Correlates of protective immunity for Ebola vaccines: implications for regulatory approval by the animal rule

Abstract

Ebola virus infection is a highly lethal disease for which there are no effective therapeutic or preventive treatments. Several vaccines have provided immune protection in laboratory animals, but because outbreaks occur unpredictably and sporadically, vaccine efficacy cannot be proven in human trials, which is required for traditional regulatory approval. The Food and Drug Administration has introduced the 'animal rule', to allow laboratory animal data to be used to show efficacy when human trials are not logistically feasible. In this Review, we describe immune correlates of vaccine protection against Ebola virus in animals. This research provides a basis for bridging the gap from basic research to human vaccine responses in support of the licensing of vaccines through the animal rule.

Figure 1. Determination of immunological end points that correlate with vaccine efficacy.

Standard assays for the determination of immune markers include those that measure humoral immunity, such as in vitro virus neutralization, ELISA (enzyme-linked immunosorbent assay) and EIA (enzyme immunoassay) (a), and others that measure cell-mediated responses, including antigen-stimulated proliferation or cytolytic activity. Correlates can also be sought in additional phenotypic (b) and functional immune markers (c) that associate with vaccine efficacy. T cell lineage markers, cytokine secretion, antibody class and effector functions can individually, or in combination, segregate with host survival outcome. Grz, granzyme; IFN, interferon; Ig, immunoglobulin; IL, interleukin; NK, natural killer; T_CM, T cell memory; T_E, T cell terminal effector; T_EM, T cell effector memory; T_H, T helper; TNF, tumour necrosis factor.

Figure 2. Assessment of antigen-specific immunoglobulin G (IgG) as a correlate of Ebola vaccine efficacy.

Immune sera from macaques immunized with genetic vaccines encoding wild-type or mutant Ebola virus glycoprotein alone or in combination with nucleoprotein showed a spectrum of IgG antibody titres measured by ELISA (enzyme-linked immunosorbent assay). Antibody titre was a quantitative predictor (surrogate) for vaccine efficacy; 100% immune protection was predicted by an antibody titre of 1:3,700.

Figure 3. Ebola vaccine development pathway using the animal rule.

Early vaccine candidates are optimized for immune potency in small animal models. Selected candidates are evaluated further in an animal model that adequately represents infection in humans (cynomolgus macaques) to establish an immune correlate of vaccine efficacy, and a pivotal animal study is performed to bridge the immune correlate between macaque efficacy studies and human Phase II clinical trials. Data from Phase III animal studies and expanded Phase II human studies are compiled for regulatory review and vaccine licensing.