Immunogenicity and safety of the adjuvanted recombinant zoster vaccine in patients with solid tumors, vaccinated before or during chemotherapy: A randomized trial

Abstract

Background: The adjuvanted recombinant zoster vaccine (RZV) has demonstrated >90% efficacy against herpes zoster in adults ≥50 years of age and 68% efficacy in autologous hematopoietic stem cell transplant recipients ≥18 years of age. We report the immunogenicity and safety of RZV administered to patients with solid tumors (STs) before or at the start of a chemotherapy cycle.

Method: In this phase 2/3 observer-blind, multicenter study (NCT01798056), patients with STs who were ≥18 years of age were randomized (1:1) to receive 2 doses of RZV or placebo 1-2 months apart and stratified (4:1) according to the timing of the first dose with respect to the start of a chemotherapy cycle (first vaccination 8-30 days before the start or at the start [±1 day] of a chemotherapy cycle). Anti-glycoprotein E (gE) antibody concentrations, gE-specific CD4+ T cell frequencies, and vaccine response rates (VRRs) were assessed 1 month after dose 1 and 1 and 12 months after dose 2. Reactogenicity and safety were assessed in the total vaccinated cohort through 12 months after dose 2.

Results: There were 232 participants in the total vaccinated cohort, 185 participants in the according-to-protocol cohort for humoral immunogenicity, and 58 participants in the according-to-protocol cohort for cell-mediated immunogenicity. Postvaccination anti-gE antibody concentrations, gE-specific CD4+ T cell frequencies and VRRs were higher in RZV recipients than in placebo recipients. Solicited adverse events (AEs) were more frequent among RZV recipients than placebo recipients. Incidence of unsolicited AEs, serious AEs, fatalities, and potential immune-mediated diseases were similar between RZV and placebo recipients.

Conclusion: RZV was immunogenic in patients with STs receiving immunosuppressive chemotherapies. Humoral and cell-mediated immune responses persisted 1 year after vaccination. No safety concerns were identified.

Keywords: herpes zoster vaccine; immunogenicity; immunosuppressive chemotherapy; patients with solid tumors; safety.

Conflict of interest statement

Peter Vink, Laura Campora, Emmanuel Di Paolo, Mohamed El Idrissi, Olivier Godeaux, Marta López‐Fauqued, Bruno Salaun, Thomas C. Heineman, and Lidia Oostvogels were employees of the GSK group of companies (GSK) at the time this study was designed, initiated, and/or conducted. Lidia Oostvogels was an employee of CureVacAG as of March 1, 2018, and is an inventor on a patent application related to the vaccine used in this study. Thomas C. Heineman was a paid GSK consultant during manuscript development and is an inventor on a patent application related to the study vaccine. Peter Vink, Laura Campora, Emmanuel Di Paolo, Mohamed El Idrissi, Olivier Godeaux, Bruno Salaun, Thomas C. Heineman, and Lidia Oostvogels hold shares/ stock options in GSK. Hartmut Kristeleit reports fees for consultancy and/or speaker bureau activities from Amgen, Roche, and Eisai. Shelly A. McNeil’s institution has a clinical trial contract with Novartis and has received research grants for conduct of clinical trials by GSK, Merck, Pfizer, and Sanofi Pasteur. Shelly A. McNeil has received honoraria for participation in scientific advisory boards from GSK, Pfizer, Sanofi Pasteur, and Merck and for provision of accredited CME to HCPs on adult immunization and zoster vaccines. Belen Rubio‐Viqueira has received honoraria for scientific advisory board participation from MSD and Lilly and reports personal fees and support from Roche for provision of training and conference attendance. Constanza Maximiano Alonso has received nonfinancial support from Mundipharma, BMS, Pharmamar, Novartis, Janssen‐cilag, MSD, and TEVA and reports personal fees from Sanofi, Pharmamar, Roche, Novartis, Janssen‐cilag, and Bayer. Enrique Grande has received honoraria for ad boards, meetings, and/or lectures from Pfizer, BMS, IPSEN, Roche, Eisai, Eusa Pharma, MSD, Sanofi‐Genzyme, Adacap, Novartis, Pierre Fabre, Lexicon, and Celgene and has received unrestricted research grants from Pfizer, Astra Zeneca, MTEM/Threshold, Roche, IPSEN and Lexicon.

Zostavax is a trademark of Merck Sharpe & Dohme corp. Shingrix is a trademark of the GSK group of companies.

© 2019 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society.

Figures

Figure 1

Study design for participants receiving the adjuvanted recombinant zoster vaccine (RZV). RZV or placebo was administered in the deltoid muscle of the nondominant arm unless clinically contraindicated (eg, previous surgical resection of the axillary lymph nodes of the nondominant arm as part of solid tumor management). Syringes represent vaccinations (RZV or placebo doses 1 and 2), test tubes represent blood sampling, and phones represent phone contact. Prevaccination (PRE‐VAC) visit occurred at or within 30 days before the day of visit 1. Visit 1 occurred 8‐30 days before the start of a chemotherapy cycle (RZV‐PreChemo, Placebo‐PreChemo) or at the start of a chemotherapy cycle (RZV‐OnChemo, Placebo‐OnChemo). Visit 2 occurred 1‐2 months after the first vaccination and at the first day (allowing a window of ±1 day) of a subsequent cycle of chemotherapy. Visit 3 occurred approximately 1 month after the second vaccination. Visit 4 occurred within months 4‐13 (at least 2 months after visit 3) at the start of the last cycle of chemotherapy and coincided with the patient’s lowest immune status. Visit 4 could replace month 5 or month 9 phone contacts (in case it coincided with the timing of these) or could coincide with Visit 5 (if the last chemotherapy cycle occurred at month 13). M indicates month.

Figure 2

Objectives of the study. In both the PreChemo (first vaccination 8‐30 days before the start of a chemotherapy cycle) and OnChemo (first vaccination at the start of a chemotherapy cycle) strata, the second vaccination took place 1‐2 months after the first vaccination and at the first day (allowing a window of ±1 day) of a subsequent cycle of chemotherapy. CI, confidence interval; CMI, cell‐mediated immunogenicity; ELISA, enzyme‐linked immunosorbent assay; gE, glycoprotein E; GM, geometric mean; LL, lower limit; M, study month; RZV, recombinant zoster vaccine; VRR, vaccine response rate.

Figure 3

Participant flow. In both the PreChemo (first vaccination 8‐30 days before the start of a chemotherapy cycle) and OnChemo (first vaccination at the start of a chemotherapy cycle) strata, the second vaccination took place 1‐2 months after the first vaccination and at the first day (allowing a window of ±1 day) of a subsequent cycle of chemotherapy. Some participants who were randomized to the PreChemo stratum and were required to wait 8‐30 days after vaccination before they could start chemotherapy chose to withdraw so as to proceed to chemotherapy immediately. ATP, according‐to‐protocol; CMI, cell‐mediated immunogenicity; M, month; n, number of patients attending a visit; pIMD, potential immune‐mediated disease; RZV, recombinant zoster vaccine; SAE, serious adverse event; TVC, total vaccinated cohort.

Figure 4

Humoral and cell‐mediated immunogenicity (CMI) of recombinant zoster vaccine (RZV). (A) Anti‐gE antibody GMCs (according‐to‐protocol [ATP] cohort for humoral immunogenicity/persistence). (B) Vaccine response rate (VRR) in terms of anti–glycoprotein E (gE) antibody concentrations (ATP cohort for humoral immunogenicity/persistence). (C) Frequencies of gE‐specific CD4[2+] T cells per 106 total CD4+ T cells (ATP subcohort for CMI, PreChemo groups only). (D) VRR in terms of CMI responses (ATP subcohort for CMI, PreChemo groups only). In both the PreChemo (first vaccination 8‐30 days before the start of a chemotherapy cycle) and OnChemo (first vaccination at the start of a chemotherapy cycle) strata, the second vaccination took place 1‐2 months after the first vaccination and at the first day (allowing a window of ±1 day) of a subsequent cycle of chemotherapy. gE, glycoprotein E; GMC, geometric mean concentration; M, study month; M1, 1 month post‐dose 1; M2, 1 month after dose 2; M6, 5 months after dose 2; M13, 12 months after dose 2; N, number of participants with available results; N’, number of participants with pre‐ and post‐vaccination results available; PRE, prevaccination (M0). With the exception of panel C, error bars indicate 95% confidence intervals.

Figure 5

Solicited adverse events (overall/participant, total vaccinated cohort). Error bars indicate 95% confidence intervals. Numerical values for the data depicted here are provided in Supporting Table S1. GI, gastrointestinal symptoms (nausea, vomiting, diarrhea and/or abdominal pain); N, number of participants with ≥1 documented dose; RZV, recombinant zoster vaccine. *Fever was not graded; percentage of participants with oral temperature >39°C are provided in the Grade 3 category.

Figure 6

Focus on the patient.