Lessons learned from a review of the development of selected vaccines

Background. Although the vaccine research and development network in the Un ited States remains vibrant, its continued success requires maintaining har monious interaction among its many components. Changing one component is li kely to affect the system overall. An examination of case studies of the de velopment of selected vaccines would allow an examination of the network as a whole. This article presents conclusions drawn from the case study revie w undertaken. Objective. Successful development of vaccines is a time-intensive process r equiring years of commitment from a network of scientists and a continuum o f regulatory and manufacturing entities. We undertook this work to shed lig ht on how well the vaccine development system in the United States performs . Method. The National Vaccine Advisory Committee examined the research and d evelopment pathways of several vaccines that reached licensure expeditiousl y (hepatitis B vaccine, Haemophilus influenzae type b conjugate vaccines); some that became licensed only after considerable delay (oral typhoid Ty21a vaccine, varicella vaccine); some that are at the point of imminent or rec ent licensure (reassortant Rhesus rotavirus vaccine, which was licensed by the Food and Drug Administration on August 30, 1998) or near submission for licensure (intranasal cold adapted influenza vaccine); and one for which c linical development is slow because of hurdles that must be overcome (respi ratory syncytial virus vaccines). Results. Some common themes emerged from the reviews of these vaccine "case histories": the expediting influence of a strong scientific base and ratio nale; the need for firm quantitation of disease burden and clear identifica tion of target populations; the critical role played by individuals or team s who act as "champions" to overcome the inevitable obstacles; availability of relevant animal models, high-quality reagents and standardized assays t o measure immune response; the absolute requirement for well designed, meti culously executed clinical trials of vaccine safety, immunogenicity, and ef ficacy; postlicensure measurements of the public health impact of the vacci ne and a track record of the vaccine's safety and acceptance with large-sca le use; and the critical need for international collaborations to evaluate vaccines against diseases of global importance that are rare in the United States (eg, typhoid fever). It was clear that the critical step-up from ben ch scale to pilot lots and then to large-scale production, which depends on a small group of highly trained individuals, is often a particularly vulne rable point in the development process. Conclusions. One fundamental lesson learned is that within the varied and c omprehensive US vaccine development infrastructure, multiple and rather dis tinct paths can be followed to reach vaccine licensure. The National Vaccin e Advisory Committee review process should be conducted periodically in the future to ascertain that the US vaccine development network, which has bee n enormously productive heretofore and has played a leadership role globall y, is adapting appropriately to ensure that new, safe, and efficacious vacc ines become available in a timely manner.