Fold Rise in Antibody Titers by Measured by Glycoprotein-Based Enzyme-Linked Immunosorbent Assay Is an Excellent Correlate of Protection for a Herpes Zoster Vaccine, Demonstrated via the Vaccine Efficacy Curve

Background. The phase III Zostavax Efficacy and Safety Trial of 1 dose of licensed zoster vaccine (ZV; Zostavax; Merck) in 50-59-year-olds showed approximately 70% vaccine efficacy (VE) to reduce the incidence of herpes zoster (HZ). An objective of the trial was to assess immune response biomarkersmeasuring antibodies to varicella zoster virus (VZV) by glycoprotein-based enzyme-linked immunosorbent assay as correlates of protection (CoPs) against HZ. Methods. The principal stratification vaccine efficacy curve framework for statistically evaluating immune response biomarkers as CoPs was applied. The VE curve describes how VE against the clinical end point (HZ) varies across participant subgroups defined by biomarker readout measuring vaccine-induced immune response. The VE curve was estimated using several subgroup definitions. Results. The fold rise in VZV antibody titers from the time before immunization to 6 weeks after immunization was an excellent CoP, with VE increasing sharply with fold rise: VE was estimated at 0% for the subgroup with no rise and at 90% for the subgroup with 5.26-fold rise. In contrast, VZV antibody titers measured 6 weeks after immunization did not predict VE, with similar estimated VEs across titer subgroups. Conclusions. The analysis illustrates the value of the VE curve framework for assessing immune response biomarkers as CoPs in vaccine efficacy trials.