Varicella-Zoster Virus–Specific Antibody Responses in 50–59-Year-Old Recipients of Zoster Vaccine

JID Varicella-Zoster Virus-Specific Antibody Responses in 50-59-Year- Old Recipients of Zoster Vaccine Myron J. Levin 2 3 Kenneth E. Schmader 1 2 John W. Gnann 0 2 Shelly A. McNeil 2 4 Timo Vesikari 2 8 Robert F. Betts 2 7 Susan Keay 2 6 Jon E. Stek 2 5 Nickoya D. Bundick 2 5 Shu-Chih Su 2 5 Yanli Zhao 2 5 Xiaoming Li 2 5 Ivan S. F. Chan 2 5 Paula W. Annunziato 2 5 Janie Parrino () 2 5 0 Medical University of South Carolina , Charleston 1 Duke University, Geriatric Research, Education and Clinical Center, Durham Veterans Affairs Medical Center , North Carolina 2 Received 17 December 2012; accepted 2 May 2013; electronically published 1 August 2013. Presented in part: 48th Annual Meeting of the Infectious Diseases Society of America , 21- 24 October 2010, Vancouver, British Columbia , Canada. Abstract 3363. Wales, PA 19454-1099 3 University of Colorado Denver Anschutz Medical Campus , Aurora 4 Dalhousie University , Halifax, Nova Scotia , Canada 5 Merck & Co., Inc., Whitehouse Station , New Jersey 6 Veterans Affairs Maryland Health Care System , Baltimore, Maryland 7 University of Rochester , New York 8 University of Tampere , Finland Prevaccination and 6-week postvaccination samples from the immunogenicity substudy (n = 2269) of the zoster vaccine (ZV) efficacy trial (N = 22 439) in 50-59-year-old subjects were examined for varicella-zoster virus-specific antibody responses to vaccination. The varicella-zoster virus geometric mean titer (GMT) and geometric mean fold rise were higher in ZV recipients than in placebo recipients (GMT, 660.0 vs 293.1 glycoprotein enzyme-linked immunosorbent assay units/mL [P < .001], respectively; geometric mean fold rise, 2.31 vs 1.00 [P < .025]). In each group there was a strong inverse correlation between postvaccination GMT and risk of subsequent herpes zoster. Although these data provide strong evidence that relates ZV-induced antibody and the risk of herpes zoster, a protective threshold was not determined. Clinical Trials Registration. NCT00534248. - herpes zoster; zoster vaccine; immunogenicity. The live attenuated herpes zoster (HZ) vaccine (zoster vaccine [ZV]; ZostavaxTM; Merck & Co., Inc.) was recommended by the Advisory Committee on Immunization Practices in the United States in 2008 for immunocompetent individuals aged 60 years, based on a large randomized, placebo-controlled Study Design The methods for this event-driven, randomized, double-blind, placebo-controlled, multicenter study (NCT00534248) are published elsewhere [10]. Subjects were randomized (1:1 ratio) to receive either ZV or placebo. To evaluate the correlation of vaccine-induced VZV antibody responses and subsequent protection against HZ, serum samples were collected from study subjects before and 6 weeks after vaccination, with VZV antibody concentrations measured by gpELISA in (1) the immunology subcohort population (10% protocol-prespecified, randomized subcohort) and (2) the case-cohort population (immunology subcohort plus all subjects in whom suspected HZ developed). Study Population Healthy subjects aged 5059 years with a history of varicella or residence in a VZV-endemic area for 30 years, were enrolled. Exclusion criteria have been described elsewhere and included evidence of immunocompromise [9]. The protocol was conducted in accordance with principles of good clinical practice and approved by the ethical review committee of each participating site; written informed consent was obtained from each subject before study entry. Intervention Lyophilized ZV and placebo were supplied in 0.7-mL singledose vials and stored at 15C or colder. Placebo contained the same stabilizers as ZV, but no live virus or virus components. ZV and placebo were reconstituted with sterile water immediately before administration. All subjects received a single 0.65mL subcutaneous injection of either ZV or placebo in the deltoid area. Follow-up Subjects were educated regarding the signs and symptoms of HZ and instructed to call their study site if HZ symptoms occurred. Contact by an interactive voice response system was undertaken monthly until study completion to ensure that suspected HZ was reported. Suspected HZ cases were evaluated by a site investigator. Initiation of treatment with antiviral therapy and pain medication was determined by the treating physician. Assessment of Suspected HZ Cases All HZ rash characteristics were recorded, and lesion swab samples were submitted for detection of VZV, herpes simplex, and human -globin DNA using a polymerase chain reaction (PCR) assay ( performed at PPD Vaccines and Biologics) [10]. Determination of Confirmed HZ Cases Suspected HZ cases were defined as confirmed HZ if VZV DNA was present in skin lesion samples. If the PCR assay was positive for -globin or herpes simplex virus DNA, and negative for VZV DNA, then the case was defined as not HZ. When there was no specimen or the specimen was inadequate, case determination was decided by a clinical evaluation committee [9]. VZV-Specific Antibody Assay The gpELISA for VZV-specific immunoglobulin G antibody (performed at PPD Vaccines and Biologics) detects antibodies to purified VZV glycoproteins from MRC-5 (normal human lung fibroblasts, Medical Research Council 5 cell line) cells infected with VZV (KMcC strain), using methods described elsewhere [11]. First, VZV glycoproteins or uninfected MRC-5 lysates were adsorbed to polystyrene microtiter wells. Experimental, control, and standard curve serum samples were incubated in coated tissue culture wells in duplicate at 23C for 4080 minutes until the difference in optical density (OD) between the VZV glycoproteincontaining ( positive) wells and control (negative) wells was >0.700, as measured in the plate reader at 405 nm approximately every 5 minutes after an initial 40-minute incubation. Color development was stopped with 50 L of 3N sodium hydroxide. Delta OD was calculated for each serum sample as the difference between the average OD of the 2 VZV antigen wells and that of the 2 MRC-5 control wells. Quantitation was performed by comparing sample delta OD with a standard curve, with results reported as concentrations of antibody in gpELISA units per milliliter. Statistics The immunogenicity objectives were (1) to determine whether administered ZV is immunogenic and (2) to assess the association between antibody response 6 weeks after vaccination and the risk of HZ. To show a significantly higher geometric mean titer (GMT) in VZV antibody titers at 6 weeks after vaccination in the ZV group compared with the placebo group, 2230 subjects for the 10% subcohort (1115 randomly selected in each group) would provide an overall power of approximately 98% at the .025 significance level (1 sided; noninferiority criterion, lower bound of 2-sided 95% confidence interval for GMT ratio [ZV/placebo] >1.4). This assumed that the true GMT ratio is 1.7 [12], the standard deviation of the natural-log-transformed titers is 1.1, and there would (...truncated)