TABLE OF CONTENTS
- Real Risks of
- Daniel J. DeNoon
- Medscape Medical News
December 12, 2002
Public Inquiries Hotline (Centers for Disease Control and Prevention):
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Shot in the Dark
By Henry I. Miller
The Scientist 16:64, Jan.
Sixty percent of Americans would opt for smallpox
immunization if the vaccine were available, according to
a recent poll, and U.S. health officials have just
negotiated the purchase of enough vaccine for everyone
in the United States. Those two facts may be a
prescription for bad medicine.
Medically and epidemiologically, smallpox is the most
feared and potentially devastating of all infectious
agents. It spreads from person to person, primarily via
droplets coughed up by infected persons, via direct
contact, and from contaminated clothing and bed linens.
Smallpox is fatal in approximately a third of previously
unvaccinated persons who contract the disease.
For weeks, the media have raised the specter of
terrorists using smallpox virus as a weapon. The German
government has bought six million doses of vaccine, and
pressure is mounting in the United States for
widespread, or even universal, vaccination. (Routine
smallpox vaccinations ceased in this country in 1972.)
The U.S. government has ordered 300 million doses of the
vaccine, and at a recent hearing, U.S. Sen. Arlen
Specter (R-Pa.) said it is just "common sense"
to make it available to everyone who wants it.
But is it really? The live vaccine consists of live
vaccinia virus, which is closely related to smallpox
virus. Impure and crude by the modern standards of
recombinant DNA-derived, or gene-spliced, vaccines such
as those that have been successfully deployed against
hepatitis B since the 1980s, the smallpox vaccine is not
very different from the one introduced by the English
physician Edward Jenner in the 18th century. It can
provoke various serious side effects, including rashes;
spreading from the inoculation site to face, eyelid,
mouth or genitalia; and generalized infection. Approximately
one in every 300,000 vaccinations causes encephalitis,
which can lead to permanent neurological damage; and
between one and three in every million die. Thus,
vaccinating the entire population would be expected to
kill as many as a thousand Americans, and maim and
disfigure many others. Moreover, that assumes that the
newer, ostensibly incrementally improved versions of the
vaccinia vaccine are no less safe: Federal regulators
have been uncharacteristically lax about requiring
evidence of safety and efficacy in a drug intended for
If the re-emergence of smallpox were likely,
vaccination would be appropriate. However, smallpox
virus no longer occurs in nature but is limited to two
known, legitimate repositories, one in the United
States, the other in Russia (and perhaps to illegitimate
ones in several other countries). It is, therefore, very
difficult to obtain, and also to cultivate and
Also, smallpox is not immediately contagious after
infection. It can be transmitted from one person to
another only after a one- to two-week incubation period
and the appearance of the characteristic rash, by which
time the victim is prostrate, bedridden, and probably
hospitalized. Therefore, the much-publicized scenario in
which suicide terrorists infect themselves and then
spread the disease widely through the population is not
a realistic one. And although universal smallpox
vaccination was phased out throughout the world during
the 1970s, individuals who were vaccinated prior to that
time retain significant immunity from these
immunizations, both against contracting the disease and
against a fatal outcome in case of infection. Scientists
know a great deal about the long-term retention of
immunity from a landmark study of 1163 smallpox cases in
Liverpool in 1902-1903. Among those infected, 7% of the
people 50 or older who had received the vaccine as
children experienced severe disease and death, while 26%
of unvaccinated people in that age group contracted
serious cases of smallpox and all died.
Even if an outbreak were to occur, public health
authorities know how to respond. Control depends on
early detection, quarantine of infected individuals,
surveillance of contacts, and focused, aggressive
vaccination of all possible contacts—an approach
dubbed "quarantine-ring vaccination."
Approximately 15 million doses of smallpox vaccine are
available in the United States, and data suggest that
these would still be effective if diluted fivefold, to
yield 75 million.
Moreover, the federal government has taken steps to
cope with the possibility of a terrorist attack
involving smallpox by educating doctors to recognize the
disease and by vaccinating small teams of experts who
can rush to any part of the country to confirm the
diagnosis and contain and treat an outbreak. The city of
New York has begun to map out various locations where
residents would go to be immunized should mass
vaccinations be necessary.
In summary, given the
difficulty of estimating the risks and benefits of
vaccinating against a nonexistent disease using a
vaccine that carries known, serious, sometimes-lethal
side effects, one must agree with the conclusion of
David Busch, head of infectious diseases at California
Pacific Medical Center in San Francisco. "It's
inappropriate" to vaccinate the entire country for
a disease whose threat is only theoretical, and
immunization should only be given "as needed, not
If federal officials act otherwise, they will be more
in the realm of public relations than public health.
Even the expenditure of upwards of a billion dollars to
stockpile 300 million doses of smallpox vaccine is
arguably in the category of political cover. Far better,
surely, to use those resources to ensure that
susceptible Americans are immunized against common and
life-threatening infectious diseases such as influenza,
hepatitis, and pneumococcal pneumonia. (Flu alone kills
20,000 in an average year.)
Sherlock Holmes admonished in A Scandal in Bohemia
that "it is a capital mistake to theorize before
one has data." It is worse to make the wrong
decision after one has data.
Henry I. Miller (email@example.com),
MD, is a fellow at the Hoover Institution and the author
(Hoover Institution Press).
Limits Smallpox Vaccine
Injured by Smallpox Vaccine Won't Qualify for Compensation
The Associated Press
WASHINGTON Dec. 15
Some people who may be injured by the smallpox vaccine
will not qualify for compensation under current law,
health officials said Saturday.
Health and Human Services Secretary Tommy Thompson said
he is open to discussing a compensation fund like the one
that aids people hurt by other vaccines, but he said there
is no legislation drafted and none is imminent.
The smallpox vaccine, which is being recommended for
some 10 million Americans, is more dangerous than any
other given in this country. It has rare but serious side
effects, and history suggests that one or two people out
of every million being vaccinated for the first time will
A provision in the Homeland Security Act bars most
lawsuits related to smallpox vaccinations. People who are
injured may sue in federal court, but they would have to
prove negligence. Given that the vaccine is inherently
dangerous, that would be very difficult.
People who get the shot through their jobs could make
claims through workers' compensation and get reimbursed
for health expenses and time lost from work, officials
But people who get sick by coming into contact with
someone who was inoculated have no real option, officials
The vaccine is made of a live virus that can cause
infections until the injection site scabs over. A
vaccinated person can spread the virus by touching the
injection site, then touching someone else. That person
would not qualify for workers' compensation.
"We do recognize that there may be gaps in the
compensation," said Dr. Julie Gerberding, director of
the Centers for Disease Control and Prevention. "We
are going to identify those gaps and look at options for
December 12, 2002
New York youngster is immunized against polio, 1955.
A New York youngster is
immunized against polio, 1955. Photo by Ernie Sisto.
people who are vaccinated against smallpox can expect to
have a very sore, swollen arm within a week or so. Many
also run fevers and ache all over as if they have the
flu, and studies have indicated that 20 percent to 30
percent feel sick enough to miss a few days of work or
More serious complications are possible. For every
million people vaccinated, 15 suffer life-threatening
complications like encephalitis, and 1 or 2 of the 15
die. Hundreds of others suffer serious skin rashes,
infections and other problems, based on studies done
before 1972, when the vaccination was routine in the
As vaccination resumes, an essential concern will be
to identify people who should not be vaccinated because
they are at high risk of being harmed.
Vulnerable people must also avoid close contact with
those who have recently been vaccinated and who are
likely to be shedding live viruses that can infect
others with the vaccinia virus, the virus used to make
the vaccine. The smallpox vaccine does not contain the
Special semi-permeable bandages may help prevent
newly vaccinated people from transmitting vaccinia to
others, but the bandages have to be worn for several
People with certain medical problems are vulnerable
because the vaccinia can multiply too much in them.
Their immune systems cannot control it. People at risk
include those with the skin rashes like eczema or atopic
dermatitis, or even a history of those conditions — a
category that includes about 15 million Americans.
The two skin problems are more common today than they
were when smallpox vaccination was routine.
People with those disorders are at risk for a
condition called eczema vaccinatum, which can cause high
fever and severe sores, scabs and deep scars. Although
only a minority of people with the skin disorders
develop serious problems, there is no way to identify
which of them are at risk.
Eczema vaccinatum can be countered with a medicine,
vaccinia immune globulin, but it is in short supply,
with only a few thousand doses available.
Also vulnerable are people whose immune systems have
been weakened by AIDS or certain cancers, or by
radiation, chemotherapy, steroids or drugs used to
prevent transplant rejection.
People with autoimmune diseases like lupus or
rheumatoid arthritis are also included in this group.
They are prone to an illness called progressive vaccinia,
in which the sore that normally forms at the vaccination
site expands abnormally, growing larger and larger,
causing tissue death and a systemic infection that may
There is no treatment for progressive vaccinia, and
its death rate can be as high as 36 percent.
Doctors say that people with H.I.V. or AIDS, totaling
about 506,000 in the United States, should not be
vaccinated. But the Centers for Disease Control and
Prevention estimates that 300,000 Americans are infected
with H.I.V. and do not know it. In addition, more than
24,000 health care workers have AIDS.
There is little medical information about how people
with AIDS or H.I.V. would react to the vaccine, because
those diseases were unknown in the era of routine
vaccination. One article, published in The New England
Journal of Medicine, described how a 19-year-old soldier
had undiagnosed H.I.V., the virus that causes AIDS, when
the military vaccinated him in 1984. He developed
progressive vaccinia and AIDS, and died.
Pregnant women are also advised to avoid smallpox
vaccination until after they have given birth, unless
they have been exposed to smallpox. Babies should also
not be vaccinated until they are at least a year old.
Risks of Smallpox Debated
Daniel J. DeNoon
Medscape Medical News
Dec. 19, 2002 — The real risks from smallpox are
addressed in several reports released online early today,
to be published in the Jan. 30, 2003, issue of the New
England Journal of Medicine (NEJM).
The messages of the reports can be summarized as:
- Justifying mass smallpox vaccination is difficult
without evidence of an impending bioterrorist attack.
- The great majority of Americans do not know basic
- The decades-old smallpox vaccine now in the U.S.
stockpile is not as safe as modern vaccines. But the
risk of spreading the live virus from the vaccine to
unvaccinated people has been greatly exaggerated.
- There hasn't been a case of smallpox anywhere in the
world for 25 years.
Risk of Smallpox Bioterrorism
A smallpox attack on an unvaccinated U.S. public would
be "catastrophic," according to D. A. Henderson,
MD, MPH, Johns Hopkins University distinguished service
professor and senior science advisor to the secretary of
the Department of Health and Human Services. Dr.
Henderson's standing — he was a leading force in the
global eradication of smallpox — convinces some
bioterrorism experts that a smallpox attack is a
Others are not so sure. One is Kent A. Sepkowitz, MD,
director of infection control at Memorial Sloan Kettering
Cancer Center and associate professor of medicine at Weill
Medical College, Cornel University, New York.
"Remember Y2K. This is a comparable
nonevent," Dr. Sepkowitz told Medscape.
Another is Thomas Mack, MD, MPH, professor of
preventive medicine at Keck School of Medicine, University
of Southern California, Los Angeles. Like Dr. Henderson,
Dr. Mack is a veteran of the world war on smallpox. He led
teams that investigated some 100 smallpox outbreaks. His NEJM
Sounding Board article argues that smallpox is overrated
as a bioterrorist weapon.
"A smallpox attack is not a worst-case bioterror
scenario," Dr. Mack told Medscape. "People
greatly exaggerate the danger to the population not
directly affected. They picture smallpox being transmitted
like wildfire, and that doesn't actually happen. It is
more like a grenade than like a dirty bomb. Once the
initial wave of infections is over, mopping up is
Unlike many other diseases, people with smallpox can't
infect other people until they start to feel ill — a
couple of weeks after infection. And if people know
they've been exposed, getting vaccinated within a few days
often can keep them from getting sick. Both these facts
mean that health workers have time to stop a smallpox
epidemic before it gets out of hand.
"Suppose the worst case: the aerosolization of
live smallpox virus applied to a substantial population,
say into a shopping center," Dr. Mack said.
"Maybe if there was some way to keep it in the air,
then, yes, under very extreme circumstances you could
infect a large number of people. But the average number of
people they infect is not going to change [from
what we've seen in natural epidemics]. They don't get
smallpox from weaponized virus any more, but from
somebody's mouth. If they are put in hospitals, they will
be dangerous. But once a first case appears, every
community will find a place to put people away from the
general hospital population."
Another NEJM article calculates the risks from
various smallpox-attack scenarios. It considers a range of
smallpox outbreaks ranging from an accidental laboratory
release to a major bioterrorist attack on a large airport.
The researchers found that even a worst-case scenario does
not justify mass public vaccination before there is an
Samuel A. Bozzette, MD, PhD, is senior scientist for
RAND Health Care and the Veterans Affairs San Diego
Healthcare System. Dr. Bozzette and colleagues estimate
that a large airport smallpox attack could kill more than
40,000 people if the public wasn't vaccinated. It would
kill nearly 13,000 people if the public were vaccinated
beforehand. All these deaths would happen only in a
"what if" scenario; nobody really knows whether
such smallpox weapons even exist. But vaccination against
smallpox would result in nearly 500 very real deaths.
"The main issues are that smallpox isn't an
instant killer, and that there is a lot of vaccine on
hand," Dr. Bozzette told Medscape. "If there is
an attack, there will be time to carry out a widespread
The study finds that advance vaccination of healthcare
workers is worthwhile -- but mass public vaccination is
not. So would Dr. Bozzette get the smallpox vaccine? What
about his family?
"I think we can look to the example of what the
President is doing with his family as what an informed
judgment might look like," Dr. Bozzette said. "I
am an infectious-disease specialist; I am going to be
vaccinated. My wife is a pathologist; she is going to be
vaccinated. But my children, my parents, my sisters and
their children are not going to be vaccinated. Our family
knows they are not helping the nation by getting
vaccinated. They understand that even if there is an
outbreak they are not likely to be infected and that there
will be time to get vaccinated."
Learning About Smallpox
One of the most striking of the NEJM articles is
a survey of what Americans know — and, mostly, don't
know — about smallpox and smallpox vaccination. Robert
J. Blendon, ScD, professor of health policy and political
analysis at the Harvard School of Public Health, and
colleagues conducted telephone interviews with a national
sample of 1,006 adults.
Among the findings:
- 84% of Americans don't know that there is currently
enough smallpox vaccine to vaccinate everyone in the
U.S. in the event of a smallpox attack.
- 63% of Americans think there's been a case of
smallpox somewhere in the world in the last five
years. And 30% think there's been a recent case of
smallpox in the U.S. The reality: there hasn't been a
case of smallpox since 1977 — anywhere.
- 78% of Americans think there is an effective
treatment for smallpox. The reality: there is no such
- 58% of Americans don't know that vaccination within
a few days of smallpox exposure can prevent disease.
- 61% of Americans say they'd get smallpox vaccination
if it were offered.
Dr. Blendon said this lack of knowledge means most
people aren't able to make informed choices about whether
to get vaccinated.
"There hasn't been a smallpox case in the U.S. —
or in the world — in recent years," Dr. Blendon
told Medscape. "Many people think there's been a
recent case and it makes them more nervous. And people
have to understand that there is not an effective
treatment — some 80% think there is — so they may not
understand the importance of early vaccination. They are
not aware of the biggest public health message. That is,
if you think you are exposed and get vaccinated in two or
three days, you won't get symptoms."
Smallpox Vaccine Risks
It is known that many people will suffer adverse
effects from the smallpox vaccine, and some — an
estimated one to five in a million — will die. If the
entire U.S. population is vaccinated, about 150 people are
likely to die.
One adverse effect of mass vaccination could be the
accidental spread of the live-virus vaccine from a
vaccinated person to an unvaccinated person.
Immunosupressed people — such as transplant recipients,
people taking immunosuppressants for arthritis and other
conditions, and cancer patients on chemotherapy — are at
enormous risk of vaccine complications.
But are these people at risk from vaccinated people?
Not much, according to the NEJM report by Dr.
Sepkowitz. The Weill Medical College professor took a
careful look at all the medical literature on the topic.
"The vaccine virus is very uncontagious," Dr.
Sepkowitz told Medscape. "It would take the wrong
person being in the wrong place at the wrong time — and
a [break with] standard infection control practices in
hospitals for a person to get secondary disease. The risk
will be small but not zero."
Dr. Mack, however, argues against mass public
"This is the most dangerous live vaccine we
have," he says. "It is going to kill people. It
may be just a few people in a million, but it still will
kill people. Overall, vaccinating people in general is not
cost-effective. It will hurt more people than it helps. I
think even vaccinating people who work in hospitals is not
effective. We will hurt more people than we save. If
someone would show me evidence that someone is planning
sustained multiple attacks, I would change my mind."
Questions About Mass Vaccination
Smallpox vaccination likely will be available for all
Americans by 2004, including nonemergency healthcare
professionals. Deciding whether to get vaccinated involves
weighing whether the benefit is worth the risk.
"Decisions are best made on a rational, factual
basis and not on the basis of fear," Edward W.
Campion, MD, NEJM senior deputy editor, told
Medscape. "Physicians do have a major role. If there
is going to be any type of widespread vaccination,
patients are going to be coming to doctors to ask, 'Should
I be vaccinated or not, what is your opinion?' "
This makes it more important than ever for physicians
to be informed and to be aware that they are role models.
"At this moment I am making the decision as [a]
front-line person to get vaccinated, but I am not having
my family vaccinated," Dr. Blendon said. "That
is important for people to know. It is more important for
patients to know what their doctor says than what a
cabinet secretary says. Physicians are critical. People
are going to be watching what they say."
N Engl J Med. Published online Dec. 19, 2002.
Vaccination: On Hold, But Lessons Learned
CDC panel recommends just starting with
frontline personnel, not the general population
The Scientist Volume 16 | Issue 14 |
29 | Jul. 8, 2002
US citizens will not be lining up for smallpox
vaccinations anytime soon, despite months of news
reports on the stockpiling of enough vaccine for every
man, woman, and child. On June 20, the US Centers for
Disease Control and Prevention's Advisory Committee on
Immunization Practices (ACIP), after evaluating
information provided at public forums in New York City,
San Francisco, St. Louis, and San Antonio, recommended
to Tommy Thompson, secretary of Health and Human
Services (HHS), not to vaccinate the entire population.1
"There was no compelling evidence that it would
be appropriate to recommend it, given what we know about
the threat level and the fact that there has been no
disease since 1977," says David A. Neumann,
director of the Alexandria, Va.-based National
Partnership for Immunization, who served as a liaison
representative to the committee.
Anthony Fauci, director of the National
Institute of Allergy and Infectious Disease,2 William
Bicknell, professor of international health at the
Boston University School of Medicine and former health
commissioner of Massachusetts,3 and others
had requested the forums to debate whether vaccination
practices to contain natural outbreaks of smallpox would
translate into a setting of deliberate infection:
bioterrorism. But leaders of the World Health
Organization's (WHO) Global Smallpox Eradication
Campaign, who worked in the trenches from 1966 to 1977,
were unanimous that the strategies used then could work
now, preventing deaths and illness from the live
According to the recommendations, teams of specified
first responders and medical personnel will be
vaccinated ahead of time, "probably somewhere
between ten and twenty thousand individuals," said John
Modlin, chairman of ACIP on June 20. State or local
governments will organize the teams. If an outbreak of
smallpox occurs, the teams will implement
"surveillance and containment through selective
vaccination of contacts," new lingo for "ring
vaccination," says Neumann. In the smallpox
eradication effort, ring vaccination successfully
identified and immunized contacts of cases, and the
contacts of the contacts, ringing the outbreaks. This is
possible because vaccinating within four days of ex-posure
prevents symptoms. Recalls Don Francis, president
of VaxGen in Brisbane California, "I was in the
last outbreak in Europe, in Yugoslavia. We had to
immunize the whole country, even outside the secondary
and tertiary contacts. There was tremendous social
concern, but it worked."
LOOKING BACK--AND AHEAD "Smallpox is
dead!" declared the front page of the WHO's
flagship magazine in May 1980, heralding an
unprecedented medical success story.4
Anticipating the end of the disease, most nations had
ceased vaccination programs years earlier. "In 1970
and 1971, people were concerned about suspending the
vaccination program, but they were shouted down. One
death per million from vaccine seemed easy to skip when
the threat of smallpox globally had been reduced to
nil," says Matthew Davis, assistant
professor of pediatrics and internal medicine at the
University of Michigan Health System in Ann Arbor, Mich.
Ceasing vaccination created young, immunologically naïve
populations, which was not deemed dangerous, despite
strong suspicions of the existence of weaponized
smallpox. Then in October 2001, anthrax spores delivered
with the US mail catapulted bioterrorism from
theoretical doomsday scenario to possible reality. With
smallpox heading the new hit parade of fears, talk of
vaccination resurfaced. Said HHS Secretary Thompson on
Nov. 28, 2001, "While the probability of an
intentional release of the smallpox virus is low, the
risk does exist and we must be prepared."
In the wake of the Sept. 11 terrorist attacks, some
nations rushed to thaw, dilute, and reinvent smallpox
vaccines, as researchers simulated and extrapolated
attack scenarios. The big question: does it make more
sense to vaccinate everyone beforehand, or wait for
disaster to "ring" the danger?
For now, CDC has opted against population-wide
vaccination because traditional smallpox vaccine is
quite crude by modern standards. The live vaccinia
vaccine is a cowpox relative, grown in calf serum or
more recently in tissue culture. The vaccine is
administered by scratching it into the arm using a
bifurcated needle. According to the last year (1968) for
which vaccine data were available in the United States,
nine deaths occurred among 14.2 million vaccinated
individuals. Extrapolation to the present US population
yields 180 deaths from vaccination. But those were the
days before AIDS, increased cancer survival, and the
rise of organ transplantation. Given these changes, says
Francis, "Vaccine use in the US population would
kill 250 to 1,000 people. If someone has HIV and doesn't
know it, God knows what would happen."
Photo: Courtesy of Vaxgen
In immunosuppressed patients,
smallpox vaccine can cause such complications as
encephalitis or a nasty skin ulceration called vaccinia
necrosum. It can also be lethal. The public would not
tolerate the risk, says Francis. "We can talk about
universal vaccination, but people would be very happy
until the first person with HIV or the first kid with
eczema is vaccinated. I can just imagine a TV camera
zooming in on a face with a big ugly hole from vaccinia
necrosum. Then it would all stop, nobody would take
it." But people would accept vaccination under
other circumstances. "I don't think anyone wouldn't
take the risk of being vaccinated if there is a definite
exposure or a person is in the second ring of
contacts," Francis adds.
The flipside of vaccine risk is the specter of
widespread smallpox. "As bad as a mass smallpox
vaccination program could be, an attack could be much
worse," says Davis. He reported his group's study
using the historical US data of one vaccine-related
death per million population at the Pediatric Academic
Societies' meeting on May 7 in Baltimore. "Consider
a smallpox attack that initially exposes 100 people in
an urban center. We found that in the first year after
the attack, we'd expect 2,160 deaths from smallpox. In
contrast, if we vaccinated 50% of all 1- to 29-year-olds
before an attack, [and] then implemented ring
vaccination after, we'd get 358 deaths, of which 58
would be due to the vaccine, and 300 to smallpox. That's
a saving of 1,800 lives over the first year," he
Despite this grim forecast, ACIP nixed population
vaccination because the bioterrorism scenario is not
likely to happen. But they could not be pinned down on
the risk estimates, which are apparently based on
classified information. Explained Modlin on June 20 to a
reporter's question about the lack of risk
quantification, "The committee has been told that
the risk is low but not zero. We obviously can't put a
number on that, but we are assuming that it's low. The
decision that we made balanced that low or very low risk
with the risk from the vaccine." Because of the
uncertainty, the recommendations are flexible. "If
additional circumstances warrant more widespread use of
vaccine in an area or a community, then those steps, of
course, would be taken," said Julie Gerberding,
acting deputy director of CDC.
Another factor arguing against population vaccination
is the conviction that ring vaccination can work.
Francis evokes a scenario of 10 exposures in New York
City's Grand Central Station that paints a different
portrait than Davis' simulation. "There would be a
major effort to identify the people exposed. Finding and
vaccinating 100 percent of them will stop the epidemic
more than vaccinating everyone in Manhattan." Plus,
smallpox is not easily spread. "You can't infect
people with smallpox unless you're clinically ill. The
idea of introducing a suicide smallpox bomber doesn't
work. He or she would have pus all over the face,"
Francis adds. And today's improved communications would
help find the contacts in ways not possible in the
eradication days. "At the meeting in Atlanta June
20, someone said that once the contacts are identified,
CNN [TV] would run them on ribbons on the bottom of the
TV screen," says Neumann.
VACCINE SOURCES Despite the recommendation for
limited vaccination, the US government is continuing to
stockpile enough vaccine for everyone, as well as
continuing efforts to improve the safety profile.
"Manufacture of smallpox vaccine stopped worldwide
with the announcement of eradication in 1980," said
Donald A. Henderson at a conference at the
University of Rochester on May 10, 2002. Henderson
headed the WHO's eradication campaign. "Not having
enough vaccine is really scary. If this baby got loose
with no vaccine, we'd be back to the days of
quarantine," says Francis.
That was nearly the case on Sept. 11, when the US
government had only 15.4 million doses of stored Dryvax
vaccine from Wyeth Laboratories of Marietta, Pa. Since
then, the government has been scrambling to acquire the
286 million doses needed to protect the entire
population. Diluting stored vaccine, making more, and
developing new sources will help in reaching the goal as
early as 2003.
Building smallpox vaccine stores was already in
progress before Sept. 11. In 2000, the US government
ordered 54 million doses from Acambis in Cambridge, UK,
increasing it to 155 million doses after Sept. 11.
Aventis Pasteur, of Swiftwater, Pa., has offered 75 to
90 million doses frozen in Lyon, France, since the
1950s. Aventis will have a cell-culture-based vaccine
ready for Europe by the end of 2002 and is working on a
highly attenuated vaccine.
Meanwhile, in November 2001, a multicenter team began
testing reconstituted Dryvax at fivefold and tenfold
dilutions. Each of 680 individuals who had never been
vaccinated against smallpox received undiluted vaccine
or either of the two dilutions.3 "We
thought the 1:10 dilution would work because there are
hundreds of thousands of particles in the standard
vaccine, and a tenth of that should be adequate. And
that's exactly what we found. There were no significant
differences in 'take' rates among the three
strengths," which were near 100 percent, explains John
Treanor, director of the Vaccine Treatment
Evaluation Unit at the University of Rochester Medical
Center. He calls the few side effects "annoying,
but not serious," including fever, headache,
myalgia, chills, nausea, fatigue, and rash. "Still,
this is much higher than [with] new vaccines being
tested today. We'd reject it if it was new today,"
he adds. Treanor estimates that the 15.4 million doses
of Dryvax can be expanded by dilution to 77 million
Other nations are building their smallpox vaccine
stores too. On April 12, 2002, the Department for Health
in the United Kingdom revealed a stockpile sufficient
for half its population, some 30 million doses, and has
ordered more from PowderJect Pharmaceuticals in Oxford.
Health Canada, the national health agency, reports
365,000 stored doses, which it plans to dilute to at
least 3 million.
Even if the vaccine is never used, and the
doom-and-gloom scenarios never come to pass, the
resurgence in interest in smallpox could have hidden
benefits. "We will be learning new things about
disease in general," points out Treanor. Henderson
concurs. "If there is suddenly dengue in south
Florida or a new flu, we'll be better equipped to deal
One thing is certain in this era of great
uncertainty: Researchers are reevaluating the very idea
of eradication of an infectious disease. Sums up Davis,
"Before 9/11, my supervisor asked me to consider
aspects of bioterrorism in my work on vaccines. I
scoffed at it. But since 9/11, everything else I do
became inconsequential. It is an entirely new era in
trying to protect our public against a variety of health
problems. In the past it was us against nature. Now it
is us versus other human beings. That's a lot more
unpredictable and requires a different set of
calculations, ones we're not sure of at this time."
Ricki Lewis (firstname.lastname@example.org)
is a contributing editor.
1. CDC Office of Communications Telebriefing
Transcript, June 20, 2002, available online at: www.cdc.gov/od/oc/media/transcripts/t020620.htm.
2. A. Fauci, "Smallpox vaccination policy--the
need for dialogue," New England Journal of
Medicine (NEJM), 346:1319-20, April 25, 2002.
3. W. Bicknell, "The case for voluntary smallpox
vaccination," NEJM, 346:1323-24, April 25,
4. World Health Organization, "Smallpox and its
eradication," 1988, available online at: www.who.int/emc/diseases/smallpox/Smallpoxeradication.html.
5. S.E. Frey et al., "Clinical responses to
undiluted and diluted smallpox vaccine," NEJM,
346:1265-74, April 25, 2002.
9th Persian physician Al-Razi (Rhazes)
publishes first treatise on smallpox, distinguishing
it from measles.
1721 UK begins inoculating citizens with
material from smallpox pustules.
1796 UK physician Edward Jenner uses cowpox
lesion material to vaccinate 8-year-old James
Phipps, who lives a long and unpocked life.
1798 Jenner publishes "An inquiry into
the causes and effects of the Variolae vaccinae"
privately, after the Royal Society rejects the
1853 UK makes infant vaccination
1966 Two million people die of smallpox
each year; WHO Global Smallpox Eradication Campaign
1972 US smallpox vaccinations cease.
1974 WHO's global Expanded Program on
Immunization vaccinates 80% of world's children
against six diseases, including smallpox.
1977 Last known natural case of smallpox,
1978 Last known case of smallpox, in UK
laboratory worker; 76 laboratories worldwide claim
to have smallpox strains.
1980 WHO declares global smallpox
1982 Vaccinations stop worldwide.
1983 Wyeth stops manufacturing Dryvax,
storing 154 million doses.
1984 All smallpox stocks destroyed except
those of US and USSR.
1993 Recombinant DNA Advisory Committee of
US National Institutes of Health lowers safety
rating for working with recombinant variola to
biosafety level I.
June Johns Hopkins Center for Civilian
Biodefense Studies conducts "Dark Winter"
simulation, revealing lack of preparedness for
Sept. 11, Terrorist attacks in US.
October Anthrax in US mail raises concerns
of smallpox used as a bioweapon.
June 20, CDC panel advises no general
Mass Inoculation Might Kill
Hundreds, Save Thousands
By Susan Okie
Washington Post Staff Writer
Wednesday, May 8, 2002; Page A03
A mass campaign to vaccinate Americans against smallpox
might result in 200 to 300 deaths and make several
thousand people severely ill -- yet could save thousands
of lives in the event of a bioterrorist attack with the
virus, according to research presented yesterday at the
Pediatric Academic Societies' annual meeting in Baltimore.
The new estimates came from studies led by
pediatricians Alex R. Kemper and Matthew M. Davis of the
University of Michigan, who said they hoped their analyses
would contribute to an unfolding national debate about
whether Americans should be offered a vaccine likely to
kill some recipients in the cause of protecting the nation
from a possible bioterrorist attack.
"There's no other vaccine that we currently give
that carries with it a risk of death," said Kemper.
"From a societal standpoint, we have to decide
whether or not we're willing to take this risk."
Infectious disease experts will gather in Atlanta today
and Thursday to begin drafting recommendations about who,
if anyone, should get the vaccine. Public discussions
scheduled for Washington and several other cities this
summer will focus on whether emergency room personnel and
other medical and public health workers should be
vaccinated, as well as on the larger question of whether
the vaccine should be made available on a voluntary basis
to all Americans.
Not everyone is a candidate for smallpox vaccination.
People whose immune systems are weakened -- by HIV,
cancer, treatment with certain drugs or various other
conditions -- cannot safely take the vaccine. Neither can
pregnant women, children under 1 year old, or anyone prone
to eczema, a skin condition that affects 10 percent of
Americans. Those who live with anyone in a high-risk group
are also excluded because vaccine recipients can pass
vaccinia, the virus in the vaccine, to close contacts. For
all of those reasons, Kemper estimated that 25 percent of
the U.S. population would be ineligible.
The vaccine's most serious potential side effects are
encephalitis (brain inflammation) and progressive vaccinia,
in which the sore produced by the vaccine spreads without
healing. Either can be fatal. People with eczema who are
vaccinated may develop eczema vaccinatum, a
life-threatening skin rash.
Based on historical data, Kemper estimated that a
campaign to vaccinate U.S. residents between the ages of 1
and 29 would cause 175 cases of encephalitis, 420 cases of
progressive vaccinia and 1,200 cases of eczema vaccinatum,
with a total of 190 deaths. If the campaign included
people between the ages of 1 and 65, there would be an
estimated 505 cases of encephalitis, 845 cases of
progressive vaccinia and 3,525 cases of eczema vaccinatum,
with 285 deaths. In either scenario, thousands of other
people would suffer less severe but still significant side
A vaccination campaign would nonetheless be likely to
save many lives if smallpox virus were used in a terrorist
attack, according to Davis, who also presented his
findings yesterday. The government's current plan for
containing an outbreak is a strategy called "ring
vaccination," in which people with suspected smallpox
and their contacts would be traced, vaccinated and
isolated from the surrounding population. Vaccinating a
person even two or three days after exposure to smallpox
offers considerable protection against the disease.
Davis and colleagues used a mathematical model to
compare the effectiveness of ring vaccination after an
outbreak with the effectiveness of a preventive mass
vaccination campaign targeting people between 1 and 29
If 50 percent of that age group had been previously
vaccinated, the number of U.S. deaths predicted from an
outbreak that began with 100 infected people would be 358,
including vaccine-related deaths. A similar outbreak would
be predicted to cause 2,160 deaths if only ring
vaccination were used. In a larger outbreak, or one that
began in several places at once, the lifesaving effect of
preventive vaccination would be even greater.
Davis said that vaccinating children and young adults
would help protect older people as well by greatly
reducing transmission during an outbreak, because smallpox
depends so heavily on person-to-person transmission.
But for a mass vaccination campaign to succeed,
Americans would have to accept "some numbers of
deaths and several thousand illnesses," Davis noted.
"Today's U.S. population is not accustomed to that
level of side effects and deaths from a vaccine."
Routine vaccination against smallpox ceased in the
United States in 1972, and experts estimate that most or
all of the population is vulnerable to infection with the
virus, which is highly contagious and carries a 30 percent
mortality rate. Although the remaining known stocks of
smallpox virus are kept in two high-security laboratories
in the United States and Russia, many experts fear that
terrorists might gain access to samples of the virus.
In Atlanta, consultants to the federal Centers for
Disease Control and Prevention will begin drafting
proposals for the Advisory Committee on Immunization
Practices (ACIP), which will issue proposed
recommendations on smallpox vaccination in June. The first
of about a half-dozen public forums is scheduled here on
Editorial: A Family Doc Looks
Jonathan L. Temte, MD, PhD
Smallpox is an abstraction, a specter of a forgotten
era and irrelevant to medicine except in the guise of
hypothetical scenarios and doomsday plots. Yet this
apparition is real, due to the antipathy of variola's
keepers toward its final destruction and our waning
immunity. During the height of their biological weapons
program, the former Soviet Union allegedly maintained
weaponized smallpox in quantities measured in tons.
Moreover, this production capacity was coupled with highly
sophisticated mechanisms for widespread and even
intercontinental dispersal. Whether additional stores
currently survive outside of the United States and Russia
is an open question. In 1969, Lane and Millar wrote,
". . . a lower proportion of immune persons in the
population will raise our susceptibility to smallpox as a
weapon of biological warfare." Against
the backdrop of last year's intentional dispersal of
anthrax spores, however, we face the prospect of mass
vaccination to counter the threat of smallpox. Is smallpox
-- to paraphrase Scrooge -- what is to come, or simply
what may come to pass?
My connection to smallpox resides in the faint doughnut
of a scar over my left deltoid. . . a reminder of the
fear, respect, and competence of a now-gone generation of
pediatricians. I was born 9 years after the last case of
smallpox was reported in the United States. By the time I
reached my teens, routine smallpox vaccination of children
ceased. Like almost all other physicians in
North America, I am part of a fully vaccinated generation.
Despite this, I managed, as a child, to slip through the
cracks and contract both mumps and measles prior to
vaccination. In medical school I saw my first and only
case of Haemophilus influenzae meningitis. As a
resident on a rural rotation, I diagnosed my last case of H
flu epiglottitis in a vaccine-avoidant 2-year old.
Although I represented the American Academy of Family
Physicians at the Centers for Disease Control and
Prevention (CDC) Measles Elimination meeting in 2000, I
have yet to see a case as a family physician. I have not
seen diphtheria or tetanus. I have a handful of patients
with postpolio syndrome, and it has been suggested -- by
at least 1 specialist -- that our adopted daughter's
partial paralysis stems from polio. The iron lung, like
smallpox, is a curiosity from textbooks of medical
From what I have read, and from the words of older and
wiser colleagues, I can appreciate the dread of most of
the vaccine-preventable diseases. My recollection of my 1
case of epiglottitis serves as a potent reminder, which I
frequently dredge up while explaining the benefits of H
influenzae type b (Hib) vaccine to anxious parents. I
have grown to embrace a great faith in the power and
success of vaccines. Nevertheless, I have been witness to
the demise of the oral polio vaccine (OPV) and the
whole-cell pertussis vaccine due to their unfavorable
adverse-effect profiles. The 0-10.5 cases per million of
acute encephalopathy resulting from the whole-cell
pertussis vaccine and the 0.4 cases of vaccine-associated
paralytic poliomyelitis per million doses of OPV were felt
to be unacceptably high. The
well-intentioned but ill-fated swine flu vaccination
campaign of 1976 is best remembered for the resulting
"epidemic" of vaccine-related Guillain-Barré
syndrome. Although family physicians were
slow to embrace varicella vaccine, its use is now
commonplace. Our reluctance was largely due to a sense of
the risks potentially outweighing the benefits in
preventing a common and relatively mild disease.
Conversely, our hesitancy to adopt the rotavirus vaccine
was unintentionally prophetic.
As a family physician providing care to an underserved
community within a larger affluent metropolitan area, I
see a highly diverse mix of patients. Our teaching clinic
attracts African-Americans, Khmer and Hmong immigrants
from Southeast Asia, Mexican-Americans, university
professors and graduate students, patients from the local
methadone clinic, and multiple other groups. Our childhood
immunization successes are countered by the transient
nature of many of our patient families, an inability to
track down old records, and a small but increasingly
proactive cohort of vaccine-avoidant parents. Safety
concerns have been identified by 11% to 25% of parents
across the nation as a barrier to immunization.
I often receive comments from my more affluent and
well-educated parents that they need to do more
"research" on the safety of vaccines,
particularly measles-mumps-rubella (MMR), before allowing
their child to succumb. Many are well versed in the
Internet-promoted claims of links to autism. Most are
immune to my retort citing good epidemiologic evidence to
the contrary.[6,7] These concerns are raised
rarely by my less affluent and less educated patients. I
daily see the benefits of herd immunity borne on the backs
of the less privileged.
Now we face vaccinia. Across the wide spectrum of
opinion, there have been advocates for mass immunization
of the entire US population, a daunting task at best.
In response, like many other physicians, I have downloaded
the 48-page "Smallpox Immunization Clinic
Guide," paying particular attention to the screening
and consent sections. In general, primary
care physicians have relationships with and
responsibilities to their communities. This stewardship
involves not only providing appropriate medical care and
preventive services, but also protecting patients through
the avoidance of high-risk medical interventions. When it
comes to the wide-scale introduction of smallpox vaccine,
we are not so much afraid of liability issues as we are of
genuinely hurting our patients.
To fully appreciate the smallpox vaccine, one needs to
understand both the potential risks of administration and
the spectrum of contraindications to the vaccine. The
vaccinia vaccine is associated with a wide variety of mild
and serious side effects. For example, 70% of children
experienced at least 1 day of temperatures higher than 100oF
for 4 to 14 days after primary vaccination; 15% to 20%
reached 102oF or higher. These
mild side effects, however, occurred within families that
barely resemble those encountered today: 2-parent/1-income
households with far less daycare use. Rates of more
significant adverse effects reported in 1963 and 1968 were
much lower (Table
Other adverse effects included erythema multiforme/Stevens-Johnson
syndrome and superinfections of miscellaneous skin rashes
and burns. Overall rates of severe complications for
primary vaccination were age dependent. Rates of 112.4
adverse events per million were noted for children younger
than 1 year; 79.0/million for 1- to 4-year-olds,
49.6/million for 5- to 9-year-olds, 32.0/million for 10-
to 19-year-olds, and returning to 111.1/ million for
adults. It is worthwhile to note that the
estimates for adverse effects were conservative, due to
probable underreporting and taken from a
population 34-39 years ago. Furthermore, it should be
noted that 20% of people with adverse effects in 1968 were
not directly vaccinated, but had contact with recent
vaccinees. In summary, significant adverse
effects from vaccinia were rare, but also occurred at
rates 2 to 3 orders of magnitude higher than those
realized by vaccines that have since been deemed
Contraindications to vaccination include allergies to
polymixin B, streptomycin, tetracycline, neomycin, and
phenol, all of which are components of the vaccine in
trace amounts. Live viral vaccines are generally avoided
during pregnancy in nonemergency situations.
Immunosuppression or contact with immunosuppressed
household members are contraindications. Disorders
including HIV, leukemia, lymphoma, generalized malignancy,
and therapies that reduce immunity can lead to enhancement
of vaccinia replication. Likewise, the use of prednisone
at a dosage of 20 mg per day or higher for 14 or more days
may also be a contraindication.
Beyond these rather clear contraindications are those
related to eczema and atopic dermatitis. Currently having
eczema, having had eczema in the past, or having household
contact with someone meeting the above criteria are all
considered contraindications. People with other chronic or
acute or exfoliative skin disorders may also be at higher
risk for developing eczema vaccinatum. In
primary care practice, one enters a rather murky zone
here. Eczema/atopic dermatitis (ICD-9: 692.9) is the 38th
most commonly recorded ICD-9 code used for billing
purposes at the 8 primary clinical training sites of the
University of Wisconsin Department of Family Medicine (UW-DFM).
It occurs in 0.58% of all visits. On closer examination,
however, this rare presence is only the tip of the
iceberg. We examined billing data through the UW-DFM
clinical data warehouse and were able to identify 61,979
individuals seen at our clinical sites between January 1,
1999 and December 31, 2001. The percentage of patients at
any one site who had been assigned to the ICD-9: 692.9
code ranged from 3.68% to 7.60%. Overall, 3298 (5.32%)
individuals had been directly associated with this
diagnostic code. The age and sex distribution of these
patients are illustrated in the Figure. We did not attempt
to identify the number of potential household contacts of
these patients, nor did we attempt to verify the
diagnosis. Regardless, the pool of patients with potential
contraindications to smallpox vaccine, based simply on
eczema/atopic dermatitis, is quite large.
Figure. (click image to zoom) Age
and sex distribution of eczema/atopic dermatitis in
primary care practices. Data were drawn from the UW-DFM
Clinical Data Warehouse for ICD-9: 692.9. Patients
assigned this diagnosis represent 5.32% of total patient
Contraindications and risk factors for smallpox
vaccination are broadcast to us from a different time and
a different culture. To obtain copies of the original
literature required a trip to the medical school library
basement and the opening of dusty, long-shelved journals.
Considering this, a number of questions come to my mind:
- How many of our patients diagnosed with eczema/atopic
dermatitis know that they have this diagnosis? Do
other family members have any idea? Would they recall
this diagnosis at a smallpox vaccination clinic?
- How many of these patients have been accurately
- Are patients with chronic skin maceration from
morbid obesity at higher risk?
- Is fungal dermatitis or acne a risk factor?
- Is there a maximum age cutoff for smallpox
- Is the presence of severe chronic disease(s) a
- Is the widespread use of contact lenses a potential
problem for accidental vaccination of the eye?
- Does chronic hepatitis C infection increase one's
risk for adverse effects?
These and other questions stem from my naiveté and my
primary care practice, as well as from a medically
transformed world. Many of the medical interventions and
many of the chronic illnesses that we deal with on a daily
basis simply did not exist during our last experience with
widespread smallpox vaccination.
For physicians here, this may be the time to run the
administrative data files and identify patients who have
possible contraindications. These conditions need to be
verified. This is also the time to provide this
information to patients, so as to prophylax against the
adverse effects of unintended immunization. In the face of
threatened or actual release of smallpox and in the panic
that will ensue, cool heads may become a very scarce
Perhaps more of a concern is what really happens if the
genie is let out of the bottle. I do not mean here in the
United States where, despite our grumbling, we are blessed
with the best of medical care, the best of rapid
communication, and the resources to respond rapidly to
mass catastrophe. What happens in a world in which 75
million subSaharan Africans suffer from HIV, and countless
others endure the immunosuppressive effects of chronic
malnutrition? What happens in the face of widespread
poverty and overcrowding, and where natural and
vaccine-induced immunity to smallpox no longer exists?
What happens where resources, communication and
transportation are insufficient to provide any ring
vaccination to slow down transmission? It is with these
questions that I am most troubled.
Jonathan L. Temte, MD, PhD,
Associate Professor of Family Medicine, University of
Wisconsin, Madison. Email: email@example.com.
Effects of Smallpox Vaccine
Frey, M.D., Frances K. Newman, M.S., John Cruz, B.S., W.
Brian Shelton, Ph.D., Janice M. Tennant, M.P.H., Tamara
Polach, B.S., Alan L. Rothman, M.D., Jeffrey S. Kennedy,
M.D., Mark Wolff, Ph.D., Robert B. Belshe, M.D., and
Francis A. Ennis, M.D.
Dose-Related Effects of Smallpox
Frey S. E., Newman F. K., Cruz J., Shelton W. B.,
Tennant J. M., Polach T., Rothman A. L., Kennedy J. S.,
Wolff M., Belshe R. B., Ennis F. A. [ Abstract
] [ Full
N Engl J Med 2002; 346:1275-1280, Apr 25, 2002;
published at www.nejm.org on Mar 28, 2002
(10.1056/NEJMoa013431). Original Articles
We conducted a double-blind, randomized trial of
three dilutions of vaccinia virus vaccine
in previously unimmunized adults in order to
assess the clinical success rates, humoral responses,
and virus-specific activity of cytotoxic T cells and
Sixty healthy adults were inoculated intradermally
by bifurcated needle with undiluted vaccine
(dose, 107.8 plaque-forming units
[pfu] per milliliter), a 1:10 dilution (dose, 106.5
pfu per milliliter), or a 1:100 dilution
(dose, 105.0 pfu per milliliter); there
were 20 subjects in each group. The subjects were
monitored with respect to vesicle formation
(an indicator of successful vaccination), the
viral titer at the time of peak lesion formation, antiviral
antibodies, and cellular immune responses.
A vaccinia vesicle developed in 19 of the 20
subjects who received undiluted vaccine
(95 percent), 14 of the 20 who received the
1:10 dilution (70 percent), and 3 of the 20 who received
the 1:100 dilution (15 percent). One month after
vaccination, 34 of 36 subjects with vesicles
had antibody responses, as compared with only
1 of 24 subjects without clinical evidence of vaccinia
virus replication. Vigorous cytotoxic T-cell and
responses occurred in 94 percent of subjects with
vesicles, and a cytotoxic T-cell response
occurred in only one subject without a
The vaccinia virus vaccine
(which was produced in 1982 or earlier) still
has substantial potency when administered by
a bifurcated needle to previously unvaccinated adults.
Diluting the vaccine
reduces the rate of successful vaccination. The development
of vesicular skin lesions after vaccination correlates
with the induction of the antibody and T-cell
responses that are considered essential for
clearing vaccinia virus infections.
(vaccinia virus) is highly effective in immunizing against
smallpox and can prevent disease when given as late
as two to three days after exposure.1
A comprehensive public health program coupled
with vaccination enabled the World Health Assembly
to declare the world free of smallpox in 1980.2
General use of the vaccine
in the United States ended in 1972. Currently, less
than half the world's population has been exposed either
to smallpox (variola virus) or to the vaccine.3
This fact prompted several government and
world health authorities to warn about the
serious threat of smallpox as a biologic weapon.3,4
The probability of a release of smallpox is
not known, but the effect could be
catastrophic in an unimmunized population.5
The immune responses required to protect a person
from smallpox after vaccination are not
completely understood. Inadvertent vaccination
resulted in severe complications and death from vaccinia
in children with a T-cell deficiency and an adult with
undiagnosed infection with human immunodeficiency
virus type 1 (HIV-1) but not in children with
Therefore, detailed analyses of T-cell responses
in addition to antibody responses after
vaccination may improve our understanding of
the effects of dilution on the immunogenicity of
vaccinia virus vaccine.
The last lots of vaccinia vaccine
manufactured in the United States, in 1982,
were produced by the classic method involving scarification
of calves followed by collection of vaccinia virus from
draining calf lymph. Concern about contamination with
bacteria or other agents from bovines makes
further use of this method unfeasible. The
which is stored at the Centers for Disease
Control and Prevention (CDC) in Atlanta, contains
approximately 108 pock-forming units per
milliliter. Supplies of lyophilized vaccine
in the United States consist of an estimated
15 million doses. In addition, 70 to 90 million doses
of frozen liquid-formulation smallpox vaccine
have been identified in long-term storage by
manufacturer (Aventis, Swiftwater, Pa.); the
U.S. government is reportedly negotiating to
acquire this vaccine.
Efforts are under way to develop a tissue-culture–derived
vaccinia virus vaccine.9
In the interim, we evaluated the available vaccine
to determine whether dilution altered the
rate of successful viral replication at the
inoculation site and immune responses.
(Dryvax, Wyeth Laboratories, Marietta, Pa.; lot no.
4998391 [titer, 107.7 plaque-forming units,
or pfu, per milliliter] and lot no. 4008257
[titer, 107.8 pfu per milliliter]) and
diluent were provided by the CDC. The vaccine
is a lyophilized product prepared from calf
lymph. The diluent contains 50 percent glycerin,
0.25 percent phenol, and 0.005 percent brilliant green
dye in water. The vaccine
was reconstituted on the day of administration according
to the package insert. The undiluted vaccine
was serially diluted with diluent. Coded
vials were stored at 4°C until use. Because
was highly viscous and difficult to manipulate,
viral titers were determined in each of the 19 vials
prepared, as described previously.10
Titers are expressed as the number of
plaque-forming units per milliliter.
Study Design and Subjects
The study was a randomized, double-blind trial
conducted at the National Institute of
Allergy and Infectious Diseases Vaccine
and Treatment Evaluation Unit in St. Louis. The
protocol was approved by the institutional
review board of Saint Louis University. All
subjects provided written informed consent and were
enrolled between April 2000 and October 2000.
Long-term follow-up to assess the duration of
immune responses is ongoing.
Healthy adults 18 to 30 years of age were eligible if
they had no vaccination scar; no history of
vaccinia virus vaccination; normal renal and
hepatic serum chemical values; negative tests for
hepatitis B surface antigen, hepatitis C virus antibody,
and rapid plasma reagin; and a negative HIV-1
enzyme-linked immunosorbent assay (ELISA).
Exclusion criteria included the contraindications
against vaccination noted in the package insert (pregnancy,
immunosuppression, and eczema), a history of vaccination
with live attenuated virus within 60 days before
the study, the receipt of blood products or
immune globulin within 6 months before the
study, and household contact, sexual contact, or occupational
exposure to pregnant women, immunosuppressed persons,
persons with eczema, or infants less than 12
months of age.
A total of 60 subjects were enrolled and were
randomly assigned to receive undiluted vaccine,
a 1:10 dilution of vaccine,
or a 1:100 dilution of vaccine.
Twenty subjects were enrolled in each group.
Group assignment was revealed to the subjects after
day 45. Laboratory personnel remained unaware of
treatment assignments until all assays were
completed. Subjects were inoculated by scarification:
a bifurcated needle that held a drop of vaccine
was pressed 15 times into the skin of the upper
arm. Vaccination sites were covered with
folded gauze and a semipermeable adhesive membrane
(Tegaderm, 3M Health Care, St. Paul, Minn.) to avoid
autoinoculation or exposure of personal contacts.
Dressings were changed every three to five
days until the lesion formed an eschar.
The primary end point was the rate of success of
vaccination. Success was defined by the
presence of a primary vesicle at the
inoculation site seven to nine days after scarification.
Other signs and symptoms of the replication of
vaccinia virus include edema, tenderness, and
erythema at the site of vaccination and
regional lymphadenopathy. Subsequently, the vesicle (Figure
1) evolves into a small ulcer over which
a scab forms, ultimately leaving a small
scar. The determination of successful vaccination was
made by a single physician who was unaware of the
subjects' treatment assignments. Secondary
end points included measurement of antibody
responses and cellular immune responses.
Typical Vesicle on the Upper Arm 10 Days after
Isolation of Virus and Antibody Assays
Swab samples of each lesion were obtained on day 7,
8, or 9 after scarification and cultured on
continuous African-green-monkey kidney cells
(BSC-40 cells), and the virus present in the swab samples
was quantitated by a plaque assay as described
assays were performed on serum samples collected just
before vaccination (day 0) and one month and one year
after vaccination; the end point was a 60
percent reduction in the number of plaques as
Serum binding antibody levels were measured
by ELISA as described previously.12
Vaccinia virus antigen and serum samples to
be used as positive and negative controls
were provided by Dr. George Ludwig (U.S. Army Medical
Research Institute of Infectious Diseases, Fort
Cryopreserved peripheral-blood mononuclear cells
obtained from all subjects on day 0 and at
six months were thawed and tested in the same
assay. Target cells were autologous Epstein–Barr virus–transformed
lymphoblastoid cells that had been infected with
vaccinia virus one day earlier and that were labeled
with chromium-51 on the day of the assay.13,14
Effector cells were exposed to virus-infected
autologous peripheral-blood mononuclear cells
for six days at 37°C and then added at various effector–target
ratios (10:1, 30:1, and 90:1) in 96-well U-bottom
plates, in triplicate, for 4.5 hours as
At each effector–target ratio, vaccinia-specific
immune lysis was calculated as the difference
between the percent lysis of infected targets
and the percent lysis of uninfected targets. The
number of effector cells required to lyse 30 percent of
target cells (referred to as lytic units) per
million cells was determined by an
with the use of commercial software (Proteins
International, Rochester Hills, Mich.).
A modified enzyme-linked immunospot assay was used to
detect live virus-specific release of
by cryopreserved peripheral-blood mononuclear
cells as previously described,16
except that stock vaccinia virus was used to
stimulate peripheral-blood mononuclear cells
at a multiplicity of infection of 1.0 pfu per
cell. The frequency of interferon-–positive
T cells specific for vaccinia virus per
million peripheral-blood mononuclear cells
was determined, and the results were considered positive
if the number of spots per million
peripheral-blood mononuclear cells in
virus-stimulated wells was twice as high as the number
of spots per million cells in the control wells
and if at least 20 spots per million
peripheral-blood mononuclear cells were present.
Preliminary studies (Ennis FA: unpublished data)
indicated that most of the T cells that
release vaccinia virus–specific interferon-
Proliferation assays were performed in replicates of
five as described previously.14,15,17
For each group of five replicates, the
stimulation index was calculated as the mean of the
three intermediate values (expressed as
counts per minute).
The objective of this study was to assess the effects
of diluted vaccinia virus vaccine
on clinical and laboratory indicators of
protective immunity. To be considered successful, a
given dilution had to evoke a response in at
least 18 of the 20 subjects in a group (a
success rate of 90 percent). Thus, a sample size of
20 involved an 8 percent chance of rejecting a vaccine
with a 95 percent success rate and a 32
percent chance of rejecting a marginally
with a 90 percent success rate. A sample size
of 20 was selected on the basis of these considerations
and the understanding that the selection of a
dilution will not depend solely on the
dichotomous measure of success or failure in
any group. Pairs of success rates were compared with use
of standard asymptotic methods for binomial
comparisons, and all three groups were
compared with use of the Kruskal–Wallis test
T-cell responses were analyzed by analysis of
variance with the use of SPSS statistical
software (SPSS, Chicago). Multiple post hoc
comparisons of the study groups were made with the use
of the Tukey adjustment for multiplicity. All t-tests
Of the 60 subjects, 2 had a fever (temperature, up to
39°C [102.2°F]) for 1 or 2 days beginning
11 and 12 days, respectively, after
vaccination. One subject reported a stiff neck on days
12 and 13 after vaccination. One subject reported
intermittent dizziness, floaters, and
tachycardia starting on day 15 after vaccination
and lasting two weeks. One subject had an intermittent
rash on the arms and legs and muscle aches on days
9 through 13. Two subjects had an elevated
alanine aminotransferase level (84
U per liter) on day 28; the elevation resolved two weeks
later in one subject and was still present at the
time of the last follow-up visit in the
other. One subject had a transient, mild
decrease in the hemoglobin level (13.4 to 11.7 g per
deciliter) on day 28. On urinalysis at six
months, one subject transiently had 11 white
cells per high-power field. Three subjects reported
that the skin around the dressing was irritated.
One subject in whom vaccination failed
reported myalgias and pain at the vaccination
site seven days after vaccination. There were no serious
adverse events. One subject who received the 1:100
dilution of vaccine
withdrew after vaccination for reasons unrelated to
the study. Fifty-five of the subjects provided blood
specimens at one year, as planned.
Vaccination success rates — defined by the
formation of a vesicle at the inoculation
site seven to nine days after vaccination —
were dose-dependent (P<0.001 by the Kruskal–Wallis
test): vaccination was successful in 19 of 20
subjects who received undiluted vaccine
(mean viral titer, 107.8 pfu per milliliter;
range, 107.4 to 108.3), 14
of 20 who received a 1:10 dilution (mean
viral titer, 106.5 pfu per milliliter; range,
106.1 to 107.0), and 3
of 20 who received a 1:100 dilution (mean viral titer,
105.0 pfu per milliliter; range, 104.2
to 105.9). The success rate was
significantly lower in the group that received the
1:10 dilution than in the group that received the
(70 percent vs. 95 percent; absolute difference, 25
percent; 95 percent confidence interval for the
difference, 3 to 47 percent; P=0.03 with the
use of asymptotic methods). Once viral
infection of the skin was initiated, the resulting lesion
was approximately 1 cm in diameter, regardless of the
dose of vaccine.
Vaccinia virus was isolated from swab samples of
skin lesions in 35 of the 36 subjects with vesicles.
Among 36 subjects with vesicles, neutralizing
antibody titers and antibody titers on ELISA
increased by a factor of at least 4 at one
month in 34 and 26 subjects, respectively (Table
1). In the 33 subjects with vesicles who
returned for follow-up at one year,
neutralization titers at one year averaged 23.7 percent
of the titers on day 28 (95 percent confidence interval,
7 to 33 percent) and ELISA titers averaged 64.3
percent of the titers on day 28 (95 percent
confidence interval, 44.8 to 96.6 percent) (Table
Clinical Success Rates and Antibody Responses to the
Various Doses of Vaccine
in Subjects Who Had Not Previously Been Vaccinated.
Cytotoxic T-Cell and Interferon-
The development of a vesicle correlated with the
development of cytotoxic T-cell responses in
31 of 32 subjects (of 4 other subjects with
vesicles, 2 had nonviable cells and 2 had a high background
response on the cytotoxic T-cell assay) and an increase
in the number of T cells positive for
by enzyme-linked immunospot assay in 31 of 34
subjects. Figure 2A demonstrates
vaccinia virus–specific cytotoxic T-cell activity
six months after scarification with undiluted vaccine,
the 1:10 dilution of vaccine,
and the 1:100 dilution of vaccine.
When the magnitude of the cytotoxic T-cell
responses was based on the percent lysis
among subjects with vesicle formation in each
group, there was no significant difference between the
group given undiluted vaccine
and the group given the 1:10 dilution (P=0.052),
but the difference between the group given undiluted
and the group given the 1:100 dilution was significant
(P<0.001). None of the subjects had vaccinia
virus–specific cytotoxic T-cell activity on
day 0 (before vaccination). One subject in
the group given the 1:100 dilution did not have a vaccinial
skin lesion but did have a virus-specific cytotoxic
T-cell response after vaccination (Figure
Figure 2. T-Cell Responses
to Vaccinia Virus Six Months after Vaccination with
a 1:10 Dilution of Vaccine,
or a 1:100 Dilution of Vaccine,
According to the Presence or Absence of Vesicle
Formation at the Inoculation Site within Seven to Nine
Days after Vaccination.
Enzyme-linked immunospot assays were used to determine
the number of cells that produced vaccinia
in peripheral-blood mononuclear cells obtained
before and six months after vaccination. As
shown in Figure 2B, the numbers were
significantly different among the three groups. The
presence of cells producing vaccinia
correlated with the development of both a vesicle
and a cytotoxic T-cell response. One subject
who received the 1:100 dilution had a
positive enzyme-linked immunospot assay and a cytotoxic
T-cell response but did not have a skin response
to the vaccine.
Three subjects with vesicle formation did not have
a positive enzyme-linked immunospot assay. In
subjects with vesicle formation, the
magnitude of the interferon-
response was significantly lower among those
given the 1:10 dilution of vaccine
or the 1:100 dilution than among those given
the undiluted vaccine
(P=0.038 and P<0.001, respectively).
Panel A shows the cytotoxic T-cell responses. The
actual values for two outliers are shown. Panel B
shows the number of cells producing vaccinia
Panel C shows the degree of lymphocyte proliferation
in response to vaccination. Two subjects with
vesicles, one each from the group given undiluted vaccine
and the group given the 1:10 dilution, had nonviable
peripheral-blood mononuclear cells (PBMC) and could
not be tested in any of the cell-mediated immune
assays, and one subject in the group given the 1:100
dilution who did not have vesicle formation did not
have blood drawn. One subject each in the group given
and the group given the 1:10 dilution who had vesicle
formation had high background values in the cytotoxic
T-cell assay, which prevented interpretation of the
results (Panel A). The stimulation index is the mean
of the three intermediate values in each replicate of
five. Higher values indicate greater proliferation of
lymphocytes. The number in parentheses indicates the
number of subjects with a stimulation index of 1, all
of whom received the 1:100 dilution. Dashed lines in
Panels B and C indicate the cutoff values for a
Lymphocyte proliferation was induced in response to
vaccinia virus in 33 of 34 subjects with
vesicle formation and in none of 23 subjects
without vesicle formation (Figure 2C).
There were no significant dose-related
differences in the stimulation index at six
months among subjects with vesicle formation, although
there were significant overall dose–response
differences in the stimulation index between
the group given undiluted vaccine
and the group given the 1:100 dilution (P=0.039),
because of the higher frequency of
nonresponse in the latter group. Examination of
peripheral-blood mononuclear cells obtained before
vaccination indicated that none of the
subjects had had previous exposure to the
virus (data not shown).
Immunization with vaccinia virus remains the only
available option for protection against
smallpox infection. The current supply of vaccine
is viable and has a good titer, but dilution of
to titers of less than 107 pfu per milliliter
reduced the rates of successful vaccination.
Serial dilution of the vaccine
stock resulted in nonlinear reductions in the titer
(e.g., a 1:100 dilution reduced the titer from 107.8
pfu per milliliter to 105.0 pfu
per milliliter). This effect may result from
the highly viscous nature of the preparation. As compared
with the 95 percent rate of success associated with
the undiluted vaccine,
the rate of success associated with the dose
of 106.5 pfu per milliliter provided by the
1:10 dilution was 70 percent. This lower rate
is similar to the 75 percent rate reported
among children who were vaccinated with a similar vaccine
and dose (107 pock-forming units per
dose of 105.0 pfu per milliliter provided by
the 1:100 dilution was associated with a
success rate of only 15 percent. These results
indicate that serial dilution of the current vaccine
to less than 106.5 pfu per milliliter
results in a loss of potency (P=0.001 for the
comparison of undiluted vaccine
with a 1:10 dilution alone and P<0.001 for
the comparison of undiluted vaccine
with both dilutions of vaccine).
There was a dose–response effect: higher doses
produced significantly stronger cytotoxic
T-cell and interferon-
responses. Given the small number of subjects
in whom vaccination with a 1:10 or 1:100
dilution was successful, additional study is needed
to confirm these observations. Findings in vaccinated
children and adults with T-cell–related
immunodeficiencies indicate that T-cell
responses are a critical element in the recovery
from pox virus infections.6,7,8
The cytotoxic T-cell and interferon-
responses in our study were much stronger than those
reported after the receipt of experimental HIV-1 vaccines
and correspond to the levels of memory T cells
specific for measles virus in adults16
and to the strength of cytotoxic T-cell responses
recorded in adults after the receipt of yellow fever
In addition, almost all subjects with vesicle formation
had strong vaccinia virus–specific cytotoxic
T-cell responses as well as increased numbers
T cells. These findings suggest that, regardless
of the dose of vaccine,
if a vesicle forms, the resulting brisk T-cell and humoral
responses will be protective.
Diluting the available vaccine
to titers of 106.5 pfu per milliliter or
less reduced the frequency rates of local viral
replication and vesicle formation — effects
that are essential stimuli for protective
immune responses, as evidenced by the lack of antibody,
cytotoxic T-cell, and interferon-
responses. Previous reports in which smallpox
vaccination in patients with defects in
either cellular or humoral immunity led to severe
vaccinia underscore the essential role of
T-cell responses and antibody in protecting
against pox viruses, such as variola.21
In our study, the induction of vaccinia
virus–specific T-cell and B-cell responses
was associated with clinically observable pox
lesions. Previous studies have shown that the response
is attenuated if the route of administration
differs from the one that we used.19,22
We found that the absence of primary skin vesicles
after the administration of diluted vaccine
was associated with the absence of vaccinia
virus–specific T-cell or B-cell responses
and is therefore likely to indicate the absence of
protective immunity. Future studies are needed to assess
the effectiveness of vaccine
titers of 106.5 to 108.0 pfu per
milliliter in both previously vaccinated and
unvaccinated populations. Evaluation of new
should address both T-cell and B-cell
responses. If vaccinations with dilutions of
the current vaccine
are administered, revaccination should be
considered in persons without vesicle formation.
Supported by a contract
(N01-AI-45250) with the National Institute of
Allergy and Infectious Diseases.
We are indebted to James Meegan, Wendy
Fanaroff-Ravick, and Catherine Laughlin at
the National Institute of Allergy and Infectious
Diseases, Bethesda, Md., and John Becher at the CDC
for their assistance and thoughtful discussions,
to Ruth Mazzeo for performing the
proliferation assays, and to the staff at the
Saint Louis University Vaccine
and Treatment Evaluation Unit.
From the Department of Medicine,
National Institute of Allergy and Infectious Diseases Vaccine
and Treatment Evaluation Unit, Saint Louis University
School of Medicine, St. Louis (S.E.F., F.K.N., W.B.S.,
J.M.T., T.P., R.B.B.); the Center for Infectious Disease
Research, University of Massachusetts Medical School,
Worcester (J.C., A.L.R., J.S.K., F.A.E); and the Emmes
Corporation, Rockville, Md. (M.W.).
This article was published at www.nejm.org
on March 28, 2002.
Address reprint requests to Dr. Frey
at the Division of Infectious Diseases and Immunology,
Saint Louis University Health Sciences Center, 3635
Vista Ave. (FDT-8N), St. Louis, MO 63110.
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Responses to Smallpox Vaccine
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Responses to Undiluted and Diluted Smallpox Vaccine
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] [ Full
Text ] [ CME
N Engl J Med 2002; 346:1265-1274, Apr 25, 2002;
published at www.nejm.org
on Mar 28, 2002
(10.1056/NEJMoa020534). Original Articles
Smallpox Vaccine Reactions
From Rashes to
Fevers, Array of Side Effects Is Uncommon Today
By Ceci Connolly
Washington Post Staff Writer
Thursday, December 5, 2002; Page A01
As physical specimens, the Baylor University students
were fit and healthy, the "crème de la crème,"
in the words of researcher Kathy Edwards. Yet when she
inoculated them with smallpox vaccine, arms swelled,
temperatures spiked and panic spread.
It was the same at clinics in Iowa, Tennessee and
California. Of 200 young adults who received the vaccine
as part of a recent government study, one-third missed at
least one day of work or school, 75 had high fevers, and
several were put on antibiotics because physicians worried
that their blisters signaled a bacterial infection.
Even for experts such as Edwards, the Vanderbilt
University physician overseeing the study, the side
effects were startling. "I can read all day about it,
but seeing it is quite impressive," she said.
"The reactions we saw were really quite
Carol Tacket administers the smallpox vaccine to Edward
Dudley in a clinical study by the University of Maryland
Medical Center. President Bush is poised to announce
plans to resume vaccinating Americans to protect the
nation from a biological assault. (Dennis
Drenner For The Washington Post)
President Bush is poised to announce plans, perhaps as
early as this week, to resume vaccinating Americans
against smallpox as part of a massive push to protect the
nation from a biological assault. As he weighs the
decision, researchers are becoming reacquainted with the
unpleasant -- often severe -- complications of the
The experiences in a half-dozen clinical trials offer
an early look at what military personnel, hospital workers
and other emergency workers will likely encounter if Bush
adopts the recommendations of his top health advisers to
vaccinate as many as 11 million people in the coming
months. What is disconcerting, say the people
participating in the clinical trials, is that when it
comes to smallpox vaccination, what had once been
considered ordinary is rather extraordinary by today's
"I just wanted to go to bed for a day or two
there," said Alison Francis, a New York University
graduate student who received the vaccine. Francis, 24,
said she felt tired and achy after getting her shot. Her
arm was heavy, warm to the touch and terribly itchy.
"I thought, 'Can you just chop off my arm?' "
Participating in the study was part patriotism and part
selfishness, she said. "Now I'm protected."
Once among the deadliest scourges on earth, smallpox
was declared eradicated worldwide in 1981. But growing
hostilities with Iraqi President Saddam Hussein, Osama bin
Laden and others have renewed fears that the virus could
be used as a potent, stealthy weapon. Vaccination is
surefire protection against the disease, but it is risky.
For every 1 million vaccinated, between 15 and 52 people
will suffer life-threatening consequences such as brain
inflammation, and one or two will die, according to
historical data. Pregnant women, babies, people with
eczema or weakened immune systems should not receive the
Federal health officials have proposed resuming
vaccination in stages, beginning with as many as 500,000
hospital workers most likely to see an initial case.
Later, as many as 10 million police, fire and medical
personnel would be offered the vaccine. The Pentagon hopes
to vaccinate 500,000 soldiers.
Over the past year, federal researchers have been
testing the 40-year-old vaccine for its safety and
potency. None of the 1,500 volunteers has died or been
seriously injured by the vaccine. But even the most
mundane cases can be disturbing to doctors and patients
unaccustomed to the live virus used in the vaccine and its
Unlike most modern vaccines, the smallpox vaccine is
administered by 15 quick pricks that "establish an
infection in your skin," said Julie Gerberding,
director of the Centers for Disease Control and Prevention
in Atlanta. "There is the immediate discomfort of
getting poked in the arm and a range of annoying
Within three to four days, a red itchy bump develops,
followed by a larger blister filled with pus. In the
second week, the blister dries and turns into a scab that
usually falls off in the third week. During the three
weeks, many people experience flu-like symptoms -- aches,
fever, lethargy -- and terrible itchiness.
"You can't scratch it; it's all bandaged up; all I
could do was smack it," said Meg Gifford, a
University of Maryland junior who participated in one
study. For a weekend, she was "pretty
miserable," suffering from a slight fever, an arm
that was hot to the touch and swollen lymph nodes in her
At the University of Rochester Medical Center,
researcher John Treanor saw a wide range of reactions,
from a small rash to swelling the size of a grapefruit.
About 5 percent of the 170 participants had rashes that
spread to other parts of the body. It took time and
experience, he said, for the team to get comfortable with
the natural course of the vaccine.
"The reactions we are seeing are totally out of
line with today's vaccine experience and absolutely in
line with historical experience," said Anthony Fauci,
director of the National Institute of Allergy and
Infectious Diseases. "In the 30 years since we had
routine vaccination, the public's tolerance level has gone
Maryland researchers have begun a second trial
revaccinating older adults to see how much immunity stays
in the system. Early indications are that people who have
been previously inoculated do not suffer as many severe
side effects. "I had a small red mark and that was
about it," said Edward Dudley, 33.
Very few of today's physicians have administered the
vaccine or treated its side effects. Even at the CDC,
where health experts work with an array of germs, smallpox
vaccinations were briefly halted when 10 people had
serious enough reactions to begin antibiotics, said Walter
Orenstein, director of the CDC's National Immunization
"The clinic physician couldn't decide if this was
a normal, primary exuberant take or a bacterial
infection," he said. He added that, in fact, the
swollen, itchy, red arms were routine.
As a first-year medical student 33 years ago, Orenstein
was so alarmed by the fever, swollen glands and red streak
up his arm after he was vaccinated that he went to the
emergency room for antibiotics. "I respect this
vaccine," he said.
If Bush moves forward with vaccination, Edwards warns
doctors to expect the array of unsightly, unfamiliar
complications that will come.
"You are going to have to be prepared to see these
individuals and to see really bad takes," she told
state health officers. "You'll wonder if they are
bacterial infections; in some cases the rash will move up
the arm and onto the chest. The vaccinee requires a lot of