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Bethesda, Md—Combination vaccines containing several antigenic components, making a single dose do double or triple duty, are essential if physicians are to take full advantage of new vaccines being developed to treat childhood diseases, but the road to their full clinical use needs some new markers. This was the essential conclusion from a meeting at the National Institutes of Health (NIH) on issues facing the development and licensure of new combination vaccines. The thrust behind developing new combination vaccines to supplement the ones already in use is that the number of injections now in or to be added to the pediatric immunization schedule is imposing an unacceptable burden on physicians and parents. The current schedule calls for giving a child 15 to 19 injections by 6 years of age—12 of them in the first 18 months of life (JAMA. 2000;283:876-878). And shortly after the Bethesda meeting, a new 7-valent pneumococcal vaccine intended for children in the first 2 years of life was licensed. One way to minimize this burden is to combine the necessary agents into fewer vaccines. Thus, "combination vaccines are not only desirable, they are essential," said Alan Hinman, MD, a consultant to the Task Force for Child Survival and Development, in Decatur, Ga. The issue is how to test such combinations for safety and efficacy under the licensing requirements of the US Food and Drug Administration (FDA), which requires that a combination vaccine not be inferior in "purity, potency, immunogenicity, or efficacy" to each agent given separately. Overall, what emerged from the meeting was the need for some radical new thinking about measurements of efficacy, determination of safety, and postlicensure surveillance. Testing for efficacy In 1993, one of the conclusions of a similar meeting on combination vaccines was that the classic approaches for evaluating the protective effect of vaccines, such as measuring levels of serum antibody, may not be feasible. Not much seems to have changed. As Hinman said, "The good news is that there aren't any new issues. The bad news is that there aren't any new answers." How does one determine if the components of a vaccine, effective when used as single antigens, are equally effective when they are combined? There seemed to be agreement that large efficacy trials may be needed for new vaccine combinations containing unlicensed components, whereas testing of a combination vaccine whose components are already licensed would not have to be as extensive. In addition, the number of antigens in a combination vaccine can influence the numbers of subjects involved in testing. Clinical significance is the issue, and correlates of protection must be developed to allow physicians to focus on what is clinically important, said Kathryn Edwards, MD, professor of pediatrics at Vanderbilt University School of Medicine. The need is particularly acute for pertussis, for there are no agreed on serological correlates of immunity. One possible correlate, said Edwards, is measuring T-cell response to immunization, because "this may be a better way of looking at pertussis vaccines." Some data on combination vaccine effectiveness was presented at the Bethesda meeting by Jay C. Butler, MD, director of the Centers for Disease Control and Prevention's Arctic Investigations Program in Anchorage, Alaska. After vaccination of Alaskan children for Hib was introduced in 1991, the number of cases of Haemophilus influenzae decreased to between 1 and 4 per year. In 1996, to reduce the number of injections, a combined Haemophilus influenzae type b (Hib) vaccine and whole-cell diphtheria, tetanus, and pertussis vaccine (DTwP) was introduced. During 1996 through 1997, there were 16 cases of Hib disease in Alaskan children under 5 years of age who had received this vaccine—four times the number before the combination was introduced. These results may be explained by a report (Lancet. 1996;348:1688-1692) of a reduced antibody response to the polysaccharide of Hib vaccine when it is combined with acellular diphtheria, tetanus, and pertussis vaccine (DTaP). The combined vaccine failed to raise the response to the protective level when administered to infants of 0.15 µg/mL. However, the week before the NIH meeting, the FDA's Vaccine and Related Biological Products Advisory Committee heard a report from Germany on Hib disease surveillance, which noted that in 1996, when a combination Hib and DTaP vaccine became available, there were 30 cases, and in 1997 there were 13. The vaccine was estimated to be more than 99% effective after three doses. Ensuring safety Safety is as important an issue as efficacy. Hinman noted that no one wants to make or use an unsafe or ineffective vaccine. Yet the current system for reporting adverse reactions is not very good, said Robert T. Chen, MD, chief of Vaccine Safety and Development in the CDC's National Immunization Program. The Vaccine Adverse Events Reporting System receives about 11,000 reports a year. "Some of these are real and some are not; some might be vaccine-related, some are not. Sorting them all out is becoming an impossible task," Chen said. Increasingly, "prelicensing evaluations for reasons of safety will increase the cost. This means fewer vaccines will get developed," warned Stanley Plotkin, MD, medical and scientific advisor to Aventis Pasteur, a pharmaceutical firm in Doylestown, Pa. The situation has led to the introduction of the Vaccine Safety Data Link, which uses computers to deal with complexity at various levels. The idea is to group the multiple adverse reactions into about 60 different categories, such as local, systemic, autoimmune, and so on. "It's a type of triage system," Chen explained, "and it might be a more efficient way of sorting through the reports so as to focus our energies on adverse reactions that are worthy of attention." The CDC has contracted with several health maintenance organizations, but so far this reporting system covers only 2% of the population, too few people to gain useful data given the large number of permutations involved. One possible way of enlarging it is to use vaccine registries. "While their primary goal is to improve vaccine coverage, they could be used to provide data on safety as well," Chen said. Judgment important The meeting, of course, had to deal with data: measurements of immunogenicity, efficacy, and safety. However, judgment is also important, said Plotkin, speaking during a discussion period. Judgments about safety may be different depending on the vaccine, he said, adding that if an effective vaccine against HIV were developed, the kind of safety data required would not be as stringent as if the vaccine under consideration was aimed at a less serious disorder. Plotkin recalled the prelicensing debates over the issue of reversion to virulence of the virus in oral polio vaccine. "The kind of safety studies that would have had to be done [today] probably would have prevented or delayed licensure of the vaccine. But at the time we felt that prevention of polio was worth the risk, so the vaccine was licensed. I don't see any way out of including judgment, rather than stark numerical ruling, in the evaluation of data," he said. At the conclusion of the meeting, Hinman concurred, saying "There is a need for judgment in addition to adherence to regulations and numbers. Let us exercise good judgment and see how we can further benefit the world's population through improved provision of safe and effective vaccines. It can only be done though increased use of combination vaccines. If we take risks, let it be in the direction of bringing health improvements to the people of the world."
JAMA – American Medical Association
Published: Mar 8, 2000
Keywords: vaccines
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