Wednesday, November 27, 2002

Vaccine tests on kids raise ethics debate

By Tim Bonfield
The Cincinnati Enquirer

To some, the very idea of using children to test a diluted dose of smallpox vaccine borders on criminal abuse in the name of science.

To others, protecting the population from smallpox reflects another security effort made necessary in a world where terrorists have crashed jets into buildings and people have sent anthrax spores in the mail.

To researchers at Cincinnati Children's Hospital Medical Center, this is no abstract academic exercise. They, along with colleagues at Harbor-UCLA Medical Center, stand at ground zero of a national ethics debate over how far the medical world should go to protect people from potential bioterror attack.

And this is a debate that any American can join by submitting their comments to a federal agency by 4:30 p.m. Monday.

What is smallpox?
Smallpox, also known as variola, is a virus that causes a high fever, a rash and blisters that can leave permanent scars. It can be fatal in up to 30 percent of unvaccinated people who become infected. But thanks to many years of worldwide vaccinations, the last case of smallpox in the United States was in 1949. The last naturally occurring case in the world was in Somalia in 1977.
How deadly was the virus?
As late as the 18th century, smallpox killed every 10th child born in Sweden and France. During the same century, every 7th child born in Russia died from smallpox. In 1798, British scientist Edward Jenner demonstrated that inoculation with cowpox could protect against smallpox. By the early 1950s, an estimated 50 million cases of smallpox still occurred worldwide each year. By 1967, the figure fell to about 10 million. By 1977, smallpox was gone.
Who still has the virus?
For years, the only two nations known to possess smallpox were Russia and the United States. More recently, the Bush administration has said the list also could include North Korea, Iraq and France.
What are the symptoms?
After exposure, it takes seven to 17 days to show early symptoms such as headache, backache, vomiting and high fever. Three days later, red spots develop on the face, arms and legs. Then they turn into pus-filled blisters.
How does the disease spread?
Smallpox can be spread from person to person through the air and through exchanges of body fluids such as saliva. It also can be spread from clothing, bed linens and other contaminated areas.
What is the vaccine?
The smallpox vaccine is called Dryvax, also called vaccinia. It is still derived from cows. While far safer than smallpox, the Dryvax vaccine itself is contagious, which means people can "catch" the vaccine without getting a shot.
What are the side effects?
Side effects of the vaccine include: a 1 in 1 million chance of death; a 3 in 1 million chance of encephalitis; a 38 in 1 million chance of cowpox blisters spreading to other parts of the body; and about 600 in 1 million chance of developing bacterial infection at the injection site.
What is the purpose of the vaccine study?
"To evaluate the potency, dose and safety of vaccinia virus vaccine (Dryvax) administered to children in the event there is a smallpox terrorist event."
How would the study work?
Forty children, ages 2 to 5, would be tested; half in Cincinnati, half in Los Angeles. Children would receive either a full vaccine dose or a diluted one. Children also would wear a special long-lasting bandage intended to reduce the risk of spreading the vaccine.
How to comment
Send written comments to Dockets Management Branch (HFA-305), Docket No. 02N-0466, Food and Drug Administration, 5630 Fishers Lane, Room 1061, Rockville. MD 20852. Send E-mail comments to: Click on "Randomized Dose Response Study of Dryvax in Children" Deadline: 4:30 p.m., Dec. 2.
Sources: Cincinnati Children's Hospital Medical Center, the World Health Organization and the Centers for Disease Control and Prevention.
Several months ago, Children's Hospital and the UCLA Center for Vaccine Research proposed launching a study to determine whether a diluted dose of smallpox vaccine would work in children, in case an attack ever happens. The study would involve 40 children, ages 2-5, volunteered by their parents; 20 from Cincinnati, 20 from Los Angeles.

The problem: The vaccine offers no benefit to the child unless America is attacked with smallpox, yet the vaccine has a 1 in 1 million chance of killing the child, and a 3 in 1 million chance of causing encephalitis.

The final decision to do the study rests with the Bush administration - via the Office for Human Research Protections, a unit of the Department of Health and Human Services. A decision is expected early next year.

But first, Uncle Sam wants to know: Should children be allowed to participate in such a study? Of the first 236 comments sent to the OHRP, the public attitude was nearly 10-to-1 against doing the study.

Many questioned the risk of a smallpox attack. Many criticized the idea of using children as research subjects. Even medical experts disagree on the ethics of this situation.

"In this case, the big unknown is, what is the risk of an attack?'' said Dr. David Bernstein, director of the division of infectious diseases at Cincinnati Children's and principal investigator of the Cincinnati part of the smallpox study.

"It's not zero.''

Calculating the dosage

Smallpox is an ancient scourge that once killed millions. But not a single case of smallpox has occurred worldwide since 1977.

For many years, the world's only known repositories of the virus were in the United States and Russia. Earlier this year, however, the Bush administration stated that Iraq, North Korea and France may also have supplies of smallpox.

The study would address what many hope to be a temporary situation. Officials have found more than 75 million doses of leftover smallpox vaccine made as far back as the 1950s. Until efforts to make more vaccine catch up, the old doses could be used in an emergency. However, there isn't enough for every American unless the doses can be diluted.

In adults, studies have already shown that a 1:5 dilution of the vaccine will still produce an immune response that may prevent a person from dying from smallpox. However, study supporters say the adult data is not enough proof that the diluted vaccine will work in children.

"Children are not just small adults," Dr. Bernstein said.

So, the researchers seek 40 children to test the vaccine. Half would get a diluted dose, half would get a full dose.

Just to get to this point, the proposed study was reviewed in detail by three institutional review boards - the hospital committees that must examine any medical experiment involving human subjects. Two approved the project, including the one for Cincinnati Children's, which voted 6-2.

That board concluded that the potential value of the study outweighed the risk to the children involved, said Dr. Irwin Light, chairman of the Cincinnati Children's institutional review board.

The Children's review board discussed many issues about the proposed study, including how to measure the risk of a smallpox attack, how the consent process would be handled, whether a hard-to-remove bandage would really work, even whether the review board itself faced liability if something goes wrong.

"There are differences of opinion. But all these issues were discussed and the decision was not taken lightly," Dr. Light said. "What we recommended was the safest study we could possibly make."

But the Harbor-UCLA board referred the decision to the U.S. Department of Health and Human Services. Representatives of the Harbor-UCLA board declined requests for comment.

According to the board's meeting minutes, the board initially voted 6-5, with one abstention, against approving the study. The proposal did not meet standards for three of four categories of allowable research involving children, members concluded.

The proposed study "was considered inappropriate since the vaccine would not offer the prospect of direct benefit to the individual child, except in the highly remote (with the information available to the committee) possibility that the individual child was exposed to smallpox," the minutes state.

However, the board voted unanimously that the study would be appropriate under a fourth category that requires referring the proposal to the federal government. That category allows research to be conducted for the benefit of society even though the study may not benefit the subjects involved.

The study could present "a reasonable opportunity to further the understanding, prevention or alleviation of a serious problem affecting the health or welfare of children," the board concluded.

Because the vaccine itself involves a live virus, the vaccine can be spread to others who touch the injection site or have other close contact with recently vaccinated people. That means there's a risk of spreading the vaccine to others who may be at risk of suffering side-effects.

To minimize the risk of others "catching" the vaccine, children would have to stay out of day care or school for 30 days. Also, neither the children nor any close family members could have skin problems such as eczema or immune-compromising health problems, such as cancer, liver disease or AIDS. Such conditions are known to increase risk of a bad reaction.

Experts say no one can get smallpox from the vaccine, because it is derived from a smallpox-like virus that affects cows.

The adults in the previous studies were not actually exposed to smallpox, nor would they be in the child study. Instead, the vaccine effectiveness is measured by tracking antibodies and other immune system markers in the blood generated by the vaccine.

A tool to fight terrorism

Supporters say the study is necessary because the threat of a smallpox attack is real enough and the consequences for the largely unvaccinated U.S. population could be staggering.

Death estimates from a smallpox attack range widely, depending on the sophistication and scale of the attack and how quickly public health authorities can establish quarantines and distribute vaccine to prevent the disease from spreading.

A weak attack and a successful response might hold casualties to a few dozen, a few hundred or a few thousand people. But in 2001, the "Dark Winter" exercise held at Andrews Air Force Base and sponsored by four leading anti-terrorism groups indicated that a strong attack and a bumbled response could result in 3 million people infected and 1 million deaths within three months of a smallpox attack.

To avoid such a worst-case scenario, some say the American public should resume mass smallpox vaccination as soon as possible. In America, smallpox vaccine was given to nearly everyone until 1972. That means millions of middle-age and older Americans got the vaccine. However, most scientists say that the protective effects of the vaccine have most likely worn off.

"Weaponized variola, the virus that causes smallpox, could possibly wipe out a generation. The potential for catastrophic consequences from a threat of unknowable credibility surely justifies these vaccine trials," wrote John Buder, a resident of Gainesville, Fla., and a member of the International Network for the History of Public Health.

But what if there is never a smallpox attack? How many deaths from vaccine complications are acceptable to defend the population against a theoretical risk?

Dr. Bruce Bridgeman, chairman of the institutional review board at the University of California Santa Cruz says the risk of a smallpox attack is "vanishingly small."

"Exposing children to a vaccine with a known complication rate with no possible benefit to either them or others borders on the criminal," he wrote in comments submitted Oct. 31.

The actual risk is small because no evidence has been made public that any rogue nation or terrorist even has the virus much less the ability to turn it into a weapon or the will to use it, Dr. Bridgeman said.

Even if the weapons exist, anyone who tries a smallpox attack takes two huge risks: the high likelihood of massive military response from America and her allies plus the very real chance that the disease could boomerang to strike the aggressor's own people.

In times of war, many battlefield decisions must be made with incomplete information. But in medical circles, the lack of evidence of risk brings up the ancient phrase from the Hippocratic oath: "First, do no harm."

Many medications given to children, from chemotherapy agents to antibiotics to prescription-strength pain killers, are far more likely than the smallpox vaccine to trigger harmful side effects - such as potentially fatal allergic reactions and severe organ damage.

But the risk-benefit equation used to give a powerful drug to a child with cancer is totally different from giving even a low-risk vaccine to a child who isn't sick, said Dr. Paul Offit, chief of infectious diseases at the Children's Hospital of Philadelphia and a member of a national advisory committee on immunization practices.

"Vaccines are held to a different standard than other medicines, and that's good, because you're talking about giving them to a healthy child," Dr. Offit said.

"In this study, you're talking about a small number of children, 40 children. So the risks of them suffering a side effect are extremely small," Dr. Offit said. "But still, that risk is bigger than their risk of getting smallpox. The only benefit is theoretical."

So far, 208 of the 236 comments submitted through Nov. 20 about the proposed smallpox study agree with Dr. Offit and Dr. Bridgeman.

The FDA refuses to accept anonymous comments. It posted comments to its Web site only if people provided their addresses and other identifying information. However, the FDA did not post addresses, or even hometowns, of individuals.

"Do not use our defenseless children as guinea pigs for defense against adult threats like bioterrorism, which may or may not materialize," reads a Nov. 5 comment from a Harold Crabill.

"I am outraged at the idea of using children to test, of all things, the smallpox vaccine!!" wrote Naomi Pestana.

But 28 people have said they support the study.

"I am the mother of five children. The youngest is almost 2," wrote Jean Kennedy. "How are we going to know this vaccine works in children unless we test it?"


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