Evaluating the Immune Response to Combination Vaccines

Clinical Infectious Diseases, Dec 2001

Assessment of the immune responses to combination vaccines in the United States has generally been based on randomized, controlled comparative trials, with such studies designed to rule out predefined differences. In designing clinical studies of the immune response to combination products, attention should be directed toward selecting the appropriate immunologic end points and control groups. Acceptable differences in immune responses between combination and control groups should be predefined, and an adequate statistical plan should be developed. In many cases, it may be necessary to evaluate simultaneous administration of other recommended vaccines, assess schedule changes for 1 or more components of a combination, and bridge immunologic data obtained from international studies to the population of the United States. We discuss the use of immunogenicity studies to support the licensure of combination vaccines when field efficacy studies are either not possible or not required and highlight some recent experiences with combination vaccines containing Haemophilus influenzae type b polysaccharide conjugates.

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Evaluating the Immune Response to Combination Vaccines

0 Division of Biostatistics, Office of Biostatistics and Epidemiology, Center for Biologics Evaluation and Research , Food and Drug Administration, Rockville, Maryland 1 Division of Vaccines and Related Products Applications, Office of Vaccines Research and Review Assessment of the immune responses to combination vaccines in the United States has generally been based on randomized, controlled comparative trials, with such studies designed to rule out predefined differences. In designing clinical studies of the immune response to combination products, attention should be directed toward selecting the appropriate immunologic end points and control groups. Acceptable differences in immune responses between combination and control groups should be predefined, and an adequate statistical plan should be developed. In many cases, it may be necessary to evaluate simultaneous administration of other recommended vaccines, assess schedule changes for 1 or more components of a combination, and bridge immunologic data obtained from international studies to the population of the United States. We discuss the use of immunogenicity studies to support the licensure of combination vaccines when field efficacy studies are either not possible or not required and highlight some recent experiences with combination vaccines containing Haemophilus influenzae type b polysaccharide conjugates. - REGULATORY APPROACH FOR EVALUATING IMMUNE RESPONSE Regulations and guidance documents. In licensing combination vaccines, the US Food and Drug Administration (FDA) is directed by the Code of Federal Regulations (CFR). A new license is required when alreadylicensed products are combined or when unlicensed components are added to a licensed vaccine [4]. Thus, already-licensed vaccines may not be mixed extemporaneously before administration unless a license has been obtained for the new combination. In addition, regulations state that safe and effective active components may be combined if each component makes a contribution to the claimed effects and combining does not decrease the purity, potency, safety, or effectiveness of the individual components (emphasis added) [5]. In applying the latter regulation, the FDA has relied on the concept that clinical studies of combination vaccines should be designed to rule out clinically significant differences, as described in the 1997 guidance document [1]. Characterizing the acceptable predefined difference is critical to the optimal design of clinical studies of combination vaccinations and will be discussed further below in the section about determining acceptable differences in immune response. Determination of effectiveness: clinical efficacy versus immunogenicity. As defined in the CFR, the effectiveness of biological products is defined as the clinically significant prevention of disease in a significant proportion of the target population, with proof of effectiveness consisting of controlled investigations [6]. Large-scale field trials demonstrating disease prevention may be needed if the combination contains a novel component without a generally accepted serologic correlate of immunity, or if it is the first of its kind in a target population. However, direct evidence of field efficacy may not be necessary for some combinations. Once a vaccine for a particular indication is licensed in the United States, placebo-controlled clinical end point efficacy trials may no longer be possible because of ethical considerations as well as the consequent reduction in clinical disease incidence. Active-controlled field efficacy studies comparing an investigational product to a licensed vaccine with the same indication are ordinarily acceptable to the FDA, but this approach may be impractical because of the large sample size involved. Demonstration of clinical efficacy may not be necessary if an accepted immune correlate of protection exists [6]. In addition, demonstration of field efficacy may not be necessary when adding new serotypes to an already-licensed multivalent productfor example, meningococcal vaccine. For rare serotypes in which clinical end point efficacy trials are not feasible, it may be possible to infer efficacy from immune response data, particularly if immune correlates of protection have been identified for serotypes in which field efficacy was demonstrated. Evaluation of functional immune responses (e.g., opsonophagocytic antibody) may help to strengthen the use of immune responses in these cases. If the new combination vaccine includes an antigen for which an immune correlate of protection has not been identified (e.g., pertussis), the approach has been to demonstrate noninferiority of the immune response S300 CID 2001:33 (Suppl 4) Ball et al. to that elicited by separate administration of the licensed vaccine (DTaP) containing that specific antigen. This approach is discussed in more detail below in the section about statistical considerations. General considerations in the des (...truncated)


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Leslie K. Ball, Lydia A. Falk, A. Dale Horne, Theresa M. Finn. Evaluating the Immune Response to Combination Vaccines, Clinical Infectious Diseases, 2001, pp. S299-S305, 33/Supplement 4, DOI: 10.1086/322578