Clinical Infectious Diseases Advance Access published March 13, 2013

MAJOR ARTICLE

Reduced Risk of Pertussis Among Persons Ever

Vaccinated With Whole Cell Pertussis Vaccine
Compared to Recipients of Acellular Pertussis
Vaccines in a Large US Cohort
Maxwell A. Witt,1 Larry Arias,1 Paul H. Katz,2 Elizabeth T. Truong,1 and David J. Witt1
Departments of 1Infectious Diseases and 2Pediatrics, Kaiser Permanente Medical Center, San Rafael, California

Keywords.

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Background. Unexpected waning of immunity after pertussis vaccination is now well described. In this study
we examined whether prior vaccination with whole-cell pertussis vaccine (wP) at any point provided superior
protection contrasted with a solely acellular pertussis vaccine (aP) series. We utilized the coincidence of a large
outbreak of pertussis with the termination of wP availability, providing populations of children who had been
vaccinated with combinations of wP and aP.
Methods. Kaiser Permanente (KP) is an integrated healthcare system with complete electronic records and a
centralized laboratory. Cases of laboratory-conrmed pertussis and vaccination data for members aged 820 years
were retrieved.
Results. Among 263 496 persons aged 820 years, 904 cases of pertussis were identied. In patients with a full
history of vaccinations administered by KP, those with 5 total doses of only aP had an 8.57 relative risk (RR) of
pertussis (P < .0001) contrasted to those with 1 wP dose. With 6 doses of aP, the RR of disease was 3.55
(P < .0001). When external vaccine records were included, the results were similar.
Conclusions. We found a markedly increased risk of disease associated with an entirely aP series. This risk
was mitigated, but not eliminated, by the presence of a sixth dose of pertussis vaccine (Tdap). Receipt of 1 or
more wP doses markedly augmented the durability of immunity from subsequent aP doses. It appears that a
wholly acellular pertussis vaccine series is signicantly less effective and durable than one that contains the traditional whole cell vaccine.
pertussis vaccine; whole cell pertussis vaccine; acellular pertussis vaccine; Bordetella pertussis.

We recently reported an unexpected waning immunity

to pertussis vaccination among older preadolescents [1].
There have been prior suggestions that the efcacy of
the acellular pertussis (aP) vaccine may not be as
robust as reported in these initial studies [24]. The unexpectedly high attack rate in this age group has now

Received 16 September 2012; accepted 23 January 2013.

Correspondence: David J. Witt, MD, Department of Infectious Diseases, Kaiser
Permanente Medical Center, 99 Montecillo Rd, San Rafael, CA 94903 (david.j.
witt@kp.org).
Clinical Infectious Diseases
The Author 2013. Published by Oxford University Press on behalf of the Infectious
Diseases Society of America. All rights reserved. For Permissions, please e-mail:
journals.permissions@oup.com.
DOI: 10.1093/cid/cit046

been conrmed during outbreaks in the states of Washington, Wisconsin, and Minnesota as well as in the
United Kingdom [58]. Possible reasons for apparent
decreased efcacy of aP have been proposed, including
observer bias in initial trials; reduced antigenic stimulation in aP; and even mutation of Bordetella pertussis [9].
Acellular pertussis vaccines were introduced in the
United States in 1991 for use as a booster, but not
until 1997 were they recommended for use in primary
vaccination. When contrasted with whole cell pertussis
(wP) vaccine, these vaccines have been assumed to be
comparably efcacious while having markedly reduced
adverse reactions [10]. For this reason, the acellular
vaccine is now the sole pertussis vaccine used in the
United States. Efcacy for the aP vaccine has been

Whole Cell Pertussis Vaccine Superiority

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METHODS
Approval for the study was obtained from the Institutional
Review Board of the Kaiser Foundation Research Institute
(Oakland, California). Kaiser Permanente is an integrated
healthcare system with its own laboratories, hospitals, and
clinics, and uses an electronic medical record. This structure
permits review of all laboratory results, hospitalizations, and
outpatient visits in Northern California. Kaiser Permanente in
Northern California is the primary source of care for 3.4
million persons.
Nasopharyngeal specimens for pertussis testing were obtained using a BD BBL Culture swab with liquid Stuart media
(catalog number 220133; Becton, Dickinson and Co, Franklin
Lakes, New Jersey) and sent for centralized laboratory testing.
Real-time polymerase chain reaction (PCR; Cepheid Corporation, Sunnyvale, California) analysis is the basis of all pertussis
testing, with required concomitant testing for both Bordetella
pertussis and Bordetella parapertussis performed using the
Cepheid GeneXpert platform, which amplies IS481 or IS1001
for detection of B. pertussis or B. parapertussis, respectively.
Vaccines used since 2002 included Infanrix, Pediarix, and
Boostrix (GlaxoSmithKline, Research Triangle Park, North
Carolina) and Daptacel, Pentacel, and Adacel (Sano Pasteur,
Bridgewater, New Jersey).
Because aP was introduced in 1991 and wP was retired
from use in the United States in 2001 and at Kaiser in 1999,

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Witt et al

we selected patients born during the years 19902001. This

population was old enough to have received wP vaccine and
young enough to have received aP vaccine. We parsed the data
to compare rates of disease in patients with specic vaccination histories.
Cases were dened as the presence of a positive PCR test
for B. pertussis and a negative PCR test for B. parapertussis.
Data were obtained for active members aged 820 years as
of 15 May 2010, a date at the peak of the California pertussis epidemic. Records on all pertussis vaccines administered
were obtained and entered into IBM SPSS (IBM, Armonk,
New York) statistics for analysis. Vaccination type, the number of doses of each (wP or aP), and the origin of vaccine documentation (administration documented within the Kaiser
Permanente system or entered from outside records) was retrieved. Cross-tabulated SPSS output data was entered into
Microsoft Excel (Microsoft, Redmond, Washington) for
further analysis.
In one analysis, members were included if they were 820
years of age as of 15 May 2010 or if they had a positive PCR
test result from 1 January 2006 to 15 November 2011 and had
received 5 or 6 doses of pertussis vaccine administered by
Kaiser Permanente at the time of disease. For a second analysis, inclusion criteria were broadened to include those who
had received 1 or more pertussis vaccine doses at Kaiser Permanente, and at least 5 or 6 total vaccine doses, including vaccinations administered outside the Kaiser Permanente system,
recorded in the Kaiser Permanente vaccine database. To be
considered as having received a dose of wP, doses of wP must
have been administered at Kaiser Permanente.
RESULTS
Of a total population of 3.2 million members, there were
263 496 persons aged 820 years. Among this population, 904
cases of pertussis were identied. In patients with a full
history of vaccinations administered by Kaiser Permanente,
the results were as follows and are detailed in Table 1. For
those with 5 doses of pertussis vaccine, having had no doses
of whole cell vaccine was associated with an 8.57 relative risk
of pertussis (P < .0001) when compared to those who had received 1 or more dose of whole cell vaccine. For those with 6
doses, those who received only acellular vaccine had a 3.55
relative risk of disease (P < .0001) contrasted to those with a
history of whole cell vaccines. In the combined 5- and 6-dose
groups, those who received only acellular vaccines had a 5.47
relative risk of disease compared to those with 1 or more
whole cell dose (P = .001).
In patients with at least 1 pertussis vaccine administered by
Kaiser Permanente, the results were similar but slightly attenuated when contrasted with those who received all vaccines

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reported as between 84% and 85% for children and 92% for
adolescents and adults [10, 11].
In our initial study, there was a notable absence of disease
in adolescents [1]. In the recent outbreaks in Washington,
Wisconsin, and Minnesota, there also was a falloff in disease
among those >13 years of age. We had also noted a trend toward higher rates of pertussis among children who had never
received prior whole cell vaccine; however, the number of
cases in this category was too limited to make conclusions [12].
Sheridan and colleagues examined their ndings in Australia
and suggested that receiving prior whole cell vaccination may
explain an enhanced durability of immune response among
older children [13]. With the unique converging opportunities presented by a pertussis outbreak in a well-vaccinated
population and a changeover in vaccine recommendations
with overlapping populations of children who had received
either some or no wP, we sought to examine the effect of prior
whole cell vaccination on the pertussis attack rate. We used
our large integrated healthcare system with combined laboratory and clinical systems, an electronic medical record, and
well-documented records of vaccinations administered to accurately ascertain rates of clinical pertussis and its relation to
prior vaccination regimens.

5.74
99.3
434.5
14 106
49 601

300.4
106.3

35 495

15
149

377.5

Members

134

12
261
wP 1 or more
Combined

13 084
44 760

91.7
583.1

8.57
786.1
31 676
249
aP only

Abbreviations: aP, acellular pertussis vaccine; AR per 105, attack rate per 100 000 population; wP, whole cell pertussis vaccine.

570.2
67 171

Members

27 190
94 361
27
410

383
3.55

Relative Risk
aP Only/wP
1 Dose
AR per
105
Vaccine
Received

Pertussis
Cases Members

AR per
105

Relative Risk
aP Only/wP
1 Dose

Pertussis
Cases

AR per
105

Relative Risk
aP Only/wP
1 Dose

Pertussis
Cases

5 or More Doses
6 Total Doses
5 Total Doses

Table 1. Pertussis Vaccine Doses and Clinical Pertussis in Patients With a Full Kaiser Permanente Record

DISCUSSION
Pertussis remains one of the most prevalent vaccine-preventable diseases in the developed world [12]. Despite widespread
childhood vaccination and a greatly reduced incidence, there
are still many cases, with outbreaks peaking every 25 years [14].
It has been suggested that aP vaccine may have reduced efcacy when contrasted with wP vaccine [2, 15]. It has also been
suggested that the aP vaccine may have a reduced durability of
immunity, and no vaccine trial has examined immunity from
these vaccines beyond 22 months [10].
In a prior study, we found lower than expected durability of
protection from disease by the primary 5-dose series of aP
vaccine. This suggests that pertussis vaccine, administered according to the current guidelines, may not adequately protect
the preadolescent and early adolescent populations [1]. It was
notable that the attack rate of pertussis during the outbreak in
California in 2010 was markedly less in adolescents, whether
or not they had received the Tdap booster. This would temporally correlate to the introduction of the aP vaccine in 1991,
which had completely supplanted vaccination with wP vaccine
in the United States by 2001. Thus, all children born after
2001 would have had only aP vaccine, whereas those born in
the preceding 10 years may have had some combination of the
2 vaccine types. This period of overlapping vaccine practices
provided an opportunity to examine relative effectiveness of

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within the Kaiser Permanente system. These results are detailed in Table 2. For those with 5 doses of pertussis vaccine,
having had no doses of whole cell vaccine was associated with
a 6.76 relative risk when compared to those with 1 or more
doses of whole cell vaccine (P < .0001). For those with 6 doses,
those who received only acellular vaccine had a 2.46 relative
risk compared to those with a history of whole cell vaccines
(P = .0002). In the combined 5- and 6-dose groups, those who
received only acellular vaccines had a 3.81 relative risk of
disease, contrasted to those who had received 1 or more whole
cell doses (P < .0001).
In those who received 5 total doses of vaccine, the mean
interval from last vaccination, among cases, was 14.7 (SD,
3.23) and 5.65 (SD, 0.24) years for wP and aP, respectively.
For those receiving 6 total doses, the interval was 3.07 (SD,
2.28) and 1.54 (SD, 0.47) years, for wP and aP, respectively.
(Figure 1)
The type of vaccine received and the distribution of conrmed cases of pertussis are presented by age in Table 3. This
table shows the near complete substitution of acellular pertussis vaccine as a primary vaccine series once available and recommended in this role in 1997 and demonstrates the reduced
rate of cases among those who have received the whole cell
vaccine.

Witt et al

671.0
58 581
393
Combined

Abbreviations: aP, acellular pertussis vaccine; AR per 105, attack rate per 100 000 population; KP, Kaiser Permanente; wP, whole cell pertussis vaccine.

176 069
149

117 488

231.5

665

377.7

3.81
115.1
33 005
38

438.3
143 064
627

103.3

2.46
100 068

17 420
18

254
6.76
867.5

128.3
15 565

42 996
373

20
wP 1 dose documented in
system,
administered by KP

aP only

Vaccine Received

253.8

Pertussis
Cases
Pertussis
AR per
Cases Members 105

Relative Risk
aP Only/wP
1 Dose

Pertussis
Cases

AR per
Members 105

Relative Risk
aP Only/wP
1 Dose

AR per
Members 105

Relative Risk
aP Only/wP
1 Dose

6 Total Doses

5 or More Total Doses

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5 Total Doses

Table 2. Pertussis Vaccine Doses and Clinical Pertussis, At Least 1 Kaiser Permanente Administered Vaccine Dose in the System

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these 2 vaccines among persons born during this time period.

The pertussis outbreak of 2010 permitted examining the relative effectiveness during a high-density exposure.
Our current results conrm a profoundly enhanced protection from pertussis for all persons who had ever received a
dose of wP vaccine, when contrasted with those who had received only aP. This effect persisted for years, demonstrated by
an enhanced effectiveness of Tdap in those who had received
wP vaccine as part of their primary series of pertussis vaccination. Increased efcacy of wP vaccine, contrasted with aP
vaccine, has been previously suggested [2]. Reasons for this
may include variations in antigenic composition of vaccine,
blocking effects of antibody to some vaccine antigens, and
even genetic changes in circulating B. pertussis strains [14].
We have also identied that this increased effectiveness
extends to enhancing the effectiveness of subsequent vaccination with aP.
We found a markedly increased risk of disease associated
with an entirely acellular pertussis vaccine series. This risk was
mitigated, but not eliminated, by the presence of a sixth dose
of pertussis vaccine (Tdap). It appears that a solely acellular
pertussis vaccine series is signicantly less effective and
durable than one that contains the traditional whole cell
vaccine.
It was necessary to calculate a relative risk of pertussis contrasting those who had received wP vaccine and those who
had not. Actual vaccine effectiveness (VE) could not be reliably calculated, as VE requires contrasting vaccinated groups
with unvaccinated groups [16]. While those who are vaccinated within the Kaiser Permanente system have clear records
with perfect ascertainment of vaccination status, those with no
vaccinations recorded or vaccinations outside of the Kaiser
Permanente system included persons who had never accessed
care, never had a primary care appointment, or could not
provide documentation of prior vaccination. This apparently
totally unvaccinated group is quite small and may, in fact, be
composed of enough vaccinated persons who do not have vaccination documented to make this group unworkable as a
comparison group for the wholly vaccinated and completely
documented groups in the calculation of VE. For this reason
we examined only persons with recorded vaccination records.
Undervaccinated persons and unvaccinated persons were thus
excluded from analysis as well, for the same reasons.
Most studies of clinical pertussis have been based on
passive reporting to health departments, lack dened population denominators, and have potential selection bias in testing
rates or methods. Our study examines a stable, dened population with well-documented vaccination histories, a welldened rate of disease, and uniformly documented laboratory
testing. The high percentage of persons in our community
who obtain their care solely from our medical centers provides

Mean time since last dose of vaccine among cases, with 95% condence interval shown.

an ideal opportunity to examine a population. Reporting bias

in our data is markedly reduced by the structurally complete
capture of patient data. The documentation of prior vaccinations permitted accurate ascertainment of vaccination status.
There were limitations to our study. It was retrospective.
Prior vaccination results in a shorter, less severe illness, which
may have contributed to minor cases being missed, leading to
an underestimation of the pertussis incidence [17]. Pertussis
testing was at the discretion of the clinician, permitting some
degree of selection bias. PCR testing was not conrmed by
concomitant bacterial culture in our study; however, PCR testing has generally been demonstrated to be highly specic [18].
Difculty discriminating certain strains of Bordetella holmesii
or Bordetella bronchiseptica from B. pertussis and B. parapertussis has been recognized [19]. B. holmesii was unlikely to have
been present in our population, as there were no specimens
positive for both B. pertussis and B. parapertussis. Amplication of both sequences (IS481 and IS1001) would have been
expected if B. holmesii were present, as this organism contains
both of these sequences in its genome [19, K. Harriman,
written communication, September 2011]. In addition, among
cases reported to the California Department of Public Health,
there were no isolates of either B. holmesii or B. bronchiseptica,
and B. bronchiseptica rarely causes disease in immunocompetent individuals [K. Harriman, written communication, September 2011, 20].

Even if the un- and undervaccinated groups could be accurately identied from our database, we would still have limitations in the inability to calculate actual VE because we are not
utilizing a single vaccine in the vaccine series, as would be theoretically required for a VE calculation [16]. We believe that
this limitation is of limited signicance if one examines the
pertussis vaccine as a complete series of vaccines. Because
there has not been, and likely never will be, a long-term study
of aP vaccine, wP vaccine, or a combination of the 2, in our
opinion this approximation is as accurate an evaluation of the
effectiveness of these vaccines as will ever be achieved. It is
also worth noting that the vaccine schedule for aP was
adapted to that of the traditional wP schedule, but had not
been studied for the complete 5-dose series, and that for the
later doses, often the initial vaccine doses had been wP [21].
The effect of the force of illness must also be considered.
Higher exposure rates would be expected to lead to higher
rates of disease. Although this might have contributed to an
amplication of the attack rate we observed in preadolescent
children, the low rate of disease in both younger children and
particularly in older teens, who had the longest interval from
prior vaccination, remains highly signicant. This distribution
of cases, with the preadolescent peak visible, is shown in
Table 3. Preadolescent peaks similar to the one we identied are
observed in the current outbreaks worldwide [5, 6, 7, 8, 22].
Observations of increasing rates of pertussis in preteens and

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Figure 1.

Table 3.

Type and Number of Pertussis Vaccine Doses and Clinical Pertussis, by Age
No. of Doses
Type of Vaccine Received
5

Acellular Only

6
1 Whole
Cell Dose
Documented

5 or 6
1 Whole
Cell Dose
Documented

Acellular Only

Acellular Only

1 Whole
Cell Dose
Documented

5 or 6, Any Type

Age, y Case Population Case Population Case Population Case Population Case Population Case Population Case Population
54

20 623

43

1110

58

21 733

50

58

21 783

9
10

60
57

15 339
5753

0
0

26
39

8
55

5695
15 375

0
2

16
69

68
112

21 034
21 128

0
2

42
108

68
114

21 076
21 236

11

26

3546

32

71

17 893

123

97

21 439

155

97

21 594

12
13

20
5

3122
2566

0
2

33
33

51
26

16 627
8929

0
1

101
105

71
31

19 749
11 495

0
3

134
138

71
34

19 883
11 633

14

1888

36

10

6557

116

16

8445

152

24

8597

15
16

1
5

2136
2030

0
1

827
172

5
6

6823
6247

2
4

485
232

6
11

8959
8277

2
5

1312
404

8
16

10 271
8681

17

1966

3448

5546

2706

11

7512

6154

17

13 666

18
19

0
1

1762
1634

3
0

4679
3527

3
0

4727
3665

0
0

6146
4344

3
1

6489
5299

3
0

10 825
7871

6
1

17 314
13 170

20

1065

2726

1973

2976

3038

5702

8740

Individuals were included if they had at least 1 vaccine documented as being administered at Kaiser Permanente.

adolescents in the era prior to aP still demonstrated the predominance of infection in infants and the youngest children,
with a smoothly decreasing rate associated with age. There
clearly has never previously been a peak of infection in the
preadolescent group [23]. The fact that the vast bulk of these
infections occurred in fully vaccinated children only emphasizes the limited durability of immunity in this group, the rst
vaccinated solely with acellular vaccine. The low rate of pertussis in the older teens reects the patterns observed in the
era prior to aP. Our ndings of higher effectiveness of wP
primary vaccination, including augmentation of effectiveness
of subsequent aP boosters, contributes to herd immunity in
this age group and thus force of infection was lower, reective
of this enhanced immunity.
In summary, we have conrmed a decreased protection
from aP vaccine when contrasted with wP vaccine. We also
identied a long-term enhancement of protection from aP in
those who have ever received prior wP as part of their primary
series. The implications of these ndings are signicant. The
current generation of children is the rst generation to have
been vaccinated solely with aP. Waning immunity is even
more severe if they have never received wP. It is of note that
widespread pertussis outbreaks have been occurring in the
United States for the last 3 years. The peak attack rates are
among those who are in this exact groupthose solely

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Witt et al

vaccinated with aP. Younger children are protected by the

more frequent doses of aP administered to this age group, but
immunity has limited durability [1]. This nding of waning
immunity associated with ongoing outbreaks of pertussis
argues for earlier booster doses of aP vaccine, on a routine
basis and particularly in an outbreak setting, and clearly is a
call for development of more effective and durable pertussis
vaccines.
Note
Potential conicts of interest. All authors: No reported conicts.
All authors have submitted the ICMJE Form for Disclosure of Potential
Conicts of Interest. Conicts that the editors consider relevant to the
content of the manuscript have been disclosed.

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