Dr. Meryl Nass, a member of the board of The Alliance for Human Research Protection and a recognized expert on Gulf War Syndrome and the use and consequences of experimental vaccines, raises serious concerns about the safety and wisdom of innoculating a large population with the unapproved experimental smallpox vaccine.

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An estimated 500,000 first responders, lab and hospital workers will receive smallpox vaccine, the DHHS announced yesterday.

This is an interesting announcement, because to my knowledge there exist no FDA-licensed smallpox vaccines.

There are three vaccine candidates whose safety and efficacy are uncertain at this time.

The first vaccine made available was Wyeth's Dryvax, which was pulled out of storage after approximately thirty years. Initial reports indicated that a 1:5 dilution yielded 70% efficacy. However, recent reports indicated that this diluted old vaccine was nearly 100% effective. Which is it? Furthermore, a 1999 report in Science (Marshall E. Bioterror Defense Initiative Injects Shot of Cash. vol 283 pp 1234-5) noted that the rubber seals on the vials were deteriorating, and that 1/4 of the vials "are suspect." Are the suspect vials being diluted to make new vaccine also?

The second vaccine comes from the Aventis stockpile, allegedly "lost" for decades. Millions of doses of vaccine do not get lost. Vaccine lots are required to have a documented testing history, and both the manufacturer and FDA should have records on file of the dates the lots were released and their specifications at the time.

For both these ancient vaccine stockpiles, there exists no approved method by which FDA can legally "relicense" them for current use based on test results generated today. There is no way long-expired product can be "regenerated" for licensure within current FDA regulations.

The third vaccine candidate is the Acambis (previously Oravax, using Baxter as subcontractor) smallpox vaccine. This is a new vaccine whose makeup, as well as its safety and efficacy profile, have not been publicly discussed. The FDA finalized a rule May 30, 2002 for accepting animal tests in lieu of human tests for efficacy of bioterrorism drugs and vaccines. This opens the door for the new vaccine to receive a full FDA license.

An article in this month's Emerging Infectious Diseases (CDC) by James LeDuc and Peter Jahrling et al indicates that the Acambis vaccine is in Phase I trials and licensure is not expected until sometime in 2003.

When will the public and medical professionals learn all the details needed to make an informed decision about using this new product? This information is not releasable by FDA until after licensure. One hopes that the vaccine will not be used until adequate safety testing has taken place: Phase I trials do not provide thorough information on drug and vaccine safety.

It thus appears that three unlicensed vaccines may soon be available for use in 500,000 Americans. Potentially severe consequences are anticipated in those with eczema, HIV infection, other forms of immune deficiency, and cancers (who are receiving radiation or chemotherapy). There may be other, unknown risk factors that predispose to serious vaccine complications.

The anticipated extent of spread of the varicella virus to contacts of the 500,000 has not been publicly discussed, nor have measures to minimize such spread, although taking such steps is a very important part of protecting the health of contacts. Recall that most of the 500,000 are involved in direct patient care: their contacts are the very people most at risk of varicella's spread.

Are the 500,000 expected to acquiesce to receiving an experimental vaccine(s)? Will they be asked to sign an informed consent, and will the consent ask them to give up any rights to compensation for injuries sustained as a result of vaccination? Will they be placed into clinical trials comparing the three vaccine candidates? Who will pay for deaths and injuries to these vaccine recipients that occur as a result of vaccination? Who will pay for deaths and injuries in their contacts?

Does it make good sense to perform this experiment with all our nation's first responders and a sizable chunk of our lab techs and physicians? Or does it make more sense to start vaccinations slowly and observe closely for problems, so they can be mitigated prior to vaccinating large numbers of critical personnel?

I am a primary care physician with a hospital practice, and I may be one of the designated half million. I daresay that if offered the vaccine, I will not be a "taker". How many of the 500,000 intend to comply with this DHHS directive?

Meryl Nass, MD

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THE NEW YORK TIMES

http://www.nytimes.com/2002/07/07/national/07SMAL.html

July 7, 2002

U.S. to Vaccinate 500,000 Workers Against Smallpox

By WILLIAM J. BROAD

The federal government will soon vaccinate roughly a half-million health care and emergency workers against smallpox as a precaution against a bioterrorist attack, federal officials said. The government is also laying the groundwork to carry out mass vaccinations of the public - a policy abandoned 30 years ago - if there is a large outbreak.

Until last month, officials had said they would soon vaccinate a few thousand health workers and would respond to any smallpox attack with limited vaccinations of the public. Since 1983, only 11,000 Americans who work with the virus and its related diseases have received a vaccination, according to the Centers for Disease Control and Prevention.

The plan to increase the number of "first responders" who receive the vaccination to roughly 500,000 from 15,000 and to prepare for a mass undertaking of vaccinations in effect acknowledges that the government's existing program is insufficient to fight a large outbreak.

The government's new vaccination safeguards come amid continued talk in Washington of war against Iraq, which terrorism experts suspect of maintaining clandestine stocks of the virus, as well as growing criticism of the government's limited plan. Only Russia and the United States have declared stocks of the virus.

A highly contagious disease, smallpox was declared eradicated globally in 1980, eight years after the United States stopped routine vaccinations.

Until its eradication, smallpox killed roughly one in three people who were infected but not vaccinated. Because immunity is believed to diminish with time, most people alive today are considered vulnerable to smallpox. But federal officials have long resisted the resumption of mass smallpox vaccinations, citing the probable risk of serious side effects, even death.

Last month, a federal advisory panel backed a plan for "ring vaccinations," in which health workers would isolate infected patients and vaccinate people in close contact with them, forming a ring of immunization around an outbreak and a barrier to its spread. In theory, such a strategy can work because the vaccine, if given within four days of exposure to the virus, protects people from the disease.

Some experts on infectious disease said the plan's main virtue was that it required little smallpox vaccine.

The government's more aggressive plans are possible because vaccine supplies are rapidly increasing as a result of crash manufacturing and stockpiling efforts begun soon after last fall's terrorist strikes, officials said. Also, studies have found that existing vaccine doses can be diluted without loss of effectiveness.

"Now we can act differently because we have more vaccine," Dr. Donald A. Henderson, senior science adviser to Tommy G. Thompson, the secretary of health and human services, said in an interview. Dr. Henderson, who led the global smallpox eradication effort, added that in a crisis "we can make vaccine available on request throughout the community."

Officials said that about 100 million doses of the smallpox vaccine (160 million if diluted) are in hand and that by late this year or soon thereafter enough will be available for every American, more than 280 million people.

Health and military experts, citing new models of how the contagion can spread and new disclosures about how the weaponized virus can sail on the wind, have recently argued that limited, local vaccinations could produce thousands if not millions of needless infections and deaths. Most critics of the ring vaccination plan advocate mass vaccinations of the United States population - but often before a smallpox attack, not after, as the government is now planning.

In addition to vaccinating more "first responders," the government plans to develop ways to speed vaccine deliveries around the country and help states plan how to carry out mass vaccinations after an attack.

Officials said the vaccinations of hospital workers and smallpox response teams, to begin fairly soon, would help train health professionals in smallpox vaccination and educate the public to the attendant risks.

The White House, Defense Department and other federal agencies are involved in the vaccination planning. "Everyone is aware," an administration official said.

Jerome M. Hauer, acting assistant secretary for emergency preparedness at the Department of Health and Human Services, said the agency hoped to send planning documents on how to best conduct mass vaccinations to cities and states in the next week or two. Mr. Hauer added that logistics changes to that end were under way at the Centers for Disease Control and Prevention in Atlanta, which oversees the production, safekeeping and distribution of the nation's stockpile of smallpox vaccine.

Other details of the plans, such as who would receive peacetime vaccinations, have yet to be approved by Mr. Thompson, officials said.

In interviews last week, health officials said the government had not abandoned its longstanding plan for ring vaccinations of people near a smallpox outbreak, the approach health workers used decades ago to eradicate the highly contagious disease from human populations. But the added steps, officials said, will make it possible to move far more aggressively if a terrorist attack ends up infecting more than 100 people or so.

Critics had said the ring approach, while useful in battling natural outbreaks, would do little or nothing against a moderately skilled enemy intent on mayhem.

"Unless the initial attack is very small and the infectiousness of the agent is quite mild, ring vaccination is not going to do much good," said Edward H. Kaplan, a Yale public health specialist who questioned the method's value at a federal meeting in Washington three weeks ago.

In a report, the Cato Institute, a policy group in Washington, called ring vaccination "woefully inadequate for countering a direct attack."

Critics argued that a number of factors had diminished the method's effectiveness since the disease was eradicated in 1980: populations are now increasingly mobile, levels of immunity are very low and advanced technologies have become commonplace, raising the odds that a smallpox attacker would be at least moderately skilled.

"Today it's a totally different scenario," said William J. Bicknell, an international health expert at Boston University who recently faulted federal smallpox policy at a Cato meeting. The ring plan, he declared flatly in an interview, "will not work."

Federal officials said the rising criticism played no direct role in shaping preparations for mass vaccinations.

"The key to responding to any public health emergency is flexibility," Mr. Hauer said. "You listen to critics, but you can't let that drive policy. You have to do what's best for public health and national security."

Ring vaccination, he added, was envisioned as simply a first line of defense that could quickly expand to much wider immunizations if necessary.

Mr. Hauer added that the ring strategy was inherently small-scale because it required health professionals to carefully trace the whereabouts and contacts of infected people. Such work is so hard and time consuming, he noted, that ring vaccination is unsuitable as the only means of fighting a wide epidemic.

He said another complication could arise if the disease broke out simultaneously in multiple cities, suggesting a strike of unknown size and danger. In that case, he said, "the forces pressing you to mass vaccinate become greater."

Dr. Henderson, the chairman of the Secretary's Council on Public Health Preparedness at the Department of Health and Human Services, said critics have falsely portrayed the government as relying exclusively on ring vaccination.

"Let me be clear," he said. "If there is an emergency, and if we have to vaccinate widely, we need to be ready for it. That's what we're doing."

Mass vaccinations are not without risk because the smallpox vaccine uses a live virus, vaccinia, a cousin of smallpox, that on occasion can cause brain damage or even kill. In the days of wide vaccination, roughly one person in a million died.

The risk may be greater for people with weakened immune systems, like AIDS patients or people undergoing chemotherapy.

The government is seeking more supplies of vaccinia immune globulin, a substance now in short supply that can prevent severe reactions in people with immune problems as well as the healthy. Officials said 700 doses are in hand and 3,000 will be available by the year's end.

Despite the vaccine's well-known dangers, federal critics have increasingly called for various styles of mass vaccination - including doing it on a voluntary or mandatory basis, before or after a smallpox attack.

At a June 15 public forum in Washington on federal smallpox vaccination policy, Dr. Kaplan, of Yale, presented a study done with colleagues from the Massachusetts Institute of Technology that described how a smallpox attack could affect a crowded metropolitan region like New York City. What began as 1,000 infections at a train station or airport, he said, would spiral over weeks and months into 97,000 deaths if fought with ring vaccination alone.

"By contrast," he said, "post-attack mass vaccination would result in only 525 deaths" from the smallpox virus, which takes about two weeks to develop in the body before symptoms become obvious.

Some federal officials call this study unrealistic. But at the meeting, such ideas gained force as new evidence came to light on how powdered smallpox can be used as a biological weapon.

Dr. Alan P. Zelicoff, a smallpox expert at the Sandia National Laboratories, reported that he and experts from the Monterey Institute of International Studies had linked a 1971 outbreak in the Kazakh Republic to a Soviet field test of weaponized smallpox.

Dr. Zelicoff, a physician, quoted a former Soviet official as saying the accident occurred when a plume of smallpox germs sailed about nine miles on the wind.

By the meeting's end, medical experts were questioning not only the ring plan but also federal assertions that the smallpox threat is low.

Dr. Kenneth I. Berns, president of the Mount Sinai Medical Center in New York City, said he judged the probability that Iraq possessed weaponized smallpox as "reasonably high" and that Saddam Hussein would use such germs in a war against the United States as "quite high."

"That's the confounding issue that we all face," Dr. Berns told the forum, according to a transcript.

Frank public discussion of the Iraqi threat, he added, "is absolutely essential."

In interviews, officials of the Department of Health and Human Services declined to comment on federal threat assessments but detailed wide contingency planning for mass smallpox vaccinations.

On June 20, a federal panel known as the Advisory Committee on Immunization Practices backed the idea of immunizing some emergency workers before any attack. Experts estimated that the immunizations would go to some 15,000 health care and law enforcement workers who would be most likely to respond to a biological attack and come in contact with victims.

But Dr. Henderson, the health department's senior adviser on bioterrorism, said the tentative new plan was for many more to be vaccinated. "We could easily be at a half-million without too much difficulty," he said.

Wide peacetime vaccinations, he said, would help educate not only the nation's medical community on the practical aspects of smallpox immunization but also the public.

If the peacetime group suffers a couple of deaths, "there will be a lot of publicity and concern," Dr. Henderson said. "It's a question of how people are going to respond."

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