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

MAJOR ARTICLE 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 Peter B. Gilbert,1,a Erin E. Gabriel,3,a Xiaopeng Miao,4 Xiaoming Li,2 Shu-Chih Su,5 Janie Parrino,5 and Ivan S. F. Chan5 1 Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center and Department of Biostatistics, University of Washington, and Biostatistics, Gilead Sciences, Seattle, Washington; 3National Institute of Allergy and Infectious Diseases, Biostatistics Research Branch, Bethesda, Maryland; 4Department of Biometrics, Biogen Idec, Cambridge, Massachusetts; and 5Merck, Whitehouse Station, New Jersey 2 (See the editorial commentary by Wittes on pages 1523–5.) 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. Herpes zoster (HZ), caused by reactivation of latent varicella zoster virus (VZV) [1], entails rash and pain that Received 3 January 2014; accepted 26 March 2014; electronically published 13 May 2014. Presented in part: Atlantic Causal Inference Conference, Cambridge, Massachusetts, May 2013; Joint Statistical Meeting, Montreal, Canada, August 2013. a P. B. G. and E. E. G. contributed equally to this work. Correspondence: Peter B. Gilbert, PhD, Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, 1100 Fairview Ave North, PO Box 19024, Seattle, WA 98109 (). The Journal of Infectious Diseases® 2014;210:1573–81 © The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: . DOI: 10.1093/infdis/jiu279 decreases daily functioning and health-related quality of life, more so with increasing age [1–10]. The phase III Shingles Prevention Study (SPS) showed that the live, attenuated zoster vaccine (ZV; Zostavax, Merck, Whitehouse Station, NJ) had an estimated 51% vaccine efficacy (VE; 95% confidence interval [CI], 44%–58%) to reduce the incidence of HZ in persons aged ≥60 years [11]. Subsequently, another phase III Zostavax Efficacy and Safety Trial (ZEST) was conducted to assess the VE of ZV in persons aged 50–59 years and showed an estimated 70% VE (95% CI, 54%–81%) [12]. Secondary analyses of the SPS suggested that 3 different measures of VZV-specific immunity were correlated with Correlates of Protection via VE Curve • JID 2014:210 (15 November) • 1573 1574 • JID 2014:210 (15 November) • Gilbert et al availability of a subject characteristic before immunization that predicts the candidate CoP [28]; such a baseline immunogenicity predictor (BIP) allows inclusion of an estimate of the immune response to the vaccine that placebo recipients would have had had they been vaccinated, thereby enabling estimation of the VE curve. This approach can be used for estimating the VE curve for subgroups defined either by levels of the vaccineinduced immune response or by both the levels of this response and the response under assignment to placebo. Several statistical methods have been developed for estimating the VE curve based on a BIP [27–32]. However, because adequately predictive BIPs have not been available, the methods have not yet been effectively applied. Fortunately, a high-quality BIP is available in the ZEST, and here we report, for the first time, an application of this framework to produce clear results that validate one biomarker as an excellent CoP (fold rise in gpELISA titers) and another biomarker as a poor CoP (week 6 gpELISA titers). By directly assessing how VE varies with participant subgroups defined by gpELISA readouts, this framework provides clearly interpretable results that lend themselves to central applications, such as comparing the utility of different immune response biomarkers as CoPs and estimating seroprotection levels. METHODS Study Design The ZEST design, including study population, vaccine intervention, follow-up, HZ end point determination, and efficacy and safety evaluation, is described in the article by Schmader et al [12]. Briefly, 22 439 North American and European subjects aged 50–59 years with a history of varicella or residence in a VZV-endemic area for at least 30 years were randomly assigned to receive a single dose of ZV or placebo in a 1 to 1 allocation. Suspected HZ cases (determined by subject-initiated contact of their study site and by monthly contact by interactive voice response system) were defined as “confirmed HZ” if VZV DNA was detected by polymerase chain reaction analysis of a skin lesion specimen or, for missing or inadequate specimens, by judgment of a clinical evaluation committee. Subjects were followed for ≥1 year until at least 96 confirmed HZ cases (ie, primary end points) occurred. VE was assessed with an intention-to-treat (ITT) analysis, counting all confirmed HZ cases, and with a modified ITT analysis, which excludes HZ cases occurring within 30 days of vaccination. Measurement of Anti-VZV Antibodies A case-cohort design [33] was used to assess CoPs, in which VZV-specific antibody responses were measured at Merck Research Laboratories in 10% of study participants selected prior to study initiation via simple random sampling and in all cases (subjects who experienced HZ after the week 6 visit). These protection from HZ: responder cell frequency–determined cellme (...truncated)