A framework for assessing immunological correlates of protection in vaccine trials

A central goal of vaccine research is to identify a vaccine-induced immune response that predicts protection from infection or disease. The term correlate of protection has been used to refer to at least 3 distinct concepts, which has resulted in confusion surrounding this topic. We propose precise definitions of these different concepts of immune correlates, using the nomenclature correlate of risk, level 1 surrogate of protection, and level 2 surrogate of protection. We suggest a general framework for assessing these 3 levels of immune correlates in vaccine efficacy trials. To demonstrate the proposed principles, we analyze data from a 1943 influenza vaccine field trial, supporting Weiss strain A - specific antibody titers as a level 1 surrogate of protection. Other real and simulated examples are also discussed.