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Harvard Public Health Review/Summer 2002

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Our Best Shot

I'm too good at what Ido," laughs Professor Marie McCormick, when asked how she got drawn into her most recent stint at the National Academy of Sciences' Institute of Medicine (IOM). What McCormick does too well is head up fast-track investigative committees for the IOM, assisting in its mission to advance and disseminate scientific knowledge about human health. Her success in this arena, most notably on the prevention of mother-to-child HIV transmission, led the organization to approach her with a new mandate in 2001: to chair the IOM's committee on immunization safety. The multidisciplinary group, consisting of McCormick and 15 other health professionals, has been charged with assessing the validity of the relationship between vaccines and adverse health outcomes, producing three comprehensive reports each year for three years. The task is daunting, and reaction to their findings thus far has ranged from relief to rancor.

Last May at a congressional hearing, an irate Representative Dan Burton (R-Ind.) squared off against McCormick and her colleagues over the immunization committee's first report, which found no evidence of a causal connection between the measles, mumps, and rubella vaccine (MMR) and autism. Burton, whose grandson was diagnosed with regressive autism shortly after receiving his MMR shot, remains adamantly convinced that the vaccine was responsible for the boy's illness and has consequently given the issue a lot of political air time. One look at the Internet shows that he's not alone in his convictions; the overwhelming majority of the immunization information on the Web today is anti-vaccine, citing connections to ailments ranging from autism to autoimmune disorders. However, the committee's work to date has found little to support these allegations. Since its initial report on MMR and autism, the committee has also found several other reputed links between vaccines and adverse events--thimerosal (a mercury-based vaccine preservative) and neurodevelopmental disorders; multiple immunizations and immune dysfunction; hepatitis B and multiple sclerosis--to have little or no empiric support.



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From the perspective of the public health community, the committee's formation and subsequent findings couldn't have come soon enough. Although one of the most successful public health initiatives in this country, there's a lingering distrust of the vaccine program. While evidence of a constantly improving vaccine monitoring system, the 1999 recall of the rotavirus vaccine and recent precautionary measures on thimerosal use and polio vaccines seem only to have heightened rather than eased parental anxiety. That certain diseases, like autism, tend to show themselves in childhood at the same time kids receive their immunizations has left many parents wondering: is it coincidence or is it causal? Add in the abundance of misinformation floating around the Internet and health professionals worry that parents' fears about extremely rare vaccine side effects will start to overshadow the unprecedented health benefits gained during the immunization era. "The evidence is not very strong for some of these associations, at best," notes McCormick, chair of the Department of Maternal and Child Health at the Harvard School of Public Health. "So they would be trading off a hypothetical risk against a very real risk of a bad disease."

Fears about vaccine safety are nothing new. During the 1800s, antivaccination leagues sprang up across the Northeastern United States in response to mandatory smallpox immunizations, amid concerns that they were dangerous and ineffective. With 20-20 hindsight, it is easy to be dismissive about their apprehension. In 1980 smallpox--which as recently as 30 years ago was endemic in 31 countries and killed more than two million people annually--was declared eradicated, due above all to a worldwide vaccination campaign lasting more than a decade. But because most parents who make immunization decisions are under age 35, vaccines may now be victims of their own success. "We now have a generation of parents and even grandparents who've never seen these diseases," says McCormick. "They don't remember what wild-type measles or congenital rubella looks like. So I think one thing is to remind people that these are not benign diseases--we went after vaccines for these diseases because they're that serious."

Under the current vaccination schedule, children in the US receive 23 shots against 11 diseases before starting kindergarten. Before the vaccines were introduced, the peak toll of ten of these diseases--diphtheria, measles, mumps, rubella (German measles), pertussis (whooping cough), polio, tetanus, hepatitis B, pneumococcus, and Hib meningitis--was nearly two million reported cases each year. And while these vaccines resulted in a substantial reduction in these diseases--up to 95 percent in several cases--studies have shown that most of them still pose a real threat to children if total immunization rates go down. A 2000 study in the Journal of the American Medical Association found that unvaccinated children (with religious/philosophical exemptions from the law) were more than 22 times as likely as their vaccinated counterparts to develop measles and almost six times as likely to develop pertussis. The researchers also concluded that because vaccines don't as yet provide 100 percent protection in every child, the more kids that go unvaccinated, the higher the risk for these diseases in vaccinated children and the greater likelihood of outbreaks. Indeed, a precipitous decline (from over 80 percent to under 30 percent) in pertussis vaccine rates in Japan and the UK during the 1970s over rumors of safety concerns led to major nationwide whooping cough epidemics.

In contrast, even the worst known complications of these vaccines are relatively rare. For example, the risk of thrombocytopenia (a rapid decline in blood platelets), which occurs in 1 per 20,000--40,000 individuals receiving the MMR vaccine, is far outweighed by the high risk of thrombocytopenia, hospitalization, and death due to natural measles alone. But is this really a comfort to parents who fear it will be their child who will fall victim to that one rare event? "I think it really depends a lot on the parent," says Tracy Lieu, associate professor in the School's Department of Health Policy and Management and a pediatrician and researcher with Harvard Pilgrim Health Care. "It's not a question that I can answer easily with a sound byte because parents come at this issue from many different angles and many different experiences. Often the underlying issues are a little more complex than 'vaccines are bad.'"

Just ask Alberto Ascherio. When reports of a possible connection between the hepatitis B vaccine and multiple sclerosis (MS) came out during a mass vaccination campaign in France during the mid-'90s, Ascherio, associate professor of nutrition and epidemiology at the School, thought he might be able to help. Working on risk factors for heart disease and neurological disorders in the landmark Nurses' Health Study, Ascherio found himself "sitting on" a vast amount of potentially useful data from a very large and highly vaccinated (they're nurses after all) population of women. His subsequent study, published in the New England Journal of Medicine, did not support an association between hepatitis B vaccination and the development of MS. For this researcher, who studied immunization programs in developing countries early in his public health career, vaccinating his own children would seem a foregone conclusion. But the real world is not so simple. Ascherio's daughter, who was born in Italy and never received her hep B vaccine, was due to be immunized just around the time her father began his vaccine study. "She was 12, about to be vaccinated, and there was this concern," recalls Ascherio. "Given that her grandmother had MS, she had something of a family history too. So I thought, should I wait? Should I vaccinate?" He smiles. "I would say our own results were reassuring, certainly."

In the end, Ascherio did vaccinate his children because he believed, in the grand public health scheme, that it was the right thing to do. (The fact that he eschews the Internet probably didn't hurt either.) And he recently presented his findings in an open session of McCormick's IOM committee, which provides a forum for both commissioned experts and advocates to express their views. Ascherio dismisses arguments of some advocates that the hep B vaccine is overkill for small children in low-risk environments because it is trans-mitted by blood and bodily fluids. "Predicting which children will be exposed to hepatitis B is very difficult," he says. Public health experts agree that identifying and selectively vaccinating children who would be at high risk later in life is virtually impossible.

But the argument for selective vaccination will likely become more powerful as more specialized and tailored vaccines come down the pike--vaccines that may not be for everyone. For them, thoughtfully weighing the risk of an adverse outcome with the benefit of the vaccine might be a more reasoned approach than mandating them outright. "I think vaccine safety, it's a field that will periodically have to face this problem," says Ascherio. "It's almost inevitable, when you're vaccinating people that some potential connection will be brought up because it's ultimately very, very difficult to exclude rare adverse effects. There's no conceivable study with enough power to exclude small increases in risks, so it's really difficult to be 100 percent certain."

While certainty is unattainable, no one will deny that being armed with the most information possible is the best way to keep everyone healthy and safe when it comes to vaccines. And it is here where McCormick agrees with the advocacy groups that the system needs to be enhanced. She hopes that her IOM committee, which (unlike previous immunization committees) is allowed to recommend new areas of investigation and policy, will give vaccine safety research a much- needed shot in the arm. "I think if you're going to mandate this kind of thing, then you have to bend over backwards to do everything you can to establish what are real adverse events," she asserts. "I think that there's an obligation to really pursue new avenues of research, to assure vaccine safety, and to be honest when you see something negative happening."

Already the CDC has begun to be more proactive in this regard. Until recently, monitoring of unexpected vaccine complications centered around a federal program called the Vaccine Adverse Event Reporting Systems (VAERS), which relies on voluntary reporting of adverse events. Under VAERS, cases may go unreported and associations remain unproven. To compensate for these shortcomings, the CDC has now set up the Vaccine Safety Datalink (VSD), which works with several large managed care organizations to track vaccine outcomes. "To do these studies well, you really need to go where the patients are," says Lieu, who works at Harvard Pilgrim on its arm of VSD. The huge stable populations of HMOs are ideal for doing active surveillance for rare outcomes that might be missed otherwise. VSD was one of the groups that confirmed the association between the rotavirus vaccine and intussusception, a rare but dangerous bowel obstruction, which resulted in its removal from the marketplace. Lieu and her colleagues are now doing a whole range of vaccine studies, from more traditional adverse-event research in areas like thimerosal and combination vaccines to more unconventional research on issues like delivery rates, immunization coverage, and cost-effectiveness (much of the latter in conjunction with the Harvard Center for Risk Analysis). "Having the Vaccine Datalink project here provides us with a foundation to look at a lot of other interesting vaccine-related questions and actually children's health questions in general," notes Lieu.

The call for more research has, for once, placed the public health and the advocacy groups on the same side of the fence. But, according to McCormick, it will likely be a long road before both sides are completely happy with the vaccine situation in this country. Each side still has its own agenda. She notes the difference in reaction to the IOM committee's study on MMR and autism, which left advocacy groups furious, and its study on multiple immunizations and immune dysfunction: "They said it was a beautiful report because it had the research agenda they've always been arguing for. So people see their own little tree in the forest." But perhaps that's the first step in leading us out of the vaccine-safety jungle.

Alexandra Molloy

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