A correlate of protection (CoP) is an immune function that correlates with and may be biologically responsible for vaccine-induced efficacy. A surrogate of protection (SoP) is an immune marker that can be used to predict vaccine efficacy when the true correlate of protection is difficult to measure or unknown. SoPs are used in immunological assays to assess vaccine efficacy without directly observing clinical endpoints. This can save time and money compared to large-scale field efficacy trials. [1]
The CoP for many rare diseases for which there are no existing vaccines developed using placebo-controlled trials is difficult to measure in the absence of efficacy data that provides information about the threshold for protection, for example, Lassa Fever, Zaire ebolavirus, Sudan ebolavirus and Marburg virus. A SoP, established through use of standardized and consistent immunoassays, human natural history data, animal model data, controlled human infection models (CHIM), when available, and human immunogenicity data, could be used in those cases. One example that uses these tools for establishing SoPs for filoviruses, with the exception of CHIM due to unavailability of a model, is shown in Figure 1.
Figure 1: Example components need to establish a surrogate of protection for filoviruses
Assays for the immune markers reasonably likely to demonstrate vaccine immune response must be identified, qualified and validated. Those assays can then be used to test samples from survivors immediately following an outbreak and over time to understand natural human immunity. Any infections from the same disease following recovery should be documented, along with the results from testing immune markers as close as possible to the time of the outbreak, to understand the threshold of protection.
Animal models can then be used to enhance understanding by using controlled infections and conducting testing of immune responses over time. Comparing the animal model responses with results from natural human infections and recovery could enable predictions to be made about the potential of a vaccine to be protective. Clinical trial immunogenicity results could be compared to results from the natural human infection and recovery and animal models to see the correlation between immune responses to establish the SoP and strengthen predications about a vaccine’s protectiveness.
Licensure of a developmental vaccine could be pursued through use of immunobridging using the SoP, shown in the right three columns of Table 1.
As noted, predictions based on CoPs or SoPs, should be confirmed by conducting post marketing effectiveness studies during outbreaks. Effectiveness studies will:
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