Surrogates of Protection

Abstract

A holy grail of vaccine research is to identify a vaccine-induced immune response that predicts protection from infection and disease. If a measurable immune response to vaccination predictive of protection from infection and disease were available, it would help to avoid new large trials and facilitate getting new products and formulations approved. An immunological surrogate of protection could reduce the sample size or shorten the duration of a trial. If a good vaccine is already licensed and recommended, a trial with a new vaccine compared to placebo would be unethical. When both vaccines are highly efficacious or the clinical outcome of interest is rare, a relative efficacy trial comparing the two vaccines would be prohibitively large. Thus, identifying a good immunological surrogate of protection could make a trial much less expensive or indeed feasible.

If the interest is in evaluating new vaccine candidates in different populations, the primary goal is to predict how well the vaccine will do in new situations. Another use of immunological surrogates of protection is in designing vaccines for future emerging pathogens such as pandemic influenza or anthrax in which clinical outcome data are not available. These latter two types of studies are sometimes called bridge studies.

Much of this book has considered the effects of vaccination on clinical and infection outcomes and on transmission measured by clinical and infection outcomes. The era of using clinical outcomes in most primary vaccine efficacy trials may slowly be coming to an end, although clinical outcomes will still be useful in observational studies. In 1993, a Hib conjugate vaccine was approved for licensure in the United States based on immunological data (Frasch 1994) following the licensure of two others based on Phase III efficacy trials (Black et al 1992; Santosham et al 1991). Meningococcal C conjugate vaccines were licensed in England on the basis of serological correlates of protection without Phase III efficacy data (Andrews et al 2003). Identifying immunological correlates of protection is one of original topics of the Gates Grand Challenges. In this chapter, we present methods to assess correlates and surrogates of vaccine protection. The main focus is on immunological surrogates of protection, but we also briefly consider carriage as an endpoint in pneumococcal vaccine studies, the subject of ongoing research.