Cellular and Humoral Responses to a Second Dose of Herpes Zoster Vaccine Administered 10 Years After the First Dose Among Older Adults

The Journal of Infectious Diseases MAJOR ARTICLE Cellular and Humoral Responses to a Second Dose of Herpes Zoster Vaccine Administered 10 Years After the First Dose Among Older Adults Myron J. Levin,1 Kenneth E. Schmader,2 Lei Pang,3 Angela Williams-Diaz,3 Gary Zerbe,1 Jennifer Canniff,1 Michael J. Johnson,1 Yupanqui Caldas,1 Alice Cho,1 Nancy Lang,1 Shu-Chih Su,3 Janie Parrino,3,a Zoran Popmihajlov,3 and Adriana Weinberg1 1 University of Colorado–Denver Anschutz Medical Campus, Aurora; 2Duke University and Geriatric Research Education and Clinical Centers, Durham Veterans Affairs Medical Center, North Carolina; and 3Merck & Co., Inc., Kenilworth, New Jersey (See the editorial commentary by Schmid on pages 1–2.) The herpes zoster (HZ) vaccine (ZV) prevents or attenuates HZ in people ≥50 years of age [1, 2]. This effect correlates with the boost in varicella zoster virus (VZV)–specific antibody and Tcell immunity (CMI) that follows vaccination [3–5], and ZV partially reverses the decline in VZV-specific CMI that characterizes aging [3, 6]. VZV-specific CMI is considered a mechanistic correlate of protection against HZ [7, 8]. In many viral infections, CD8+ T cells are the main effectors of viral clearance, while CD4+ T cells have mainly a helper role. However, in herpesvirus infections, CD4+ T cells have both helper and effector roles and are a major focus of VZV-specific immune defense studies [9–11]. Previous publications characterized the central memory CD4+ T-cell response to ZV by using proliferation Received 10 June 2015; accepted 1 September 2015; published online 9 October 2015. a Merck employee at the time of this research. Correspondence: M. J. Levin, University of Colorado Denver Anschutz Medical Campus, 13001 E 17th Pl, Aurora, CO 80045 (). The Journal of Infectious Diseases® 2016;213:14–22 © The Author 2015. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail . DOI: 10.1093/infdis/jiv480 14 • JID 2016:213 (1 January) • Levin et al assays and the effector CD4+ T-cell response by using interferon γ (IFN-γ) enzyme-linked immunosorbent spot (ELISPOT) assays [3, 6, 12]. Less is known about the CD4+ effector memory T cells that have the ability to rapidly upregulate cytokine production and other effector mechanisms upon encountering their cognate antigen and that may play a critical role in controlling the early stages of VZV reactivation. Terminally differentiated effector responses to ZV constitute another T-cell subset of interest, particularly in elderly individuals [13]. Differentiated effectors initially produce high levels of cytokines but eventually become exhausted and lose their ability to participate in antiviral infections [14]. The exhausted T-cell population increases with aging [15]. During aging there is a progressive decline in immune responsiveness to vaccination and a shortening of the duration of vaccine-induced immunity [16]. This characteristic of immune senescence is apparent in studies of vaccines administered to elderly individuals, such as those targeting influenza virus and pneumococcus [17–19]. The licensed ZV (Zostavax, Merck & Co., Inc., Kenilworth, New Jersey) exemplifies this pattern. In the pivotal trial, a single dose of ZV showed a 51.3% efficacy in preventing HZ and a 66.7% efficacy in preventing Background. Herpes zoster vaccine (ZV) was administered as a second dose to 200 participants ≥70 years old who had received a dose of ZV ≥10 years previously (NCT01245751). Methods. Varicella zoster virus (VZV) antibody titers (measured by a VZV glycoprotein–based enzyme-linked immunosorbent assay [gpELISA]) and levels of interferon γ (IFN-γ) and interleukin 2 (IL-2; markers of VZV-specific cell-mediated immunity [CMI], measured by means of ELISPOT analysis) in individuals aged ≥70 years who received a booster dose of ZV were compared to responses of 100 participants aged 50–59 years, 100 aged 60–69 years, and 200 aged ≥70 years who received their first dose of ZV. The study was powered to demonstrate noninferiority of the VZV antibody response at 6 weeks in the booster-dose group, compared with the age-matched first-dose group. Results. Antibody responses were similar at baseline and after vaccination across all age and treatment groups. Both baseline and postvaccination VZV-specific CMI were lower in the older age groups. Peak gpELISA titers and their fold rise from baseline generally correlated with higher baseline and postvaccination VZV-specific CMI. IFN-γ and IL-2 results for subjects ≥70 years old were significantly higher at baseline and after vaccination in the booster-dose group, compared with the first-dose group, indicating that a residual effect of ZV on VZV-specific CMI persisted for ≥10 years and was enhanced by the booster dose. Conclusions. These findings support further investigation of ZV administration in early versus later age and of booster doses for elderly individuals at an appropriate interval after initial immunization against HZ. Clinical Trials Registration. NCT01245751. Keywords. herpes zoster vaccine; VZV antibodies; VZV cell-mediated immunity (CMI). postherpetic neuralgia in adults ≥60 years old [1]. That trial had a mean observation period of 3.13 years (the longest period was 4.9 years, for 1 subject). Subsequent observation of >14 200 participants for an additional 3.3–7.8 years demonstrated a decline in efficacy, although the vaccine-induced protection remained significant for at least 5 years [20]. Further follow-up to evaluate long-term persistence, which included years 7–11 after ZV receipt, demonstrated a further decline in efficacy to 21.1% for preventing HZ and to 35.4% for preventing postherpetic neuralgia [21]. As an initial step in investigating the potential for reversing this decline in efficacy, we determined that a booster dose of ZV administered to adults ≥70 years of age elicits a VZV antibody response that is noninferior to that of ZV administered as a first dose, and we compared the cellular and humoral immune responses to this booster dose of ZV in older vaccinees to those in younger vaccinees (NCT01245751). Any underlying chronic illness was stable. Subjects signed informed consent for the protocol that was approved by the institutional review boards at the University of Colorado Anschutz Medical Campus and Duke University Health System. Exclusion Criteria Exclusion criteria comprised the following: prior history of HZ, history of hypersensitivity reaction to any vaccine component, receipt of immunoglobulin or blood products during the 5 months prior to vaccination and throughout the study, vaccination with any live virus or inactivated vaccine within 4 weeks before or after receiving ZV, recent receipt of immunosuppressive therapy or suspected immune dysfunction or immune suppressing illness, or receipt of systemic antiherpesvirus therapy during the study period. No prior ZV was permitted for subjects in groups 2 (...truncated)