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Clinical Trial
. 2019 Jul 9;322(2):123-133.
doi: 10.1001/jama.2019.9053.

Effect of Recombinant Zoster Vaccine on Incidence of Herpes Zoster After Autologous Stem Cell Transplantation: A Randomized Clinical Trial

Adriana Bastidas  1 , Javier de la Serna  2 , Mohamed El Idrissi  3 , Lidia Oostvogels  4 , Philippe Quittet  5 , Javier López-Jiménez  6 , Filiz Vural  7 , David Pohlreich  8 , Tsila Zuckerman  9 , Nicolas C Issa  10 , Gianluca Gaidano  11 , Je-Jung Lee  12 , Sunil Abhyankar  13 , Carlos Solano  14 , Jaime Perez de Oteyza  15 , Michael J Satlin  16 , Stefan Schwartz  17 , Magda Campins  18 , Alberto Rocci  19   20 , Carlos Vallejo Llamas  21 , Dong-Gun Lee  22 , Sen Mui Tan  23 , Anna M Johnston  24 , Andrew Grigg  25 , Michael J Boeckh  26 , Laura Campora  1 , Marta Lopez-Fauqued  1 , Thomas C Heineman  27 , Edward A Stadtmauer  28 , Keith M Sullivan  29 ; ZOE-HSCT Study Group Collaborators
Collaborators, Affiliations
Clinical Trial

Effect of Recombinant Zoster Vaccine on Incidence of Herpes Zoster After Autologous Stem Cell Transplantation: A Randomized Clinical Trial

Adriana Bastidas et al. JAMA. .

Erratum in

  • Incorrect Axis Scale in Figure.
    [No authors listed] [No authors listed] JAMA. 2019 Aug 27;322(8):785. doi: 10.1001/jama.2019.11467. JAMA. 2019. PMID: 31454023 Free PMC article. No abstract available.

Abstract

Importance: Herpes zoster, a frequent complication following autologous hematopoietic stem cell transplantation (HSCT), is associated with significant morbidity. A nonlive adjuvanted recombinant zoster vaccine has been developed to prevent posttransplantation zoster.

Objective: To assess the efficacy and adverse event profile of the recombinant zoster vaccine in immunocompromised autologous HSCT recipients.

Design, setting, and participants: Phase 3, randomized, observer-blinded study conducted in 167 centers in 28 countries between July 13, 2012, and February 1, 2017, among 1846 patients aged 18 years or older who had undergone recent autologous HSCT.

Interventions: Participants were randomized to receive 2 doses of either recombinant zoster vaccine (n = 922) or placebo (n = 924) administered into the deltoid muscle; the first dose was given 50 to 70 days after transplantation and the second dose 1 to 2 months thereafter.

Main outcomes and measures: The primary end point was occurrence of confirmed herpes zoster cases.

Results: Among 1846 autologous HSCT recipients (mean age, 55 years; 688 [37%] women) who received 1 vaccine or placebo dose, 1735 (94%) received a second dose and 1366 (74%) completed the study. During the 21-month median follow-up, at least 1 herpes zoster episode was confirmed in 49 vaccine and 135 placebo recipients (incidence, 30 and 94 per 1000 person-years, respectively), an incidence rate ratio (IRR) of 0.32 (95% CI, 0.22-0.44; P < .001), equivalent to 68.2% vaccine efficacy. Of 8 secondary end points, 3 showed significant reductions in incidence of postherpetic neuralgia (vaccine, n=1; placebo, n=9; IRR, 0.1; 95% CI, 0.00-0.78; P = .02) and of other prespecified herpes zoster-related complications (vaccine, n=3; placebo, n=13; IRR, 0.22; 95% CI, 0.04-0.81; P = .02) and in duration of severe worst herpes zoster-associated pain (vaccine, 892.0 days; placebo, 6275.0 days; hazard ratio, 0.62; 95% CI, 0.42-0.89; P = .01). Five secondary objectives were descriptive. Injection site reactions were recorded in 86% of vaccine and 10% of placebo recipients, of which pain was the most common, occurring in 84% of vaccine recipients (grade 3: 11%). Unsolicited and serious adverse events, potentially immune-mediated diseases, and underlying disease relapses were similar between groups at all time points.

Conclusions and relevance: Among adults who had undergone autologous HSCT, a 2-dose course of recombinant zoster vaccine compared with placebo significantly reduced the incidence of herpes zoster over a median follow-up of 21 months.

Trial registration: ClinicalTrials.gov Identifier: NCT01610414.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Bastidas reported being employed by and holding stock options in GlaxoSmithKline (GSK). Dr El Idrissi reported being employed by and holding stock options in GSK. Dr Oostvogels reported being employed by GSK during conception and/or conduct of the study and being currently employed by CureVac AG; being an inventor on a patent owned by GSK relevant to recombinant zoster vaccine; and holding stock in GSK. Dr López-Jiménez reported receipt of grants from Hospital Ramon y Cajal. Dr Vural reported receipt of grants and personal fees from GSK. Dr Issa reported receipt of grants from GSK, Merck, and Astellas and personal fees from Akros Pharma. Dr Gaidano reported receipt of trial patient fees from GSK and personal fees from Abbvie, Roche, Gilead, Janssen, and Morphosys. Dr Perez de Oteyza reported receipt of grants from GSK, Pharmacyclics, Vivia-Biotech, Morphosys, and Helsinn; grants and personal fees from Roche, Janssen, Takeda, and Celgene; and personal fees from Servier and Gilead. Dr Satlin reported receipt of grants from GSK, Allergan, Merck, Biofire Diagnostics, and Biomerieux and consulting fees from Achaogen and Shionogi. Dr Schwartz reported receipt of grants from GSK and personal fees and nonfinancial support from Amgen, Basilea Pharmaceutica, Gilead, Jazz Pharmaceuticals, Merck Sharp & Dohme, and Pfizer. Dr Campins reported receipt of grants and personal fees from GSK; participation as an investigator in clinical trials from GSK and Novartis; and participation in expert meetings and symposiums organized by Pfizer, GSK, Sanofi-Pasteur, Merck Sharp & Dohme, and Novartis. Dr Rocci reported receipt of consultancy fees from Takeda and Sanofi and honoraria from Takeda, Celgene, Novartis, Amgen, and Janssen and advisory board membership for Novartis, Amgen, and Janssen. Dr Johnston reported receipt of personal fees from Roche, Janssen Cilag, Celgene, and Merck Sharp & Dohme. Dr Grigg reports advisory board membership for Novartis, Gilead, Roche, Merck Sharp & Dohme, Takeda, and Bristol-Myers Squibb. Dr Boeckh reported receipt of grants and personal fees from GSK, Merck, and Chimerix and personal fees from Clinigen. Dr Campora reported being an employee of GSK; owning shares in GSK; and receipt of personal fees from GSK. Dr Lopez-Fauqued reported being an employee of GSK. Dr Heineman reported being an employee of GSK during conception and/or conduct of the study; holding stock and stock options in GSK; being an inventor on a patent owned by GSK relevant to recombinant zoster vaccine; being a paid consultant for GSK. Dr Stadtmauer reported receipt of grants from GSK. Dr Sullivan reported receipt of grants and personal fees from GSK; personal fees from Kiadis Pharmaceutical and Roche Genentech; and a grant from the National Institute of Allergy and Infectious Diseases awarded to his university. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Participant Flow in the Zoster Efficacy Study in Patients Undergoing Hematopoietic Stem Cell Transplantation
aThe total number of persons screened for eligibility was not recorded.
Figure 2.
Figure 2.. Cumulative Incidence of Herpes Zoster Overall (Modified Total Vaccinated Cohort)
On the x-axis, 0 corresponds to 1 month after study dose 2; ie, 5 to 6 months after hematopoietic stem cell transplantation. Cumulative incidence at 42 months since 30 days after dose 2 was 20.3% in the placebo group and 9.5% in the recombinant zoster vaccine group. The median follow-up time at risk was 22.0 (interquartile range, 13.4-32.4) months in the recombinant zoster vaccine group and 19.9 (interquartile range, 10.0-29.9) months in the placebo group.
Figure 3.
Figure 3.. Humoral Immunogenicity Results (Per-Protocol Cohort for Humoral Immunogenicity/Persistence)
In panel A, error bars indicate 95% confidence intervals. In panel B, error bars indicate ranges; bar tops and bottoms, interquartile ranges; horizontal middle lines, medians; and white squares, geometric means.
Figure 4.
Figure 4.. Cell-Mediated Immunogenicity Results (Per-Protocol Cohort for Cell-Mediated Immunity/Persistence)
In panel A, error bars indicate 95% confidence intervals. In panel B, error bars indicate ranges; bar tops and bottoms, interquartile ranges; and horizontal middle lines, medians. Panel B data are for CD4 T cells expressing at least 2 of 4 assessed activation markers (interferon γ, interleukin 2, tumor necrosis factor α, and CD40 ligand).
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