March 1996
ROCKVILLE, Md.—The first vaccine containing acellular pertussis is safe and effective for infants, according to a Food and Drug Administration (FDA) advisory panel.
The diphtheria-tetanus-acellular pertussis (DTaP) vaccine (Tripedia, Connaught) reviewed by the FDA's Vaccines and Related Biological Products Advisory Committee is already licensed in the United States for the fourth and fifth doses. It is the first acellular pertussis vaccine to come before the advisory committee for an infant indication.
The application follows the recently completed European studies that showed a variety of acellular pertussis vaccines are safe and effective when used for the primary immunization series (see Infectious Diseases in Children 1995;8[11]:11-18 [not on the website]).
Unlike whole-cell pertussis vaccines, acellular vaccines contain only selected proteins thought to confer immunity. The acellular pertussis products that have been tested contain from one to five components; Tripedia contains two (pertussis toxin and filamentous hemagglutinin). The acellular pertussis component is manufactured by The Research Foundation for Microbial Diseases of Osaka University (Biken).
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The efficacy data presented to the advisory committee were collected from two trials, one conducted in Sweden from 1986 to 1987 and the other from a recently completed German study. Although the Swedish study was a large, randomized, double-blind study, more weight was placed on the German case-control study because the dosing regimen mirrored that of the United States (i.e., 2, 4, 6, and 18 months).
The efficacy rates varied by study and by how strictly pertussis was defined. Using a definition of less severe disease, the Swedish found an efficacy rate of 69%, and the German trial determined the rate to be 82%. When pertussis was defined by paroxysmal cough lasting 21 days or longer, the efficacy rates for both trials were more than 80%.
Although panel members were uncertain how those rates would translate to U.S. children, they were convinced that the vaccine would be sufficiently effective in infants. In addition, acellular pertussis vaccines may have a "hidden" efficacy over and above that demonstrated in clinical trials.
"The exact figure of efficacy is probably less important," according to Caroline Breese Hall, MD, Professor of Pediatrics and Medicine, University of Rochester School of Medicine and Dentistry, New York. "The long-term pragmatic outcome is going to be even greater efficacy just because of the acceptability of this particular vaccine."
The vaccine is hoped to be more widely accepted because of its safety profile. Both local reactions—such as tenderness, erythema, and swelling—and systemic reactions were significantly lower for children who received acellular pertussis vaccine compared with those who received whole cell vaccine.
The committee members agreed that the available data indicate that the vaccine is safe, but they also noted that large-scale postlicensure studies are necessary to identify the rare neurologic adverse events that are believed to be associated with whole-cell pertussis vaccines.
"In most circumstances, we do not expect to have a clear idea of what rare, very serious, unexpected event rates would be in a premarketing study," according to Thomas Fleming, PhD, Department of Biostatistics, University of Washington, Seattle. "It is my sense, looking at the data, that the rate of frequently occurring and less common adverse events are at least as favorable if not more favorable [than with the whole cell vaccine]...This is where we would hope to have a product that would, in fact, be better than the whole-cell [pertussis vaccine]."
The committee suggested other areas where additional research is warranted. For example, minimal data were available concerning simultaneous administration of DTaP with other routine pediatric vaccines.
Perhaps the most complex issue surrounding all pertussis vaccines is that no reliable marker has been found that predicts the effectiveness of a vaccine. Antibody levels do not necessarily correlate to immunogenicity.
"In all of the trials that have been conducted so far, no correlate of protection has been found," said Carlton Meschievitz, MD, Executive Director for Medical Affairs, Connaught.
The FDA will make the final decision on licensure. Although it usually follows the recommendation of its advisory committees, it is not bound by their decision.
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