Introduction to smallpox: (Look at slides -pictures of smallpox)

Smallpox was caused by variola virus, a member of the genus Orthopoxvirus.

The disease is best known for the disfiguring pox marks that cover the body during
an infection. The pox are painful pus-filled blisters that are found on the face, hands
and trunk, and even in the mouth. It is to be distinguished from chicken pox, which
is caused by herpes virus, another family completely. The pox of chicken pox are
smaller, although they can sometimes be confused for SMALLPOX.

Smallpox has been eradicated by a worldwide vaccination campaign using a vaccine
that consisted of a live, supposedly harmless, virus that was closely related to
smallpox, called vaccinia. Although it was thought to the cowpox virus used by
Jenner in the 18
th
century as a prevention, after modern techniques examined the
virus in the vaccine it was found to be neither smallpox nor cowpox. It was given
the name vaccinia to commemorate the fact that it was a virus whose source was
the vaccine.

All smallpox, vaccinia and cowpox viruses are Orhtopoxviruses. This family has a
double stranded DNA genome (and mutates less often than RNA viruses). The
vaccine consists of scrapings obtained from the flanks of vaccinia-infected calves.
The virus used in the vaccine was propagated for years in the flanks of cows who
were raised to be incubators specifically for this purpose.

Even before cowpox was used as a vaccine, many cultures tried a similar strategy to
prevent smallpox by taking scrapings from the blisters of people who were infected
with smallpox itself, to inoculate an uninfected person. Apparently, scraping
smallpox virus into the skin (scarification) had fewer casualties than contracting
smallpox through the natural route, which was through respiratory droplets. And it
did provide some protection to disease although it also caused smallpox outbreaks.

When inoculation with smallpox was in vogue, bioterroism stories abounded in
which humans were used as walking vessels of the disease. During the American
Revolution, prisoners of war were inoculated by their captors (ostensibly to protect
them from smallpox) and then released to go back home where they could spread
smallpox.

So while Jenners idea might seem outrageous to us, it was a better option than the
current modality at the time, which was to use smallpox itself. Despite the fact that
inoculation with cowpox was much less harmful than smallpox inoculation, there
was still a great deal of controversy surrounding the use of live tissue derived from
animals. And it recently came to light when vaccinia was brought out of storage in
2001, in response to the anthrax bioterror attacks, that there were a fair amount of
unpleasant side effects resulting from vaccinia inoculation, since it was after all a
live virus.

The vaccine is administered unlike any vaccine we have studied.
A tiny fork with 2 prongs (the bifurcated needle) was used to poke the arm (after
dipping it in vaccine) no less than 15 times.

The vaccine was effective, and was even more effective if a booster shot was given.

In summary, 5 things made it possible to eradicate smallpox
.
a) People who had been naturally infected with smallpox were immune for life.
This indicated that an immune response once provoked, by artificial as well
as by natural means, would have a good chance of providing life long
memory. (Thus, vaccination with vaccinia had a good chance of preventing
smallpox for life).

b) Although major variants of smallpox existed, (Variola major (highly virulent)
and Variola minor (less severe), there was little variation on the virus making
it possible for essentially one vaccine to cover both variants (smallpox is a
DNA virus, not as prone to mutation as RNA viruses like flu and HIV).

c) Everyone infected with smallpox became symptomatic, making it possible to
identify the infected, and to identify their contacts so they could be
vaccinated. This made it possible to halt the chain of transmission.

d) Smallpox virus, variola, could only infect humans, so there would be no
hidden reservoirs in zoonotic or environmental sources.

e) The scar of the vaccination was noticeable, so that it people would not have
to be vaccinated more than once


Why did we stop vaccinating for smallpox in the US when we
continue to vaccinate against other diseases that we have eliminated
from the US (such as diphtheria)?

Complications of vaccination
We now appreciate that existing smallpox vaccinia vaccine has a high
incidence of adverse side-effects, some of which include death (1/million
vaccinations). The risk of adverse events is sufficiently high that
vaccination is not warranted unless a time comes when a real risk of
exposure exists. We stopped vaccinating babies in our country when we
realized there were deaths due to the vaccine when no natural cases
occurred. 1 death per million resulted from primary vaccination (first time)
and less than that (one death per four million) following revaccination.
(Owing to the fact that immunity conferred some advantage).
In 2002 when the military was vaccinated as a prophylaxis against a
smallpox attack, non fatal myopericarditis emerged as a side effect.
Coronary artery disease with some deaths, also occurred in vaccinees up
to 1 month after the vaccine was received, but it was not certain whether or
not the vaccine caused it.
Due to these risks, Vaccine administration is recommended mainly in
individuals exposed to the virus or facing a real risk of exposure (see
above).
Complications of vaccination: (See images in power point)
Four main complications are associated with vaccination, three of which
involve abnormal skin eruption. (See paper in chalk/ smallpox/readings,
adverse effects)
Generalized vaccinia
This occurred in otherwise healthy individuals. 69 days after vaccination,
a generalized rash sometimes covering the body. The prognosis was good
despite its gross appearance.
Eczema vaccinatum
occurred in vaccinated persons or unvaccinated contacts who were
suffering from or had a history of eczema. In these cases, an eruption
occurred at sites on the body that had been previously or currently affected
by eczema. These lesions became intensely inflamed and sometimes
spread to healthy skin. Symptoms were severe. The prognosis was
especially grave in infants with large areas of affected skin.
University of Chicago case
Progressive vaccinia (vaccinia necrosum)
occurred only in persons who had an immune deficiency. In these cases
the local lesion at the vaccination site failed to heal, secondary lesions
sometimes appeared elsewhere on the body, and all lesions spread
progressively until the patient died, usually 25 months later. The current
much larger pool of persons suffering from immunodeficiency due to HIV
make this side effect much more likely now.
Postvaccinial encephalitis (35% deadly)
the most serious complication occurred in two main forms. One was seen
most often in infants under 2 years of age, the other was in those over 2.
The first was characterized by violent convulsions. Recovery was often
incomplete, leading to cerebral impairment and paralysis.
The second form, had an abrupt onset, with fever, vomiting, headache,
followed by such symptoms as loss of consciousness, amnesia, confusion,
restlessness, convulsions and coma. The fatality rate was about 35%, and
occurred rapidly, usually occurring within a week.
A 1968 study:
The best estimates of the frequency of these complications came from a
study in 1968 conducted by the United States involving over 14 million
vaccinated persons. Altogether nine deaths occurred.
In the most common adverse effect, Eczema vaccinatum (EV), there were
74 cases and no deaths. But 60 additional cases of EV occurred in
contacts of vaccinated persons, with one death.
Generalized vaccinia occurred in 143 cases, with no deaths.
Progressive vaccinia occurred in 11 persons, with 4 deaths.
Encephalitis was observed in 16 persons, with 4 deaths.
It was estimated that approximately one death per million resulted from
complications following primary vaccination and one death per four million
following revaccination.
Since no new cases of smallpox, occurred and there more deaths due to
the vaccine than the disease it became undesirable to use the vaccine. so
in 1972 immunization stopped in many countries, including the US.

In 1979, eradication was successful and the WHO could recommend that
routine vaccination against smallpox be stopped in all countries, except for
researchers working with smallpox and related viruses.

By 1986, routine vaccination had ceased in all countries.

A safer vaccinia-based vaccine, produced in cell culture, is expected to
become available shortly. There is also interest in developing a
monoclonal anti-variola antibody that could be used in passive
immunization of exposed and infected individuals, which could also be
administered to persons infected with HIV. Why worry about exposure if it
is eradicated?