Study Design

ZOE-70 was a randomized, placebo-controlled, phase 3 trial conducted in 18 countries in Europe, North America, Latin America, and Asia–Australia to evaluate the efficacy, immunogenicity, and safety of HZ/su in adults 70 years of age or older. The investigators were unaware of the study-group assignments during the trial. This trial had the same design as ZOE-50 and was conducted concurrently at the same sites.26

The trial protocol, available with the full text of this article at NEJM.org, was approved by the appropriate independent ethics committee or institutional review board at each study center. Written informed consent was obtained from all participants before study entry. ZOE-70 was conducted in accordance with the provisions of the Declaration of Helsinki and the International Conference on Harmonisation Good Clinical Practice guidelines. During the study, potential research compliance issues were investigated, and appropriate actions were taken when needed. ZOE-70 was monitored by an independent data and safety monitoring committee that met regularly during the course of the study to review all safety data in an unblinded manner, as described previously for ZOE-50.26

Medical writing was provided by 4Clinics, France, with funding support from GlaxoSmithKline Biologicals. All the authors reviewed and approved the final submitted version of the manuscript. The last author vouches for the completeness and accuracy of all the data and the analyses presented and for the fidelity of the trial to the protocol.

Eligibility, Randomization, and Blinding

Adults 70 years of age or older were eligible for inclusion in the trial unless they had a history of herpes zoster, had previously been vaccinated against varicella or herpes zoster, or had an immunosuppressive condition (see the Supplementary Appendix, available at NEJM.org, for a complete list of inclusion and exclusion criteria). Participants who were 70 years of age or older were first randomly assigned to either ZOE-5026 or ZOE-70 and then were randomly assigned in a 1:1 ratio to either the HZ/su group or the placebo group with the use of an online centralized randomization system. Participants were stratified according to region (Asia and Australia, Europe, Latin America, and North America) and age group (70 to 79 years vs. ≥80 years [in a 3:1 ratio]). The investigators, participants, and persons responsible for evaluating the study end points were unaware of whether HZ/su or placebo had been administered.

Vaccination

HZ/su contains 50 μg of recombinant VZV glycoprotein E and the liposome-based AS01 B adjuvant system (which contains 50 μg of 3-O-desacyl-4′-monophosphoryl lipid A [MPL] and 50 μg of Quillaja saponaria Molina, fraction 21 [QS21, licensed by GSK from Antigenics, a subsidiary of Agenus]). Vaccine or placebo (0.9% saline solution) was administered (0.5 ml) into the deltoid muscle at month 0 and month 2. Participants were to be followed for at least 30 months after the second dose through monthly contacts and annual clinic visits.

Trial End Points

The primary objective of ZOE-70 was to evaluate the efficacy of HZ/su, as compared with placebo, in reducing the risk of herpes zoster among adults 70 years of age or older. The primary objectives of the pooled analysis involving participants from ZOE-50 and ZOE-70 were to evaluate the efficacy of the vaccine, as compared with placebo, in reducing the risk of herpes zoster and the risk of postherpetic neuralgia in the overall population of participants 70 years of age or older from the two studies. The secondary objectives included the evaluation of vaccine efficacy against postherpetic neuralgia among participants 50 years of age or older and the evaluation of vaccine safety and reactogenicity. (A complete list of objectives is provided in the Supplementary Appendix.)

Evaluation of Safety and Reactogenicity

In ZOE-70, a randomly selected subgroup of age-stratified participants recorded injection-site reactions (pain, redness, and swelling) and systemic reactions (fatigue, fever, gastrointestinal symptoms, headache, myalgia, and shivering) on diary cards for 7 days after each injection. Redness and swelling at the injection site were scored as 0 if the affected area was less than 20 mm in diameter, 1 if the affected area was 20 to 50 mm, 2 if the affected area was more than 50 to 100 mm, and 3 if the affected area was more than 100 mm. Fever was scored as 0 for a body temperature lower than 37.5°C, 1 for 37.5°C to 38.0°C, 2 for 38.1°C to 39.0°C, and 3 for higher than 39.0°C (the preferred route for recording temperature was oral). All other symptoms were scored as 0 for absent, 1 for easily tolerated, 2 for interferes with normal activity, and 3 for prevents normal activity.

Unsolicited reports of adverse events were recorded for 30 days after each dose for all participants. All serious adverse events were recorded for all participants for 12 months after the second dose. Serious adverse events that were considered to be related to the study vaccine or to trial participation, events resulting in death, and potential immune-mediated diseases were evaluated in all participants throughout the trial.

Suspected Cases of Herpes Zoster

A suspected case of herpes zoster was defined as new unilateral rash with pain (broadly defined to include allodynia, pruritus, or other abnormal sensations) that had no alternative diagnosis. Suspected cases of herpes zoster were evaluated as described previously.26 Lesion samples were obtained from patients with suspected herpes zoster for polymerase-chain-reaction (PCR) analysis. A suspected case was confirmed as herpes zoster if the PCR assay was positive for VZV. The case was classified as not herpes zoster if the PCR assay was VZV-negative and β-actin–positive (control). If the PCR results were indeterminate (VZV-negative and β-actin–negative) or if samples were not available, the final diagnosis was determined by unanimous agreement among the five members of an ascertainment committee, the members of which were unaware of the study group assignments. If the committee opinion was not unanimous, the case was classified as inconclusive and was considered not to be herpes zoster for the purposes of the statistical analyses.

Assessment of Postherpetic Neuralgia Cases

Participants with a suspected case of herpes zoster were asked to attend a schedule of assessment visits and to complete the Zoster Brief Pain Inventory27 questionnaire daily for 28 days and weekly thereafter, until the participant had been pain-free for 4 weeks or for at least 90 days after the onset of the rash. The “worst pain” score (item 3: “Please rate your pain by circling the one number that best describes your pain at its worst in the last 24 hours,” rated on a scale of 0 to 10, with higher numbers indicating worse pain) was used to determine whether a participant had postherpetic neuralgia.27 As in previous studies, postherpetic neuralgia was defined as a worst pain score of 3 or higher for pain that persisted or developed more than 90 days after the onset of herpes zoster rash.19,28

Statistical Analysis

Safety was analyzed in the total vaccinated cohort, which included all participants who could be evaluated and who had received at least one dose of HZ/su or placebo. Efficacy was analyzed in the total vaccinated cohort and in the modified vaccinated cohort (the primary cohort for the efficacy analysis), which excluded participants who did not receive the second dose or who had a confirmed herpes zoster episode within 1 month (30 days) after the second dose. All the analyses included participants 70 years of age or older, with the exception of the analysis of vaccine efficacy against postherpetic neuralgia, which included participants 50 years of age or older.

Vaccine efficacy was defined as 1 minus the ratio of herpes zoster incidence in the HZ/su group to that in the placebo group, multiplied by 100. All significance tests were two tailed. P values of 0.05 or less were considered to indicate statistical significance. All statistical analyses were performed with SAS software, version 9.3 (SAS Institute), and StatXact software, version 9.0 (Cytel).