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

Abstract

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 biomarkers measuring 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.

Clinical trials registration: NCT00534248.

Keywords: causal inference; correlate of immunity; immune correlate of protection; principal stratification; signature of protection; statistical analysis; surrogate endpoint; vaccine efficacy trial.

Figure 1.

For vaccine and placebo recipients in the immunological substudy, the left 2 box plots depict the log₁₀ baseline titers by treatment arm, the middle 2 box plots depict the log₁₀ week 6 titers by treatment arm, and the right 2 box plots depict the log₁₀ fold rise from baseline to week 6 by treatment arm, with the y-axis denoting the multiplicative fold rise scale. The edges of the boxes are 25th and 75th percentiles, the horizontal lines inside the boxes are medians, and the vertical whiskers represent the 2.5th and 97.5th percentiles. Data points are shown for random samples of 100 participants. gpELISA, glycoprotein-based enzyme-linked immunosorbent assay.

Figure 2.

For vaccine recipients in the immunological substudy, the left panel depicts the correlation between the log₁₀ fold rise in titers from baseline to week 6 and the log₁₀ baseline titers (with the y-axis denoting the multiplicative fold rise scale). The right panel depicts the association between log₁₀ week 6 titers and log₁₀ baseline titers.

Figure 3.

A and B, Estimated vaccine efficacy curves across levels of vaccine-induced fold rise in titers from baseline to week 6, using the probit estimated likelihood method [27] and the Weibull estimated likelihood method [35], respectively, with 95% bootstrap confidence intervals. The lower x-axis indicates the multiplicative fold rise in titers. C, Estimated VEs with 95% bootstrap confidence intervals for subgroups defined by the lower, middle, and upper tertiles of vaccine-induced fold rise in titers, using the nonparametric estimated likelihood method [27].

Figure 4.

Estimated vaccine efficacies (VEs) for the no response, partial response, and high response subgroups described in Methods, using the Cox model with multiple imputation method [32].

Figure 5.

A and B, Estimated vaccine efficacy curves across levels of vaccine-induced log₁₀ week 6 titers, using the probit estimated likelihood method [27] and the Weibull estimated likelihood method [35], respectively, with 95% bootstrap confidence intervals. The lower x-axis indicates the multiplicative fold rise in titers. C, Estimated VEs with 95% bootstrap confidence intervals for subgroups defined by the lower, middle, and upper tertiles of vaccine-induced week 6 titers, using the nonparametric estimated likelihood method [27] (the lower confidence limit for the middle tertile is −224%).

Figure 6.

A and B, Estimated vaccine efficacy curves across levels of log₁₀ baseline titers, using the probit estimated likelihood method [27] and the Weibull estimated likelihood method [35], respectively, with 95% bootstrap confidence intervals. The lower x-axis indicates the multiplicative fold rise in titers. C, Estimated VEs with 95% bootstrap confidence intervals for subgroups defined by the lower, middle, and upper tertiles of baseline titers, using the nonparametric estimated likelihood method [27].