Natural history and pathogenesis as they affect clinical trials

Careful observations on the natural history of infectious diseases have been the inspiration behind many successful vaccines, including Jenner's successful demonstration of protection against smallpox. Many "experiments of nature" provide powerful data on the key components of protective immunity. An understanding of the basis of protective immunity in absolute terms or, more realistically, through the proxy of surrogates of immunity, lies at the heart of clinical trials of vaccines. An understanding of infectious disease pathogenesis is also critical in defining and distinguishing immunisation strategies that aim to prevent infection (e.g. measles vaccine) as distinct from prevention of disease (e.g. tetanus toxoid). Coupled to classical epidemiology and the careful analysis of clinical data, the tools of molecular and cell biology have revolutionised the tools available for vaccine research, including clinical trials. Molecular techniques have provided tools for investigating the population structure of pathogens. The importance of population diversity and its associated antigenic variation is a key factor in designing and carrying out clinical trials of vaccines.