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Safety and Efficacy of the Smallpox Vaccine


TABLE OF CONTENTS


 

  • A Smallpox Shot in the Dark

    • By Henry I. Miller

    • The Scientist 16[2]:64, Jan. 21, 2002

 

  • Law Limits Smallpox Vaccine Compensation

    • Some Injured by Smallpox Vaccine Won't Qualify for Compensation

    • The Associated Press

 

  • Real Risks of Smallpox Debated
    • Daniel J. DeNoon
    • Medscape Medical News

 

  • Resuming Smallpox Shots Carries Risk

    • By DENISE GRADY

    • New York Times

    • December 12, 2002

 

  • Smallpox Vaccination: On Hold, But Lessons Learned

    • CDC panel recommends just starting with frontline personnel, not the general population

    • By Ricki Lewis

    • The Scientist, Volume 16, Issue 14 (29) Jul. 8, 2002

 

  • Studies Cite Smallpox Vaccine Tradeoff

    • Mass Inoculation Might Kill Hundreds, Save Thousands

    • By Susan Okie

    • Washington Post Staff Writer

    • Wednesday, May 8, 2002; Page A03

 

 

  • Dose-Related Effects of Smallpox Vaccine

    • 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.

    • New England Journal of  Medicine 2002; 346:1275-1280

 

  • Smallpox Vaccine Reactions Jolt Experts. From Rashes to Fevers, Array of Side Effects Is Uncommon Today

    • By Ceci Connolly

    • Washington Post Staff Writer

    • Thursday, December 5, 2002; Page A01

 

 

United States Department of Health and Human Services

Smallpox

http://www.smallpox.gov/

Public Inquiries Hotline (Centers for Disease Control and Prevention):
English (888) 246-2675

 


A Smallpox Shot in the Dark

By Henry I. Miller

The Scientist 16[2]:64, Jan. 21, 2002

http://www.the-scientist.com/yr2002/jan/opin_020121.html


Anthony Canamucio

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 healthy individuals.

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 disseminate.

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 as desired."

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 (miller@hoover.stanford.edu), MD, is a fellow at the Hoover Institution and the author of To America's Health: A Proposal to Reform the Food and Drug Administration (Hoover Institution Press).


Law Limits Smallpox Vaccine Compensation

Some Injured by Smallpox Vaccine Won't Qualify for Compensation

The Associated Press

http://abcnews.go.com/wire/Living/ap20021215_711.html

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 die.

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 said.

But people who get sick by coming into contact with someone who was inoculated have no real option, officials allowed.

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 closing them."


Resuming Smallpox Shots Carries Risk

By DENISE GRADY

December 12, 2002

http://www.nytimes.com/2002/12/12/health/12POX.html

http://www.nytimes.com/2002/12/12/health/12POX.html?pagewanted=print&position=top

A New York youngster is immunized against polio, 1955.
A New York youngster is immunized against polio, 1955. Photo by Ernie Sisto.

Most 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 school.

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 United States.

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 smallpox virus.

Special semi-permeable bandages may help prevent newly vaccinated people from transmitting vaccinia to others, but the bandages have to be worn for several weeks.

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 be uncontrollable.

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.


Real Risks of Smallpox Debated

Daniel J. DeNoon

Medscape Medical News

http://www.medscape.com/viewarticle/446692_print

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 smallpox facts.
  • 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 worst-case scenario.

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 relatively simple."

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 attack.

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 vaccination program."

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 treatment.
  • 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 vaccination.

"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.

 

 


Smallpox Vaccination: On Hold, But Lessons Learned
CDC panel recommends just starting with frontline personnel, not the general population

By Ricki Lewis

http://www.the-scientist.com/yr2002/jul/lewis_p29_020708.html

The Scientist Volume 16 | Issue 14 | 29 | Jul. 8, 2002

the scientist logo

Image: Courtesy of the CDC
 THE FACE OF SMALLPOX

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 vaccine.

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 Inc.

 Donald Francis

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 says.

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 doses.

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 with it."

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 (rickilewis@nasw.org) is a contributing editor.

References

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, 2002.

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.

 

SMALLPOX TIMELINE

  • 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 paper.

  • 1853 UK makes infant vaccination compulsory.

  • 1966 Two million people die of smallpox each year; WHO Global Smallpox Eradication Campaign begins.

  • 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, in Somalia.

  • 1978 Last known case of smallpox, in UK laboratory worker; 76 laboratories worldwide claim to have smallpox strains.

  • 1980 WHO declares global smallpox eradication.

  • 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 bioattack.

  • 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 vaccination.


Studies Cite Smallpox Vaccine Tradeoff
Mass Inoculation Might Kill Hundreds, Save Thousands

By Susan Okie
Washington Post Staff Writer
Wednesday, May 8, 2002; Page A03

washingtonpost.com

http://www.washingtonpost.com/wp-dyn/articles/A49456-2002May7.html

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 effects.

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 years old.

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 June 25.


Guest Editorial: A Family Doc Looks at Smallpox

Jonathan L. Temte, MD, PhD

From Medscape Infectious Diseases
Posted 10/17/2002

http://www.medscape.com/viewarticle/443051

Medscape

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.[1] 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."[2] 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.[2] 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 history.

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.[3] 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.[4] 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.[5] 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.[8] 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.[9] 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.[3] 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 1)[10-12]:

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.[11] It is worthwhile to note that the estimates for adverse effects were conservative, due to probable underreporting[2] 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.[11] 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 unacceptable.

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.[3]

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.[3] 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 population.

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 diagnosed?
  • 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 vaccination?
  • Is the presence of severe chronic disease(s) a relative contraindication?
  • 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 resource.

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: jtemte@wingra.fammed.wisc.edu.

 


Dose-Related Effects of Smallpox Vaccine

Sharon E. 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.

Original Article
Volume 346:1275-1280 April 25, 2002 Number 17

http://content.nejm.org/cgi/reprint/346/17/1275.pdf

Dose-Related Effects of Smallpox Vaccine
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 Text ]  
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

ABSTRACT

Background
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 interferon-{gamma}–producing T cells.

Methods
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.

Results
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 interferon-{gamma} responses occurred in 94 percent of subjects with vesicles, and a cytotoxic T-cell response occurred in only one subject without a vesicle.

Conclusions
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.


 

Smallpox vaccine (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 agammaglobulinemia.6,7,8 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 lyophilized vaccine, 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 a vaccine 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.

Methods

Vaccine

The vaccine (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 the vaccine 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.

Figure 1. Typical Vesicle on the Upper Arm 10 Days after Scarification.
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 previously.10 Neutralization 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 described previously.11 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 Detrick, Md.).

Cytotoxicity Assays

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 described previously.14,15 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 exponential-fit method16 with the use of commercial software (Proteins International, Rochester Hills, Mich.).

Interferon-{gamma} Assays

A modified enzyme-linked immunospot assay was used to detect live virus-specific release of interferon-{gamma} 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-{gamma}–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-{gamma} are CD8+.

Proliferation Assays

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).

Statistical Analysis

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 acceptable vaccine 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 for trend.18

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 were two-sided.

Results

Clinical Findings

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.

Success Rates

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 undiluted vaccine (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.

Antibody Responses

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 1).

Table 1. 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-{gamma} Responses

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 virus-specific interferon-{gamma} 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 vaccine 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 2A).

Figure 2. T-Cell Responses to Vaccinia Virus Six Months after Vaccination with Undiluted Vaccine, 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.

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 virus–specific interferon-{gamma}. 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 undiluted vaccine 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 positive response.

Enzyme-linked immunospot assays were used to determine the number of cells that produced vaccinia virus–specific interferon-{gamma} 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 virus–specific interferon-{gamma} 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-{gamma} 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).

Lymphocyte Proliferation

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).

Discussion

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 the vaccine 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 milliliter).19 The 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-{gamma} 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-{gamma} 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 vaccine.20 In addition, almost all subjects with vesicle formation had strong vaccinia virus–specific cytotoxic T-cell responses as well as increased numbers of interferon-{gamma}–producing 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-{gamma} 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 cell-culture–derived vaccines 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.

Source Information

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 and Vaccine 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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Related Letters:

Responses to Smallpox Vaccine
Sauri M. A., Frelinger J. A., Garba M. L., Belshe R. B., Frey S. E.
[ Full Text ]  N Engl J Med 2002; 347:689-690, Aug 29, 2002. Correspondence

This article has been cited by other articles:

 

  • Committee on Infectious Diseases, (2002). Smallpox Vaccine. Pediatrics 110: 841-845 [Abstract] [Full Text]  
  • Sauri, M. A., Frelinger, J. A., Garba, M. L., Belshe, R. B., Frey, S. E. (2002). Responses to Smallpox Vaccine. N Engl J Med 347: 689-690 [Full Text]  
  • (2002). Efficacy and Safety of Resurrected and Diluted Smallpox Vaccine. Journal Watch Infectious Diseases 2002: 1-1 [Full Text]  
  • Breman, J. G., Henderson, D.A. (2002). Diagnosis and Management of Smallpox. N Engl J Med 346: 1300-1308 [Full Text]  
  • Frey, S. E., Couch, R. B., Tacket, C. O., Treanor, J. J., Wolff, M., Newman, F. K., Atmar, R. L., Edelman, R., Nolan, C. M., Belshe, R. B., the National Institute of Allergy and Infectious D, (2002). Clinical Responses to Undiluted and Diluted Smallpox Vaccine. N Engl J Med 346: 1265-1274 [Abstract] [Full Text]  
 

Clinical Responses to Undiluted and Diluted Smallpox Vaccine
Frey S. E., Couch R. B., Tacket C. O., Treanor J. J., Wolff M., Newman F. K., Atmar R. L., Edelman R., Nolan C. M., Belshe R. B., the National Institute of Allergy and Infectious Diseases Smallpox Vaccine Study Group. [ Abstract ] [ Full Text ] [ CME Exam ]  
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 Jolt Experts
From Rashes to Fevers, Array of Side Effects Is Uncommon Today

By Ceci Connolly
Washington Post Staff Writer
Thursday, December 5, 2002; Page A01

http://www.washingtonpost.com/wp-dyn/articles/A11192-2002Dec4.html

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 remarkable."


Dr. 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 vaccine.

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 standards.

"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 vaccine.

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 side effects.

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 reactions."

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 armpit.

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 way down."

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 Program.

"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 TLC."


 

 

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