Control Testing of Combined Vaccines: A Consideration of Potential Problems and Approaches

Abstract

Abstract. Vaccines comprising combinations of diphtheria, tetanus and pertussis (DTP) components with Haemophilus influenzae b polysaccharide—protein conjugates (DTP-Hib) are now available. Combinations of DTP-Hib with additional components such as inactivated poliomyelitis vaccine, hepatitis B vaccine, meningococcal and pneumococcal polysaccharide-protein conjugates, are under development. Other combinations, such as Hib vaccine with meningococcal A, B and C components and possibly pneumococcal conjugates, or non-capsulated Haemophilus components combined with pneumococcal conjugates, developed against bacterial meningitis and otitis media respectively, are of potential interest. Combination vaccines against enteric infections and including potentially cholera, typhoid, ETEC, Shigella, rotavirus and possibly Campylobacter and Helicobacter components, may become available in the longer term. The control of these combinations is likely to be based on pharmacopoeial requirements for the individual components. However, the evaluation of combinations may not be straightforward and the interaction of the components with each other may influence reactogenicity, immunogenicity and stability and will complicate laboratory control tests. Indications of this have already arisen with some DTP-Hib combinations but are likely to increase as additional components are added. For example, the use of diphtheria and tetanus proteins as carriers for multiple polysaccharide conjugates may lead to excessive antitoxin production and epitope suppression of anti-polysaccharide responses. Other problems may result from competition for binding sites on adjuvant molecules. The requirements for new vaccine combinations need to be considered carefully and should not be made solely on assumptions based on the properties of individual components.