; however, the amount that is shed varies between
individual products. Another side effect of attenuated CAV-l vaccine is
its ability to produce anterior uveitis and corneal edema with opacifica-
tion (''blue eye") in a small percentage of dogs. It is not documented that
CAV-2 vaccines cause uveitis. Although inactivated vaccines produce a
lesser serologic response, they are not shed by the host, nor do they
cause anterior uveitis. In the absence of exposure to virulent virus,
periodic boosters of inactivated adenovirus vaccine might be required
to sustain immunity.
The half-life of maternal antibody to ICH is similar to that of CDV:
approximately 8.5 days. By the time a puppy reaches 14 to 16 weeks of
age, maternal antibody is not usually detectable. Vaccination for ICH is
.f
482 GREENE et aI
"
thus typically combined with that for The initial vaccines can be
administered when puppies are 6 to 8 weeks of age and every 3 to 4
weeks until they reach 16 weeks of age. Although booster inoculation is
recommended annually in adult dogs, challenge studies have demon-
strated that the duration of immunity is at least 7 years when attenuated
CAV-2 is used as the vaccine antigen.
29
The duration of immunity of
killed CAV-2 vaccine and the MLV CAV-2 (intranasal) is not k..'1own.
MLV CAV-2 has been shown to immunize dogs against the respira-
tory (CAV-2) and hepatic (CAV-l) adenoviruses. Considering the risks
associated with administration of CAV-l to dogs, the use of the MLV
CAV-l vaccine is not recommended.
CANINE INFECTIOUS TRACHEOBRONCHITIS
Infectious tracheobronchitis (ITB), or kennel cough, is a complex
clinical infection caused by a number of respiratory pathogens that can
infect dogs alone or in combination. Causative viruses include distemper
(CDV), adenovirus (CAV-2), parainfluenza virus, herpesvirus, and Reovi-
rus. Bordetella bronchiseptica is a recognized bacterial pathogen.
4
, 13 Secre-
tory antibody (not that in serum) provides protection against infections
of the upper respiratory mucosal surfaces. Parenteral and intranasal
vaccines exist for CAV-2, parainfluenza virus, and B. bronchiseptica. Al-
though protection against most agents develops after routine vaccination
programs, vaccines against some agents such as herpesvirus or Reovirus
are not available. The duration of immunity produced by many vaccines
against respiratory has not been well established, but the
labels of most products recommend annual boosters. It is unlikely that
dogs derive significant immunity beyond 12 months subsequent to intra-
nasal vaccination. For intranasal B. bronchiseptica vaccine, the duration
of immunity may actually be less than 12 months.
The performance of parenterally administered infectious tracheo-
bronchitis (ITB) vaccines is quite different from that of intranasally
(topically) administered vaccine. Parenterally administered vaccine for
ITB provides a duration of immunity of up to 7 months or longer
depending on the antigen.
7
, 29 It is not known whether parenteral admin-
istration of ITB antigens culminates in the development of an effective
local (upper respiratory tract) immune response. Maternal antibody in-
terferes with parenterally administered vaccine. On the other hand,
vaccine labeled for intranasal (topical) administration can be adminis-
tered in puppies as young as 3 weeks of age (depending on the product),
seems to induce a local immune response that is not interfered with by
maternal antibody, and has a relatively rapid onset (3-5 days). It should
be noted that although pneumonia caused by virulent B. bronchiseptica
CANINE VACCINATION 483
has been reported in immunocompromised human beings, inadvertent
nasal or ocular exposure to avirulent live canine B. bronchiseptica vaccine
is not known to have caused clinical illness or symptoms in human be-
ings . .
Vaccination with separate parenteral products usually begins in
puppies at 6 weeks of age and is safe for pregnant animals. Animals
should receive at least two doses 2 to 4 weeks apart, and complete
protection is not expected until 2 to 3 weeks after the second vaccination.
Intranasal parainfluenza and Bordetella vaccines may protect within 72
hours after their use; thus, they can be used to help prevent illness in
an outbreak in a kennel or in pets before hospitalization or boardingY
Vaccination against respiratory pathogens does not induce sterile immu-
nity. In other words, vaccinated animals that are challenged are expected
to become infected and may exhlbit a mild short clinical illness. Clinical
signs of upper respiratory infection may develop subsequent to intrana-
sal administration of vaccine. Signs are generally mild or unnoticeable.
CANINE PARVOVIRAL ENTERITIS
Canine parvovirus-2 (CPV-2) vaccines are available as inactivated
or MLV products. Recombinant vaccines are not currently available but
are being developed. MLV products offer faster, more effective protection
against disease and shedding of virulent virus after challenge than
inactivated vaccines. For this reason, older dogs that are housed with
younger susceptible animals should be vaccinated with MLV vaccines.
In case of an outbreak, MLV vaccines should always be used. MLV CPV-
2 products are consistently shed in the feces of vaccinated dogs. Infected
contact animals may develop weak positive reactions on fecal parvovirus
enzyme-linked immunosorbent assay (ELISA) tests but will not develop
disease. Maternal antibody blockade is the predominant reason that
parvoviral vaccination is inconsistent in protecting pups during their
primary vaccination series. 10, 16 Attenuated or inactivated vaccines do
not break through maternal immunity as effectively as virulent canine
parvovirus, To overcome the period of maternal antibody blockade,
manufacturers have raised the titers or lowered their serial passage.
B
, 2B, 29
Recommendations for use of these potent parvoviral vaccines are a
complete series beginning at 6 weeks of age. Repeat vaccines are given
every 3 to 4 weeks until dogs are 16 weeks old despite the fact that
some products have label claims of protection by 12 weeks of age, The
last inoculation should be given at 16 weeks of age for breeds such as
Doberman Pinschers and Rottweilers, which have been identified as
being poorly responsive to CPV vaccination. In the absence of maternal
immunity, where pups are presented after 16 weeks of age, one MLV
".
484 GREENE et aI
.'
CPV-2 inoculation may be sufficient for protection agaillst parvoviral
infection. Vaccination with MLV CDV with concurrent CPV-2 vaccination
does not cause immunosuppression as h ~ been observed in coinfection
with virulent CPV-2 virus. Alternating between distemper and parvovi-
ral vaccines in young puppies on a weekly or longer interval is thus not
needed or recommended.
If an animal recovers from a documented parvoviral infection, it is
recommended to wait 4 weeks before vaccinating it so that the immune
response is recovered. Immunity to parvoviral infection is probably
lifelong; however, boosters are given because of the convenience af-
forded by combination products. Because of the great environmental
resistance of parvoviruses, young pups should be kept away from parks,
boarding facilities, and dog shows until the vaccination series is com-
plete. Veterinarians should attempt to limit suspected parvovirus-in-
fected dogs from coming into contact with susceptible puppies in their
veterinary hospital waiting rooms and wards. Vaccination of cats against
feline panleukopenia protects them against CPV-2b infection.
There has been a genetic and resultant antigenic shift of canine
parvovirus since its initial evolution in 1978. Nevertheless, cross-protec-
tion still exists between the old CPV-2 strains in the vaccine and the
new field isolates (CPV-2a and CPV-2b). Similarly, immunodiagnostic
tests based on monoclonal antibodies to original isolates are still sensi-
tive in detecting newer strains of virus. Newer field isolates can infect
cats. There is limited evidence to suggest that vaccines based on 2b
strains do not infect cats.
Duration of immunity of MLV CPV-2 vaccines is several years (at
least 7 years based on challenge studies),29 and overvaccination is a
consideration. The duration of immunity subsequent to administration
of inactivated (killed) CPV products has been shown to protect puppies
from challenge for at least 16 months after vaccination.25 Under field
conditions, dogs may be partially protected by weaker MLV or inacti-
vated products yet still boost their immunity when exposed to virulent
virus.
CORONAVIRAL INFECTION
Most vaccines licensed for canine coronavirus (CCV) are inactivated
canine coronaviral or feline coronaviral strains. One attenuated (MLV)
canine coronaviral product exists. Manufacturers recommend that two
doses of vaccine be given 2 to 3 weeks apart beginning in puppies at 6
to 8 weeks of age, with the last one being given at least after 12 weeks
of age. The vaccines seem to be safe; however, allergic reactions may
occur more commonly when inactivated coronaviral vaccines are com-
CANINE VACCINATION 485
bined with leptospiral bacterins. To avoid potential interactions, CCV
vaccine could be used in puppies between 6 and 9 weeks of age,
and Leptospira vaccination could be instituted thereafter. Otherwise, the
clinician may prefer to decide whether or not it is important or necessary
that both products be administered.
CCV challenge studies are not indicative of "protection" since it is
not possible to produce experimental disease in dogs over 12 weeks of
age. Furthermore, manufacturer recommendations to administer CCV
booster vaccines annually are difficult to justify based on the fact that
CCV does not cause disease in adult dogs. CCV produces significantly
less morbidity and minimal mortality compared with CPV-2. Experimen-
tally, combined infections with CPV-2 and CCV have been shown to
produce clinical disease that is more severe than with either infection
alone. I Nevertheless, it has also been shown that vaccination with CPV
can prevent clinical disease when both viruses are present.
19

28
The routine and frequent use of CCV vaccine in dogs is difficult to
rationalize. Clinical infection typically occurs in puppies 6 weeks of age
or yOl.\Ilger. Some studies have suggested that the duration and quality
of immunity derived from natural exposure and infection are actually
preferred over attempts to immunize by way of vaccination.28 In the
absence of reliable commercial or in-hospital diagnostic assays for CCV,
the prevalence of clinical disease associated with CCV infection in dogs
is unknown but is considered to be extremely low, even in high-density
shelter environments. Yet CCv, both killed and MLV, is commercially
incorporated into several multivalent vaccines combined with distemper,
adenovirus, parainfluenza virus, and parvovirus antigens. The fact that
multivalent vaccines containing CCV outsell vaccines that do not contain
CCV in the United States suggests that routine CCV inoculation of dogs
throughout life is common. CCV vaccine is considered to be among the
least important vaccine antigens given to dogs today, however, and has
been identified by several authors as a vaccine that, quite simply, is not
needed.
9
,28
LEPTOSPIROSIS
Most leptospiral vaccines for dogs contain inactivated serovars of
canicola and icterohaemorrhagiae. Vaccination with these products is not
recommended in animals less than 9 weeks of age because of the aller-
genic nature of these products. Leptospira bacterin is usually used to
reconstitute the lyophilized components in combination vaccines. Lepto-
spira bacterins may not produce as high a level or as long a duration of
immunity as other agents. Although postvaccination titers often decline
to undetectable levels, unpublished challenge studies suggest that immu-
486 GREENE et aI
nity in some dogs is sustained for 1 year. Inactivated Lepospira vaccines
may not, however, protect against the .. carrier state that may develop
after exposure to virulent organisms. Qne vaccine manufacturer has
employed a technology that involves separating surface proteins, or
immunogens, of Leptospira from extraneous cellular debris, thereby
avoiding the need to use whole-cell bacteria. It is not known whether or
not this technology can reducethe incidence of adverse events in young
dogs and toy breeds over that recognized with conventional whole-
cell bacterins. Leptospiral vaccines have been considered optional by
veterinarians in many areas because of the perceived low incidence
of the disease, short duration of immunity, and risk of postvaccinal
hypersensitivity. The use of Leptospira vaccine is probably responsible
for the reduced prevalence of disease caused by L. canicola and L.
icterohaemorrhagiae.
Recently, it has been shown that the incidence of confirmed cases of
canine leptospirosis may be increasing in the United States.
S

33
Further-
more, dogs are being diagnosed with infections by serovars of L. interro-
gans that we do not routinely vaccinate against. Serovars of L. grippoty-
phosa, L. pomona, L. bratislava, and others are reported throughout the
United States and have been linked to acute renal failure.
6

33
Another
interesting point is that many of these reports are on dogs living exclu-
sively in urban areas. The risk of infection is not limited to dogs living
outdoors in rural environments. Vaccines containing conventionally used
serovars of L. canicola and L. icterohaemorrhagiae do not cross-protect
against other serovars known to infect dogs.
s
Less than 2 years ago, Leptospira vaccines were introduced that are
believed to protect against serovars L. grippotyphosa and L. pomona.
Additional Leptospira serovars are likely to be introduced in the near
future. Nevertheless, the incidence of acute anaphylaxis among young
dogs (especially those under 12 weeks of age) and toy breeds (regardless
of age) makes the decision to include routine vaccination of dogs with
all available Leptospira serovars difficult. Without regional incidence data
for canine leptospirosis, practitioners still have insufficient information
at their disposal to make a reasonable risk:benefit analysis regarding use
of leptospira vaccines.
LYME BORRELIOSIS
Commercial inactivated (killed) whole-cell bacterins and one recom-
binant outer surface protein A (OspA) vaccine is licensed in the United
States.
14
, 26 In Europe, the vaccines are of the whole-cell type. Vaccines
have been shown by challenge studies conducted by the manufacturer
of the recombinant outer surface protein A vaccine to provide a duration
CANINE VACCINATION 487
of immunity for up to 1 year. Vaccination protected challenged dogs
from spirochetemia and clinical limping episodes as compared with
unvaccinated dogs. Lyme borreliosis vaccines are recommended by the
manufacturer for use in dogs as young as 9 to 12 weeks of age,' and
primary vaccination consists of two inoculations 3 weeks apart. Immuni-
zation should be given early in life to high-risk dogs living in endemic
regions. It should be noted that all vaccines stimulate antibody that
produces a positive test result with the indirect fluorescent antibody
serodiagnostic test. Dogs having a positive indirect fluorescent antibody
test should be retested using either of two tests: the Western blot tech-
nique, which may discriminate between infection and vaccine-induced
antibody, or the recently introduced in-hospital ELISA test (SNAP 3Dx
Assay; IDEXX Laboratories, Westbrook, ME), which has been shown to
react only to antibody from a unique C6 surface peptide.
21
The ELISA
test does not cross-react to antibody produced by any of the commercially
available vaccines on the -market in the United States.
Claims of hypersensitivity induced by whole-cell Lyme vaccines
have been reported. The most common observation is postvaccination
lameness among dogs that did not show clinical or serologic evidence
of infection. Unfortunately, the vaccines contain a limited number of
strains, which may not cross-protect against the known isolates of B.
burgdorferi. Routine testing of dogs using the in-hospital ELISA test in
regions of the United States where Lyme borreliosis is suspected or is
known to occur in human beings can provide new information per-
taining to the regional incidence of infection among the canine popula-
tion. Today, that information is largely extrapolated from human inci-
dence data maintained by the Centers for Disease Control and
Prevention. In the meantime, routine vaccination of dogs against B.
burgdorferi is not indicated outside regions of known high disease preva-
lence.
GIARDIASIS
Infection with the protozoan Giardia Lamblia is known to affect mam-
mals and birds worldwide. Differences exist in the pathogenicity and
host range of various strains. Colonization of the intestinal lumen results
in intestinal villus shortening and malabsorptive diarrhea. Neonatal
animals are most susceptible to infection.
3
Areas with impounded unfil-
tered surface water that is used for recreation or drinking are most often
associated with infection. Unsanitary conditions can lead to endemic
infections. An inactivated adjuvanted vaccine is available for vaccination
of puppies and kittens. The first dose can be given in animals as young
as 8 weeks of age. Neither routine or annual revaccination is indicated

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490 GREENE et al
with this product, except in the unusual situation where recurrent expo-
sure and infection are documented a,pd cannot be controlled using
conventional hygienic methods. This v a ~ c i n e has been shown to dimin-
ish fecal shedding of the infectious cysts for up to 1 year. The vaccine
also reduces the rate and quantity of infection when given before expo-
sure. If the prevalence of infection is high in a group of animals or in a
specific area, this vaccine might be an adjunct to help control the disease.
It is not recommended for administration to all dogs, and its use must
be coupled with other management procedures. The current vaccine has
been shown to cause granuloma-like masses at the inoculation site.
It is important to note that accurate identification of Giardia in dogs
with diarrhea is not as straightforward as it may seem. As such, false-
positive diagnoses of giardiasis are probably common. Conventional
saline fecal flotation techniques are not adequate to diagnose Giardia
cysts in feces. Furthermore, direct fecal examination is limited by the
experience of the microscopist and by the fact that many other structures
in the feces of dogs such as yeast bodies are easily confused with Giardia
cysts. Feces should be subjected to centrifugal flotation in a 33% zinc
sulfate solution. The slide should be scanned with a X 10 objective
magnification.
RABIES
Rabies vaccines have been extremely effective in reducing the preva-
lence of this disease in dogs. As a result, the prevalence of human
disease has decreased substantially, although the relative prevalence of
feline rabies has increased in the United States. In most countries, inacti-
vated (killed) vaccines are used. Inactivated virus vaccines have been
shown to provide a minimum duration and level of immunity compara-
ble to those of MLV products. They often contain high viral content
and potent adjuvants, however, which can sometimes produce acute or
chronic hypersensitivity reactions. An avipoxvirus-vectored recombinant
rabies vaccine that produces minimal inflammatory reactions has been
licensed for use in catsY A single rabies vaccine is generally adminis-
tered in animals 3 to 4 months of age. A second dose should be adminis-
tered 1 year after the first dose regardless of the dog's age. Subsequent
boosters are required every 1 or 3 years thereafter as mandated by state
law or local statutes.
CONCLUSIONS
New technologies for vaccine development
ll
, 32 and infectious dis-
ease diagnosis
21
are likely to be introduced in the near future. With this
CANINE VACCINATION 491
new technology comes the opportunity to vaccinate companion animals
against even more infectious agents than is currently practiced in the
United States today. As we look forward, it becomes particularly im-
portant to review current vaccination standards applied to dogs with
respect to current knowledge of duration of immunity (Table 2), aware-
ness of the incidence and likelihood of injurious or even fatal adverse
events associated with vaccination, and individual risk factors that d i c ~
tate which vaccines are most appropriate at which stage of life.
References
1. Appel MjG: Does canine coronavirus augment the effects of subsequent parvovirus
infection? Vet Med (Praha) 83:360-366, 1988
2. Appel MjG, Gillespie JH: Canine distemper virus. Virology Monographs 11:1-97, 1972
3. Barr SC: Giardiasis in dogs and cats. Compend Contin Educ Pract Vet 16:603-{;14, 1994
4. Binn LN, Eddy GA, Lazar EC, et al: Viruses recovered from laboratory dogs with
respiratory disease. Proc Soc Exp BioI Med 126:140-145, 1967
5. Bolin CA: Diagnosis of leptospirosis: A reemerging disease of companion animals.
Semin Vet Med Surg (Small Anim) 11:166-171, 1996
6. Brown CA, Roberts AW, Miller MA, et al: Leptospira interrogans serovar grippotyphosa
. infection in dogs. jAVMA 209:1265-1267, 1996
7. Burr H, Coyne M, Gay C, et al: Duration of lmmunity in Companion Animals after
Natural Infection and Vaccination. Research Report. Pfizer Animal Health, Exton, PA,
1998, pp 1-21
8. Burtonboy S: Performance of a high titre attenuated canine parvovirus vaccine I in
pups with maternally derived antibody. Vet Rec 128:377-381, 1991
9. Carmichael LE: Canine viral vaccines at a turning point-a personal perspective. In
Schultz RD (ed): Veterinary Vaccines and Diagnostics. San Diego, Academic Press,
1999, pp 289-307
10. Carmichael LE: Vaccines for dogs. In Pastoret PP (ed): Veterinary Vaccinology. Amster-
dam, Elsevier, 1997, pp 327-331
11. Donnelly JJ: DNA vaccines. Annu Rev lmmunol 15:617-M8, 1997
12. Duval D, Giger U: Vaccine-induced immune-mediated hemolytic anemia in the dog. j
Vet Intern Med 10:290-295, 1996
13. Ford RB, Vaden SL: Canine infectious tracheobronchitis. In Greene CE (ed): Infectious
Disease of the Dog and Cat, ed 2. Philadelphia, WB Saunders, 1998, pp 33--38
14. Hartman EG, Van Houten M, Frik JF, et al: Humoral immune response of dogs after
vaccination against Leptospirosis measured by an IgM and IgE specific ELISA. Vet
lmmunollmmunopathol 7:245-254, 1984
15. Hogenesch H, Azcona-Olivera J, Scotte-Moncrieff C, et al: Vaccine-induced autoimmu-
nity in the dog. Adv Vet Med 41:733--747, 1999
16. lida H, Fukuda S, Kawashima N, et al: Effect of maternally derived antibody levels
on antibody responses to canine parvovirus, canine distemper virus and infectious
canine hepatitis virus after vaccinations in beagle puppies. Exp Anim 39:9-19, 1990
17. Kontor Ej, Wegrzyn Rj, Goodnow RA: Canine infectious tracheobronchitis: Effects of
an intranasal live canine parainfluenza-Bordetella bronchiseptica vaccine on viral shed-
ding and clinical tracheobronchitis (kennel cough). Am j Vet Res 42:1694-1698, 1981
18. Larson Lj, Schultz RD: Comparison of selected canine vaccines for their ability to
induce protective immunity against canine parvovirus infection. Am j Vet Res 58:360-
363, 1997
19. Larson Lj, Schultz RD: Efficacy of immunity induced by canine coronavirus (CCV)
vaccines compared against immunity after natural infection with CCV [abstract].
Conference for Research Workers in Animal Disease 77:64, 1996
".!: .. _.
492
20. Larson LJ, Schultz RD: High-titer canine parvovirus vaccine: Serologic response and
challenge-of-immunity study. Vet Me<;l (Praha) 91:210-218, 1996
21. Liang FT, Jacobson RH, Straubinger RK, et al:-Characterization of a Borrelia burgdorferi
VlsE invariable region useful in canine Lyme disease serodiagnosis by enzyme-linked
immunosorbent assay. J Clin Microbiol 2000
22. Morgan JIi, Cooper J: State of the art: Bacterial vaccines. [abstract]. In Proceedings of
the Second International Veterinary Vaccines and Diagnostics Conference, Oxford,
2000, p 19
23. Pardo MC, Bauman JE, Mackowiak M: Protection of dogs against canine distemper
by vaccination with a canary pox virus recombinant expressing virus fusion and
hemagglutinin glycoproteins. Am J Vet Res 58:833-836, 1997
24. Pastoret PP: State of the art: Viral vaccines [abstract]. In Proceedings of the Second
International Veterinary Vaccines and Diagnostics Conference, Oxford, 2000, p 17
25. Povey RC, Carman PS, Ewert E: The duration of immunity to an inactivated adju-
vanted canine parvovirus vaccine. Can Vet J 24:245-248, 1983
26. Rice Conlon JA, Mather TN, Tanner P, et al: Efficacy of a nonadjuvanted, outer surface
protein A recombinant vaccine in dogs after challenge by ticks naturally infected with
Borrelia burgdorferi. Veterinary Therapeutics 1:96-107, 2000
27. Richards J, Rodan I, Elston T, et al : 2000 Report of the American Association of Feline
Practitioners and Academy of Feline Medicine Advisory Panel on Feline Vaccines,
Nashville, 2000
28. Schultz RD: Current and future canine and feline vaccination programs. Vet Med
(Praha) 3:233-254, 1998
29. Schultz RD: Duration of immunity to canine vaccines: What we know and don' t know.
In Proceedings for the Canine lnfectious Diseases Workshop: From Clinics to Molecular
Pathogenesis, James A. Baker Institute, August 1999(Available on-line: www.ivis.org/
proceedings/Baker_Can_lnf_Dis/ )
30. Sikes RK, Peacock GV, Acha P, et al: Rabies vaccines: Duration of immunity study in
dogs. JAVMA 159:1491-1499, 1971
31. Van Kampen KR: Rabies vaccines. In Rabies: Guidelines for Medical Professionals.
Trenton, NJ, Veterinary Learning Systems, 1999, pp 67-71
32. Weiner DB, Kennedy RC: Genetic vaccines. Sci Am 282:50-57, 1999
33. Wohl JS: Canine leptospirosis. Compend Contin Educ Pract Vet 11:1215-1241, 1996
Address reprint requests to
Richard B. Ford, DVM, MS
Professor of Medicine
Department of Clinical Sciences
College of Veterinary Medicine
North Carolina State University
Raleigh, NC 27605
e-mail: richard_ford@ncsu.edu
VACCINES AND VACCINATIONS 0195-5616/ 01 $15.00 + .00
VACCINE-ASSOCIATED ADVERSE
EVENTS
E. Kathryn Meyer, VMD
Widespread vaccination of pets against commonly encountered
pathogens is credited with greatly reducing the morbidity and mortality
previously associated with infectious diseases.
3
, 18, 21 , 35 Likewise, success-
ful control of human public health threats such as rabies would not be
possible without vaccination programs for domestic animals.28 As with
any medical procedure, however, the benefits of vaccination are accom-
panied by risks.
3
, 35
Recent concerns regarding serious adverse events that may be asso-
ciated with vaccination such as feline sarcomas
14
, 17, 22, 23 and autoimmune
disorders
7
, 9, 18 have stimulated the veterinary profession to re-examine
existing vaccination protocols with an increased sensitivity to potential
risks. Because patient characteristics such as age, breed, immune status,
and state of health may affect the risks and benefits of vaccination,
veterinarians are beginning to view vaccination as an individualized
medical procedure rather than a standard protocol applicable to all
animals of a given species.
7
, 10, 18, 25 As such, the risks and benefits for the
individual animal should be considered before vaccination recommenda-
tions are made. Veterinarians should keep in mind, however, that out-
breaks of previously controlled but endemic diseases may occur if the
number of vaccinated animais in a given population falls below a certain
threshold. 38
Although this article focuses on adverse events associated with
From the United States Pharmacopeia Veterinary Practitioners' Reporting Program, United
States Pharmacopeia, Rockville, Maryland
VETERINARY CLINICS OF NORTH AMERICA: SMALL ANIMAL PRACTICE
VOLUME 3] NUMBER 3 MAY 200]
493
494 MEYER
vaccination (e.g., risks), a balanced discussion cannot be presented with-
out examination of the benefits associ'ated with vaccination as well.
Consequently, vaccine benefits are addr886ed first to properly orient the
reader for subsequent discussion of risks.
BENEFITS OF VACCINATION
The projected benefits of vaccination for the individual animal are
based on the efficacy of the specific vaccine in preventing clinical dis-
ease.
32
Other factors that may affect the projected benefits of vaccination
include the likelihood of exposure and infection as well as the severity
of health consequences if infection does occur. 10 For example, the benefit
of vaccinating an animal with an efficacious vaccine is limited if the
potential for exposure is low and the clinical disease is mild. Consider-
ation of projected benefits supports the philosophy of customizing vac-
cine recommendations for the individual animal provided that popula-
tion immunity is not jeopardized.
Vaccine efficacy, which is the reduction in disease risk that results
from an animal's having been vaccinated, can be estimated in manufac-
turer-generated prelicense challenge studies. Subsequent validation may
be achieved through postmarketing monitoring and independent clinical
or epidemiologic evaluations.
Prelicense Efficacy Studies
Under the 1913 Virus-Serum-Toxin Act, further amended by the
1985 Food Security Act, the United States Department of Agriculture's
(USDA's) Animal and Plant Health Inspection Service (APHIS) is respon-
sible for ensuring that veterinary biolOgics are pure, safe, potent, and
effective. To this end, all veterinary biologics are licensed through the
USDA APHIS Service Center for Veterinary Biologics (CVB) Y The results
of vaccine efficacy studies required for USDA CVB licensure dictate the
wording that appears on the product's labelingY For example, "For
prevention of disease due to (a certain microorganism)" requires 80%
efficacy in prevention of clinical disease in vaccinated and challenged
animalsY "As an aid in the prevention" or "as an aid in the reduction
of" requires that the product produce a significant effect, although the
type and level of effect are not stipulated and may not be related or
relevant to the clinical condition of the animals.
20
41
Most prelicense vaccine efficacy trials involve a small number of
animals. For example, USDA-defined efficacy studies for canine distem-
per and hepatitis (adenovirus) vaccines require the inclusion of 20 vacci-
VACCINE-ASSOCIATED ADVERSE EVENTS 495
nates and 5 unvaccinated controls. 49. 50 For modified-live Chlamydia psit-
taci vaccines for cats, 20 vaccinates and 10 controls are required to
establish efficacy.53 Subsequent to licensing, challenge studies are period-
ically performed to provide in vitro potency testing standards. Potency
testing is performed by the manufacturer before the release of each
batch. 51. 52
The interval for revaccination is ideally based on duration of immu-
nity studies. Minimum duration of immunity studies are required for
rabies vaccines and products containing "new product fractions."41 A
"new product fraction" is an antigen that was not commercially available
at the time the efficacy guidelines were published on May 12, 1995.
Duration of immunity studies are not required to support label revacci-
nation recommendations for all current and future vaccine products
containing many commonly used canine and feline antigens, including
rhinotracheitis/ calicivirus/panleukopenia (FVRCP) , chlamydia, and fe-
line leukemia virus (FeLV) for cats and distemper, adenovirus (canine
hepatitis), leptospira, parainfluenza, parvovirus, and coronavirus for
dogsY
Postlicensure Measurement of Vaccine Efficacy
Postmarketing vaccine efficacy can be estimated through epidemio-
logic studies and clinical efficacy studies; however, such studies are not
plentiful in the veterinary medical1iterature. The monitoring of. disease
incidence over time relative to vaccinption practices can also prOvide
information to support the effectiveness of vaccine programs; however,
systematic monitoring of canine and feline infectious disease, with the
exception of rabies, is not routinely performed.
Because rigorous independent scientific evidence documenting vac-
cine efficacy is not readily available for all commonly used canine and
feline vaccines, veterinarians must rely on other sources of information.
These sources include the licensing status of a vaccine, manufacturer-
generated product information, and clinical impression of vaccine per-
formance. Postmarketing surveillance systems can serve to collect re-
ports on suspected lack of efficacy concerns as well. Despite the paucity
of hard scientific evidence, clinical experience supports the impression
that widespread vaccination has decreased the incidence of many poten-
tially fatal canine and feline infectious diseases.
3
19. 21 . 35 The continued
control of these infectious diseases is dependent on continued protection
of the animal population through appropriate vaccination with effective
products.
l o

38
.,
496 MEYER
RISKS OF VACCINATION
.,
The risks of vaccination are describeQ..as the potential adverse effects
that may occur as a result of vaccine administration.
32
The risk posed to
an individual is based on the frequency of adverse reactions occurring
after vaccination in the general population of similar animals as well on
as host and environmental risk factors Y Ideally, reliable information
regarding the likelihood and severity of potential adverse reactions or
effects should be readily available to veterinarians so that appropriate
vaccination recommendations can be made. Of equal importance is
the communication of vaccination risk information to owners.!3 If risk
information is shared, the owner can take part in the decision-making
process and is better equipped to properly monitor the animal for
potential adverse events associated with vaccination.
Prelicensing Measurement of Risk
As part of the licensing procedure, applicants for a veterinary prod-
uct license are required to conduct field tests, especially to confirm
product safety.42 Prelicensing field tests may involve several hundred or
thousand animals at three geographic sites (Steve Karli, Director, USDA
Center for Veterinary Biologies [CVB] Unit of Inspection and Compli-
ance, personal communication, January 2000) Although the group is
larger and usually more diverse than that involved in the efficacy stud-
ies, certain types of reactions may not be detected. These include rare
events, events that occur after repeated exposure, and events that occur
in a subgroup (e.g., specific breed, age) .13.32 For vaccines used in people,
the nature and frequency of adverse events encountered during field
trials are included on vaccine labeling.
32
In contrast, adverse event infor-
mation collected through field trials is not routinely required to appear
on veterinary vaccine labeling, although a statement regarding the po-
tential for anaphylactic reactions and the use of epinephrine as "anti-
dotal" is required for all parenterally administered vaccines.
Postmarketing Measurement of Risk (Surveillance)
Continual evaluation of adverse events associated with medical
products once they are available for widespread use is critical to safety
monitoring.
32
Postmarketing surveillance is particularly important for
biologics, where changes in cultured organisms used to produce the
product can affect the safety of the product by altering its virulence or
immunogenicity. Similarly, mutations in field pathogens can cause
VACCINE-ASSOCIATED ADVERSE EVENTS 497
changes in a product's effectiveness, which may only be recognized on
a clinical level. Furthermore, practitioner reporting can playa vital role
in identifying potentially dangerous lapses in product quality such as
contamination or Inisbranding, allowing the situation to be investigated
and rectified.
Postmarketing surveillance can provide an excellent tool to identify
rare reactions not discovered during prelicensing studies, monitor recog-
nized reactions, characterize potential risk factors or conditions that may
predispose to reactions, and detect particular product lots with unusual
reporting patterns (e.g., increased number of reported reactions or un-
usual types of events}.32 For human vaccines, adverse event information
collected through postmarketing surveillance is used to update existing
label infonnation.
32
In veterinary medicine, adverse event information
derived from postmarketing surveillance is not routinely required on the
product's label,38 although "special additional requirements" to specific
product labels can be made.
48
For example, the statement "Occasionally,
transient corneal opacity may occur following the administration of this
product" is a label requirement for vaccines containing modified-live
canine adenovirus-I .
Although individual manufacturers may voluntarily include re-
ported adverse events on labeling, there is a disincentive for companies
to do SO.20 A vaccine with adverse events voluntarily listed on its label
may be perceived as more dangerous than a comparable vaccine that
does not include this label information. Unfortunately, veterinarians
may erroneously believe that no adverse events are associated with the
comparable product because none are listed on the label.
Two general types of surveillance mechanism exist-active and
passive.
32
For active surveillance, the vaccination status of all patients in
a specified population is correlated with clinical outcomes. Because an
active reporting program is designed so that all adverse events for the
given population are reported, underreporting is theoretically elimi-
nated. Although the data provided are comprehensive, the system is
expensive. Active reporting systems usually include only a small number
of participants and, as a result, may be unable to detect rare events. It
has been suggested that large corporate veterinary practices could pro-
vide the framework for an active reporting systemY Patients could be
monitored prospectively to estimate the incidence of specific vaccine
reactions.
In contrast to active systems, passive surveillance systems are based
on the voluntary reporting of adverse events.
32
Passive systems are
simpler and less expensive. Because the population is not limited, pas-
sive systems offer the potential for detecting rare or unusual events.
Limitations for passive surveillance systems include variable reporting
standards, underreporting, and bias of reporters. Various stimuli to
498 MEYER
passive reporting can make analysis of data challenging. For example, a
spike in reports involving a certain type of reaction or product may
truly reflect an increased incidence or 1nay simply reflect increased
awareness and reporting of that type of event, the incidence of which is
actually remaining constant.
Surveillance is a form of descriptive epidemiology; thus, the fre-
quency and distribution of reported adverse reactions are recorded with-
out regard to predetermined causal relations.
32
As such, surveillance
data lack specificity, and causal relations cannot be definitively estab-
lished.
32
,38 Because of the lack of specificity, passive reporting programs
are best used to identify potential associations between products and
adverse events.
32

38
Once the potential association or trend is identified,
more rigorous controlled mechanisms can be used to better clarify the
possible relation. 13, 32. 38
Vaccine-associated feline sarcomas provide an example of how pas-
sive surveillance has been used to identify a potential association, with
subsequent research supporting the associationY A trend of increasing
vaccine site sarcomas submitted to a veterinary pathology laboratory
was first identified.1
5
Further study demonstrated that vaccine site sarco-
mas differed morphologically, biologically, and histochemically from
sarcomas occurring at nonvaccine sites.
s
, 14, 17 Epidemiologic studies have
also demonstrated an association between vaccination and sarcoma de-
velopment in cats.
22

23
The results of a prospective controlled epidemio-
logic study (Philip Kass, DVM, PhD, North American Multicenter Study
of Determinants of Feline Vaccine-Associated Sarcomas) funded by the
Vaccine-Associated Feline Sarcoma Task Force (VAFSTF) and conducted
in 1998 and 1999 are expected to provide more insight iflto the risk
factors involved with the development of vaccine-associated feline sarco-
mas (VAFSs).
POSTMARKETING SURVEILLANCE SYSTEM FOR
HUMAN VACCINES
The Vaccine Adverse Event Reporting System (VAERS) provides a
centralized surveillance system through which vaccine manufacturers,
health care professionals, and consumers report adverse events after the
administration of any vaccine licensed for use in human beings in the
United States.
32
The VAERS is coadministered by the Department of
Health and Human Services, US Food and Drug Administration (FDA),
and the Centers for Disease Control (CDC). This surveillance system
was established to manage the adverse event reporting that is mandated
in the National Childhood Vaccine Injury Act (NCYIA). The NCVIA,
passed in 1986, requires health professionals and vaccine manufacturers
VACCINE-ASSOCIATED ADVERSE EVENTS 499
to report adverse events associated with vaccine administration in peo-
ple. Approximately 12,000 reports are submitted to the VAERS annually,
of which an estimated 40% are provided by manufacturers, 25% are
generated by healtJ:1. care providers, and 33%' are from public health
departments (Marcel Salive, MD, MPH, Chief, Epidemiology Branch,
FDA, Center for Biologics Evaluation and Research, Division of Biostatis-
tics and Epidemiology, personal communication, October 1999). Direct
consumer reports comprise approximately 2% of the reports.
Because the V AERS system is a passive surveillance program, ac-
knowledged limitations include underreporting, deficient data quality,
simultaneous administration of multiple vaccine antigens, reporting bias,
inclusion of events not causally related to vaccination, lack of control
group, and lack of information on the number of vaccines given.
32
The
strengths of the system include the fact that it is the only system covering
the entire US population, includes the largest number of case reports,
and can assess the safety of specific vaccine lots. The VAERS provides
timely availability of data from a geographically diverse population; is
able to detect possible new, unusual, or rare adverse events; and can
generate hypotheses that may be tested in other databases.
The CDC and FDA evaluate information from the VAERS database.
The CDC focuses on aggregate information so as to detect unusual
epidemiologic trends and associations.
43
The FDA reviews individual
reports, assessing whether a reported event is represented in product
labeling and monitoring the system for trends involving individual
vaccine manufacturers and vaccine lots. Various actions can be initiated
by the FDA based on VAERS data, including labeling changes, postmar-
keting epidemiologic investigations, safety alerts or "Dear Health Profes-
sional" letters, inspections of the manufacturing facility, or market with-
drawal of the vaccine. Adverse event information included on vaccine
labels is periodically updated with VAERS information.
33
Safety-related
information directed to health care professionals is actively disseminated
by the VAERS, and information collected in its database is available to
the public through the National Technical Information Services (tele-
phone: 703-487-4650) or through the Freedom of Information staff (tele-
phone: 301-827-2000).32
VETERINARY VACCINE POSTMARKETING
SURVEILLANCE
In 1998, the American Veterinary Medicine Association (AVMA)
Executive Board approved the following recommendation, submitted by
the AVMA Committee on Biologic and Therapeutic Agents:
500 MEYER
,
l'
The AVMA supports vaccinovigilance, which is monitoring of
vaccines and other immunobiologics via a publicly available central
reporting system. The system showd include reports of adverse
reactions or the failure of biologics to pilJtect animals from disease.
We recommend that these reports follow a standardized, systematic
template. Any compilation or interpretation of these reports should
be provided in a form that is useful to biological firms and
veterinarians. Such reporting is not currently a function of the
United States Department of Agriculture (USDA) APHIS Center for
Veterinary Biologics, but should be. The need for vaccinovigilance
is significant and urgent. Animal health, public health, and food
safety are protected by credible reporting. Additional funding is
required to support adequate vaccinovigilance.
Unlike the situation in human medicine, there is no regulation
analogous to the NCVIA that mandates veterinary reporting of vaccine-
associated adverse events. As regulations currently exist, vaccine manu-
facturers are not required to record adverse event reports that they
receive from veterinarians and consumers. 20, 21 Furthermore, vaccine
manufacturers are not currently required to routinely submit adverse
event reports to the USDA, although USDA personnel may request
adverse event records for review during manufacturer site inspections,
In contrast, manufacturers of veterinary drugs and pesticides are
subject to mandatory reporting of adverse events, Veterinary drug manu-
facturers are required to forward adverse event reports regarding new
animal drugs to the FDA Center for Veterinary Medicine (CVM), where
they are entered into the FDA CVM Adverse Drug Event Reporting
System for monitoring and analysis.
54
Label changes that describe re-
ported reactions Lan be required based on adverse event reporting,
Summaries of adverse event reports are available on the FDA CVM
website (www.fda.gov / cvm/ fda/TOCs/ adetoc.htrnl). Adverse events
associated with pesticides used in animals are also subject to mandatory
manufacturer reportingY Product registrants are required to submit to
the US Environmental Protection Agency a summary of all adverse
events received during a 90-day period within 60 days of the end of the
collection period,55
Although the USDA CVB does not systematically receive reports of
all adverse reactions reported to vaccine manufacturers, it does accept
reports directly from practitioners and consumers through its Unit of
Inspection and Compliance. This unit also accepts copies of reports
involving veterinary biologics received by the United States Pharmaco-
peia (USP) Veterinary Practitioners' Reporting (VPR) Program. The VPR
Program is a voluntary reporting program provided by the USP, in
cooperation with the AVMA, as a service to the veterinary community
(see page 511 for additional information about the USP VPR Program.)
'Proceedings of the 136th Annual Session of the American Veterinary Medical Associa-
tion House of Delegates, New Orleans, LA, July 10-14, 1999; P 122.
VACCINE-ASSOCIATED ADVERSE EVENTS 501
The USDA CVB reviews adverse event data and takes action on a
case-by-case basis. Unfortunately, the number of practitioners reporting
to the USDA, either directly or through the USP, is small when compared
with those who report directly to the manufacturer. In a survey of 266
veterinarians, 97% of respondents who reported problems did so directly
to the manufacturer, although only 8% reported to the regulatory agency
or the USP (USP Survey of Veterinarians' Attitudes and Behaviors Re-
garding Reporting, unpublished data collected at the North American
Veterinary Conference, Orlando, FL, 1998). This reporting trend was
supported by USP interviews with industry liaisons, who estimated that
95% of the reports they received from veterinarians were submitted
directly to the company, with only 5% of the reports coming in through
the USP. The USDA CVB receives approximately 100 reports a year
directly from veterinarians and' consumers,38 but a growing number of
reports are submitted to the USDA through the USP VPR Program.
During 1999 alone, the USP VPR Program shared 981 biologic reports
with the USDA CVB. This number pales, however, when compared with
the estimated 10,000 adverse events that are reported annually to animal
vaccine manufacturers.38 Consequently, the data available to the USDA
CVB for vaccine safety monitoring would increase substantially if manu-
facturers were required to submit their adverse event information to a
centralized surveillance program.
The USDA CVB has a draft regulation, which is in its final stages
of program comment and review, for mandatory industry reporting of
adverse events related to biologics (Steven A. Karli, Director, CVB Divi-
sion of Inspection and Compliance, personal communication, December
1999). The CVB plans to publish the proposed rule in the fiscal year 2001.
ADVERSE EVENTS ASSOCIATED WITH VACCINATION
Adverse events associated with vaccination have been well de-
scribed and are categorized in various ways.3. 7. 35 For purposes of this
discussion, adverse events associated with vaccines are classified as
systemic or local reactions. Unless otherwise noted, the USP data pre-
sented in the following sections reflect information from the 1719 bio-
logic reports submitted to the VPR Program between August 1, 1995
and September 30, 1999.
Systemic Reactions
Nonspecific Systemic Reactions
Clinical signs such as anorexia, lethargy, fever, and soreness begin-
ning a few hours after vaccination and persisting for 24 to 36 hours are
502 MEYER
reported in association with vaccination.
34

39
The causes of these nonspe-
cific reactions may include vaccine orgaQism replication of modified-live
vaccines, exposure to endotoxins, adjuvtnt toxicity, or immune system
responsiveness.
24
34 Most reactions are mild, but in some cases, the
animals are so severely affected that supportive care may be required.
Because vaccines are designed to stimulate an immune response, these
kinds of reactions are to be expected and have even been referred to as
"normal toxicity" associated with vaccination.
34
35. 40 In a clinical study
involving 2288 routinely vaccinated cats and kittens, nonspecific sys-
temic signs were reported at a rate of 1.2%.39 This study also showed
that reactions were more likely to occur when multiple vaccines were
administered and that cats older than 1 year of age were more likely to
experience reactions than younger animals. Most systemic vaccine reac-
tions reported to the USP VPR Program involve nonspecific reactions
that are presumed to be the result of the animal's immune response to
the vaccine.
Type I Hypersensitivity (Anaphylaxis)
Type I hypersensitivity, or anaphylaxis, is a well-characterized ad-
verse event associated with vaccine administration.
3

4O
It is mediated by
IgE and predominantly involves lymphoid tissues associated with body
surfaces such as the skin, intestines, and lungs. In the classic type I
reaction, interaction between the antigen and mast cell or basophil-
bound IgE causes degranulation, releasing vasoactive amines and initiat-
ing production of inflammatory mediators and cytokines.
3
35. 40 The clini-
cal signs associated with anaphylaxis vary with species, although the
most severe anaphylactic reaction in all species involves cardiovascular
collapse, or anaphylactic shock.
Because anaphylactic reactions can persist for 24 to 48 hours, pro-
longed monitoring and multiple doses of corticosteroids, antihistamines,
or epinephrine may be required. Four reports made to the USP VPR
Program involved animals (three dogs, one cat) that were successfully
treated for anaphylactic reactions occurring immediately after vaccina-
tion but died at home several hours later.
Dogs. For acute anaphylactic reactions in dogs, as reported to the
USP VPR Program, clinical signs were most often reported in the skin
(51 %; most often manifested as urticaria usually involving the face
and ears), in the gastrointestinal tract (40%; vomiting with or without
diarrhea), and less frequently, in the respiratory tract (6%; respiratory
distress). Fifty-nine reports of anaphylactic shock in dogs were reported
to the USP, with 10 involving fatal outcomes. Four of the dogs reported
to develop anaphylactic shock were vaccinated by their nonveterinarian
owners. Two of these dogs did not survive. Thirty-eight different brands
VACcrNE-ASSOClATED ADVERSE EVENTS 503
were represented, including various combinations of distemper, adenovi-
rus, leptospira, parainfluenza, and parvovirus antigens as well as rabies,
coronavirus, Bordetella bronchisepticum, Borrelia burgdorferi, and Giardia
lamblia'. No trend suggesting an association between anaphylaxis and a
particular brand or type of vaccine was found.
Cats. The clinical signs of anaphylaxis in cats that were reported to
the USP VPR Program showed a different pattern than those reported
in dogs, with 66% involving the gastrointestinal tract (usually vomiting
with or without diarrhea), 22% involving the respiratory tract, and 12%
involving the skin. Thirty-nine cases of anaphylactic shock in cats were
reported, with nine fatal outcomes. None of these animals had been
vaccinated by nonveterinarian owners. Twenty-six different brands of
vaccines were listed as suspected products, including rabies, FVRCP
with or without a chlamydia FeLV, and feline infectious' perito-
nitis vaccines. As with dogs, no particular trend suggesting an associa-
tion between anaphylaxis and a particular brand or type of vaccine was
evident. In a published field study tracking adverse reactions in 2288
routinely vaccinated cats and kittens, the reported rate of anaphylaxis
(repeated vomiting, diarrhea, or respiratory signs) was 0.26%.39
Ferrets. The USP VPR Program received 83 reports involving 130
ferrets that developed anaphylaxis subsequent to routine vaccination with
one brand of canine distemper vaccine (Fervac-D; United Vaccines, Madi-
son, WI) and one brand of rabies vaccine (Imrab; Merial Limited, Athens,
GA). These brands are the only vaccines licensed in the United States for
use in ferrets. Fifty-four of the 83 reports involved administration of the
distemper vaccine alone, although 20 involved concomitant administra-
tion of distemper and rabies vaccines. Nine reports involved the rabies
vaccine only. These reports of vaccine-associated anaphylaxis account for
99.8% of all reports in the USP VPR Program database involving ferrets.
The reported clinical signs for the ferrets were remarkably similar,
with nearly all affected animals developing vomiting and diarrhea,
usually hemorrhagic, within minutes of vaccination. Respiratory distress
and derma to logic manifestations were also reported but less commonly.
In one report, 4 of 5 unrelated ferrets in one household vaccinated at
the same time experienced anaphylactic reactions. Similarly, 3 of 4 ferrets
in another household suffered anaphylaxis when they were vaccinated
as a group. One veterinarian reported six cases of anaphylaxis in the
last 26 ferrets vaccinated at his clinic.
Of the 83 cases of anaphylaxis in ferrets, 49 involved cardiovascular
collapse. All but 8 of the ferrets . recovered from the reaction with treat-
ment, which usually included corticosteroids, antihistamines, and occa-
sionally epinephrine. Because the information was gathered through a
passive surveillance system, it does not prove causality or provide
information on the reaction rate. Anaphylaxis is a well-documented
504 MEYER
reaction to vaccination, however, and the uniform description of the
nature and tirrllng of the ferrets' reactions is consistent with vaccine-
induced anaphylaxis. More rigorous m e ~ d s such as controlled experi-
mental or clinical studies to estimate the reaction rate are required to
better quantify the situation. If the reaction rate is considered unaccept-
able, reformulation of the vaccine may be considered to reduce the risks
asso,ciated with vaccination. Additional label information describing the
rate and type of reaction, with treatment recommendations, would
prove helpful.
Type /I Hypersensitivity (Cytotoxic Type)
Type IT hypersensitivity involves cell destruction mediated by anti-
bodies.
34

4O
Examples of this type of reaction include phagocytic removal
of platelet-bound antigen when opsonized by antibody. This may ac-
count for the transient thrombocytopenia found in some studies after
modified-live canine distemper virus vaccination of dogs.
34
If a vaccine
contains normal cell antigens such as erythrocyte antigens, it may induce
antierythrocyte antibodies, which can lead to immune-mediated hemo-
lytic anemia.
35
No adverse events identified by the author as type II
hypersensitivity to a vaccine have been received by the USP VPR Pro-
gram.
Type 11/ Hypersensitivity (Immune Complex-Mediated)
Type III hypersensitivity involves the formation of antigen-antibody
immune complexes. This initiates a number of biologic processes, of
which the most significant is the complement cascade.
4O
An example of
type III hypersensitivity in dogs is the condition referred to as blue
eye.
5
34. 40 Blue eye describes the corneal edema associated with antigen-
antibody complexes in the cornea that can occur after administration of
adenovirus-l modified-live virus vaccine or infection with the wild
virus. The USP VPR Program has received one report of blue eye in a
dog that was vaccinated by its owner with an over-the-counter distem-
per combination vaccine. Although modem vaccines generally used by
veterinarians contain an adenovirus-2 fraction that is not associated with
the development of blue eye, vaccines containing adenovirus-l fractions
are still available in the United States to consumers as over-the-counter
products. The statement "Occasionally, transient corneal opacity may
occur following the administration of this product" is required on the
label,48 In contrast to the situation in the United States, blue eye is no
longer encountered as a vaccine complication in Australia, because only
canine adenovirus-2 is used in modified-live canine adenovirus vac-
cines.
3
Corneal edema of undefined cause, which can clinically mimic
VACCINE-AS5CX:IATED ADVERSE EVENrS 505
adenovirus-I-associated blue eye, is reported rarely in various species
after vaccination with a variety of different vaccine types (Dave Hustead,
DVM; Fort Dodge Laboratories, Overland Park, KS; personal communi-
cation, March 2000).
Autoimmune Disease
There is some concern that vaccination may trigger autoimmune
disease/' 9 In a controlled retrospective clinical study, a temporal associa-
tion was made between vaccine administration in dogs and the clinical
onset of immune-mediated hemolytic anemia.
9
An experimental study
evaluated the immune response of puppies routinely vaccinated with
commercially available distemper, adenovirus, leptospira, parainfluenza,
and parvovirus plus coronavinis and rabies vaccines. IS The results dem-
onstrated that autoantibodies, particularly against fibronectin and lami-
nin, developed after vaccination in these animals. The clinical signifi-
cance of these findings has not yet been determined. Eight reports of
suspected autoimmune hemolytic anemia in dogs developing within 2
to 14 days of vaccination have been submitted to the USP VPR Program.
Immunosuppression
Whether vaccination can cause clinically relevant immunosuppres-
sion in animals (and under what circumstances) has not been clearly
established. One experimental study showed a decrease in lymphocyte
numbers and response to mitogens in dogs vaccinated concomitantly
with a Rockborn strain of canine distemper and adenovirus-lor adeno-
virus-2.33 In the same study, similar changes were not noted when dogs
were vaccinated with a Snyder Hill strain of canine distemper and
adenovirus-lor adenovirus-2. Other studies involving puppies receiving
a series of routine vaccines did not demonstrate lymphopenia or a
decrease in lymphocyte blastogenesis test results; however, the strain of
canine distemper used was not indicated. I S. 27 It is difficult to draw
general conclusions from these studies, because different brands of vac-
cines can differ in their effects. Furthermore, the clinical significance of
decreased lymphocyte counts and decreased lymphocyte blastogenesis
is not entirely clear. It has been suggested that these changes may reflect
changes in lymphocyte trafficking between blood and lymphatics rather
than true immunosuppression.
35
In cats, the authors of a published case report suggest that vaccina-
tion with an intranasal modified-live panleukopenia virus vaccine may
have contributed to immunosuppression in five kittens that resided in
the same cattery.12 This immunosuppression may have allowed fatal
overwhelming systemic infection with Salmonella typhimurium organ-
506 MEYER
isms, which were harbored in the kittens' tracts. No
vaccine-associated adverse events described by the authors as immuno-
suppression have been submitted to tUe USP VPR Program.
Vaccine Virulence
Residual virulence of modified-live vaccines can cause adverse
events in vaccinated animalS.
3
, 34 Causes can be associated with the
product or the animals to which it is administered. Modified-live calicivi-
rus and herpes virus vaccines can be associated with sneezing and nasal
discharge 4 to 9 days after vaccination, even in healthy cats appropriately
vaccinated, simply because of the residual virulence of the attenuated
organisms.
34
,39 Likewise, a polyarthropathy has been associated with
calicivirus, with antigens detected in synovial macrophages of cats either
vaccinated with a modified-live vaccine or exposed to the field virus.
2
,6
Reactions occurring 7 to 21 days after vaccination in cats, characterized
by fever, anorexia, and lethargy and occasionally accompanied by joint,
spinal, or generalized pain, have been associated with vaccines con-
taining modified-live C. psittaci.
39
Increased reaction rates were associated
with increasing antigenic content of the chlamydia fraction of the vac-
cine.
The characteristics of the vaccinated animal can affect the manifesta-
tion of residual virulence. For example, attenuated microorganisms that
are considered safe to use in healthy adult animals may cause disease
when neonates are exposed to them, either directly through vaccination
or through organisms shed by a recently vaccinated animaP6 Vaccination
of pregnant animals with modified-live vaccines can result in fetal abnor-
malities such as cerebellar hypoplasia in kittens associated with feline
parvovirus virus
3
, 37 and myocardial disease in puppies associated with
canine parvovirus.
34
Immunocompromised dogs vaccinated with modi-
fied-live canine distemper vaccines have been reported to develop post-
vaccinal encephalitis.
35
Vaccination of an inappropriate species with
modified-live vaccines has also been reported to result in virulence,35
Erroneous route of administration of a vaccine can contribute to the
development of vaccine induced disease as a result of residual virulence.
Parenteral feline herpes and calicivirus vaccines have been reported to
cause clinical disease if aerosolized and inhaled by the cat.
3
, 34, 35
Inadequate inactivation of killed products or reversion to virulence
in modified-live products can result in severe vaccine-induced disease.
Modified-live rabies vaccines have been reported to produce clinical
rabies in vaccinated dogs and cats.u,44 Postvaccinal encephalitis in dogs,
believed to be associated with reversion to virulence of vaccine distem-
per virus, has been reported in the literature.
4
VACCINE-ASSOCIATED ADVERSE EVENTS 507
Adverse Events Associated with Product Contamination
Systemic adverse events can be associated with contamination of
v a c c ~ e s with viruses, fungi, mycoplasma, or bacteria.
24
Contamination
can occur during vaccine production as well as in the hands of the
individual administering the product. Contamination with fungi and
bacteria are generally easily seen and detected, because the appearance
of the product is changed. Although vaccine contamination has been
reported rarely, it can be associated with serious outcomes. The most
dramatic cases of contamination are often seen with viruses. The contam-
ination of a canine modified-live vaccine with bluetongue virus was
associated with death and abortion in pregnant dogs. 1. 45
In an effort to minimize the release of contaminated products, each
batch of animal vaccines is tested for purity by the manufacturer, and
the test results are reviewed by the USDA before batch release.
51
52
Testing for extraneous bacteria, mycoplasma, and fungi is included.
The USDA validates manufacturer-generated test results through check
testing on selected serials. In 1999, the USDA CVB took regulatory action
four times to address issues involving product sterility (Steven A. Karli,
Director, CVB Division of Inspection and Compliance, personal commu-
nication, March 1999). Nevertheless, postmarketing surveillance remains
an important tool in identifying potentially contaminated products that
manage to enter the marketplace. Four cases of suspected vaccine con-
tamination involving four different products have been submitted to the
USP VPR Program.
Lack of Efficacy
Lack of efficacy is considered to be an adverse event by the Pharma-
co vigilance Working Group of the International Cooperation on Har-
monisation of Technical Requirements for Registration of Veterinary
Medicinal Products and can be monitored through postmarketing sur-
veillance systems. Because no vaccine can claim 100% efficacy, sporadic
reports of a vaccine' s failure to protect are likely to be encountered.
When numerous reports of efficacy concerns regarding the same product
are detected through a surveillance system, investigation of the situation
may be warranted. The USP VPR Program has received 13 reports of
suspected lack of efficacy for veterinary vaccines. Of these 13 reports, 8
involved distemper outbreaks in mink herds that were vaccinated per
label instruction. Two reports involved clinical distemper in dogs despite
vaccination with a canine distemper combination vaccine, and 1 report
involved a dog that was not protected from clinical Lyme disease after
vaccination against B. burgdorferi. The final 2 reports involved a cat
vaccinated with an FVRCP vaccine that subsequently developed panleu-
508 MEYER
kopenia and a horse that became infected with rabies, d e s p i f ~ vaccina-
tion.
Local Vaccine Reactions
Pain
It is not uncommon for animals to experience pain during or subse-
quent to vaccination. Immediate pain can be caused by vaccine adminis-
tration' near a nerve, the vaccine's osmolality or pH, or the temperature
of the vaccine when it is administered.
34
Localized pain after vaccination
is often related to the body's inflammatory response at the site of vaccine
administration. Reports of lameness in cats vaccinated in the hind limbs,
in accordance with the VAFSTF guidelines, have been received by the
USP VPR Program. Many cats described in the reports experienced
severe pain and became completely nonambulatory, particularly when
vaccines were administered in both hind limbs on the same day. Lame-
ness has been reported to persist for days to weeks after vaccination.
Benign Swelling, Nodules, and Masses
Immediate swelling at the injection site can be caused by the actual
volume of the vaccine that is deposited subcutaneously or intramuscu-
larly in small animals.
34
Later, swelling can be related to influx of intersti-
tial fluid and inflammatory cells. A local reaction of some type is an
expected resl,llt of immunologically stimulating the vaccinated animal
and is not considered an adverse event by some authors.
35

4O
Palpable nodules or masses often occur at vaccination sites. Causes
can be related to hypersensitivity reactions or general inflammatory
reactions. Local hypersensitivity reactions can be stimulated by the anti-
gens, diluent, adjuvants, contamination, or endotoxins. Type I (immedi-
ate), type III (immune-complex), and type IV (delayed) hypersensitivity
reactions can be involved in local reactions.24, 34, 35 Granulomas can occur
locally and are frequently associated with adjuvant products, particu-
larly depot adjuvants.
3
, 34 Granulomas are often sterile and painless, and
they resolve over weeks to months. Focal necrotizing granulomatous
panniculitis associated with rabies vaccination has been described in
cats and dogs.
16
It is difficult to clinically differentiate benign vaccine site reactions
based on causation, particularly if histopathologic testing is not per-
formed on affected tissues. Consequently, the USP VPR Program data
for all local swelling and benign nodules and masses occurring at injec-
tion sites are grouped together. Ninety-nine such reports involving dogs
VACCINE-ASSOCIATED ADVERSE EVENTS 509
were submitted to USP VPR Program. The products most frequently
associated with the local reactions were either rabies vaccines or distem-
per combination vaccines. For cats, USP data include 110 reports of
benign lumps developing at the site of vaccination. Rabies vaccines
were most frequently associated with non-neoplastic masses in cats,
accounting for 72% of all products reported. This trend is supported in
a small experimental trial, where nine cats were vaccinated with rabies,
FVRCP, and FeLV vaccines.
36
All cats developed a palpable inflammatory
lesion at the site of rabies vaccination. In contrast, a palpable lesion was
found at the FVRCP vaccination site in only one cat, and FeLV vaccina-
tion did not result in any palpable lesions.
Vaccine-Associated Feline Sarcomas
The VAFSTF (www.avrna.org/ vafstf) was formed in response to the
increased incidence of soft tissue sarcomas occurring at vaccine sites. The
goals of the VAFSTF are to facilitate investigation of the epidemiology,
etiopathogenesis, treatment, and prevention of these malignancies as
well as to disseminate information to veterinarians and the cat-owning
public. The VAFSTF has formally recommended that practitioners report
VAFSs to the manufacturer and the USP VPR Program. The USP has
collaborated in VAFSTF-funded epidemiologic research to define risk
factors for VAFS development and has supplied data that were reviewed
during the development of VAFSTF guidelines for the diagnosis and
management of VAFSs. The USP provides the only centralized national
repository of VAFS reports. A total of 506 reports of VAFSs resided in
the USP VPR Program database as of December 31, 1999. A detailed
discussion of vaccine-associated sarcomas is provided elsewhere in this
issue.
Vaccine Site Alopecia
Localized alopecia after vaccination with inactivated rabies vaccine
has been reported and is believed to be the result of vasculitis caused
by antigen-antibody complexing.
34

46
In one published report, 10 of 13
affected dogs were Poodles.
46
The USP VPR Program has received six
reports of small-breed dogs (Chihuahua, Pomeranian, Bichon Frise, Mal-
tese mixed breed, Shih Tzu, and Papillon) that developed thin skin and
hair loss at the site of vaccination. Five of the reports involved a rabies
or rabies combination vaccine, although one report involved a distemper
combination vaccine.
510 MEYER
"
Abscesses
Vaccine site abscesses can occur as a result of bacterial or fungal
contamination of the product or conta1'nination introduced at the time
of administration.
34
Only four reports of abscesses after vaccinations in
dogs or cats have been reported to the USP VPR Program. Two reports
described cats that developed abscesses at the site of Microsporum canis
vaccine administration. Two reports involved dogs with reported vaccine
site abscesses. One abscess developed subsequent to rabies vaccination,
although the other developed after the administration of a distemper
combination vaccine.
Local Reactions Associated with Intranasal Vaccines
An intranasal FVRCP vaccine that is applied to the nostrils and eyes
of the cat has been available since the late 1970s but has recently
increased in popularity as a result of efforts to minimize injectable
vaccine use. Over a 3-year period, the USP VPR Program received 72
reports from practitioners regarding intranasal FVRCP vaccines. Re-
ported local reactions include nasal ulcers, oral ulcers, and conjunctivitis.
The causes of these adverse events have not been determined.
OPTIONS FOR REPORTING
Postmarketing surveillance plays a vital role in identifying and
monitoring potential risks associated with vaccine administration as well
as with product efficacy. The depth of the surveillance system's database,
however, is dependent on active reporting by practicing veterinarians.
Observations on product performance in the clinical setting are valuable
but must be shared with the manufacturer, the USDA, and the veterinary
community to have maximal impact on product safety. Veterinarians
wishing to report adverse events or quality concerns associated with
vaccines may contact any or all of the following: the product manufac-
turer/labeler, the USDA CVB, or the USP VPR Program. The differences
among these reporting options are outlined below.
Product Manufacturer
When veterinarians do report adverse events, they usually report
them directly to the manufacturer. It is particularly important for veteri-
narians to contact the manufacturer in cases of death or serious injury;
at that time, the manufacturer may provide assistance regarding diag-
VACCINE-ASSOCIATED ADVERSE EVENTS 511
nostics and therapy. Additionally, the manufacturer may require detailed
information regarding the incident. The telephone number for the manu-
facturer's technical support division is often available on the package
labeling, in veterinary reference texts, in the telephone directory, or
through the Internet. The USP VPR Program (telephone: 800-487-7776)
can provide company contact information to veterinarians upon request.
Vaccine manufacturers are not required to record postvaccinal ad-
verse event reports that they receive from veterinarians.
22
Although
reports recorded by the manufacturer can be requested for review during
USDA facility inspections, which can occur every 18 to 24 months,
manufacturers are not required to systematically forward these reports
to the USDA eVB at regular intervals. Information submitted directly to
manufacturers is not entered into the USP's electronic database of veteri-
nary reports nor is it shared with the AVMA.
United States Department of Agriculture Center for
Veterinary Biologics
Veterinarians may report adverse events to the USDA eVB by
telephone or by completing a paper reporting form (telephone: 800-752-
6255; wwww.aphis.usda.gov/vs/cvb/ic/index.htm). Because the USDA
eVB does not currently collect adverse event reports from industry,
all information is submitted directly to the USDA by consumers and
veterinarians or through the USP VPR Program. Adverse event report
information received by the USDA is not published. Information submit-
ted directly to the USDA is not entered into the USP VPR Program
database of veterinary reports nor is it routinely shared with the AVMA.
United States Pharmacopeia Veterinary Practitioners'
Reporting Program
The USP is a private, not-for-profit organization dedicated to the
public health. The USP VPR Program, presented in cooperation with the
AVMA, accepts reports on any type of problem experienced with any
product, including vaccines, drugs, and pesticides, used in any species
of animal. Reports are accepted by telephone, fax, mail, or through the
Internet (telephone: 800-487-7776/ 800-4USP-PRN; www.usp.org). The
USP forwards information from each report to the manufacturer Ilabeler
of the product, the regulatory agency responsible for regulating that
particular type of product, and the AVMA. The information is also
entered into the USP's national repository of veterinary reports.
Information received through the USP VPR Program is made avail-
512 MEYER
" ,
~ 1 i r I
able to the veterinary community in a variety of ways. If requested, the
VPR Program can provide veterinarians ... submitting a report with general
information regarding similar reports in the VPR Program database.
More detailed printed information can ~ e obtained by individuals or
organizations pursuant to the USP's Document Disclosure Policy. Infor-
mation from the database is also presented in scientific articles such
as the Journal of the American Veterinary Medicine Association's feature
"USP-Reporting Back to You"29-31 and lectures at veterinary continuing
education meetings. Information from the USP's database has been re-
viewed by the VAFSTF in the development of its guidelines and has
been used to identify issues for discussion by the AVMA's Committee
on Biologic and Therapeutic Agents.
CONCLUSIONS
Although vaccination plays a vital role in maintaining animal
health, there are risks associated with this medical procedure. Veterinari-
ans are beginning to re-examine dogmatic vaccine protocols and consider
risks and benefits before making vaccine recommendations. Risks should
be effectively communicated to pet owners so that informed consent can
be obtained and the animal can be properly monitored and promptly
treated for vaccine-associated adverse events.
Unfortunately, veterinarians are hindered in this important task
because of a lack of evidence-based information regarding vaccine risks.
Prelicensing safety testing of vaccines involves a relatively small number
of animals, and the results are not routinely required on product label-
ing. Postmarketing surveillance of vaccine safety is carried out by the
USDA CVB; however, the data available for analysis are limited because
manufacturers are not currently required to systematically forward ad-
verse event information that is reported to them by veterinarians. Veteri-
narians' clinical observations of product performance are important;
however, unless they are shared, they are of reduced value. By reporting
their pertinent observations, veterinarians can take an active role in
postmarketing surveillance of vaccine safety. Using a system that shares
data with all involved parties and maintains the information in a central-
ized database, where it can be easily accessed for appropriate analysis,
benefits the veterinary profession and the patients it serves.
References
1. Akita GY, Ianconescu M, MacLachlan NJ, et al: Bluetongue disease in dogs associated
with contaminated vaccine [letter]. Vet Rec 134:283-284, 1994
VACCINE-ASSOCIATED ADVERSE EVENTS 513
2. Bennett D, Gaskell RM, Mills A, et al: Detection of feline calicivirus antigens in the
joints of infected cats. Vet Rec 124:329-332, 1989
3. Brooks R: Adverse reactions to canine and feline vaccines. Aust Vet J 68:342-344, 1991
4. Cornwell HJ, Thompson H, McCandlish IA, et al: Encephalitis in dogs associated with
a batch of canine distemper (Rockborn) vaccine. Vet Rec 122:54-59, 1988
5. Curtis R, Barnett KC: The "blue eye" phenomenon. Vet Rec 112:347-353, 1983
6. Dawson S, McArdle F, Bennett D, et al: Investigation of vaccine reactions and break-
downs after feline calicivirus vaccinations. Vet Rec 132:346-350, 1993
7. Dodds WJ: More bumps on the vaccine road. Adv Vet Med 41:7l5-732, 1999
8. Doddy FD, Glickman LT, Glickman NW, et al: Feline fibrosarcomas at vaccination sites
and non-vaccination sites. J Comp Pathol 114:165-174, 1996
9. Duval D, Giger U: Vaccine-associated immune-mediated hemolytic anemia in the dog.
J Vet Intern Med 10:290-295, 1996
10. Elston T, Rodan H, Flemming D, et al: 1998 Report of the American Association of
Feline Practitioners and Academy of Feline Medicine Advisory Panel on Feline Vac-
cines. JAVMA 212:227-241, 1998
11. Esh ]B, Cunningham JG, Wiktor TJ: Vaccine-induced rabies in four cats. JAVMA
180:1336-1339,1982
12. Foley jE, Orgad U, Hirsch DC, et al: Outbreak of fatal salmonellosis in cats following
use of a high-titer modified-live panleukopenia virus vaccine. JAVMA 214:67-70, 1999
13. Glickman LT: Weighing. the risks and benefits of vaccination. Adv Vet Med 41:701-
7l3,1999
14. Hendrick MJ: Feline vaccine-associated sarcomas. Cancer Invest 17:273-277, 1999
15. Hendrick MJ, Goldschmidt MH: Do injection site reactions induce fibrosarcomas in
cats? [letter) JAVMA 199:968, 1991
16. Hendrick MJ' Dunagan CA: Focal necrotizing granulomatous panniculitis associated
with subcutaneous injection of rabies vaccine in cats and dogs: 10 cases (198s--B9).
JAVMA 198:304-305, 1991
17. Hendrick MJ, Shofer FS, Goldschmidt MH, et al: Comparison of fibrosarcomas that
developed at vaccination sites and at nonvaccination sites in cats: 239 cases (1991-92).
JAVMA 205:1425-1429, 1994
. 18. Hogenesch H, Azcona-Olivera J, Scott-Moncrieff C, et al: Vaccine-induced autoimmu-
nity in the dog. Adv Vet Med 41:733-747, 1999
19. Horzinek M: Vaccination: A philosophical view. Adv Vet Med 41:1-7, 1999
20. Hustead DR: Why do vaccine labels say the funny things they do? Adv Vet Med
41:633-641, 1999
21. Hustead DR, Carpenter T, Sawyer DC, et al: Vaccination issues of concern to prac-
titioners. JAVMA 214:1000-1002, 1999
22. Kass PH, Barnes WG, Jr, Spangler WI, et al: Epidemiologic evidence for a causal
relation between vaccination and fibrosarcoma tumorigenesis in cats. JAVMA 203:396-
405,1993
23. Lester S, Clemett T, Burt A: Vaccine site-associated sarcomas in cats: Clinical experience
and a laboratory review (1982-1993). J Am Anim Hosp Assoc 32:91-95, 1996
24. Martinod S: Adverse effects of vaccination. In Pastoret P-P (ed): Veterinary Vaccinology.
New York, Elsevier, 1997, pp 574-580
25. Martinod S: Vaccination practices in veterinary medicine: Standardization versus tai-
lored to needs? Adv Vet Med 41:657-{i68, 1999
26. McCandlish IA, Cornwell HJ, Thompson H, et al: Distemper encephalitis in pups after
vaccination of the darn. Vet Rec 130:27-30, 1992
27. McMillen GL, Briggs DJ, McVey DS, et al: Vaccination of racing greyhounds: Effects
on humoral and cellular immunity. Vet Imrnunol ImrnunopathoI49:101-13, 1995
28. Meltzer Ml, Rupprecht CEo A review of the economics of the prevention and control
of rabies. Part 1: Global impact and rabies in humans. Pharrnacoeconornics 14:365-
383, 1998
29. Meyer EK: Adverse events associated with albendazole and other products used for
treatment of giardiasis in dogs. JAVMA 213:44-46, 1998
30. Meyer EK: Rare, idiosyncratic reaction to acepromazine in dogs. JAVMA 210:1114-
1115, 1997
514 MEYER
31. Meyer EK: Toxicosis in cats erroneously treated with 45 to 65% products.
JAVMA 215:198--203, 1999
32. Niu MT, Salive ME, Ellenberg SS: Post-marketing surveillance for adverse events
after vaccination: The National Vaccine Adve.Lse Event Reporting System (VAERS). A
MEDWATCH Continuing Education Article. Bethesda, National lnstitutes of Health/
Foundation for Advanced Education in Science (NlH/ FAES), and Rockville, US Food
and Drug Administration (FDA), 1998
33. Phillips T, Jensen JL, Rubino M], et al: Effects of vaccination on the canine immune
system. Can J Vet Res 53:154-160, 1989
34. Povey RC, Carman PS: Risks of vaccination. In Pastoret P-P (ed): Veterinary Vaccinol-
ogy. New York, Elsevier, 1997, pp 546-551
35. Roth JA: Mechanistic bases for adverse vaccine reactions and vaccine failures. Adv Vet
Med 41:681-700, 1999
36. Schultze AE, Frank LA, Hahn KA: Repeated physical and cytologic characterizations
of subcutaneous postvaccinal reactions in cat. Am J Vet Res 58:719-724, 1997
37. Sharp NJ, Davis BI, Guy JS, et al: Hydranencephaly and cerebellar hypoplasia in two
kittens attributed to intrauterine p.arvovirus infection. J Comp PathoI121:39-53, 1999
38. Siev 0: An introduction to analytical methods for the postmarketing surveillance of
veterinary vaccines. Adv Vet Med 41:749-775, 1999
39. Starr RM: Reaction rate in cats vaccinated with a new controlled-titer feline panleuko-
pen.ia-rhinotracheitis-calicivirus-Chlamydia psittaci vaccine. Cornell Vet 83:311-323, 1993
40. Tlzard IR: Veterinary Immunology: An Introduction, ed 5. Philadelphia, WB Saun-
ders, 1996
41. United States Department of Agriculture: USDA Veterinary Services Memorandum No
800.200, Veterinary Biologics General Licensing Considerations, Subject: Efficacy Stud-
ies. May 12, 1995
42. United States Department of Agriculture: USDA Veterinary Services Memorandum No
800.50, Basic License Requirements for Applicants. September 7, 1999
43. USFDA VAERS: How are VAERS reports analyzed? VAERS Frequently Asked Ques-
tions. [FDA VAERS Web site] Available at: http: //www.fda.gov/ cber/ vaers/ faq.htm.
Accessed September 16, 1999
44. Whetstone CA, Bunn TO, Emmons RW, et al: Use of monoclonal antibodies to confirm
vaccine-induced rabies in ten dogs, two cats, and one fox. JAVMA 185:285-288, 1984
45. Wilbur LA, Evermann ]F, Levings RL, et al: Abortion and death in pregnant bitches
associated with the canine vaccine contaminated with bluetongue virus. JAVMA
204:1762-1765, 1994
46. Wilcock BP, Yager J: Focal cutaneous vasculitis and alopecia at sites of rabies vaccina-
tion in dogs. JAVMA 88:1174-1177, 1986
47. 7 USC Subsection 136-136y.
48. 9 Code of Federal Regulations, Part 112.7.
49. 9 Code of Federal Regulations, Part 113.201.
50. 9 Code of Federal Regulations, Part 113.202.
51. 9 Code of Federal Regulations, Part 113.5.
52. 9 Code of Federal Regulations, Part 113.6.
53. 9 Code of Federal Regulations, Part 113.7l.
54. 21 Code of Federal Regulations, Part 510.300, 510.301, and 510.302.
55. 40 Code of Federal Regulations, Part 159.184(d}.
Address reprint requests to
United States Pharmacopeia
12601 Twinbrook Parkway
Rockville, MD 20852
Attn: David Nash, DVM
VACCINES AND VACCINATIONS 0195-5616/ 01 $15.00 + .00
THE POTENTIAL FOR LIABILITY
IN THE USE AND MISUSE OF
VETERINARY VACCINES
Duane Flemming, DVM, JD
Historically, most veterinarians have not paid much attention to the
regulations regarding vaccines. Familiarity with the vaccine laws was
not,really necessary, because by relying on the label instructions, veteri-
narians could, in most cases, shift the focus of any wrongdoing from
themselves to the vaccine manufacturers. As it was fairly difficult to get
reliable expert testimony against veterinarians, and because most of the
vaccine manufacturers had fairly deep pockets, there was not much
opposition to this strategy or much reason to change it. Recent develop-
ments in the law and in the practice of veterinary medicine have forced
veterinarians to take a new look at their use of vaccines and to re-
evaluate their liability in using them.
UNITED STATES DEPARTMENT OF AGRICULTURE OR
FOOD AND DRUG ADMINISTRATION
Many veterinarians still believe that their use of animal vaccines is
highly regulated by the United States government through the Food
and Drug Administration. They could not be more wrong. Through a
combination of court decisions, regulatory changes, and interagency
agreements, the government has effectively established that the Virus-
From the Contra Costa Animal Eye Clinic, Pleasant Hill, California
VETERINARY CLINICS OF NORTH AMERICA: SMALL ANIMAL PRACTICE
VOLUME 31 ' NUMBER 3 MAY 2001 515
516 FLEMMING
Serum-Toxin Act (VSTA) administered by the US Department of Agricul-
ture and not the Food, Drug, and CosIIltic Act administered by the US
Food and Drug Administration has iuwdiction over licensed animal
"biologics" (vaccines) in the United States.
a
b Because VSTA contains no
reference to the use of animal biologics after their sale to the end user,
federal control effectively ends with their sale.< Although there are usage
guidelines within specific state or federal eradication/control programs,
and perhaps as isolated rules within some state practice acts, there are
no overarching federal regulations concerning the use of licensed animal
'The Code of Federal Regulations (9 CFR Part 101.2 (w)) defines biologics as "all viruses. serums,
toxins, and analogous products of natural or synthetic origin, such as diagnostics, antitoxins, vaccines,
live microorganisms, killed microorganisms, and the antigenic or immunizing components of microor-
ganisms intended for use in the diagnosis, treatment, or prevention of diseases of animals."
bBefore 1900, there was no effective regulation of the production of drugs or vaccines in the United
State. In 1906, the Federal Food and Drug Act (Chapter 3915, 34 Stat 768) prohibited the interstate
shipment of adulterated food, drinks, and drugs. This act was administered by the Department of
Chemistry, a division of the USDA. This did not provide adequate protection, so in 1913, the Virus-
Serum-Toxin Act (VSTA) (21 USC Part 151-158) was created to give the government regulatory control
over the manufacture of biologics intended for interstate shipment. This act was administered by the
Bureau of Animal Industry. In 1927, food and drug regulation was shifted from the USDA's Bureau of
Chemistry to a new USDA subdivision, the Food, Drug, and Insecticide Administration, later to become
the Food and Drug Administration (FDA)(44 Stat 515 and 44 Stat 1002). In 1938, the Federal Food,
Drug. and Cosmetic Act (FOCA) (21 USC 321) extended federal regulatory control to cover any "article
intended to diagnose, mitigate, treat or prevent disease in . . . animals" or "articles (other than food)
intended to affect the structure or function of the body of ... animals." In 1940, the FDA was transferred
from the USDA to a new agency, the Federal Security Agency, which, in tum, became a part of the
Department of Health, Education, and Welfare. This series of transfers resulted in federal regulatory
control of animal biolOgiCS by two separate federal agencies: the FDA and the USDA. In 1968, Congress
attempted to direct supervision of animal biologics back to the USDA by amending the FOCA (21 USC
Part 392[b]) to state that "Nothing in this chapter shall be construed as in any way affecting, modifying,
repealing. or superseding the virus, serum, toxin, and analogous product provisiOns, applicable to
domestic animals in the Act of Congress approved March 4, 1913 (VSTA)." In 1978 and 1980, in two
lawsuits (Animal Health Institute vs USDA, 487 F supp 376, and Grand Laboratories vs Harris, 488 F
supp 618), the courts re-established a dichotomy of jurisdiction by holding that the FDA had jurisdiction
over the intrastate and the USDA over the interstate manufacture and sale of animal biologiCS. In 1982,
the USDA and FDA attempted to resolve the issue in a memorandum of understanding (47 Fed Reg
28458{1982]). This agreement specified that the FDA would regulate animal biolOgiCS only where the
VsTA did not apply or where the VsTA offered no remedy at law. This, in effect, limited the FDA to
regulatory control only over unlicensed biologics entered into interstate commerce. Finally, in 1991,
another attempt was made to solve the jurisdictional dispute by modifying the federal regulations (21
CFR 510.4) to provide that "an animal drug produced and distributed in full conformance with the
animal virus, serum, and toxin law of March 14,1913 (VsTAj and any regulation issued thereunder
shall not be deemed to be subject to section 512 of the Federal Food, Drug. and Cosmetic Act." This
regulation was upheld by the Eighth Circuit Court of Appeals (US vs Pro-A Incorporated, 968 F2d 681)
thus leaving as current law that licensed "animal viruses, serums, toxins, and analogous products
of natural or synthetic origin, such as diagnostics, antitoxins, vaccines, live microorganisms, killed
microorganisms and the antigenic or immunizing components of microorganisms intended for use in
diagnosis, treatment, or prevention of diseases of animals" are subject to VSTA and thereby USDA
regulation and that any regulations generated under the FOCA do not apply to animal vaccines.
'The Virus, Serum, and Toxin Act of 1913 (21 USC Part 151-158) in part provides that "it shall be
unlawful for any person, firm, or corporation to prepare, sell, barter, or exchange in any place under
the jurisdiction of the United States, or to ship or deliver for shipment from one State or Territory or
the District of Columbia, any worthless, contaminated, dangerous, or harmful virus, serum, toxin, or
analogous product intended for use in the treatment of domestic animals, and that no person, firm or
corporation shall prepare, sell, barter, exchange, or ship as aforesaid any virus, serum, toxin, or
analogous product manufactured within the United States and intended for use in the treatment of
domestic animals, unless and until the said virus, serum, toxin, or analogous product shall have been
prepared, under, and in compliance with, regulations prescribed by the Secretary of Agricuiture, at an
establishment holding an unsuspended and unrevoked license issued by the Secretary of Agriculture
as hereinafter authorized."
THE POTENTIAL FOR LLABfLITY IN THE USE AND MISUSE OF VACClNES 517
vaccines in the United States. These laws and regulations, in effect, have
created a void in which a veterinarian's use of an animal vaccine is
largely uncontrolled.
FEDERAL PREEMPTION
To complicate matters further for the veterinarian, in 1996, the
United States Supreme Court refused to review the Seventh Circuit
Court's decision in Lynbrook Farms versus SmithKline Beecham Corpo-
ration.
d
In that decision, the Seventh Circuit Court upheld the contention
that VSTA preempted all state court tort remedies, which would have the
effect of imposing requirements that were different from or in addition to
those imposed by the US Department of Agriculture regarding the safety,
efficacy, potency, or purity of a product. This action, in effect, eliminated
vaccine manufacturers as defendants in all vaccine tort cases not alleging
that the vaccine was improperly manufactured. Allegations regarding
the use or misuse of the vaccine product after sale were not preempted."
This ruling left the veterinarian pretty much alone and vulnerable to a
client upset by any bad outcome perceived by the client or his or her
attorney as vaccine related.
As a result, new claims not related to manufacturing defects are
now likely to be centered around malpractice and the failure of the
veterinarian to adhere to the prevailing standards of practice in main-
taining, selecting, or administering the vaccines as well as around allega-
tions that the vaccines were administered without obtaining the proper
informed consent. In addition, breach of warranty is also likely to
become a more frequently litigated issue.
STANDARD OF CARE
If something goes terribly wrong, and the quality of care provided
by a veterinarian is called into question in a court of law, the prac-
titioner's actions are compared with the prevailing standard of care.
Standard of care is a legal term that may be simply defined as the care a
practitioner of similar knowledge, experience, and training would de-
liver under the same or similar circumstances. Stated another way,
would another veterinarian have done what I did in the same circum-
stances?
d79 F3d 620.
<The issue of preemption has been well covered in American Veterinary Medical Law
Association Proceedings. See: Veterinarian and Vaccine Manufacturer Liability After
SmithKline: Implications for Both Sectors (A Panel Presentation), 1997 and Federal Preemp-
tion of Vaccine Product Liability Litigation-Rationale and Result, 1998.
518 FLEMMING
The label instructions provide a fairly clear standard of care for
the storage and handling of most vaccines. To preclude liability, the
veterinarian would only have to show <that he or she maintained the
vaccine according to those label instructions.
The prevailing standard of care for the use of, or even the basic
need for, a particular vaccine is, however, in a state of flux. This is
exemplified by comments from an increasing number of veterinary
virologists, veterinary colleges, professional organizations, and prac-
titioners regarding the revaccination interval for certain vaccine anti-
gens.
3
.
5

7
By themselves, a few published articles or stated opinions of
recognized experts do not define a new standard of care; rather, it is
their adoption and use by a substantial portion of the veterinary commu-
nity that is significant. Vigorous debate within the profession is undoubt-
edly going to result in a new standard of care in the selection and use
of vaccines.
Although many veterinarians may resist and delay the adoption of
new protocols because of financial considerations or more simply be-
cause "we have always done it this way," they should consider that
adherence to the old ways as the established standard of care may, in
the light of new knowledge, not protect them, because " ... conformity
to custom is not in itself an exercise of care as a matter of law."13
The veterinarian's exposure to liability starts with the issue of
whether there is a need to vaccinate at all and, if so, the choice of the
agent to vaccinate against. To which infectious diseases is this animal
likely to be exposed? Is this cat, for example, going to be exposed to
feline leukemia virus or herpes? How about chlamydia or coronavirus?
What are the short- and long-term risks in vaccinating or not vaccinating
this animal for a particular disease? Was there a risk-benefit analysis,
and what was its outcome? Was it reasonable to vaccinate this animal
for this disease? In some situations, the answers are simple. In others,
they are complex and fraught with potential error. In Caran Versus the
United States, the case centered around the standard of care.
14
The
government was found liable for injuries to a 4-month-old child resulting
from the inoculation of an adult dose of typhoid inoculum. The practice
of using adult doses in children was outside the standard practice unless
a taken history revealed that the child was going to travel in a typhoid-
endemic country. In this case, negligence was proved, because no history
was taken and the doctor could not establish that the child was even
going to be exposed to typhoid.
INFORMED CONSENT
A large part of the standard of care involves the issue of informed
consent. Some veterinarians seem to believe that their clients are incapa-
ble of understanding complex medical issues and that it is the veterinari-
mE POTENTIAL FOR LIABILITY IN 1HE USE AND MISUSE OF VACCINES 519
an's responsibility to decide for them the appropriate medical careY By
not obtaining truly informed consent, these veterinarians are simply
inviting legal action. In fact, courts have long held that a physician
cannot, without first obtaining their consent, inoculate or vaccinate per-
sons, even those exposed to the risk and dangers of a contagious disease,
to protect them from contracting such a disease.
4
, 9 This ruling also
applies to veterinarians, who should not inoculate animals, even those
with known exposure to disease, without obtaining the owner ' s in-
formed consent.
In Harries versus the United States, the issue was, in part, informed
consent.
1S
The plaintiff developed encephalitis after a smallpox vaccina-
tion. Liability was predicated on the asserted failure of the physician to
advise the plaintiff that the vaccination could cause encephalitis. Judg-
ment was for the defendant but only because the plaintiff failed to
prove that the smallpox vaccination was the proximate cause of the
encephalitis. Veterinarians should advise their clients of any known and
significant potential adverse consequence that could result from the
proposed vaccination.
In Hitchcock versus the United States, another case dealing with
informed consent, the government was found negligent, in part, for not
disclosing that the vaccination was not required or recommended, that
the vaccination had limited and undetermined benefits, and that the
possibility of injury through allergic reaction existed.
16
The factors dis-
cussed in that case all apply, at one time or another and in one form or
another, to the veterinary use of vaccines.
The current informed consent standard is the "reasonable patient
standard." Under this standard, the scope of disclosure is measured not
by the physician's standards but by the patient's needs and whether the
information is material to the patient's decision.
8
As a broad general statement, material information is information
that a reasonable person in the client's position would use to make an
intelligent decision whether to accept or reject a recommended medical
procedure. Under this standard, the veterinarian should disclose the
nature of the condition and the proposed treatment plus any reasonable
dangers in the veterinarian's knowledge that are incident to or may
result from the treatment. When a procedure inherently involves a
known risk of death or serious harm to the animal, it is the veterinarian's
duty to disclose to the client the possibility of such an outcome and to
explain in lay terms any significant potential complications that might
occur.
For any consent to be valid, it must be based on a clear understand-
ing of the information presented. Veterinarians must remember that to be
understood, the information must be effectively communicated. Detailed
technical expositions of fact are not legally required and usually are not
520 FLENflMmNG
desired. Most clients are overwhelmed with masses of unintelligible
technical data that they are ill equipped" to comprehend or use in reach-
ing a health care decision. Conversely, a blunt and insensitive recitation
of the facts can also impede the process ~ f client understanding:
In providing the necessary information, the veterinarian should take
into account the experience, education, and linguistic abilities of the
client. First-time pet owners may require more information from the
veterinarian to make a valid decision about their animal than breeders
with much greater experience. A foreign language-speaking client may
not understand the risks involved in vaccination when the necessary
information is provided in English. Similarly, a person with limited
education may not comprehend technical information suitable for a
college graduate with advanced training in science or medicine. Al-
though the veterinarian is not expected to do a complete background
check on his clients, he or she is expected to use his or her senses to
evaluate a client and to tailor the presentation to that individual's
particular needs.
Under the informed consent doctrine, the veterinarian is not ex-
pected to be the client's financial advisor, nor is it the veterinarian' s
duty to save the client money. The veterinarian is expected to provide
information to t h ~ client regarding all the reasonable alternatives avail-
able for vaccination. It is up to the client and not the veterinarian to
approve or disapprove the expenditure.
Once the veterinarian has provided the appropriate information and
effectively communicated it to the client, he or she should, as a separate
act, specifically ask for and obtain the client's consent to the proposed
procedure. In fact, the failure to specifically obtain the client's informed
consent after appropriate disclosure could itself be construed as negli-
gence and result in legal liability for veterinary malpractice. The consent
does not necessarily have to be in writing, although that is the best way
to legally establish the granting of informed consent.
It is unwise for any veterinarian to pursue vaccination or any course
of treatment that is hazardous or capable of producing a harmful effect
without first securing the client's specific statement of understanding
and consent.
WARRANTY
In seeking compensation for their losses, unhappy clients may also
look to issues of warranty and the breach thereof. In a 1996 California
case, Shelby/Fullerton versus Grand Labs/Veterinary Pharmaceuticals/
Thomas Worthington/Chino Veterinary Services, the jury found for the
plaintiffs in the amount of $1,541,948 for losses resulting from the negli-
THE POTENTIAL FOR LIABILITY IN THE USE AND MlSUSE OF VACCINES 521
gent use of a vaccine.
17
The decision was based, in part, on a warranty
from the veterinarian that the vaccine was safe for use in calves under
3 months of age. Veterinarians should remember that few, if any, vaccines
are 100% free of adverse effects or are 100% certain to prevent the
indicated disease. In this context, the veterinarian's words to the client
are particularly important. If a veterinarian guarantees that a particular
vaccine product is absolutely safe or that it is going to prevent disease
and it either is not or does not, he or she may be liable not for malprac-
tice but for breach of warranty. Important to the veterinarian, this cause
of action may not be covered by veterinary malpractice insurance.
VETERINARIAN'S CHOICE
Assuming that the veterinarian and the client have made a proper,
informed, and joint judgment about the need for vaccination against a
particular disease, the veterinarian alone must still choose the proper
vaccine to use. With the myriad of vaccine types currently available and
soon to be available, a veterinarian has a plethora of choices as to type:
live virus; modified-live, attenuated, or killed virus; and monovalent or
multivalent vaccine. Did a wrong choice injure the animal directly, or
did it result in failure to provide the promised immunity? In Anderson
versus Blackfoot Livestock Commission Company, selection of the
proper vehicle for conveying immunity was exactly the issue.
ls
In that
case, the plaintiff sued a veterinarian and others for, in part, the veteri-
narian's negligence in the inoculation and vaccination of swine. The
plaintiff purchased hogs that had been represented as vaccinated for hog
cholera by the defendant veterinarian from the Blackfoot Commission
Company. Shortly after the purchase and transportation to his farm, 241
hogs died from what was determined later to be hog cholera. The State
of Idaho testified that it required the use of serum in hog sales yards
because serum provided immediate protection against hog cholera and
sales yards are "exposed places." The defendant veterinarian used modi-
fied-live virus alone. Testimony was taken about the type of immunity
attained with serum verus that obtained with modified-live virus. Judg-
ment was, as relates to this issue, against the veterinarian.
Having selected the appropriate vaccine and presumably cared for
it in the proper manner, the veterinarian must select the proper route of
administration. There are now a variety of routes available: nasal, ocular,
subcutaneous, intramuscular, and intravenous. What is the effect of
choosing the wrong route? Did the veterinarian's choice injure the ani-
mal or adversely affect the desired immunity? In Philips versus Leuth,
the plaintiff appealed from a directed verdict for the defendant veterinar-
ian.
19
The veterinarian was charged with negligence in the vaccination
522 FLEMMING
of hogs. This time the allegation was based, in part, on an improper
method of performing the vaccination. At trial, evidence was entered as
to the usual location for vaccination ~ d the proper sterilization of
needles. The plaintiff contended that the defendant veterinarian did not
place the hogs in the proper position, that he did not use proper restraint
for the insertion of needles, and that the injections were not made into
the proper parts of the body. Not surprisingly, the "expert" testifying in
this case was a competing veterinary surgeon. ' The Court denied the
appeal and noted, among other things, that the plaintiffs case had a lot
of "dead wood" in it, including interrogatories relating to whether the
hogs were standing or sitting when vaccinated and how many there
were of each. Regardless of the outcome of this particular case, it is
illustrative of the kinds of claims veterinarians have faced and may face
again. Certainly, questions are currently being asked within the profes-
sion about the appropriate routes and sites for vaccination, especially in
cats.
6

10
SUMMARY
The lack of specific rules regarding the use of animal vaccines by
veterinarians leaves them vulnerable to legal action for negligence or
breach of warranty. A veterinarian's liability may depend on the answers
to the questions asked previously in this article. The answers ultimately
depend on the specific circumstances of the case. Although no one can
ensure that he or she is never going to be sued, veterinarians can go a
long way in defending themselves against these kinds of allegations by
conforming to the standards of practice as they apply to the care and
use of vaccines; by adhering closely to the doctrines of informed consent;
and by not providing undue warranty to the vaccine product he or
she sells.
References
1. American Veterinary Medical Law Association: Veterinarian and vaccine manufacturer
liability after Smith-Kline: Implications for both sectors [panel presentation]. In Pro-
ceedings of the American Veterinary Medical Law Association, 1997
2. American Veterinary Medical Law Association: Federal preemption of vaccine product
liability litigation: Rationale and result. In Proceedings of the American Veterinary
Medical Law Association, 1998
3. Philips TR, Schultz RD: Canine and feline vaccines. In Bonagura JD (ed): Kirk's Current
Veterinary Therapy XI. Philadelphia, WB Saunders, 1992, p 205
4. Davis v. Rodman 227 SW 612, ]921.
5. Elston T, Rodan 1, Flemming D, et al: 1998 Report of the American Association of
THE POTENTIAL FOR LIABlUTY IN THE USE AND MISUSE OF VACCINES 523
Feline Practitioners and Academy of Feline Medicine Advisory Panel on Feline Vac-
cines. JAVMA 212:227-241, 1998
6. Hershey AE, Soreruno KU, Hendrick M], et ale Prognosis for presumed feline vaccine-
associated sarcoma after excision: 61 cases (1986-1996). JAVMA 216:58-64, 2000
7. Hu&tead DR, Carpenter T, Sawyer DC, et ale Commentary: Vaccination issues of
concern to practitioners. JAVMA 214:1000--1002, 1999
8. Flemming 0: The informed consent doctrine: What you should tell your clients.
California Veterinarian 51:12-13, 1997
9. O'Brien v. Cunard SS Company, Ltd. 28 NE 266, 1891.
10. Weigand CM, Brewer WG: Vaccination-site sarcomas in cats. Compend Contin Educ
Pract Vet 18:869-875, 1996
11. Whitford RE: Doctor to doctor practice tips. DVM Magazine April 12, 2000
12. 117 S Ct 178, 1996
13. 30 Am Jur 2nd, Evidence Part 1123
14. 548 F2d 366, 1976
15. 350 F2d 231, 1965
16. 665 F2nd 354, 1981
17. RCV 65023 consolidated with RCV 01521
18. 375 P2d 704, 1962
19. 204 NW 301, 1925
Address reprint requests to
Duane Flemming, DVM, JD
Contra Costa Animal Eye Clinic
2100 Monument Boulevard, Suite 7
Pleasant Hill, CA 94523-3440
e-mail: animaleyedoctormindspring.com
VACCINES AND VACCINATIONS 0195-5616/ 01 $15.00 + .00
RECENT ADVANCES IN THE
TREATMENT OF VACCINE-
ASSOCIATED SARCOMAS
Gregory K. Ogilvie, DVM
Soft tissue sarcomas have been difficult tumors to treat in feline
oncology, because it is difficult to estimate the extent of the margins of
tumor.
l
3. 5-8. 10 This results in many patients that do not receIve appro-
priate therapy, which, in turn, means a high recurrence rate. This prob-
lem has grown steadily in the last decade since vaccine-associated sarco-
mas were first recognized. Indeed, the increasing prevalence of this
malignant condition has eroded the trust that exists between clients and
their family veterinarian. The profession has had to respond quickly to
determine how to treat and prevent this devastating disease. In essence,
this is a critical care concern for the health and well-being of the profes-
sion as much as it is for our feline patients and the clients that entrust
us with their care.
The purpose of this article is to briefly review background informa-
tion about vaccine-associated sarcomas followed by diagnostic proce-
dures essential to understand how to determine the extent of the primary
and metastatic tumor as well as to understand the general health of
the patient. Finally, and just as importantly, this article addresses the
importance of understanding the nonmedical needs of the client who is
faced with this perplexing problem.
From the Department of Oncology and Internal Medicine, Animal Cancer Center, College
of Veterinary Medicine and Biomedical Sciences, Department of Clinical Sciences,
Veterinary Teaching Hospital, Colorado State University, Fort Collins, Colorado
VETERINARY CLINICS OF NORTH AMERlCA: SMALL ANIMAL PRACTICE
VOLUME 31 NUMBER 3 MAY 2001 525
526 OGILVIE
Table 1. SITES AT WHICH SOFT TISSUE SARCOMAS OCCURRED IN 170 CATS
Location
Vaccination Sites
Interscapular / scapular
Flank/ paral urnbar
Dorsolateral thorax
Dorsal area of back or neck
Femoral region
Nonvaccination Sites
Head (including oral cavity)
Limbs (including scapular and inner thigh)
Bone
Tail
Other
Dubious Vaccination Site
Ventrolateral neck
TOTAL
Number (%)
30 (17.6)
27 (15.9)
19 (11.2)
17 (10.0)
11 (6.5)
31 (18.2)
13 (7.6)
3 (1.8)
4 (2.4)
10 (5.9)
5 (2.9)
170 (100)
From Doddy FD, Glickman LT, Glickman NW, et al: Feline fibrosarcomas at vaccination sites and
nonvaccination sites. J Comp Pathol 114:165-174, 1996, with permission.
DIAGNOSIS
Signalment
Vaccine-associated sarcomas have been identified in middle-aged to
older cats of either gender and any breed.
1
, 5. 7, 10 It should be recognized,
however, that vaccine-associated sarcomas are most often documented
in cats that are younger than cats with other sarcomas of a similar
histologic type not associated with vaccines (Tables 1 and 2). The more
often a cat is vaccinated, the higher is the risk of vaccine-associated
sarcomas. Vaccine- and injection-associated malignancies have been re-
ported to develop within weeks to years after injection.
Physical Examination Findings
A vaccine-associated sarcoma is noted as a firm swelling at or near
a site of previous vaccination. Note that this lump or thickening may
Table 2. SARCOMAS AS A RATIO OF TOTAL FELINE ACCESSIONS AND RATIO OF
INJECTION SITE SARCOMAS (IS) TO NON-INJECTION SITE SARCOMAS (NIS)
1989 1990 1991 1992 1993 1994
Total cat accessions 1855 1244 1314 1215 1184 1129
FSAtotal ratio 1.13 1.69 2.97 1.65 3.04 2.92
lS:N1S 0.54 1.00 1.47 1.86 2.6 4.33
From Doody FD, Glickman LT, Glickman NW, et al: Feline fibrosarcomas at vaccination sites and
nonvaccination sites. J Comp Pathol 114:165-174, 1996, with permission.
ADVANCES IN TREATMENT OF VACCINE-ASSOCIATED SARCOMAS 527
appear days to years after vaccination. Occasionally, the lump may occur
in sites ventral to the site of vaccination, presumably as a result of
ventral migration of the causative agent. Metastatic disease, although
relatively rare, can result in regional lymphadenopathy or respiratory
signs such as tachypnea or dyspnea secondary to pulmonary metastases.
Clinical Evaluation Procedures
A definitive procedure cannot be planned and the client cannot be
informed of the potential risks and benefits of these procedures unless
the identity of the tumor is obtained, the extent of the primary or
metastatic disease is elucidated, and the condition of the patient is
documented.
The first step is to obtain a tissue sample either by fine-needle
aspiration or biopsy. Fine-needle aspirate cytology can be helpful in
eliminating other causes of a mass such as an abscess, granuloma,
foreign body, or persistent vaccine- or injection-associated "reaction."
Note that some vaccine granulomas can have "reactive" fibroblasts,
which may have characteristics that can be confused with a malignant
process. These changes include multiple nucleoli and mitotic figures, for
example. When there is any doubt, a histologic biopsy of these lesions
is imperative. This preoperative incisional biopsy is often viewed as a
vital prelude to definitive treatment of this highly invasive malignancy.
Regardless of whether a biopsy or aspirate is performed, these proce-
dures should be done such that the biopsy tract can be completely
surgically excised or included in the radiation therapy field. Vaccine-
and injection-associated sarcomas can fall under a number of histologic
diagnoses, including fibrosarcoma, neurofibrosarcoma, nerve sheath tu-
mor, hemangiopericytoma, malignant fibrous histiocytoma, schwan-
noma, leiomyosarcoma, and rhabdomyosarcoma.
6
, 7, 10
Although obtaining a diagnosis of the cause of the primary tumor
is of immense importance, so is determining the presence of metastatic
disease. Chest and regional (tumor) radiographs are essential to identify
metastatic disease or the extent of the primary neoplasia, or to evaluate
the patient for underlying disease. Palpation and an aspirate or biopsy
of enlarged lymph nodes is vital to document any metastatic disease to
the regional lymph nodes. Computerized tomography (CT), magnetic
resonance (MR) imaging, or diagnostic ultrasonography is ideal to deter-
mine the extent of the primary tumor,
Although it is critical to obtain an initial diagnosis and to search for
metastatic disease, it is also important to assess the general condition of
the patient. A hemogram, platelet count, biochemical profile, and urinal-
ysis as well as T4, feline leukemia virus, and feline immunodeficiency
528 OGTLVIE
virus tests are often helpful to document malignancy-relafed disorders or
problems unrelated to the cancer that Viould potentially affect treatment
decisions and prognosis. ..
No one test can definitively distinguish a vaccine- or injection-
associated sarcoma from a sarcoma of unrelated origin. Histopathologic
evaluation may provide indirect evidence that the sarcoma in question
may be vaccine associated. Regardless, the treatment is the same. Differ-
ential diagnoses include but are not limited to primary tumor, metastatic
tumor, abscess, granuloma, foreign body, and postvaccinal reaction.
Client Support
Vaccine-associated sarcomas result in a unique situation for most
veterinarians, because this disease is likely induced. Clients with cats
with vaccine- or injection-associated malignancies are often scared and
overwhelmed. They may be angry with the vaccine manufacturers and
the veterinarian or feel guilty for authorizing a preventative procedure
that resulted in harm to their cat. Clients often believe that cancer is an
evil, frightening, and threatening disease which is emotionally over-
whelming. These feelings of vulnerability and lack of control need be
acknowledged as the truth about this disease and the treatment options
are carefully explained. Because of the emotional nature of this disease,
clients with cats with these malignancies are often initially unable to
process information and make decisions. All explanations, facts, figures,
and decisions should be written or recorded fpr subsequent review.
Although the disease may be perceived as an emergency, decisions
regarding treatment need not be made quickly. These significant deci-
sions may best be made after the client has had time to thoughtfully
and rationally consider the treatment options and all the information
presented.
Because cancer steals power and control from the client, the results
of diagnostic tests not only direct therapy and allow the clinician to
provide a prognosis but empower a client with information, thus
allowing that individual to make intelligent and appropriate decisions
in this stressful setting. Clients usually appreciate being educated about
the individual risks and benefits of each diagnostic test. By including
them as a member of the veterinary health care team, most clients take
an active roll to benefit the patient and. the veterinary health care team.
TREATMENT
Therapy is divided into treatment of the primary tumor and meta-
static disease and support of the patient.
ADVANCES IN TREATMENT OF VACCINE-ASSOCIATED SARCOMAS 529
Primary Tumor
Treatment of the primary tumor is best divided into two categories:
cats With small- to medium-sized tumors and cats with large bulky
tumors that cannot be comfortably removed with a definitive surgical
procedure. Regardless the size of the tumor, cure is most likely with the
first procedure.
3
"Salvage" procedures are often palliative and expensive.
Small- to Medium-Sized Tumors
Wide and deep surgical excision taking the tumor and a "cuff" of
normal tissue around these highly locally invasive tumors is essential.
Removing the tumor with 2-cm margins laterally and one fascial layer
deep to the tumor is indicated. CT or MR imaging is often a valuable
tool to help direct the tumor excision. Adjunctive therapy with radiation
and chemotherapy is often recommended. Radiation therapy is initiated
at suture removal, and chemotherapy is initiated approximately 2 weeks
after the completion of radiation therapy. Concurrent supportive, nutri-
tional, and pain management is essential for these patients.
The use of therapies to enhance tumor control via modulation of
the immune system remains largely unproved. Nonspecific immunomo-
dulation using a mixed bacterial vaccine, or levamisole, had no obvious
effect on recurrence rates or survival after surgical excision.
2
Acemannan
is a nonspecific immunomodulator that has been evaluated in a small
number of cats with fibrosarcoma. Cats were injected with 2 mg/kg
intralesionally weekly for 6 weeks before surgery and megavoltage
radiation therapy (60 Gy). The cats then received 1 mg/kg intraperitone-
ally weekly for 6 weeks and then monthly. Of four cats treated this way,
one had tumor recurrence 8 months after surgery and the other three
had no recurrence between 14 and 19 months after surgery.11 The true
contribution of acemannan to survival in these cats is difficult to evalu-
ate.
Tenogeneic cells (Vero hIL-2) that secrete human recombinant in-
terleukin-2 were infiltrated peritumorally at the time of surgical resection
and implantation of iridium-192 seeds for brachyradiotherapyY This
infiltration was repeated 5 days later and five times again over the next
2 months. Of 16 cats treated by this protocol, 2 had local recurrence
and 3 had metastases for an overall median survival of 16 months. In
comparison, 11 of 16 cats that did not receive Vero hIL-2 cells had tumor
recurrence and a median survival of 8 months. Antibodies to the cells
were detected after 5 days of treatment, and most cats had a local
inflammatory reaction to injection. One cat developed anaphylaxis.
l3
As
a result, this treatment modality is not openly recommended.
530 OGILVIE
Large Unresectable Tumors
Tumors that cannot be comfortably excised with one definitive
procedure may be "downsized", or cytoreduced, with radiation therapy
or, in some cases, chemotherapy using doxorubicin or carboplatin, for
example. These tumors can sometimes be surgically removed subse-
quently. If radiation is used initially followed by surgery, chemotherapy
is recommended at the time of suture removal. Radiation therapy doses
are determined with CT- or MR-guided two- or three-dimensional radia-
tion planning and frequently involve 3 to 6 weeks of therapy using 18
to 30 daily doses of 2- to 3.3-Gy fractions to a total dose of 54 to 64 Gy.'
Bolus equivalent material is often needed, especially when treating a
previous incision or biopsy site that may be contaminated with cancer
cells. Chemotherapy is as listed below. Concurrent supportive, nutri-
tional, nausea, and pain management is often essential for these patients.
Possible Microscopic Metastatic Disease
There is little information regarding chemotherapy in the treatment
of soft tissue sarcomas in cats. The higher metastatic rates now reported
and the reduction in the rate of local recurrence after the use of surgery
and radiation therapy mean that chemotherapy may have an increasing
role in the management of soft tissue sarcomas in cats. Drugs that
anecdotally seem to have no efficacy are vincristine, methotrexate, and
cyclophosphamide. Doxorubicin has been used to treat cats with local
recurrence after surgery with apparent success. The use of carboplatin
chemotherapy did not seem to improve survival rates in another study.n
In one study, seven cats that had recurrence of sarcoma after surgery
and radiation received either doxorubicin, mitoxantrone, or carboplatin.
4
The two chemotherapy agents that have been most often recommended
for the treatment of vaccine-associated sarcomas are doxorubicin and
carboplatin.
Until more information is known, many recommend the use of
doxorubicin (25 mg per square meter of body surface area or 1 mg/ kg
every 3 weeks administered intravenously slowly over 20 minutes in
cats with normal renal and cardiac function) or carboplatin (200-220 mg
per square meter of body surface area every 4 weeks administered
intravenously slowly over 20 minutes in cats with normal renal function)
therapy, which is initiated after surgery and radiation therapy. Before
either drug is administered, a hemogram should be evaluated to ensure
that there are at least 3000 neutrophils per microliter. Metocloprarnide is
often helpful for reducing anorexia, nausea, and vomiting.
A D V A N C ~ IN TREATMENT OF VACCINE-ASSOCIATED SARCOMAS 531
Client
The goals, risk, and benefits of each treatment must be carefully
outlined, recognizing that the only words more frightening than cancer
are chemotherapy and radiation therapy. Clients must be empowered
with the ability to intervene on behalf of their cat to support, nurture,
and prevent any adverse effects associated with surgery (e.g., to control
pain, a 2.5-mg fentanyl transdermal patch may be administered every
72 hours as needed or acupuncture may be used), chemotherapy (to
control nausea, 0.4 mg/ kg of metoclopramide may be given orally every
6-8 hours), and radiation (to control pain, a 2.5-mg fentanyl transdermal
patch may be administered every 72 hours as needed or acupuncture
may be used). The common goal of compassionate care must be carefully
reviewed.
Adjunctive Treatments
Palliative radiation therapy (3-8 Gy fractions as needed or on days
0, 7, and 21) may be helpful in some cases for reducing inflammation
and discomfort.
Supportive Treatment
Three of the many goals of compassionate care are to ensure that
the patients do not have discomfort, that they are not nauseated, and
that they have adequate nutritional support. Discomfort can be treated
with nonsteroidal analgesics such as feldine (0.3 mg/ kg administered
orally every 48 hours), opiates such as a 2.5-mg fentanyl transdermal
patch administered every 72 hours as needed, or acupuncture. Mild to
moderate cases of nausea can be prevented or treated with 2.5 mg of
metoclopramide administered orally every 8 hours as needed, whereas
moderate to Significant nausea and vomiting may be best treated with
parenteral metocloprarnide (1-2 mg/ kg/ d constant rate infusion [CRID,
dolasetron mesylate (0.6-1 mg/ kg administered intravenously slowly
every 24 hours), or ondansetron hydrochloride (0.1-0.3 mg/ kg adminis-
tered intravenously or orally every 12 hours) . Adequate hydration can
be treated with analgesics, antiemetics, pain relievers, comfortable sur-
roundings, and appetite stimulants such as 2 mg of cyproheptadine
administered orally every 12 to 24 hours or 0.25 to 5 mg/ kg of megestrol
acetate administered orally daily for 3 days and then every 48 to 72
hours as needed for anorexia.
532 OGILVIE
Patient Management
"
Postoperative analgesics are essentIal as is a common plan with the
client to monitor the patient's comfort l ~ e l . The incision must be kept
clean and dry. The client should be given oral and written instructions
to monitor his or her cat to ensure that the incision is not hot or swollen.
Sutures should be watched to make sure that the patient does not
remove them. Information about how to contact the veterinary staff and
a strategy for after-hours care should be provided before discharging
the patient.
The most common adverse effects associated with radiation therapy
include (but are not limited to) hair loss, skin color change, and altered
hair color regrowth as well as moist or dry desquamation requiring
cleansing with mild soap and water. Petroleum-based oils or creams are
contraindicated in the management of these cases.
Chemotherapy can be a frightening concept to most clients who
care for their cat with a vaccine-associated sarcoma. As mentioned
earlier, nausea should be prevented, and the client should be carefully
instructed to monitor for an elevated body temperature, especially at
the time of chemotherapy nadir (7-10 days for doxorubicin; day 21 for
carboplatin).
PROGNOSIS
Favorable prognostic indicators include small size, lack of metastatic
disease, and tumor-free margins. Similarly, unfavorable prognostic indi-
cators include large tumor, presence of metastatic disease, prior unsuc-
cessful surgery, and tumor at surgical margins suggesting that recurrence
is likely.
A recent study was completed documenting the prognostic signifi-
cance of the skill of the surgeon.
9
In that study, cats that had surgery for
a vaccine-associated sarcoma by a surgeon at a referral institution had
dramatically longer tumor-free time compared with those cats that were
operated on by less skilled surgeons. Overall survival curves and tumor
control were determined.
The median time of tumor control was 94 days. Median tumor
control for tumors treated with excision performed at a referral institu-
tion (274 days) was significantly longer than that for tumors excised
by a referring veterinarian (66 days) . A radical first excision yielded
significantly longer median tumor control (325 days) than did a marginal
first excision (79 days). Cats with tumors located on the limbs had longer
median tumor control (325 days) than cats with tumors located at other
sites (66 days). The median overall survival time was 576 days. Signifi-
ADVANCES IN TREATMENT OF VACCINE-ASSOCIATED SARCOMAS 533
cant differences in survival times between groups were not detected.
Few cats (13.8%) receiving only surgical treatment had long-term (>2
years) survival, suggesting that radiation and chemotherapy are highly
indicated as adjunctive therapies.
References
1. Bergman PJ: Etiology of feline vaccine-associated sarcomas: History and update.
JAVMA 213:1424-1425, 1998
2. Brown NO, Patnaik AK, Mooney SC, et al: Soft tissue sarcomas in the cat. JAVMA
173:744-779, 1978
3. Couto CG, Macy DW: Review of treatment options for vaccine-associated feline sar-
coma. JAVMA 213:1426-1427, 1998
4. Cronin K, Page RL, Spodnick G, et al: Radiation therapy and surgery for fibrosarcoma
in 33 cats. Vet Radiol U1trasound 39:51-56, 1998
5. Doddy FD, Glickman LT, Glickman NW, et al: Feline fibrosarcomas at vaccination sites
and non-vaccination sites. J Comp Pathol 114:165-174, 1996
6. Esplin DG, McGill LD, Meninger AG, et al: Postvaccinal sarcomas in cats. JAVMA
202:1245-1247, 1993
7. Hendrick MJ: Historical review and current knowledge of risk factors involved in
feline vaccine-associated sarcomas. JAVMA 213:1422-1423, 1998
8. Hendrick MJ, Brooks JJ: Postvaccinal sarcomas in the cat: Histology and immunohisto-
chemistry. Vet Pathol 31:126-129, 1994
9. Hershey AE, Sorenmo KU, Hendrick MJ, et al: Prognosis for presumed feline vaccine-
associated sarcoma after excision: 61 Cases (1986-1996). JAVMA 2 1 6 : 5 ~ 1 , 2000
10. Kass PH, Barnes WG, Spangler WL, et al: Epidemiologic evidence for a causal relation
between vaccination and fibrosarcoma tumorigenesis in cats. JAVMA 203:396-405, 1993
11. King GK, Yates KM, Greenlee PG, et al: The effect of acernannan irnrnunostirnulant in
combination with surgery and radiation therapy on spontaneous canine and feline
fibrosarcomas. J Am Anim Hosp Assoc 31:439--447, 1995
12. Kleiter M, Leschnik M: Postoperative chemotherapie zur behandlung eines zweifach
rezidivierten vakzine-assoziierten fibrosarkoffiS. Kleintierpraxis 43:295-302, 1998
13. Quintin-Colonna F, Devauchelle P, Fradelizi D, et al: Gene therapy of spontaneous
canine melanoma and feline fibrosarcoma by intra tumoral administration of histoin-
compatible cells expressing human interleukin-2. Gene Ther 3:1104-1112, 1996
Address reprint requests to
Gregory K. Ogilvie, DVM
Animal Cancer Center
DepartrnentofClUUcai Sciences
Veterinary Teaching Hospital
Colorado State University
Fort Collins, CO 80523
e-mail: gogilvievth.colostate.eduorgogilvie@aol.com
VACCINES AND VACCINATIONS 0195--5616/ 01 $15.00 + .00
RECOMBINANT VACCINE
TECHNOLOGY IN VETERINARY
MEDICINE
Kent R. Van Kampen, DVM, PhD
Vaccines are an integral part of the practice of veterinary medicine.
The oldest types of vaccines are made from whole pathogens, viral or
bacterial, that have been treated with chemicals or heat to render them
inactive. These antigens are combined with antibiotics, adjuvants, and
other substances in a suspension that is used for injection. Pathogens
have also been attenuated by subjecting them to abnormal growth condi-
tions, multiple passages, and selection for various characteristics of
reduced virulence or pathogenicity. After this attenuation, the modified
pathogen is used as a live vaccine.
Inactivated vaccines almost always required the addition of adju-
vants. The duration of immunity is often 1 year or less. There may be
reactions at the site of administration that include swelling, redness, and
some pain. Residual lumps at the site of injection are common with the
use of these vaccines.
Live attenuated vaccines usually impart a strong immunity. Because
of their live nature, the vaccines may be subject to contamination during
manufacturing. There is also a danger of reversion to virulence as the
organisms replicate in the body of the vaccinated animal.
An ideal vaccine should meet certain criteria of safety and efficacy.
The immunity induced should be strong and prolonged. The vaccine
should be free of significant adverse side effects. The antigen(s) should
be stable under a variety of conditions of handling. If possible, the profile
of immunization should be different from that of an active infection. The
From the Van Kampen Group, Inc., Hoover, Alabama
VETERINARY CLINICS OF NORTH AMERICA: SMALL ANIMAL PRACTICE
VOLUME 31 NUMBER 3 MAY 200]
536 RECOMBINANT VACCINE TECHNOLOGY
route of administration of the vaccine should be easy for the veterinarian
to administer.
NEW TECHNOLOGY
A new range of vaccines using a technology distinctly different
from the inactivated or live attenuated vaccines has been developed.
This technology has been labeled "recombinant" and has been imple-
mented by the revolution of genetic engineering that allows genetic
material to be exchanged between various organisms. With recombinant
technology, these new vaccines focus the immune response to specific
antigens known to be associated with protection against disease. It is
not necessary to expose the immune system to dozens of antigens found
in whole pathogens. Since these vaccines do not contain pathogens,
there is little chance for in vivo recombination and return to virulence
of the pathogen. Some of these recombinant vaccines also allow for
multiple routes of administration.
METHODOLOGIES
Genetic engineering allows microorganisms to have their genetic
material segmented into sequences that are complete or incomplete
genes. These genetic sequences can be re-arranged and inserted into
alternate organisms for the purpose of producing proteins, encoding
other antigens, producing substances that induce physiologic or desired
immune responses. This technology can also be used to insert specific
genes into cells that are congenitally devoid of these genes. This is called
gene therapy.
In making vaccines using recombinant technology, the pathogen's
genetic material is subjected to enzymatic action that results in segmenta-
tion. The resultant RNA or DNA is identified as to its function, if known.
The desired genetic material is selected. If the genetic material is RNA,
it is incubated with reverse transcriptase and cDNA is obtained. DNA
or cDNA is then inserted into a recipient host that is usually a yeast, a
bacterium, or a virus. One or more genetic segments may be inserted by
recombination into the recipient organism. In order to produce a good
vaccine, knowledge of specific antigens associated with immunologic
protection is required.
For purposes of regulating the use of recombinant vaccines, the
United States Department of Agriculture has classified these new vac-
cines into three categories. They are
Type I Recombinant - subunit vaccines
Type IT Recombinant - gene-deleted vaccines
Type III Recombinants - vectored vaccines
VAN KAMPEN 537
TYPE I RECOMBINANT SUBUNIT VACCINES
In this technology, an antigen is produced during the culture of the
synthetic, recombinant organism. A gene encoding a particular antigen,
the product of which confers protection, is selected from the pathogen.
This gene is inserted into another host organism such as a yeast, bacte-
rium, or virus. The modified host organism is cultured (propagated)
during which time the product of the inserted gene is produced. The
gene product is then isolated, purified, and used as the antigen in the
vaccine. This antigen mayor may not be adjuvanted for use as a vaccine.
One such vaccine in veterinary medicine is a recombinant Lyme
disease vaccine, licensed for use in dogs. This vaccine protects against
the organism Borrelia burgdorfi that is transmitted by ticks. A single gene
encoding the outer surface protein A (OspA) is taken from the Borrelia
organism and inserted into a nonpathogenic E. coli. The E. coli is then
cultured, the gene product produced in the cytoplasm, the organism
lysed, and the OspA purified. The purified protein is then suspended
without adjuvant and administered to the dog by injection. The resultant
immune profile will be distinctly different from that of an infected ani-
mal.
TYPE II RECOMBINANT GENE-DELETED VACCINES
In this classification, a pathogen is subjected to genetic manipulation
that results in the removal of one or more genes. This actioQ reduces
the pathogenicity and the virulence of the pathogen. The gene-deleted
pathogen is then replicated and used as the vaccine. The immune system
reacts to the type IT recombinant in such a manner that the serologic
profile will not contain an antibody to the deleted gene products. That
means that the immune profile of an infected animal will differ from
that' of the vaccinated animal.
The gene-deleted vaccine used most commonly in veterinary medi-
cine is against the viral infection, pseudorabies. The difference in the
immune profiles of the vaccinated and the infected animals allows
vaccination in the face of an outbreak of disease and subsequent culling
of infected animals from the herd. This has resulted in significant control
of pseudorabies.
TYPE III RECOMBINANTS: VECTORED VACCINES
This process begins by isolating gene(s) from the pathogen that are
associated with protection against disease. These genes are then inserted
538 RECOMBINANT VACCINE TECHNOLOGY
into a gene-deleted vector that may be a bacterium' or a virus. The
synthetically modified organism is then proliferated or replicated. The
organism is then purified, suspended, and used as the vaccine. These
vaccines are activated when by a variety of routes. The
inserted gene(s) product(s) is/are produced when the synthetic organism
enters the cells of the vaccinate. The antigen is taken up by antigen
presenting cells (APCs) and the immune system produces an antibody
or cellular immune response.
Licensed veterinary vaccines using recombinant vectored technol-
ogy are primarily poxvirus based. The poxviruses are large, stable, and
can be made nonreplicating for use as va.ccine vectors. A vaccinia vec-
tored rabies vaccine containing the genetic insert encoding the rabies
glycoprotein has been licensed by the USDA for controlling rabies in
raccoons. Canarypox vectored vaccines, including rabies and canine
distemper, are licensed for use in cats and dogs, respectively. In the
disteII).per vaccine, two genes, the hemagglutinin and the fusion genes,
were inserted. A fowl pox vector is also the vehicle for delivering genes
that protect against Newcastle disease and avian influenza. This vector
is a replication competent recombinant and research has demonstrated
that as few as five viral particles inoculated as the vaccine can provide
protection against a specific disease.
Other viral vectors that have been used experimentally in veterinary
medicine include adenovirus and retroviruses. Bacterial vectors such as
Salmonella, Shigella, and Mycobacterium have also been researched.
None of these vectors have been licensed for use in the veterinary field.
Additional Readings
1. Babiuk LA, Lewis J. Van Den Hurk S, et al; DNA imrmmization; Present and future. III
Schultz RD (ed); Veterinary Vaccines and Diagnostics. Advances in Veterinary Medicine.
41:163-179, 1999
2. Horzinek MC: Vaccination; A philosophical view. III RD Schultz (ed); Veterinary Vac-
cines and Diagnostics. Advances in Veterinary Medicine. 1999
3. Adams LG, Ford RB, Gershwin LJ. et al; Recombinant vaccine technology. Veterinary
Exchange. Compendium Cont Ed Pract Vet (sup pi). 19;5-16, 1997
4. Pastoret PP, Brochier B; The development and use of a vaccinia-rabies recombinant oral
vaccine for the control of wildlife rabies; a link between Jenner and Pasteur. Epidemiol
Infect 116(3);235-240, 1996
5. Pastoret PP, Brochier B, Languet B, et al ; Stability of recombinant vaccinia-rabies vaccine
in veterinary use. Dev Bioi Stand 87;245-249, 1996
6. Paoletti E; Application of pox virus vectors to vaccination; An update. Proc Natl Acad
Sci USA 93(21);11349-11353, 1996
Address reprint requests to
Kent R. Van Kampen, DVM, PhD
The Van Kampen Group, Inc.
1008 Lake Winds Drive
Hoover, AL 35244
VACCINES AND VACCINATIONS 0195-5616/ 01 $15.00 + .00
WHAT YOU CAN AND CANNOT
LEARN FROM READING A
VACCINE LABEL
David R. Hustead, DVM
Although most veterinarians look at vaccine labels each day, they
rarely see them. When practitioners sense a need. to read labels, they
find that the labeling answers some of their basic questions but that
these labels often fail to address many relevant issues. In addition,
veterinarians find that the issues addressed are often presented Simplisti-
cally and that labels are sometimes just wrong. This article addresses
how and why we have come to this point in our profession and what
practitioners need to do to better understand the products most of them
use on a daily basis.
First, what is a vaccine label? A product label is normally defined
as the written information that is furnished with the product at its time
of sale. Per federal regulations, this written information must be ap-
proved by the relevant federal authority, and it must accompany the
product at the time of sale (9 Code of Federal Regulations [CFR] Part
101.4)." This written information normally includes the text found
' The federal government regulations are published in the Code of Federal Regulations
(CFR). Section 9 of the CFR contains the regulations written by the United States Depart-
ment of Agriculture (USDA) that deal with animals and animal products. Subchapter E of
Section 9 of the CFR contains the regulations dealing with vaccine manufacture and
distribution. Subchapter E contains parts 100 through 124. The written reference to 9 CFR
Part 101.4 is a commonly used shorthand abbreviation to refer to Section 9 of the CFR
Subchapter E Part 101.4.
From Fort Dodge Animal Health, Overland Park, Kansas
VETERINARY CLINlCS OF NORTH AMERICA: SMALL ANIMAL PRACTICE
VOLUME 3} NUMBER 3 MAY 2oo} 539
540 HUSTEAD
attached to the bottles or boxes of the product. If a "package insert" is
included with the product, this woul ... d be part of the approved label.
Separate package inserts are often not included with vaccines, because
the information provided on the botttes or boxes is considered to be
sufficient by the manufacturer, and it fulfills all federal regulations. This
is in stark contrast to pharmaceutical products, where a package insert
would almost always be provided because of the amount of text nor-
mally provided with these types of products. At its broadest definition,
a vaccine label would include any and all written information a company
might produce that is likely to be seen by customers and that mentions
attributes or characteristics of the product. Examples of a label by this
definition would include advertisements in magazines or journals, sales
bulletins, and technical monographs. For the purposes of this article, the
term vaccine label is used for the more narrow definition to include just
those materials provided with the product at the time of sale.
USERS' EXPECTATIONS
Veterinarians and all vaccine users expect to be able to read a
vaccine's label to gain understanding about the characteristics of the
product in addition to how it is best used in animals. At one level, these
expectations are entirely reasonable. A label must provide identification
of the product and provide the reader with important information about
the product. A vaccine's label use directions should be clear, easy to
follow, and realistic to implement the given realities of animal husbandry
practices. Because these are products steeped in the scientific process,
the directions for use should be based on the data that are collected to
support the vaccine' s licensing. At another level, these expectations are
incredibly naIve. The effective use of a vaccine requires at least a work-
ing knowledge of the diseases of concern, practical immunology, preven-
tive medicine theory and application, applied clinical medicine, and
animal husbandry. That is a tall order for college curricula, let alone a
vaccine package label.
VACCINE LABEL REALITY
The information that appears on a vaccine label is greatly influenced
by the scientific process and the regulatory process that licenses the
vaccine for sale. Because the reader has learned the science elsewhere,
this article looks at regulatory issues that most veterinarians were never
exposed to in school. To understand what is and what is not on a
vaccine's label, one must have a practical understanding of the regula-
READING A VACCINE LABEL 541
tory process. Most veterinarians know that the drugs they use in the
United States must be approved by the Food and Drug Administration
(FDA) (21 CFR Part 510). These same veterinarians are often surprised
to find out that animal vaccines are licensed by the United States Depart-
ment of Agriculture (USDA) (9 CFR Part 101). This dichotomous ap-
proval process is unusual in human medicine, where a single regulatory
agency would handle both types of products. This dichotomy is also
unusual in most of the world for animal health drugs and vaccines. The
USDA and FDA approach product regulation from two different points
of view. To practitioners, this difference means that their understanding
of the approval process for drugs cannot be generalized toward an
understanding of the vaccine licensing process.
The USDA was given authority over animal vaccine sales by the
.Virus-Serum and Toxin Act of 1913 as amended in 1985 (9 CFR Part
101). This means that the USDA has been approving the text of vaccine
labels for a considerable period of time. Many labeling practices have
slowly evolved over this period. Like most complex bureaucratic pro-
cesses, vaccine labeling procedures change slowly, because inadequacies
are found in the current system. Changes are then instituted to better fit
the current view of reality. Rarely are changes in labeling practices forced
on products that are already licensed unless the manufacturer attempts
to license a "new" product based on the "old" product or the USDA
reviews the product because of concerns about the product's suitability
for sale. Changes in product labeling tend not to occur after a product
has been licensed. New USDA regulations are normally applied to
products that have not yet been licensed and not to products already
licensed and available. To practitioners, this means several things. First,
some vaccine labels are quite old, containing text that has been in place
for decades without modification. Second, similar vaccines for the same
disease could have different label texts, and, at the same time, relatively
different vaccines could have similar label texts. It is unlikely that the
reader can determine whether these similarities or differences in label
text are the result of differing biologic behaviors of the products or are
the result of the rules in place at the time each product was licensed.
This process also means that the text found on a vaccine label is almost
always behind the profession's current expectations and, rarely, if ever,
leads vaccine users toward better product understanding. Any reading
of a current vaccine label must be viewed within the context of the rules
that existed when it was licensed.
The USDA exerts its Virus-Serum and Toxin Act authority by requir-
ing that vaccines be licensed by the USDA before their sale (9 CFR Part
102). To obtain a vaccine license, the manufacturer must provide the
USDA with sufficient information so that the USDA can determine
whether the product is pure, potent, safe, and effective (9 CFR Part 102).
542 HUSTEAD
A vaccine' s potency and purity rarely affect the information found on
its labeling; thus, they are ignored in tbis article. The reader is cautioned
that the approval process for purity and potency has a dramatic impact
on the products that are used. The criteria for purity and potency testing
and assessment are beyond the scope of this discussion.
WHAT A VACCINE LABEL CAN TELL YOU
Type of United States Department of Agriculture
License
Products that have been routinely licensed by the USDA do not
have a statement on the label that the product is approved by the USDA
This is in contrast to FDA-approved products, where the label states
"approved by FDA" A vaccine approved by the USDA has a notation
on the label that provides the USDA license number. This notation looks
something like "U.s. Vet. License No. XXX." This license number is for
the establishment that produces the vaccine and is not unique to the
product. The presence of the USDA license number does inform the
reader that the product has been approved by the USDA This vague
licensure statement is in contrast to tl).e text found on products that are
conditionally licensed by the USDA If a product has a USDA conditional
license, this status is directly stated on the label. Most readers are not
aware that the USDA has two different licenses for vaccines. The form
of approval that most users are familiar with is often referred to as a
full license. The other is a conditional license (9 CFR Part 102). Condi-
tional licenses for vaccines are intended to be used when there is a
special circumstance that creates medical need for a vaccine, but for
reasons of expediency or technical limitations, the vaccine has not under-
gone the protocols normally expected for a full license. To obtain a
conditional license, a vaccine must demonstrate purity, potency, and
safety in the same manner as a full license. The difference is only
in efficacy determinations. For a conditional license, a vaccine must
demonstrate an "expectation of efficacy" instead of a "demonstration of
efficacy." Conditional licenses are temporary and are generally reviewed
every year. The USDA expects the manufacturer to collect additional
information to either continue the conditional license or to work toward
a full license. Failure to collect additional data appropriate for licensure
could result in loss of the conditional license. It is important that prac-
titioners understand that conditionally licensed products normally do
not have the same level of effectiveness data as fully licensed products.
In addition, a conditionally licensed product could lose its license and
be removed from the marketplace before becoming fully licensed. The
READING A VACCINE LABEL 543
conditional licensure statement is thus an important part of a vaccine la-
bel.
True Name
Readers of a vaccine label can learn the identification of each anti-
genic component of the product by reading its true name. The true
name is the most prominent printed information found on the label. By
regulation (9 CFR Part 112 and Veterinary Services Memorandum
800.54), the true name of the product can not be overshadowed by any
other lab"el text. The text on the label with the largest print is thus the
true name of the product. The federally mandated true name lists the
antigenic fractions contained in the product. The order of listing is
regulated. At the end of the antigenic listing are indications as to
whether the fractions are "live" or "killed" and the type of organism
(i.e., viral, bacterial, fungal, protozoan). An example of a true name is
"Feline Leukemia Vaccine killed ViruS."b In some ways, the true name is
similar to a generic name for a drug in that it identifies active fractions
of the product. On the other hand, the true name is not similar to a
generic name because it does not uniquely identify the active ingredients
of the product to the user. Some basic user questions about the antigenic
constituents in the vaccine should be resolved by reading the true name
of the
Trade Name
The trade name of a product is the name the manufacturer gives
the product. This name can be almost anything and is optional. Trade
names are used to help users remember products or easily identify them.
For example, if a company makes a canine vaccine called "Puppyshot,"
this trade name does not necessarily mean the vaccine can only be used
in puppies. Normally, this trade name only informs readers about the
contents of the product if they already know what the trade name
describes. Vaccines that are conditionally licensed do not have a trade
name on the label.
Effectiveness Claims
All vaccines make claims about their effectiveness on the label. A
vaccine label contains a statement similar to the following: "For vaccina-
bFel-O-Vax LvK (Fort Dodge Animal Health, Overland Park, KS).
544 HUSTEAD
...
,
tion of healthy dogs to prevent signs of disease associated with Wection
of canine distemper virus." This statement is much more important than
most users are aware. The intended animal species is listed here. In this
example, dogs are the only intended species for this vaccine. In addition,
part of the statement is to use the vaccine in healthy animals. This is
important, because animals that are unhealthy may not mount an ade-
quate immune response.
4
The label informs readers that only healthy
animals should be vaccinated. This statement also addresses the common
desire of veterinarians to use vaccines in a therapeutic manner. Because
animals that need therapy are not healthy, the healthy animal statement
tells readers that therapeutic use is outside the product's intended uses.
A second important area of the effectiveness claim is the phrase "to
prevent signs of disease." To most readers, these words seem obvious.
Most users believe that is exactly what vaccines are supposed to do. It
is important to note that this phrase is a level of effectiveness claim. To
better understand the issue of level of expected claims, a short explana-
tion of how effectiveness claims are determined follows.
Efficacy testing to support a license is normally a laboratory-based
in vivo assessment of the product' s ability to stimulate an immune
response that is anticipated to confer protection to an individual on
subsequent natural challenge (9 CFR Part 113). Initial efficacy studies
are almost always based on challenge studies, comparing the clinical
disease observed in vaccinates with the disease observed in nonvacci-
nates after challenge. Although the law would allow efficacy determina-
tions to be based on serologic responses observed in vaccinates after
vaccination, such a practice for initial vaccine approval would be un-
usual. Normally, these' challenge studies are conducted in the target
species, but laboratory animal substitutes are allowed occaSionally. All
laboratory-based methods of vaccine study are only approximations of
the real world. Some of these approximations better simulate clinical
reality than do others. Just a few factors that would affect the laboratory-
based challenge so that it more accurately reflects clinical reality would
include the animals selected (mongrels versus purebreds or multiple
purebreds), the similarity of the challenge virus to clinical isolates, the
dose of challenge administered (approximating real challenge situations),
a route of inoculation similar to that of clinical settings, and a clinical
scoring system that accurately reflects the clinical disease that is seen.
Using the species of interest in these studies should more accurately
estimate clinical reality than if a surrogate species were used.
It is difficult to precisely describe the efficacy testing that is con-
ducted for vaccines, because there are a large number of antigens tested,
each antigen has unique testing issues, and each antigen can have
multiple test procedures. With this said, there are some elements com-
mon to most efficacy determinations that can be described. The potency
READING A VACCINE LABEL 545
of the test vaccine used in efficacy studies is normally at the lowest level
anticipated to be used in the field. Doing so is intended to provide a
reasonable level of assurance that the vaccine efficacy shown in these
studies is the least likely to be seen by routine users because they use
vaccines with higher levels of antigenic components. The number of
animals in an efficacy study is somewhat variable, but 20 vaccinates is
a common number. For a challenge study to support a "prevention .of
disease" label claim, 80% of the vaccinates should be free of infection or
disease in contrast to the nonvaccinated controls, which would be ex-
pected to demonstrate a reasonable amount of disease (9 CFR Part 113
and Veterinary Services Memorandum 800.200). It is the relative differ-
ence between the disease observed in the nonvaccinated controls and
the vaccinates that is the descriptor of vaccine effectiveness. The reader
should note that this standard is achieved with less than 100% of
vaccinated animals expected to demonstrate an adequate response to
vaccine administration. It is a universally recognized fact that essentially
all biologic responses, including immune responses to vaccines, are not
uniform in a population of animals.
4
Because of the random variability
of animals (a result of genetic and environmental factors), the immune
responses of most individuals are close to the average response, but
some responses are greater and some are less. (This is immediately
obvious after viewing student examination scores or athletic perfor-
mances as long as there are a large number of participants.) This distribu-
tion of biologic responses ensures that not all animals respond to vaccine
administration. The federal requirement for adequate vaccine efficacy to
be defined at less than 100% is a demonstration of this immovable fact.
The efficacy testing procedures for some antigens are precisely
described in the federal regulations (9 CFR Part 113). If a disease efficacy
study procedure is described in the USDA regulations, that ' codified
study procedure must be used to establish a product's efficacy. There
are many antigens that do not have codified efficacy procedures. When
this occurs, the manufacturer wanting to develop a product for a specific
disease must develop a method of assessing the product's efficacy.
Before this method can be used by a manufacturer, the method must be
approved by the USDA (Veterinary Services Memorandum 800.200). As
a work product of a commercial organization, the noncodified procedure
is not normally disclosed to others by the USDA.
As previously described, products that demonstrate efficacy by re-
ducing disease in 80% of the vaccinates as compared with the nonvacci-
nated controls after challenge are permitted to make the label claim "to
prevent disease or to prevent signs of disease." This wording is in
contrast to the text "to aid in the prevention of disease," which is
commonly found on vaccine labels. Although these two statements look
similar, each describes a differing claim of effectiveness. Products whose
546 HUSTEAD
"
labels claim that the product serves "as ~ aid in prevention" do not
have to demonstrate efficacy at the levels previously described (Veteri-
nary Services Memorandum 800.200). The requirement for this claim is
to demonstrate that after challenge, the vaccinates are less sick than the
controls. For diseases where the challenge produces a mild disease with
a wide range of signs, it is not uncommon for the challenge to only
demonstrate vaccine effectiveness that supports the "aid in prevention"
claim. Vaccine labels containing the phrase "as an aid in prevention" are
informing the reader that the level of effectiveness demonstrated by this
product may be less than that of a similar product with the claim "to
prevent." On the other hand, the claim difference may be the result of
inadequacies in laboratory-based challenge evaluations for clinical effi-
cacy. The reader of the label is expected to understand the significance
of the difference in wording.
Use Directions
The product's use directions normally tell the reader how to admin-
ister the product in the average animal. A typical use direction is to
"administer one 1 mL dose subcutaneously. Repeat in 3 weeks." These
directions should be followed, because they are likely to be the only
protocol that was used in the safety and efficacy studies for the product' s
licensure. There is also a statement on essentially all animal vaccines
that says "annual revaccination is recommended." This set of directions
is a historically accepted repeat vaccination interval for essentially all
domestic animal vaccines.
Safety Information
All vaccines must provide a warning about the potential for anaphy-
laxis and the need to treat it with epinephrine (9 CFR Part 112). The
amount of additional safety information on an animal vaccine is sparse
and somewhat variable. Some products carry additional safety informa-
tion that is viewed as necessary by the manufacturer or the USDA.
Dose Volume
The volume to be administered is stated on the label. For companion
animals, the standard is 1 mL, but there are other doses. The dose
volume that is stated is the one dose volume that was tested by the
manufacturer during the licensing process.
READING A VACCINE LABEL 547
Storage Conditions
Vaccine labels contain storage directions (9 CFR Part 112.6), for
example, "Store in the dark at 2_7', do not freeze." Like most biologic
specimens, vaccines are adversely affected by storage in light and heat.
The label recommendation is a reflection of this concern, because long-
term storage is enhanced by storage in the dark at low temperatures.
The effect of freezing on most vaccines is poorly understood. Although
freezing does prolong the storage of many biologic specimens, it does
induce changes in biologic materials.
3
These changes may have effects on
vaccine antigenicity or immunogenicity. In addition, adjuvant systems
common in many vaccines can be affected by freezing and thawing.
2
The biologic impact of these changes is normally not well understood;
thus, the recommendation is not to freeze the product.
Preservatives
If a vaccine contains nonimmunologic agents or chemicals, they are
identified on the label (9 CFR Part 112). The most common items listed
here are residual amounts of inactivating agents, antibiotics, or antifun-
gal agents.
WHAT A VACCINE LABEL DOES NOT TELL YOU
United States Department of Agriculture Licensure
Statement
There are vaccine products that are sold in the United States that
are not licensed by the USDA. These products are sold in the state where
they are made. These intrastate products are not directly licensed by the
USDA, but the USDA does approve the state regulations that license the
products (9 CFR Part 107.2). At the time of this writing, California is the
only state to have such intrastate vaccine products (D. Siev, DVM,
personal communication, 2000).
True Name
There are many limitations of the true name found on vaccine
labels. The true name fails to uniquely identify a product, it fails to
inform the reader about the precise identification of the "strain" of
organism used in the product, it often fails to mention if vaccine organ-
548 HUSTEAD
isms are whole organisms or subunits, and it ignores' completely the
presence or absence of an adjuvant. Fo,r a single-antigen product, a true
name informs the reader about the a n t i ~ e n i c component in the product,
but after that, the true name system tends to confuse more than it
informs. For a combination product (one that contains more than one
disease antigen), especially where some fractions are live and some are
killed or contain different sources of organisms (e.g., bacterial and viral
antigens), the true name often confuses users about the identity of the
organisms contained in the product. This is because all the information
about the antigens follows the listing of the antigens, often without
regard to the order in which the antigens are listed. It can be difficult or
even impossible to tell which antigens are "live" and which are "killed."
For example, the true name of a licensed vaccinee is "Bovine Rhinotra-
cheitis-Bovine Virus Diarrhea-Parainfluenza-3--Respiratory Syncytial Vi-
rus Vaccine, Modified-Live and Killed Virus." In this example, some of
the fractions are live and some are killed. Which is which? The true
name does not say. Products that are dissimilar can have the same true
name. This occurs when two combination products have the same anti-
gen listings but diffel' in which antigens are live and which are dead.
The true names for these products can be identical. An example would
be when the true names of two licensed vaccines are identical to the
true name just given; however, when these two products are compared,
each has different live and killed antigenic fractions.
d
e This ability of
the true name to confuse rather than to inform is unfortunate, because
these issues can make differences in users' understanding, uses, and
expectations for efficacy and safety of vaccines.
Limitations of Efficacy Claims
There are many limitations to the efficacy claims found on vaccine
labels. First and foremost is the level of expectations that many users
have concerning the effectiveness of vaccines. Vaccine labels inform
readers that the products can prevent disease; thus, it is not unreasonable
for practitioners and lay users of vaccines to have expectations that most
vaccines can essentially protect all animals from disease if challenged.
Although this may seem to be true from clinical experience with some
vaccines, the reality of immune responses and the licensing process is
that vaccines tend to work at levels that are considerably less than 100%.
Second, users of vaccine expect to be able to read a product's label to
' Prism 4 (Fort Dodge Animal Health, Overland Park, KS).
dFusion 4 (Merial, Iselin, NJ) .
' IBR-Plus 4-Way (Merial, Iselin, NJ).
READING A VACCINE LABEL 549
gain an understanding about the product's clinical efficacy. If products
are not tested under clinical conditions, the clinical effectiveness is likely
unknown. The efficacy that is stated on the label is a function of the
labonitory-based approximation of clinical conditions. Third, prac-
titioners often desire to use vaccine labels to compare products they may
purchase so that they may select the ones with the highest levels of
effectiveness. Such comparisons between products may be possible. if
each vaccine has a similar label claim and if they were licensed using a
codified efficacy test system. In reality, differences between even codified
protocols may make direct comparison difficult. If two vaccine products
use different noncodified systems, especially if the details of those proce-
dures are not well known (except to the manufacturer and the USDA),
any meaningful comparison is likely impossible, regardless of what is
said on the label. Two similar 'vaccines can have differing claims. The
two common efficacy claims have been described. For products with the
"aid in prevention" claim, do they have real lower levels of efficacy, or
are these claim differences the result of low levels of disease in the
nonvaccinates, small reductions in disease in the vaccinates as compared
to the controls, or just regulatory "red tape"? Finally, what can the reader
infer when two products have label claims for different syndromes of
the same disease? Is the vaccine with more claims the better vaccine?
As an example, most feline leukemia vaccines claim to prevent persistent
viremia. Some feline leukemia vaccines also contain claims to prevent
transient or latent viremia. Because feline leukemia efficacy studies are
still noncodified by the USDA, manufacturers use several methods to
demonstrate efficacy. They are free to adapt their studies to obtain data
not collected by other manufacturers. This allows for data collection to
support additional claims. Do these additional label claims imply addi-
tional efficacy or just a reflection of the study conducted? Do these
additional claims have clinical relevancy to the patient? It is clear that
vaccine label efficacy claims must be read carefully for them to have any
relevant meaning to the user.
Optimal or Acceptable Initial Revaccination Interval
The initial revaccination interval on the vaccine's label is most likely
the one interval that was studied. If no other data are collected for the
product's license, no alternative uses are discussed on the label. In
addition, there is no requirement for the manufacturer to determine if
this interval is the most optimal. Neither does the label tell the reader
about less than optimal but still acceptable intervals. What is the longest
interval between initial vaccinations that can still stimulate an appro-
priate response? What is the practitioner to say to the kitten owner who
550 HUSTEAD
.
returns 10 weeks after the kitten's initial vaccination? Do you start over?
Does it make a difference if you are using a killed or live vaccine? The
label does not address these common questions.
Annual Revaccination Recommendations for All
Essentially all vaccine labels say that annual revaccination is recom-
mended. The annual revaccination recommendation that is found on
essentially all current USDA vaccine labels is a historically accepted
practice. To make this claim on a vaccine label, the USDA does not
require manufactures to prove that their vaccine provides immunity for
a year or that this annual period is biologically important. There is a
USDA policy (Veterinary Services Memorandum 800.200) requiring that
new and novel vaccine antigens (antigens for which a vaccine does not
already exist) have duration of immunity data collected before that
product receives a license. This duration information is then presented
as a recommended revaccination interval that is as long as the tested
interval. Even this regulation does not require that this demonstration
of duration of immunity be relevant to the animal's biology. Unfortu-
nately, there may be considerable difference between a demonstrated
interval of efficacy and an optimal revaccination interval. If a vaccine
demonstrates protection from disease at 1 year after vaccination, it only
makes sense that the revaccination interval is not 1 year but some time
longer than 1 year. In addition, the new USDA standard still does not
address the question of the optimal or acceptable revaccination intervals
that would be needed to maintain lifetime immunity. To further compli-
cate this issue, the new regulation gives us two kinds of products with
the same annual revaccination label claim. One set is the old products
with a historic claim, and one set is the new products, where the
manufacturer has demonstrated that immunity conferred by the vaccine
is present 1 year after vaccination. From a reader's perspective, this
becomes quite confusing. Essentially all vaccine labels say to vaccinate
annually, but some can show this annual claim has support and some
cannot. In neither case has the biologic necessity of the practice been
demonstrated, and all this is a long way from determining the optimal
revaccination interval of individuals in the population.
Use in Animals That Are Not Average Adults
For many years vaccine labels did not indicate the minimum age of
administration. This was assumed to be a matter of veterinary prac-
titioner discretion. Today, newly licensed vaccines say to use in animals
READING A VACCINE LABEL 551
older than a specified age as a result of a new USDA policy (Veterinary
Services Memorandum 800.200). This is helpful for the label readers,
because the USDA requires demonstration of efficacy and safety in the
age of animal noted on the label, but the vaccine user is again confronted
by similar vaccines that have dissimilar use directions. How is the user
to know if this labeling difference is important biologically or just a
regulatory issue? There are other examples of differing label texts abQut
use in animals that are not average adults that are based on important
biologic differences, but this importance becomes confused in labeling
text. As an example, a modified live virus panleukemia vaccine label
says not to administer the product to pregnant cats. This is because
the statement is required (9 CFR Part 112.7) for this product, but this
requirement is based on real safety concerns in the unborn kitten with
the live virus growing in its brain and causing disease. This same
concern is not addressed on killed vaccine labels, because reversion to
virulence of the killed organism is not possible; hence, no regulation
requires a statement. Does that absence of a precaution mean that it is a
good idea to vaccinate pregnant cats with a killed vaccine? Rarely does
a vaccine label address expected responses in older animals, because
there is a dearth of information about the vaccine needs of older animals
. and the responses that vaccines are likely to induce. Some labels' text
about uses in animals that are not average adults can be driven by
regulations or biologic factors. The reader has problems knowing which
is which. In addition, practitioners are cautioned that the lack of informa-
tion about a particular use on labels should not be viewed, by default,
as a tacit recommendation for that use.
Administration by an Alternate Route
Vaccine labels do not discuss use by alternate routes, because manu-
facturers rarely gather data on other possible routes. There can be
differences in the immune responses observed after administration of
vaccines by different routes.! Whether these differences have a clinical
impact on animals is not normally known. There can be important safety
concerns about giving vaccines by alternate routes. As an example,
injectable modified live virus vaccines for feline h e r p e ~ can revert to
virulence if they gain access to mucous membranes as a result of acciden-
tal aerosols or if the cat licks at vaccine that contaminates an injection
site.' These issues are commonly ignored on vaccine labels. Vaccine users
should only administer vaccine by the routes indicated on the vaccine's
label, and practitioners are cautioned that the lack of information about
a particular use on labels should not be viewed, by default, as a tacit
recommendation for that use.
552 HUSTEAD
:
' .
Limitations of Safety Information
...
The minimalistic approach to safeQ4. information on vaccine labels
was described previously. Vaccines must be determined to be safe by
the USDA for licensure (9 CRF Part 113). It is the reality of the biologic
process that vaccine administration is associated with adverse responses
in some animals.' A vaccine is considered safe by the USDA if it does
not cause undue local or systemic responses (9 CFR Part 101.5). There is
no regulatory definition of undue responses, and different groups of
vaccine users would probably define undue responses quite differently.
To better explain the limitations on the safety information provided on
vaccine labels, a short explanation of how these undue responses are
characterized and how their absence is demonstrated is in order.
Product safety is generally demonstrated in a field trial (9 CFR Parts
103 and 113). There are no precise safety determination procedures in
the USDA regulations. As a result, safety testing can be even more
varied than the previously described efficacy testing. On the other hand,
there are common elements to most safety test procedures. A safety
study is generally performed by private practice veterinarians in multi-
ple geographic locations. The veterinarians use the test product in pa-
tients as part of a preventive medicine program. The product used in
the test is said to be representative of the product that is going to be
sold commercially. The number of animals involved in the trial is not
codified in the regulations, but, normally, at least 300 and, commonly,
500 to 1000 animals are used. The general protocol for these studies
involves informing the animal's owner about the study, administering
the test vaccine, observing the animal for a short period of time (i.e., 30
minutes), instructing the owner to observe the animal for adverse ,re-
sponses until it is presented to the veterinarian again, instructing the
owner to report any adverse responses observed, representing the animal
for a booster vaccination a few weeks later, and then repeating this
procedure. All responses that are considered adverse are recorded. The
responses that are recorded are then categorized as vaccine-mediated or
non-vaccine-mediated responses.
The USDA approach to safety implies that vaccines can be catego-
rized as safe or unsafe and that only the safe ones get to the marketplace.
If these safe products have a small amount of safety text on the label,
this would imply that the USDA and the manufacturer have determined
that the safety information provided on the label is sufficient for the
product's use. Does this amount of safety information adequately inform
vaccine users? What can be said with certainty is that the quality and
quantity of safety information on an animal vaccine label is much less
than that found on the labels of common human vaccines. As an exam-
ple, a currently approved human vaccine for diphtheria, tetanus, and
READLNG A VACCINE LABEL 553
pertussis has 49 column inches of text on its approved package insert
about safety concerns associated with vaccine administration (Diphtheria
and Tetanus Toxins and Pertussis Vaccine USP; Pasteur Merieux Con-
naught, Swiftwater, PA, 1999 package insert). The label lists many ad-
verse responses with estimates of their frequency. Tl)ere are also guide-
lines as to which responses parents should pay more attention to and
advice on when to call a health care provider if adverse responses are
observed. It could be argued that this amount of text is overkill; at
the same time, it is obvious that the average physician has access to
considerably more information about vaccine safety than the average
veterinarian. In contrast, it is not unusual for an animal vaccine label to
essentially ignore the safety concerns of vaccine administration, with the
exception of anaphylaxis. Anticipated USDA regulations are likely to
result in more safety information being placed on the label by requiring
significant responses seen in the safety studies to be noted on the
product's label, but these rules are not in place at the time of this writing
(USDA reviewer, personal communication, 1999).
What should practitioners take home from these safety issues? First,
safety studies look for clinically obvious problems that are readily associ-
ated with vaccine administration and are seen within a short period
after vaccination. An adverse consequence of vaccine administration that
does not have a clinically obvious sign is not likely to be seen. Second,
these studies are designed to demonstrate responses that are fairly
common. If an adverse consequence is seen in 1 of 1000 vaccinates, a
study that includes 500 animals has essentially a 50:50 chance of seeing
the adverse response. Many practitioners vaccinate more than 1000 ani-
mals per year; thus, they would be expected to see things not described
in these studies. As adverse responses become less frequent, these stud-
ies become less likely to evaluate the response. Third, these studies are
highly subjective and require considerable interpretation on the part of
the people involved. These studies depend on the people conducting
the observations to be able to effectively observe responses in animals.
They must then accurately describe the observation and its proposed
association with vaccination in the study papers. As the study is inter-
preted, the observations must be accurately categorized, or their signifi-
cance may be lost. Any breakdown in the process of communication
makes the information less applicable to practitioners. Fourth, if the
observers of the animals in the study are less observant than the average
veterinarian or animal owner, significant responses may be ignored. This
is a common problem with studies conducted in commercial kennels or
herds. On the other hand, a single practitioner in a safety study may be
overly responsive to animals' postvaccination responses. All these factors
may change the way these data are collected and analyzed. For the
vaccine label, all these factors eventually get distilled down to a few
554 HUSTEAD
short safety statements that in all probability do not accurately reflect
the clinical safety of the product as ob.served by all users.
In the same manner as efficacy claims, differences in safety claims
between similar products are hard to understand. Comparing two simi-
lar products may reveal differences in the safety information provided.
Is the product with more detailed safety information on its label less
safe? Maybe that is true, but maybe the manufacturer of one product
has decided to more fully describe the adverse responses that are actu-
ally seen with this product or with similar products. Maybe the manufac-
turer simply wants to limit its liability by more fully describing safety
concerns inherent in all vaccines. As a result, vaccines with the same
safety text on their labels may behave differently in animals, and, at the
same time, vaccines with differing label texts may behave the same.
Differing claims for safety and efficacy on vaccine labels may be clini-
cally important, or they may not. How is the reader to know?
Dose Volume
Beyond the single dose volume recommended on the label, vaccine
labels tell nothing about the biologic issues associated with dose volume.
The most common question from practitioners about this label direction
is "Why does a Toy Poodle get the same dose as a Great Dane?" The
only real answer is that no one knows for sure. The dose volume that is
stated is the one dose volume that was tested in the licensing process.
During the preceding discussion on safety and efficacy testing, the issue
of breed was ignored. There are no regulated standards for the testing
of breeds in animals. As a result, testing might be done in a single
breed (i.e., Beagle or purposefully bred mongrels). From a regulatory
perspective, the immune responses of all animals in the species get
lumped into a single group. Although this is an open question, there is
no information available to this author demonstrating that from an
efficacy perspective, vaccine dose would be expected to be smaller for
smaller animals. On the other hand, it is generally believed that the
number of immune-sensitive cells in a species is fixed by the species
and not the size of the individual animal.
s
In addition, vaccine effective-
ness as demonstrated in a laboratory has been shown to be related to
dose for some vaccines.
2
It is not known if this reduction in laboratory
efficacy translates into less clinical efficacy, but that remains a concern.
Using a smaller than directed dose volume could have reduced effective-
ness in some animals. From a safety perspective, it is commonly argued
from a clinical perspective that smaller animals are less likely to suffer
adverse responses if they are given smaller doses of vaccine. This author
.is unaware of any controlled data that support this claim. Until further
READING A VACCINE LABEL 555
work is done to define the safety or efficacy implications on breed or
size of animals, the answer that is standard in the vaccine industry is
that one size fits all.
Storage Conditions
Vaccine labels ignore all vaccine storage issues except storage at the
recommended temperature range. They tell you little about what to do
if the vaccine is stored outside these storage limits. It is well known that
vaccines, like most biologic specimens, are negatively affected by storage
in light and heat. Just how much heat and light negatively affect the
product is not precisely known. Vaccine manufacturers are required to
provide assurances that products are acceptable for use for the time
period shown by the expiration date on the label (9 CFR Part 112). It is
common in the vaccine industry for these expiration dates to be 2 to 3
years after the manufacture date. Vaccine labels have adopted storage
condition recommendations that are most advantageous to the long-
term storage of the product. There is a dearth of research on what
happens to vaccines stored outside their label storage conditions. It is
common biolOgic knowledge that small excursions from the label storage
directions would be expected to have a small impact on the product. On
the other hand, these excursions would be expected to be cumulative
over the life of the product. At a practical level, storage of many vaccines
at room temperature for a couple of hours is of little significance, but
what if that storage occurs every day for a few days or weeks? What if
that storage occurs over the weekend on the receiving dock? If vaccine
users want the manufacturer's assurance that the product they use can
be expected to perform like the product used in the safety and efficacy
testing performed for the product's licensing, their only recourse is to
store it per the directions on the label. The actual biologic impact of
storage under any other environmental conditions is probably unknown.
CONCLUSIONS
Vaccine labels have important functions and can provide excellent
service if they are read. On the other hand, current vaccine labels
reflect specific word selection, or the absence of text, unique to the
manufacturer or the USDA and are not always correctly understood by
veterinarians. These characteristics of vaccine labels can make a user's
effective information gathering difficult. Understanding the USDA label-
ing regulations and how vaccine labels evolved may resolve some of the
user 's confusion regarding the use of a particular product. It is clear
556 HUSTEAD
.,.
that there is ample scope for improvements in USDA reg'Uiations, which
have a direct impact on vaccine labels.,. A few higher priority improve-
ments would include a system of identification that informs users about
a vaccine's unique antigenic components and identifies the presence of
nonantigenic but immunogenic components (adjuvants), increased use
of codified efficacy testing procedures that accurately reflect clinical
reality, improved use directions that effectively deal with the classes of
animals that all practitioners may need to vaccinate, and improved
information on the actual clinical safety of vaccines. When users desire
product information that they cannot locate on the product's label,
an excellent resource is the technical staff of the manufacturer. These
individuals should be able to discuss why the label does not adequately
address a specific question and should be able to provide additional
information. Be a well-informed vaccine user. It is important to you,
your client, and your patient.
References
1. Greene C: Infectious Diseases of the Dog and Cat. Philadelphia, WB Saunders, 1998,
p 104
2. Nervig MN, Gough PM, Kaeberle ML, et al: Advances in Carriers and Adjuvants for
Veterinary Biologics. Ames, lA, Iowa State University Press, 1986, pp 55, 115-120
3. Runnels RA, Monlux WS, Monlux AW, et al: Principles of Veterinary Pathology. Ames,
lA, Iowa State University Press, 1965, pp 80-81
4. Tizard IR: Veterinary lrrununology. An Introduction. Philadelphia, WB Saunders, 2000,
pp 244, 247-251
Address reprint requests to
David R. Hustead, DVM
International Technical Director
Fort Dodge Animal Health
Overland Park, KS 66225
e-mail: dhustead@fdah.com
VACCINES AND VACCINATIONS 0195-5616/ 01 $15.00 + .00
RABIES POSTEXPOSURE
PROPHYLAXIS
Human and Domestic Animal Considerati011.8
M. Gayne Fearneyhough, BS, DVM
Since the middle of this century, an average of one or two human
rabies cases has been reported annually in the United States. The 1996
estimated cost for rabies biologic agents required for postexposure pro-
phylaxis (PEP) for people exposed to a rabid or potentially rabid animal
was between $26.5 and $65.3 million.
s
In three studies conducted since
1980, the total annual expenditure to prevent rabies in the United States
was found to be at least $230 million, and it may be as much as $1
billion annually.7 A cursory analysis of the public health significance of
rabies in the United States could easily result in the conclusion that a
disproportionate number of resources are allocated to the disease, espe-
cially when the numbers of cases of human rabies and rabies in domestic
animals have declined over the last 50 years. A more detailed examina-
tion of the epidemiologic nature of rabies reveals a valid cause for
concern, however, with rapidly expanding epizootics of wildlife rabies
in raccoons in the eastern United States, in foxes in Texas and the
northeastern United States, and in coyotes in Texas. An additional cause
for concern is the identification of a viral variant transmitted by bats,
which may represent an increased public health threat. That threat has
caused modification to the Centers for Disease Control and Prevention
(CDC) recommendations for PEP in people experiencing potential expo-
sure to a bat.
4
Prior Director, Oral Rabies Vaccination Program, Texas Department of Health, Zoonosis
Control Division, Austin, Texas from 1993-2000
VETERINARY CLINICS OF NORTIl AMERJCA: SMALL ANIMAL PRACTICE
VOLUME 31 NUMBER 3 MAY 2001 557
558 FEARNEYHOUGH
Although rabies causes only one ortwo human deaths annually in
the United States, it is important to UI1derstand an estimated 40,000
to 100,000 human deaths result worldwide from rabies each yearY
Consequently, as a society, we tend to have a strong and sometimes
unreasonable fear of exposure to the rabies virus. That fearful response
may be attributed in part to the graphic depiction of the disease by the
entertainment industry in motion pictures such as "Old Yeller" and
"Cujo." Fear of rabies may stimulate someone with a potential exposure
to rabies to seek medical intervention and thereby save a human life.
Conversely, fear also causes patients to demand treatment when a threat
does not exist and may result in the inappropriate use of valuable
medical resources. Practicing veterinarians, medical professionals, or
public health workers may find that they are the most informed partici-
pants in a risk analysis process after a potential human or animal
exposure to rabies. When administered according to recommendations
provided by the Advisory Committee on Immunization Practices (ACIP),
PEP has been shown to be essentially 100% effective. Given that rabies
is universally fatal, it is essential that accurate and timely decisions be
made concerning the administration of PEP.
A 1946 report by the Committee on Animal Health of the National
Research Council determined that rabies was a preventable disease and
proposed that a coordinated effort to achieve that goal be developed
under the leadership of the United States Department of Agriculture
(USDA) and individual state veterinarians.lJ Control measures that fo-
cused on domestic animal vaccination, local animal control programs,
public education, and wildlife depopulation were proposed. In 1938,
there were 9412 cases of rabies reported in animals (mostly in domestic
species) and 47 human deathsY As late as 1960, most rabies cases were
still reported in domestic species. Beginning in 1990, however, there
was a dramatic increase in reported cases of wildlife rabies, primarily
attributed to the raccoon rabies epizootic in the eastern United States.
From 1990 to 1993, a 225% increase was reported in raccoon rabies cases
(from 1812 to 5885) in the mid-Atlantic and northeastern states. By 1996,
more than 90% of the 7124 animal rabies cases reported in the United
States to the CDC were in wildlife species.
s
, 13
Although a coordinated national program did not develop, some or
all of the principles for rabies control that were proposed in 1946 were
employed at the state and local levels. It is reasonable to assume that
those measures have had a favorable impact on the reduction of human
and domestic animal rabies cases over the last 50 years. Nevertheless,
the changing face of rabies with the identification of new animal reser-
voirs and new viral variants has necessitated that rabies control and PEP
recommendations constantly evolve. That evolutionary process should
RABfES POSTEXPOSURE PROPHYLAXIS 559
employ the application of new technology to continue to prevent human
deaths through the appropriate application of PEP and the development
of ~ o v a t i v e programs to reduce the presence of rabies in wildlife.
RABIES RISK ASSESSMENT
The evaluation process to ascertain an individual's risk of exposure
to rabies first involves the determination of whether a bite or nonbite
exposure may have occurred. If an exposure has occurred that could
result in rabies virus transmission, it is critical that proper wound
management techniques be used immediately. The simple process of
proper wound cleansing and irrigation with adequate soap and water
can reduce the potential for rabies.
2
Assessment of the wound and
appropriate use of antibiotic therapy and tetanus prophylaxis should
also be considered. .
The end result of what can be a complicated risk assessment process
is the decision of whether to initiate PEP. A decision to withhold PEP
while awaiting the outcome of a laboratory test or the outcome of a
quarantine period for the biting domestic animal constitutes a decision
to not treat the patient at that time. If a patient has been exposed to
rabies, the greatest chance for survival may depend on prompt initiation
of PEP. The process of reaching a risk assessment decision can be
complicated and clouded by emotional and legal considerations. The
following summary of risk assessment considerations is taken from the
recommendations of the ACIP and the National Association of State.
Public Health Veterinarians (NASPHV) as published in the Morbidity
and Mortality Weekly ReporU 10 These recommendations constitute the
minimum criteria that should be considered in evaluating a patient's
risk for rabies exposure. Figure 1 represents a rabies PEP decision tree.
Type of Exposure
The primary mechanism of rabies transmission involves a bite
wound, which allows the passage of virus-containing saliva across a
previously intact skin barrier. Bites to the face and hands carry the
highest risk, but the site of the bite should not influence the decision to
begin PEP. Nonbite exposure by means of scratches, abrasions, open
wounds, or mucous membranes that are exposed to saliva or other
infective material (i.e., brain tissue, cerebrospinal fluid) may also consti-
tute an exposure. Petting a rabid animal; exposure of intact skin to
blood, urine, or feces of a rabid animal; or contact with fluids that may
560 FEARNEYHOUGH
Figure 1. Rabies postexposure prophylaxis decision trae.
have been infective but have dried does not constitute an exposure.
Nonbite exposure from aerosolized rabies virus in caves, laboratory
settings, or organ transplants (i.e., corneas) has occurred but represents
unlikely an exposure situation.
RABIES POSTEXPOSURE PROPHYLAXIS 561
Exposing Animal
Wild Animal Bites
Bites by wild carnivores and bats should be considered an exposure
to rabies and require initiation of PEP for the patient. The biting animal
should be humanely killed immediately, and the brain should be tested
for rabies, especially in species that may be defined as high risk for
rabies exposure such as raccoons, skunks, foxes, and bats. The recent
epizootic of canine rabies in coyotes along the Texas-Mexico border and
the practice of translocating coyotes for hunting purposes may make it
prudent to also consider them a high-risk species. PEP may be delayed
if the bite occurs in a geographic area of the United States that is free of
terrestrial rabies and if the results of immunofluorescence testing are
available within 48 hours. If treatment is initiated and the biting animal
is shown not to be rabid, treatment may be discontinued. Exotic animals
and valuable specimens that have been confined and have been deter-
mined by public health authorities to represent a limited risk may be
quarantined for 30 days in lieu of testing. Rodent and lagomorph species
are almost never found to be infected with rabies, and local health
departments should be consulted concerning bites by those animal
groups. Rabies in groundhogs accounted for 70% of the 179 cases among
rodents reported to the CDC from 1971 through 1988, however.2 An
analysis of data reported by Krebs and associates
9
from 1991 through
1996 indicates an annual average of 52 cases of rabies in groundhogs,
with most of those cases attributed to the raccoon variant of the rabies
virus. The Conference of State and Territorial Epidemiologists and the
NASPHV consider exotic pets and domestic animals crossbred with wild
animals to be wild animals.
10
A bite by any of those animals should be
handled as an exposure to a wild animal.
Modifications to PEP recommendations were presented to the ACIP
in 1996, because data indicated that bats were associated with an increas-
ing number of human rabies cases. From 1990 through 1996, bat rabies
variants were associated with 15 of 17 indigenously acquired cases of
human rabies. An identifiable bite was reported in only 1 of those cases,
suggesting that minimal or unnoticed physical contact with bats may
result in viral transmission.
8
In situations in which a bat is physically
present and the person(s) cannot reasonably exclude the possibility of a
bite exposure, PEP should be given unless prompt capture and testing
of the bat have excluded rabies virus infection.
3
This recommendation
has particular significance for children, mentally challenged adults, and
intoxicated individuals, who may be unable to responsibly assess
whether contact with a bat has occurred. If a bat is found in a room
with an unattended child or is found present in a room in which a child
562 FEARNEYHOUGH
or adult was sleeping and physical contact cannot be excluded, PEP
should be initiated immediately, and, it available, the bat should be
tested for rabies. Negative immunofluorescence antibody testing results
from a certified laboratory are justification for discontinuing PEP.
Domestic Animal Bites
The NASPHV makes recommendations to be used in the manage-
ment of animals that bite human beings (Ref. la, p 83) .10
Circumstances of the Bite
An unprovoked bite by a domestic animal may constitute an in-
creased risk for rabies in the biting animal and contributes to a decision
to initiate PEP for the patient. People fear being bitten by an animal;
thus, it is reasonable to assume that most bites inflicted on human beings
by domestic animals are not intentionally provoked. It is important to
emphasize that the human definition of provocation may not be consis-
tent with conditions that elicit aggressive or defensive behavior in a
domestic species. Although not often seen as provocative behavior by
people, actions such as invading the ill-defined physical territory of an
animal, disturbing an animal during eating, staring into the eyes of a
dominant animal, playing by children that may attempt to force an
animal to the ground, and blowing into the face of an animal are but a
few examples of human behavior that may produce an aggressive re-
sponse in a normal animal.
Vaccination Status of the Exposing Animal
Knowledge that a biting domestic animal is currently vaccinated
with a vaccine licensed for that species does not remove all concern for
involvement of rabies, because no vaccine can be considered to be 100%
effective. Animal vaccines licensed for use in the United States have
achieved a high level.of immunogenicity, however, and their use in a
domestic species for which a license has been approved markedly re-
duces the potential for rabies involvement. Knowledge of a current
vaccination in the biting animal, when combined with a lack of epidemi-
ologic evidence of terrestrial rabies in the geographic area and reduced
risk associated with conditions of the bite, may allow for justification of
a la-day quarantine period for a biting animal. Employing a la-day
quarantine period has obvious benefits to the owner of a valuable animal
compared with euthanizing the animal and testing the brain. If the
RABIES POSTEXPOSURE PROPHYLAXlS 563
animal is available for quarantine and the risk assessment process indi-
cates a low probability for rabies, PEP can be delayed for the patient;
however, PEP should be initiated immediately at the first sign of rabies
in the' quarantined animal (Table 1).
RABIES IMMUNIZING PRODUCTS FOR USE IN HUMAN
BEINGS
There are two types of immunizing products for use in human
beings: immune globulins that provide rapid passive immune protection
for a short time (half-life of about 21 days) and vaccines that induce
an active immune response (requires about 7-10 days to develop, but
immunity may persist for at least 1 year). Both types of products should
be used concurrently for rabies PEP in those persons who have never
received prior immunization against rabies. It is recommended that the
package insert be consulted before any of these products is used.
14
Table 1. CURRENT ADVISORY COMMITTEE ON IMMUNIZATION PRACTICES RABIES
POSTEXPOSURE HUMAN PROPHYLAXIS GUIDE
Animal Type
Dogs and cats
Skunks, raccoons, bats,
foxes, and most other
carnivores; groundhogs
Uvestock, rodents, and
lagomorphs (rabbits
and hares)
Evaluation and
Disposition of Animal
Healthy and available for
10 days
Rabid or suspect rabid
Unknown or escaped
Regarded as rabid tmless
geographic area is
known to be free of
rabies or until animal is
proved negative by
laboratory testt
Consider individually
Postexposure Prophylaxis
Recommendations
Should not begin PEP unless
animal develops clinical
signs of rabies'
Immediate PEP
Consult public health officials
Immediate PEP
Consult public health
officials; bites of squirrels,
hamsters, guinea pigs,
gerbils, chipmunks, rats,
mice, other rodents,
rabbits, and hares almost
never require antirabies
treatment
'During the 10-day holding period, begin treatment with human rabies inunune globulin and
human diplOid cell vaccine or purified chick embryo cell culture at first sign of rabies in a dog or cat
that has bitten someone. The animal with clinical signs should be euthanized inunediately and tested.
tThe animal should be euthanized and tested as soon as possible. Holding for observation is not
recommended. Discontinue vaccine if inununofluorescence test nesults of the animal are negative.
PEP = postexposure prophylaxis.
From Centers for Disease Control and Prevention: Rabies prevention-United States, 1991, recom-
mendations of the lmmunization Practices Advisory Committee (ACIP). MMWR Morb Mortal WkIy
Rep 4O(RR-3):1-19, 1991.
564 FEARNEYHOUGH
Table 2. POSTEXPOSURE TREATMENT PRODUCTS-HUMAN RABIES
IMMUNE GLOBULlN*
Product Name

Manufacturer
...
Irnogam
BayRab
Pasteur Merieux Connaught Laboratories (Swiftwater, PAl
Bayer Laboratories (Pittsburgh, PAl
Administered at time of first dose of vaccine only. Patient weight is needed to determine dose.
Dose is 20 lU/ kg (2 mL per 33 Ib).
Rabies Immune Globulin
Human rabies immune globulin (HRIG) (Irnogam Rabies-HT,
Pasteur Merieux Connaught, Swiftwater, PA; and BayRab, Bayer Labora-
tories, Pittsburgh, PA) is antirabies gamma globulin concentrated by
cold ethanol fractionation from the plasma of immunized human donors.
Rabies neutralizing antibody content is standardized to contain 150 IU /
mL. It is supplied in 2-mL (300 IU) and 10-mL (1500 IU) vials for
pediatric and adult use, respectively (Table 2). Irnogam Rabies-ill has
received an additional heat treatment step to further reduce the risk of
the transmission of known or unknown blood-borne viruses.
Vaccines
Human Diploid Cell Vaccine
Human diploid cell vaccine (HDCV) is an inactivated virus vaccine
prepared from rabies virus grown in human diploid cell culture and
then inactivated (Table 3) . Vaccine is supplied as 1-mL single-dose vials
of freeze-dried vaccine with accompanying diluent for intramuscular
(1M) injection (Irnovax Rabies Vaccine, Pasteur Merieux Connaught) and
O.l-mL single-dose syringes of freeze-dried vaccine with accompanying
diluent for pre-exposure intradermal use (Irnovax Rabies LD., Pasteur
Merieux Connaught). Both formulations must be used immediately after
reconstitution.
Table 3. POSTEXPOSURE TREATMENT PRODUCTS-HUMAN RABIES VACCINES
Product Name Manufacturer
Irnovax: human diploid cell vaccine Pasteur Merieux Connaught Laboratories
(Swiftwater, PAl
RabAvert: purified chick embryo cell culture Chiron Behring GrnhH & Company
(Hessen, Germany)
RABIES POSTEXPOSURE PROPHYLAXIS 565
Purified Chick Embryo Cell Culture
Purified chick embryo cell (PCEC) culture is a sterile freeze-dried
vaccine obtained by growing the Flury-fixed virus strain, low-egg pas-
sage 'in primary cultures of chicken fibroblasts (see Table 3). PCEC
culture (RabAvert, ChiTon Behring GmbH & Company, Hessen, Ger-
many) is licensed in the United States for IM use in pre-exposure
immllllization and PEP. The schedules and dosage for PCEC culture are
the same as for HDCY. It may be used as a booster dose even if another
rabies vaccine was used for the primary series.
Serious adverse reactions associated with some rabies vaccines in-
clude systemic, anaphylactic, and neuroparalytic reactions. Serious ad-
verse reactions occur at lower rates with HDCV or PCEC vaccines than
with previously available types of rabies vaccine.
POSTEXPOSURE PROPHYLAXIS IMMUNIZATION
PROTOCOL
Postexposure antirabies immllllization should include administra-
tion of rabies antibody (HRJG) and vaccine (HDCV or PCEC culture).
An exception to this guideline is made for exposed persons who have
been previously immunized with the recommended pre-exposure or
postexposure regimens of HDCV or PCEC culture (or who have been
immllllized with other types of vaccines and have documented an ade-
quate rabies antibody titer). In those cases, HRJG would not be given,
and only two doses of vaccine would be given on day 0 and day 3
(Table 4).
The combination of immune globulin and vaccine is recommended
for persons not previously immllllized for bite exposures and nonbite
exposures, regardless of the interval between exposure and treatment.
The sooner treatment is begun after exposure, the better is the chance of
effectiveness. If there was a delay in recognizing a rabies exposure,
treatment may be started even months after that exposure occurred.
Five 1-mL doses of HDCV or PCEC culture should be given IM in
the deltoid region in adults or on the anterolateral thigh in infants. The
intradermal route should not be used for PEP. The first dose should be
given as soon as possible after exposure; additional doses should be
given on days 3, 7, 14, and 28 after the first dose. Antibody response
after the recommended vaccination regimen has been uniformly satisfac-
tory; thus, routine postvaccination serologic testing is not normally rec-
ommended. In unusual instances, however, such as when the patient is
immunodeficient or immunosuppressed, serologic testing (rapid fluo-
rescent focus inhibition test) is indicated. This test is available with fast
566 FEARNEYHOUGH
..
,
Table 4. RABIES POSTEXPOSURE PROPHYLAXIS SCHEDULE
IN THE UNITED STATES
Patient Vaccination
Status Treatment ..
Not previously vaccinated Local wound cleansing
HRIG
Vaccine
Previously vaccinated:j: Local wound cleansing
HRIG
Vaccine
Regimen
All postexposure treatment
should begin with
immediate thorough
cleansing of all wounds with
soap and water
20 IV/kg of body weight; as
much as possible of the full
dose should be infiltrated
into and around the
wound(s), and the remainder
should be administered 1M
at an anatomic site distant
from vaccine administration;
HRIG should not be
administered in the same
syringe as vaccine; Because
HRIG may partially suppress
active production of
antibody, no more than the
recommended dose should
be given
1 mL of HDCV or PCEC
culture 1M (deltoid areat) on
days 0, 3, 7, 14 and 28
All postexposure treatment
should begin with
immediate thorough
cleansing of all wounds with
soap and water
HRIG should not be
administered
1 mL of HDCV or PCEC
culture IM (deltoid areat) on
days 0 and 3
'These regimens are applicable lor all age groups, including children.
tThe deltoid area is the only acceptable site 01 vaccination lor adults and older children. For
younger children, the outer aspect 01 the thigh may b ~ used. Vaccine should never be administered in
the gluteal area. .
:j:Any person with a history 01 pre-exposure vaccination with HDCV or PCEC, prior postexposure
prophylaxis with HDCV or PCEC, or previous vaccination with any other type 01 rabies vaccine and
documented history 01 antibody response to the prior vaccination.
HRJG = human rabies immune globulin; 1M = intramuscularly; HDCV = human diploid cell
vaccine; PCEC = purified chick embryo cell
From Texas Department of Health: Rabies Prevention in Texas 1997. Austin, DC, Texas Department
of Public Health stock no 6-108, 1997; with permission.
turnaround through the Department of Veterinary Diagnostics, Veteri-
nary Medical Center, Kansas State University, Manhattan, Kansas 66506
(telephone: 785-532-5650).
The selection of sites for IM injections of vaccine seems to be critical
RABrES POSTEXPOSURE PROPHYLAXIS 567
for vaccine efficacy. In adults and larger children, HDCV or PCEC
culture should be given in the deltoid area. In infants and small children,
the anterolateral thigh should be used. In the two laboratory-confirmed
cases of human rabies after postexposure treatment with HDCV and
HRlG within 24 hours, the HDCV was administered in the gluteal area.
Presumably, subcutaneous fat in the gluteal area may interfere with
proper 1M administration of the vaccine and thus reduces the immuno-
genicity of the vaccine.
HRlG is administered only once at the beginning of antirabies
prophylaxis to provide immediate antibodies until the patient responds
to vaccination with active production of antibodies. If HRlG was not
given at the initiation of vaccination, it can be given up to the eighth
day after the first dose of vaccine. From the eighth day on, HRIG is not
indicated, because an antibody response to the vaccine is presumed to
have occurred.
The recommended dose of HRlG is 20 IU /kg or approximately 9
IU/lb (2 mL per 33 lb) of body weight. As much of the full dose of
HRlG as possible should be thoroughly infiltrated into and around the
wound(s). Any remaining volume should be administered 1M at a site
distant from vaccine inoculation. No more than the recommended dose
of HRlG should be given because it may partially suppress active pro-
duction of antibody.
POSTEXPOSURE PROPHYLAXIS TREATMENT
OUTSIDE THE UNITED STATES
If PEP treatment is begun outside the United States with locally
produced biologic agents, it may be desirable to provide additional
treatment when the patient reaches the United States. For specific advice
in such cases, contact the local health department.
POSTEXPOSURE THERAPY OF PREVIOUSLY
IMMUNIZED PERSONS
Pre-exposure immunization does not remove the need for PEP; it
merely reduces the extent of treatment. On exposure to rabies, an immu-
nized person who was vaccinated with the recommended regimen of
HDCV or PCEC culture or who has previously demonstrated rabies
antibody should receive two 1M doses (1 mL each) of HDCV or PCEC
culture, one immediately and one 3 days later (see Table 4). HRlG
should not be given in these cases. Full primary postexposure antirabies
treatment (HRlG plus five doses of HDCV or PCEC culture) may be
568 FEARNEYHOUGH
..
necessary in the case of unknown immune status in a previously vacci-
nated person who did not receive the recommended HDCV or PCEC
regimen. In such cases, if antibody can be demonstrated in a serum
sample collected before vaccine is given, treatment can be discontinued
after at least two doses of HDCV or PCEC culture.
ACCIDENTAL HUMAN EXPOSURE TO ANIMAL RABIES
VACCINE
Accidental inoculation or vaccine contact with mucous membranes
may occur in human beings during administration of rabies vaccines to
animals. Such exposure to inactivated rabies vaccine constitutes no
known rabies hazard.
PRECAUTIONS AND CONTRAINDICATIONS
Immunosuppression
Corticosteroids and other immunosuppressive agents, antimalarials,
and immunosuppressive illnesses (such as HIV infection) can interfere
with the development of active immunity and predispose the patient to
the development of rabies. Immunosuppressive agents should not be
administered during postexposure therapy unless they are essential for
the treatment of other conditions. When rabies PEP is administered to
persons receiving corticosteroids or other immunosuppressive therapy
or to persons having an immunosuppressive illness, it is especially
important that the patient be tested for rabies antibody to ensure that
an adequate response has developed.
Pregnancy
Because of the potential consequences of an inadequately treated
rabies exposure and limited data indicating that fetal abnormalities have
been associated with rabies vaccination, pregnancy is not considered a
contraindication to PEP. If a substantial unavoidable risk of exposure to
rabies exists, pre-exposure prophylaxis may also be indicated during
pregnancy.
RABIES POSTEXPOSURE PROPHYLAXIS 569
Allergies
Persons with histories of hypersensitivity should be gjven rabies
vaccines with caution. When a patient with a history suggesting hyper-
sensitivity to HDCV or PCEC culture must be gjven that vaccine, antihis-
tamines can be provided; epinephrine should be readily available to
counteract anaphylactic reactions, and the person should be carefully
observed.
MANAGEMENT OF PETS EXPOSED TO RABID
ANIMALS
The management of cases of domestic animals exposed to rabies
can be difficult because of the lack of an immediate perceived threat to
human life. The exposure incident obviously could later result in human
exposure if the domestic animal should develop rabies. As a result, the
recommendation normally has been to sacrifice the exposed animal.
Management of these cases may also be further complicated by the
emotional value of the animal as well as conflict over the rights of
ownership of private property and disposition of that property when
little or no human health risk exists. The NASPHV recommends postex-
posure management for animals exposed to a rabid animaLB
Confusion has occurred with respect to (1) . the la-day observation
period for a dog, cat, or ferret that has bitten or scratched a human
being and (2) the period of strict isolation required for an unvaccinated
dog, cat, or ferret that has been exposed to a rabid animal. Generally,
when clinical symptoms of rabies are first evident, the rabies virus also
becomes present in the saliva, and a dog, cat, or ferret survives no longer
than 3 to 5 days. If the animal is clinically normal 10 days after the
biting incident, it is not considered likely for rabies virus to have been
present in its saliva at the time of the bite. As a result, exposure to rabies
virus could not have resulted from the bite, and PEP is not indicated. A
dog, cat, or ferret may develop rabies more than 10 days after having
bitten a person, but the animal would not be considered to have been
infective at the time of the bite.
The la-day observation period is not applicable for a dog, cat, or
ferret exposed to a rabid animal. The average incubation time for rabies
in those species is generally 3 to 8 weeks; thus, an observation period of
45 days for vaccinated animals and 180 days for unvaccinated animals
is recommended. Consequently, the la-day observation period is useful
in ensuring that a dog, cat, or ferret was not able to transmit rabies at
the time of a biting incident, but it is not applicable for those species
under observation after an exposure to a rabid animal.
570 FEARNEYHOUGH
POSTEXPOSURE PROPHYLAXIS JUSTIFICATION FOR
DOMESTIC ANIMALS
The primary concern of the risk -assessment process to determine
the appropriateness of PEP for a human patient must be the patient's
safety. Rabies is universally fatal; thus, there is a tendency to administer
PEP to the human patient when there may be even a limited potential
for rabies exposure. That conservative approach to management of the
human patient has also resulted in recommendations for sacrificing an
animal exposed to or potentially exposed to rabies. Such recommenda-
tions are not usually based on a callous approach to the value of the
animal but rather on a concern that the exposed animal might later
develop rabies and represent a serious public health threat. The reluc-
tance to advocate the use of PEP in animals is also complicated by the
fact that there are limited scientific data published to demonstrate the
effectiveness of PEP when administered to domestic animals.
A 1996 study by Clark and Wilson
5
does provide data to demon-
strate the effectiveness of PEP in unvaccinated domestic animals. This
retrospective study was conducted using two PEP protocols on 1345
unvaccinated domestic animals that were exposed to rabies and reported
to the Texas Department of Health over a 16-year period. The first PEP
protocol was used from 1979 through 1987 and involved 713 animals
(440 dogs; 57 cats; 145 cattle; 53 horses; and 18 sheep, goats, and pigs).
The exposed animals were immediately vaccinated and revaccinated 1
month before release from a 6-month period of isolation (there is no
vaccine for goats and pigs). The second protocol was
used from 1988 through 1994 and involved 632 animals (406 dogs; 106
cats; 69 cattle; 43 horses; 7 sheep, pigs, and goats; and 1 llama). In the
second protocol, the exposed animals were vaccinated immediately and
given booster vaccinations during the third and eighth weeks of a 90-
day isolation period (there is no USDA-licensed vaccine for llamas). This
study determined that 711 of 713 animals (99.7%) given PEP using the
first protocol and 629 of 632 animals (99.5%) given the second protocol
survived.
Another study in' 1991 conducted by Blancou and associates! to
determine the efficacy of the human PEP protocol used 68 sheep experi-
mentally infected with fox rabies virus. The infected sheep were divided
into three groups and were given cell culture vaccine on days 0, 3, 7,
and 14; HRlG at 26 IU/ kg on day 0; or a combination of vaccine and
immune globulin. Seventy-one percent of the controls died; the treatment
protocol using a combination of vaccine and immune globulin was
found to be 100% effective. These results seem to indicate that there may
be justification for PEP for domestic animals. Additional studies are
needed to identify animal PEP protocols capable of producing a high
RABIES POST EXPOSURE PROPHYLAXIS 571
level of survivability, conforming to public health concerns, and yet
being economically applicable to domestic animals.
SUMMARY
The emphasis on rabies control and prevention in the United States
seems to be a function of our perception of proximity of the threat.
Wildlife rabies epizootics within a state may be of little concern to the
uninformed urban dweller. Additionally, many parts of the western
United States are free of terrestrial rabies; were it not for the presence of
bat rabies, people in those areas would likely interpret rabies control as
a minor public health concern. It is essential that federal, state, and local
public health programs emphasize the importance of rabies control
through activities that include rabies education, sponsorship of legislated
requirements for domestic animal vaccination, support for local animal
control programs, and the promotion of recommendations that encour-
age the appropriate use of PEP. We are almost guaranteed that rabies is
going to remain a major public health issue well into the next century
because of expanding wildlife rabies epizootics, identification of new
rabies viral variants with increased public health concern, emotional and
legal concerns associated with rabies exposure, and increasing national
cost associated with rabies control and prevention. Nevertheless, the
development of new laboratory technology that allows an understanding
of the epidemi9logic nature of the rabies virus based on an evolving
genetic history and the interrelationship with wildlife reservoirs should
allow access to valuable tools for rabies control. When combined with
programs using new developments in oral rabies vaccine that can immu-
nize whole populations of wildlife reservoirs, that technology offers
encouragement in our effort to control one of the diseases of antiquity.6
ACKNOWLEDGMENTS
The author thanks Dr. Erik Svenkerud and Pamela J. Wilson of the Texas Department
of Health for their assistance and editorial comments.
References
1. Blancou J, Baltazar RS, Molli I: Effective postexposure treatment of rabies-infected
sheep with rabies immune globulin and vaccine. Vaccine 9:432-437, 1991
2. Centers for Disease Control and Prevention: Rabies prevention-Urtited States, 1991,
recommendations of the immunization Practices Advisory Comrrtittee(ACIP). MMWR
Morb Mortal Wkly Rep 40(RR-3):1-19, 1991
3. Centers for Disease Control and Prevention: Rabies prevention. MMWR Morb Mortal
Wkly Rep 445:209, 1996
572 FEARNEYHOUGH
4. Childs JE, Krebs JW, Rupprecht CE: Epidemiology of bat rabies in the VSA. Presented
at the Eighth Annual International Meeting of Rabies in the Americas, Kingston,
Ontario, Canada, November 2-6, 1997
5. Clark KA, Wilson PI: Postexposure rabies prophylaxis and preexposure rabies vaccina-
tion failure in domestic animals. JAVMA 1996
6. Feameyhough MG, Wilson PI. Clark KA, et al: Results of an oral rabies vaccination
program for coyotes. JAVMA 212:498-502, 1998
7. Fishbein DB, Robinson LE: Rabies. N Engl I Med 329:1632-1638, 1993
8. Krebs JW, Long-Marin SC, Childs JE: Causes, cost, and estimates of rabies postexposure
prophylaxis treatment in the United States. Journal of Public Health Management and
Practice 4:56-62, 1998
9. Krebs JW, Smith JS, Rupprecht CE, et al: Rabies surveillance in the United States
during 1996. JAVMA 211:1525-1539, 1997
10. National Association of State Public Health Veterinarians: Compendium of animal
rabies control, 1998. MMWR Morb Mortal Wkiy Rep 47(RR-9):1-9, 1998
11. National Research Council: Committee on Animal Health report: Rabies and its control.
JAVMA 108:293-302, 1946
12. Rupprecht CE, Smith JS, Fekadu M, et al: The ascension of wildlife rabies: A cause for
public health concern or intervention? Ernerg Infect Dis 1:107-113, 1995
13. Rupprecht CE, Smith JS, Krebs I. et al: Current issues in rabies prevention in the
United States, health dilemmas, public coffers, private interests. Public Health Rep
111:400-407, 1996
14. Texas Department of Health: Rabies Prevention in Texas 1997. Austin, TX, Texas
Department of Public Health, stock no 6-108, 1997
Address reprint requests to
M. Gayne Fearneyhough, BS, DVM
516 Lariat Lane
Dripping Springs, TX 78620
e-mail: feamey@flash.net
VACCINES AND VACCINATIONS 0195-5616/01 $15.00 + .00
IMPORTATION OF DOGS AND
CATS TO RABIES-FREE AREAS
OF THE WORLD
Deborah J. Briggs, MS, PhD, and Kristen Schweitzer, BS
The World Health Organization (WHO) defines a rabies-free area as
"one in which an effective import policy is implemented and, in the
presence of adequate disease surveillance, no case of indigenously ac-
quired rabies infection has been confirmed in humans or any animal
species at any time during the previous two years."6 The presence or
absence of rabies virus in the indigenous bat population is not induded
in the WHO definition. Countries and areas where no rabies was re-
ported in 1997 are published at the WHO world wide web site and
include but are not limited to: Australia, Bahamas, Fiji, Finland, Guam,
Hawaii, Hong Kong, Iceland, Japan, New Zealand, Papua New Guinea,
Portugal, St. Kitts and Nevis, Singapore, Sweden, and the United King-
dom.
6
Prior to the advent of highly efficacious killed rabies vaccines,
lengthy quarantine laws for dogs and cats entering rabies-free areas
were used as a means to prevent the introduction or reintroduction of
rabies. However, quarantine periods of 4 to 6 months have become
increasingly unacceptable to many people relocating to rabies-free areas
that wish to take their family pet with them. Resulting public pressure
from a very mobile society has caused the governments of many rabies-
From the Rabies Laboratory, Kansas State University, College of Veterinary Medicine,
Manhattan, Kansas
VETERINARY CLINlCS OF NORTH AMERICA: SMALL ANIMAL PRACTICE
VOLUME 31 NUMBER 3 MAY 2001 573
574 BRlGGS & SCHWEITZER
free areas to re-evaluate their quarantine system. In the Eighth Report
of the WHO Expert Committee on Rabies alternate recommendations to
lengthy quarantine requirements were m a d ~ t o ensure the protection of
rabies-free areas while simultaneously reducing the length of time re-
quired for a dog or cat to be held in a quarantine facility.6 Several rabies-
free areas have embraced all or part of the WHO recommendations
while others are in the process of reviewing or updating their import
requirements for dogs and cats from countries in which rabies is absent
or well controlled. Rabies-free areas that have replaced their lengthy
quarantine periods for dogs and cats being imported from the continen-
tal United States with alternate measures include Australia, New
Zealand, St. Kitts and Nevis, St. Vincent and the Grenadines, Malta,
Guam, and Hawaii. Between 1995 and 2000, more than 15,000 dogs and
cats have been imported into these areas with no reports of rabies being
introduced or reintroduced.
When preparing to move to a rabies-free area that has strict importa-
tion regulations regarding dogs and cats, meeting the criteria to qualify
for a reduced quarantine program requires time, patience, and advanced
preparation. There are several commercial companies that specialize
in pet moving services, relieving the owner of the tedious and often
complicated preparation that is necessary to fulfill governmental require-
ments. If a pet relocation specialist is chosen by the owner to help with
the move, the specialist should be reputable and preferably belong to
the Independent Pet and Animal Transport Association International,
Inc. (!PATA) . Members of the !PATA are registered or licensed by the
USDA (in the United States) and form a network of pet shippers
throughout the world. If the pet owner decides to forego the services of
a pet relocation service, they should contact the consulate of the destina-
tion country to determine the regulations required for importing their
animal.
REQUIREMENTS
The requirements for importing dogs and cats can generally be
obtained through the department of agriculture in the country in ques-
tion or through their governmental consulate in Washington, D.C. Most
countries require an import permit at some point in the application
process. Also, some countries prohibit the importation of certain breeds
of dogs and cats. If, upon arrival, an animal has not fulfilled the prear-
rival requirements or is a prohibited breed, the owner is usually respon-
sible for removing the animal from the country. Alternatively, the animal
could be placed in extended quarantine or in the worst case scenario,
euthanized.
IMPORTATION TO RABIES-FREE AREAS 575
Rabies-free areas depend on their import regulations to prevent the
introduction or reintroduction of rabies virus. The countries listed in
Table 1 have implemented rigid rabies vaccination and antibody testing
schedUles to reduce the length of time dogs and cats must remain in
quarantine. It is critical to review and understand these regulations with
a veterinarian knowledgeable in vaccination and transportation policies
well in advance of anticipated departure. For example, to meet the
qualifications for the minimum 30-day quarantine in Australia, a dog or
cat must be vaccinated against rabies and have blood withdrawn for a
rabies neutralizing antibody titer test (RNATT) 150 days prior to export.
All blood samples for RNATT must be sent to a laboratory approved
by the government of the destination area. If an identifying microchip
or tattoo is required, it must be in place prior to having the blood
withdrawn. In addition, the blood sample and the accompanying pa-
perwork must be labeled with the draw date and identifying microchip
or tattoo number. Currently, Hawaii regulations state that only animals
identified with AVID (Norco, CA) or Home Again (Schering Plough
Animal Health, Kenilworth, NJ) microchips are valid for entry. Australia
and New Zealand regulations require the signature of an official USDA
area veterinarian on all paperwork prior to the animal leaving the
country of export. The regulations in Hawaii, Guam, St. Kitts and Nevis,
and St. Vincent and the Grenadines require the official RNATT testing
laboratory to send the results directly to the governmental office in their
country. Some regions have special provisions for certified service dogs
that allow the dog to bypass quarantine if additional required testing,
permits and vaccinations have been completed in advance.
Two RNATT are recognized by the Office des International Epizoot-
ies (OIE),1 the World Organization for Animal Health: the rapid fluores-
cent focus inhibition test (RFFIT) and the fluorescent antibody virus
neutralization test (FAVN). In general, most rabies-free areas will accept
the results from either test; however, some areas may only accept the
results from serum tested by one methodology (Table 1). Rabies-free
areas may require more than one serologic test to be performed prior to
entry and some areas require an additional test to be performed after
the animal has arrived. The consulate of the respective rabies-free area
should be contacted for specific requirements. The RFFIT and the FAVN
are based on the same principle and have been proven to produce
similar results on duplicate serum samples.
4
Rabies virus neutralization assays measure the animal's humoral
immune response after vaccination. When an RNATT is required, the
results must be equal to or greater than 0.5 International Units of rabies
neutralizing antibody per mL of serum (IU/mL). The level of 0.5 IUI
mL was originally selected as the value at or above which inhibition of
rabies virus could not be attributed to nonspecific interference factors
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~

578 BRIGGS & SCHWEITZER

Table 2. PRE-EXPORT CHECKLIST FOR DOGS AND CATS
r
,
' .
j Contact agriculture department of export destinaH"on to obtain written requirements,
j Apply for importation permit. ..
j Permanently identify the pet with a microchip,
j Administer any necessary vaccinations,
j Conduct all necessary laboratory tests,
j Make airline reservations and obtain airline requirements,
j Make reservations at the quarantine station at destination (if necessary)
j Purchase an lATA approved animal carrier,
j Obtain an approved veterinarian's signature on all necessary paperwork, including a
health certificate,
j Treat the animal for internal and external parasites of concern,
present in some serum samples. Therefore, a rabies virus neutralizing
antibody level of 0.5 IU/ mL or greater can be attributed to the presence
of rabies virus neutralizing antibody present in the serum sample, pre-
sumably after the animal has been vaccinated. The level of rabies virus
neutralizing antibody required to protect a dog or cat from a challenge
of rabies virus has received much debate.
2

5
It is difficult to correlate
rabies neutralizing antibody titers to protection because cellular immu-
nity is also involved in successfully surviving a challenge with rabies
virus, In addition, serologic titers may fall below 0.5 IU/ ml in animals
considered to be 'current' in their rabies vaccination, Therefore, in the
United States, there is no level of rabies neutralizing antibody that is
considered 'protective.' Rabies virus neutralization assays are a valuable
tool to measure whether an animal responded to a rabies vaccination
and in some cases have identified animals that have an underlying
immunosuppressive condition that may prevent them from responding
adequately to rabies vaccines.
3
In addition to RNATI, most rabies-free areas require other assays
to be conducted, Generally, more tests are required for dogs than for
cats (i.e., Brucella canis, Ehrlichia canis, Leptospira canicola, microfilaria, and
others). Most rabies-free areas have some required treatment or test for
internal and external parasites as well. Once the date of importation is
determined by the owner, a list of tasks and timelines should be devised
(Table 2). The schedule of specific laboratory tests, vaccinations, exami-
nations, and other treatments differ for each country, and inadvertently
missing one of the target dates can delay an animal from being allowed
entry into the destination country.
SHIPPING REGULATIONS
When traveling from the mainland United States to a rabies-free
area, the fastest and most humane method to transport animals long
rMPORTAll0 TO RABIES-FREE AREAS 579
distances is by air. Unfortunately not all airports in rabies-free areas
have adequate facilities to accept animals. Therefore it is necessary to
contact the consulate of the destination country for airport customs
information. To ensure that the animal arrives safely in the destination
country, several factors should be taken into consideration prior to
booking the animal's flight.
The International Air Transport Association (lATA) Live Animals
Regulations are recognized as the world standard for transporting ani-
mals by commercial airlines. However, some countries have more strin-
gent standards than the lATA and should be contacted to clarify their
requirements for shipping live animals. Additionally, the USDA Animal
Welfare Act has instituted standards governing the shipping of animals
that could influence travel plans. There are temperature guidelines for
shipping live animals that make it difficult to ship an animal in summer
or winter. For example, the temperature in route must be between 45
and 85 degrees Fahrenheit or the airline may not accept the animal for
transport. Some airlines will accept a statement signed by a veterinarian
stating that the animal is acclimated to extreme temperatures. The breed
of the animal should also be considered prior to shipment as snub-nosed
dogs generally are intolerant to high temperatures. Additionally, the
weather at all scheduled stopovers should be investigated prior to arriv-
ing at the airport to avoid extreme temperatures en route. Recent changes
in the Federal Aviation Administration (FAA) guidelines regarding the
transportation of dangerous goods have increased security measures for
all cargo which may affect the shipment of a pet as the animal may have
to be removed from the carrier for inspection.
The lATA Live Animals Regulations include detailed information
for choosing an appropriate shipping container and for safeguarding
the welfare of the animals during the shipping process. The container
requirements mandated by the lATA are based on the species, number,
and size of the animal(s) to be shipped. The size requirement for animal
containers was carefully determined to prevent injury during travel
while still allowing the animal to travel in comfort. When a shipping
container is purchased, it should first be determined whether the pet
will be shipped as cargo in a heated and ventilated hold or whether the
pet will accompany the owner in the cabin. For small animals traveling
in the cabin, a soft carrying bag is sufficient, but a small rigid carrier
may also be used. For animals traveling in the hold, the container must
be rigid and conform to the lATA Live Animals Regulations. It must be
big enough for the animal to stand normally, tum around, and lie down.
Kennels must have the correct amount of ventilation openings for good
air circulation during all flights. Food and water dishes should be
attached to the kennel, yet accessible from the outside. Additional dry
food should be supplied. The container should be labeled "This Way
580
BRIGGS & SCHWEITZER
-,,"
.'
Up" and "Live Animal" along with the name, address: and phone
number of the owner as well as care instructions for the animal. In
addition, any medication that has/is b e i n ~ g i v e n must be recorded with
the name of the drug, route, and time of administration. Tranquilizers
are not recommended for animals traveling by air. Drugs can have
different reactions in animals at pressure above 8000 feet.
The USDA requires that no more than two live puppies or kittens,
8 weeks to 6 months in age, of comparable size, and weighing 20 pounds
or less be transported in the same primary enclosure. Anytime multiple
animals are to be shipped in the same container, the size, temperament,
and type of animals should be considered as even animals that share
the same household may become stressed and aggressive toward each
other when traveling by air. To help eliminate stress it is also advisable
to purchase the container ahead of time to allow' the animal to become
accustomed to it prior to travel. It is also a good idea to feed the animal
inside the container so that it takes 'ownership' of the space.
It is the responsibility of the shipper to make sure that all of the
required documentation has been obtained and is securely attached to
the airway bill. The shipper must provide the airline with two copies of
the Shipper's Certification for Live Animals. The number and species of
animals must also be stated on the airway bill. A current health certifi-
cate signed by a veterinarian is usually necessary. The airline that has
been chosen to transport the pet should be contacted to determine
whether they would accept the pet on the selected day and flight. The
airline must be contacted at least 48 hours in advance of departure to
ensure that there is adequate space available for the animal.
Some airlines restrict the number of animals that they carry on any
one flight. Therefore advance reservations are strongly recommended.
The length of check-in time required for the pet should be determined.
If the pet is traveling with the owner in the cabin and may become
stressed in the airport crowds, this can be kept to a minimum by
checking in as late as possible. If the animal will be traveling in the
hold, the owner should check the pet in at least 2 hours in advance, but
not more than 4 hours. The food, but not water, intake should be reduced
the day prior to travel. Dogs should be taken for a walk prior to setting
out for the airport and if possible again before checking in. This will
allow the animal to urinate and defecate prior to boarding. A light meal
2 hours prior to departure may help calm the animal, but it is unwise
to feed it a heavy meal. If the animal is being shipped as air freight, the
shipper should confirm the operating hours of the air freight facility so
that the animal may be claimed upon arrival. Weekdays are preferable
to weekends for shipping because departments are generally working at
full staff, and transfers are easier along the route.
Some airlines will not accept animals handled by anyone other than
IMPORTATION TO RABIES-FREE AREAS 581
a shipper, and therefore it may be necessary to hire an animal shipper
who can make all of the necessary reservations and take full charge of
the pet for the owner. Finally, prior to shipment, reservations at quaran-
tine facilities (if quarantine is required) should be made, and the owner
should have a clear understanding as to how and when the animal will
be transported to these facilities.
FUTURE DIRECTIONS
A new era in rabies prevention was initiated in 1992 when the
WHO Expert Committee on Rabies recommended alternate procedures
to replace lengthy quarantine periods for dogs and cats entering rabies-
free areas. Australia and New Zealand were the first countries to imple-
ment reduced quarantine procedures followed a few years later by
Hawaii and St. Kitts and Nevis. Recently, several other Caribbean islands
have or are currently evaluating reduced quarantine policies. St. Vincent
and the Grenadilles, Trinidad and Tobago are among those areas that
have recently implemented new importation regulations. St. Lucia,
Montserrat, the Cayman Islands, and the British Virgin Islands are in
the process of reviewing their importation regulations. Although the
reduced quarantine programs in these rabies-free areas are relatively
new, they have received worldwide attention and to date have been
very successful. The new quarantine programs depend on positive iden-
tification through microchips or tattoos, documented rabies vaccinations,
serologic testing, and health certificates. If the programs instituted in .
these countries continue to be successful, increased pressure will be put
on other rabies-free areas to follow their example.
In 1998 a panel of experts headed by Professor Ian Kennedy met in
Great Britain to reevaluate rabies and the quarantine regulations that
had been in place ill that country for almost a century. The experts
concluded that if dogs and cats were allowed to travel from Great Britain
to the European Union (EU), European Economic Area (EEA) member
states, or to rabies-free islands and back again, there would only be a
marginal increase in risk of reintroducing rabies. In light of these find-
ings, the Ministry of Agriculture, Fisheries and Food (MAFF) instituted
a new policy called the Pet Travel Scheme (PETS) was first implemented
early in 2000. This allows dogs and cats from approved areas in Europe
to enter Great Britain without being held in quarantine for 6 months.
Dogs and cats are required to be implanted with a microchip, vaccillated
against rabies, and have a RNATT conducted by a MAFF approved
laboratory. The owner must apply for a PETS certificate from an ap-
proved veterinarian. The PETS certificate is valid for travel to and from
Great Britain begillning 6 months after the date of the blood sample for
582 BRIGGS & SCHWEITZER
Table 3. RABIES-FREE ISLANDS ELIGIBLE FOR PETS
Antigua and Barbuda
Barbados
Falkland Islands
Guadaloupe
Japan
Mayotte
New Zealand
St. Kitts & Nevis
Vanuatu
Ascension Isl!nd
Bermuda
Fiji
Hawaii
Marinique
Montserrat
Reunion
St. Vincent
Wallis and Futuna
..
Australia
Cayman Islands
French Polynesia
Jamaica
Mauritius
New Caledonia
St. Helena
Singapore
the RNATI is withdrawn and expires on the date the animal is sched-
uled for a rabies vaccination booster (not more than a year later). An
approved veterinarian must treat the dog or cat for internal and external
parasites within 48 hours prior to travel. Using this system, eligible dogs
and cats can bypass quarantine and enter Great Britain through an
approved airline, rail, or ferry. As of January 31, 2001, dogs and cats
from certain rabies-free islands (Table 3), considered "Long Haul" areas,
were also eligible to enter Great Britain under PETS. These changes
mark some of the most radical and sweeping changes that have ever
occurred in Great Britain's quarantine laws.
The fqrecast for the future replacement of quarantine systems in
many other countries is encouraging. Certainly when rabies-free areas
relax their rigorous quarantine laws, they need to be replaced by vigilant
importation requirements. Certified laboratories and federally licensed
veterinarians need to continue to work closely with the government
officials of rabies-free areas to ensure that documentation is accurate and
that potentially rabies-infected dogs and cats are identified and pre-
vented from entering the country. Only under these circumstances will
the risk factors remain low and residents of rabies-free areas be assured
that rabies will not be introduced to their country.
References
1. Anonymous: Rabies. In OIE Manual of Standards for Diagnostic Tests and Vaccines, ed
3. Office of International des Epizooties, Paris France, 1996, pp 211-213
2. Aubert MF: Can vaccination validated by the titration of rabies antibodies in serum of
cats and dogs be an alternative to quarantine measures? Bureau Hyg Trop Med 68:R2-
R22, l993
3. Briggs OJ: Kansas State University Rabies Laboratory. Unpublished data from laboratory
submissions, 1998
4. Briggs, OJ, Smith, JS, Schweitzer K, et al: A comparison of two serological methods for
detecting the immune response after rabies vaccination in dogs and cats being exported
to rabies-free areas. Biologicals 26:347-355, 1998
IMPORTATION TO RABIES-FREE AREAS 583
5. Tizard I: Use of serologic testing to assess immune status of companion animals. J Am
Vet Med Assoc 213:54-60, 1998
6. WHO Expert Committee on Rabies, 8th report. (WHO Technical Report Series, No. 824).
World Health Organization, Geneva, Switzerland, 1992, p 41 or www.who.int / emc-
documents / rabies/docs/ wsr97/ wsr97 _al.html
Address reprint requests to
Kristen Schweitzer, BS
Kansas State University College of Veterinary Medicine
Mosier 0-247
1800 Denison Avenue
Manhattan, KS 66506-5612
e-mail: schweitz@Vet.ksu.edu
VACCINES AND VACCINATIONS
INDEX
Note: Page numbers of article titles are in boldface type.
Abscess(es), at site of vaccination, 510
Adenovirus-1, canine, vaccines containing,
481
Adenovirus-2, canine, vaccines containing,
481
Adenovirus infection, canine, 481-482
Adverse events, vaccine-associated,
493-514
Alopecia, at site of vaccination, 509
American Association of Feline
Practitioners, and Academy of
Feline Medicine, Advisory Panel on
Feline Vaccines, 455
Vaccine Panel, recommendations of,
458-461
American Veterinary Medicine
Association, 499
Council on Biologic and Therapeutic
agents, 440
Anaphylaxis, associated with vaccine
adrnllUstration,502-504
Animal shelter(s), vaccination program for,
assumptions in, 444
Darwinian approach to, 444
filtered approach to, 444
unlimited funds approach to, 444-445
Antibody titers, versus annual
vaccinations, 442-443
Antigens, selection of, 443-445
in shelter environment, 443-445
vaccine, used in dogs, duration of immu-
nity of, 488-489
Autoimmune disease, associated with
vaccination, 505
Bordetella bronchiseptica, 482
Bordetella bronchispetica infection, in cats,
466-467
clinical signs of, 468
vaccine to prevent, 468
Borreliosis, Lyme, 486-487
Calcivirus infection, feline, 457-462
vaccination against, 462
adverse events associated with,
462-463
Canine adenovirus infection, 481-482
Canine corona viral infection, 484-485
Canine distemper, 480-481
modified live virus vaccines against, 480
Canine distemper vaccines, recombinant,
480
Canine infectious tracheobronchitis, 482
vaccination against, 483
viruses causing, 482
Canine leptospirosis, 485-486
Canine parvoviral enteritis, 483-484
recovery from, vaccination following,
484
Canine parvovirus-2 vaccines, 483
duration of immunity confe+red by, 484.
recommendations for use of, 483-484
Canine vaccination, 473-492
recommendations for, revision of, 474
Cats. See also Dogs, and cats.
anaphylactic reactions in, associated
with vaccines, 503
Bordetella bronchispetica infection in, 467-
468
dermatophytosis in, 466-467
giardiasis in, 468-469
vaccination guidelines for, 455-472
vaccination of, American Association of
Feline Practitioners and Academy of
Feline Medicine on, 458-461
vaccine-associated fibrosarcoma in, 447-
448
vaccine-associated sarcomas in, 463, 493,
498, 509
vaccines and vaccinations for, 439-440
Chlamydia psittaci, 465
Chlamydiosis, clinical signs of, 465
vaccination against, 465
Coronaviral infection, canine, 484-485
vaccines for, 484
585
586 INDEX
Corona viral infection (Continued)
challenge immunity studies of, 485
Corona viruses, feline, 465
Cytotoxic hypersensitivity, associated with
vaccine administra tion, 504
Dermatophytosis; in cats, 466-467 .
Distemper, canine, 480-481
modified live virus vaccines against,
480
Distemper-measles vaccine, combined,
480-481
Dogs, anaphylactic reactions in, associated
with vaccines, 502-503
and cats, irnporta tion of, to rabies-free ar-
eas of world, 573-583
future directions in, 581-582
requirements for, 574-578
shipping regulations for, 578-581
pre-export checklist for, 578
rabies vaccines for, 490
vaccination of, 473-492
Feline calcivirus infection, 457-462
Feline coronaviruses, 465
Feline infectious peritonitis, 465
vaccination in, benefit of, 466
Feline panleukopenia, 456
Feline parvovirus, cause of, 456
vaccination against, 456
Feline vaccination guidelines, 455-472
Feline viral rhinotracheitis, 457-462
Ferrets, anaphylactic reactions in,
associated with vaccines, 503-504
Fibrosarcoma, feline vaccine-associated,
447-448
Giardia lamblia, 487
disease caused by. See Giardiasis.
Giardiasis, 487-490
diagnosis of, 468
in cats, 468-469
transmission of, 468-469
treatment of, 468
vaccine licensed for, 469
HypersensitivLy, Type I, associated with
vaccine administration, 502-504
Type II, 'associated with vaccine adminis-
tra tion, 504
Type III, associated with vaccine admin-
istration, 504-505
Immune complex-mediated
hypersensitivity, associated with
""vaccine administration, 504-505
associated with
vaccination, 505-506
Infectious peritonitis, feline, 465
vaccination in, benefit of, 466
Informed consent, veterinarian and,
518-520
International Air Transport Association
Live Animals Regulations, 579
Kennel cough, 482
Killed virus vaccine, modified-live virus
versus, 443
Leptospira vaccines, 486
Leptospirosis, canine, 485-486
Leukemia virus infection, feline,
transmission of, 464
vaccination against, 464-465
Local reactions, to vaccinations, 508-510
Lyme borreliosis, 486-487
Measles-distemper vaccine, combined,
480-481
M icrosporu m ca 11 is, 466
vaccination against, 466-467
Modified-live virus vaccine(s), for cats, 462
for dogs, 483
versus killed virus vaccine, 443
"Naked" DNA vaccines, 450-451
National Childhood Vaccine Injury Act,
498-499
Nodules, and masses, in response to
vaccination, 508
Nosodes, 452
Nucleic acid vaccines, 450-451
Pain, in response to vaccination, 508
Panleukopenia, feline, 456
Panleukopenia virus vaccine, intranasal
modified-live, 505
Parvoviral enteritis, canine, 483-484
recovery from, vaccination following,
484
Parvovirus, feline, cause of, 456
vaccination against, 456-457
Pets, exposed to rabid animals,
management of, 569
Rabid animals, pets exposed to,
management of, 569
Rabies, as preventable disease, 558
reporting of, 463
risk of, assessment of, 559-563
transmission of, 463
type of exposure to, 559-560
Rabies-free area, WHO definition of, 573
Rabies immune globulin, 564
Rabies immunizing products, allergies
and,569
for use in human beings, 563--565
human diploid cell vaccine, 564
immunosuppression and, 568
pregnancy and, 568
purified chick embryo cell culture, 564,
565
Rabies neutralizing antibody titer test, 575
Rabies postexposure prophylaxis, 557-572
circumstances of bite and, 562
cost of, 557
decision tree, 560
for domestic animals, justification for,
570-571
in previously immunized persons, 567-
568
in wild animal bites, 561-562
lack of national program concerning, 558
mortality associated with, 558
outside of United States, 567
precautions in, and contraindications to,
568-569
protocol for, 565--567
vaccination status of exposing animal
and, 562-563
Rabies vaccines, administration of, statutes
governing, 463
for dogs, 490
Reovirus, 482
Rhinotracheitis, feline viral, 457-462
vaccination against, 462
adverse events associated with,
462-463
Sarcoma(s), feline, soft-tissue, sites of, 526
vaccine-associated, 463, 493, 498, 509
client support in, 528
clinical evaluation procedures in,
527
diagnosis of, 526-528
physical examination findings in,
526-527
treatment of, 529-530
adjunctive, 531
client management in, 531
in microscopic metastatic disease,
530
prognosis in, 532-533
INDEX 587
recent advances in, 525-533
supportive, 531-532
Standard of care, veterinarian and, 517-518
Swelling, benign, in response to
vaccination, 508
Systemic reactions, to vaccinations,
501-508
Tracheobronchitis, canine infectious, 482
vaccination against, 483
viruses causing, 482
United States Department of Agriculture,
animal vaccines and, 515--517
Center for Veterinary Biologics, 511
vaccine labels and, 541, 542, 545, 547,
551, 552-553
United States Food and Drug
Administration, animal vaccines and,
515--517
United States Pharmacopeia Veterinary
Practitioners' Reporting Program, 500,
511-512
Vaccination(s), adverse events associated
with, 493-494, 501-510
reporting of, 500
against feline leukemia virus infection,
464
against feline parvovirus, 456-457
annual, 440-442
antibody titers versus, 442-443
benefits of, 494-495
canine, 473-492
health maintenance prior to, 455
local reactions to, 508-510
of cats, American Association of Feline
Practitioners and Academy of Feline
Medicine on, 458-461
overall objectives of, 456
protocols for, for companion animals,
448
response to, environmental factors influ-
encing, 449-450
risk(s) of, 496-498
postmarketing measurement of, 496-
498
prelicensing measurement of, 496
surveillance of, 496-498
site of, abscesses at, 510
alopecia at, 509
systemic reactions to, 501-508
vaccines and, 439-583
importance of, 439
588 INDEX
Vaccination(s) (Ccmtinued)
strategic issues concerning, 439-453
Vaccination guidelines, feline, 455-472
Vaccine(s), ability to respond to, factors
negatively affecting, 455
adverse event associated with, 445-447
causes of, 447
reporting criteria for, 446-447
and vaccinations, 439-583
importance of, 439
strategic issues concerning, 439-453
animal, Urtited States Department of
Agriculture and, 515-517
Urtited States Food and Drug Adminis-
tration and, 515-517
attentuated, 445, 451
canine, 473
administration of, recommended
guidelines for, 475-479
labeling of, and product inserts for,
474
canine distemper, recombinant, 480
choice of, by veterinarian, 521-522
combined distemper-measles, 480-481
contamination of, adverse events associ-
ated with, 507
core, 443
deterrrtination of, 449
efficacy measurement of, postlicensure,
495
efficacy studies of, prelicense, 494-495
federal preemption and, 517
for rabies immunization, 564-565
accidental human exposure to, 568
immunity conferred by, 480
intranasal, local reactions associated
with,510
lack efficacy of, as adverse event, 507
liability associated with, 448
modified-live virus, for cats, 462
for dogs, 483
versus killed virus vaccines, 443
multidose vials of, 448, 456
noncore, 443
over-the-counter sales of, 451-452
polyvalent, 456
annual administration of, 474
postrnarketing surveillance of, 446, 498-
499
potential risks of, options for reporting,
510-512
rabies, for dogs, 490
recombinant, 450-451
in veterinary medicine, 535-538
methods of producing, 536
new technology in, 536
Type I subunit, 537
Il gene-deleted, 537-538
lJ\\llf.1t TAM,

,
<;.
-

,.
>'
Type III vectored,638
USDA classification of, 536-537
risk assessment associated with, 448-450
safety of, 445-448
and administration of, 456-469
veterinary, postrnarketing surveillance
of,499-501
use and misuse of, potential for liabil-
ity in, 515-523
Vaccine Adverse Event Reporting System,
498-499
Vaccine antigens, used in dogs, duration of
immunity of, 488-489
Vaccine-associated adverse events, 493-514
Vaccine label, alternate route of
administration on, 551
annual revaccination recommendations
on, 550
definition of, 539-540
dose volume on, 546, 554-555
efficacy claims of, 543-546
limitations of, 548-549
minimun age of administration on, 550-
551
preservatives listed on, 547
reading of, what can be and cannot be
learned from reading, 539-556
reality of, unaerstanding of regulatory
process and, 540-542
revaccination interval and, 549-550
safety information on, 546
limitations of, 552-554
storage conditions on, 555
storage directions on, 547
trade name of product and, 543
true name of product and, 543
true name on, 547-548
US Department of Agriculture and, 541,
542,545, 540551, 552-553
use directions on, 546
user 's expectations of, 540
Vaccine manufacturer, veterinarians
reporting adverse events to, 510-511
Vaccine virulence, resid ual, 506
Veterinarians, choice of vaccines by,
521-522
informed consent and, 518-520
reporting of adverse events to vaccine
manufacturer, 510-511
standard of care and, 517-518
Warranty, and breach of, veterinary clients
and, 520-521
World Health Organization, definition of
rabies-free area of, 573
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