Efficacy, safety, and immunogenicity of a booster regimen of Ad26.COV2.S vaccine against COVID-19 (ENSEMBLE2): results of a randomised, double-blind, placebo-controlled, phase 3 trial

Abstract

Background: Despite the availability of effective vaccines against COVID-19, booster vaccinations are needed to maintain vaccine-induced protection against variant strains and breakthrough infections. This study aimed to investigate the efficacy, safety, and immunogenicity of the Ad26.COV2.S vaccine (Janssen) as primary vaccination plus a booster dose.

Methods: ENSEMBLE2 is a randomised, double-blind, placebo-controlled, phase 3 trial including crossover vaccination after emergency authorisation of COVID-19 vaccines. Adults aged at least 18 years without previous COVID-19 vaccination at public and private medical practices and hospitals in Belgium, Brazil, Colombia, France, Germany, the Philippines, South Africa, Spain, the UK, and the USA were randomly assigned 1:1 via a computer algorithm to receive intramuscularly administered Ad26.COV2.S as a primary dose plus a booster dose at 2 months or two placebo injections 2 months apart. The primary endpoint was vaccine efficacy against the first occurrence of molecularly confirmed moderate to severe-critical COVID-19 with onset at least 14 days after booster vaccination, which was assessed in participants who received two doses of vaccine or placebo, were negative for SARS-CoV-2 by PCR at baseline and on serology at baseline and day 71, had no major protocol deviations, and were at risk of COVID-19 (ie, had no PCR-positive result or discontinued the study before day 71). Safety was assessed in all participants; reactogenicity, in terms of solicited local and systemic adverse events, was assessed as a secondary endpoint in a safety subset (approximately 6000 randomly selected participants). The trial is registered with ClinicalTrials.gov, NCT04614948, and is ongoing.

Findings: Enrolment began on Nov 16, 2020, and the primary analysis data cutoff was June 25, 2021. From 34 571 participants screened, the double-blind phase enrolled 31 300 participants, 14 492 of whom received two doses (7484 in the Ad26.COV2.S group and 7008 in the placebo group) and 11 639 of whom were eligible for inclusion in the assessment of the primary endpoint (6024 in the Ad26.COV2.S group and 5615 in the placebo group). The median (IQR) follow-up post-booster vaccination was 36·0 (15·0-62·0) days. Vaccine efficacy was 75·2% (adjusted 95% CI 54·6-87·3) against moderate to severe-critical COVID-19 (14 cases in the Ad26.COV2.S group and 52 cases in the placebo group). Most cases were due to the variants alpha (B.1.1.7) and mu (B.1.621); endpoints for the primary analysis accrued from Nov 16, 2020, to June 25, 2021, before the global dominance of delta (B.1.617.2) or omicron (B.1.1.529). The booster vaccine exhibited an acceptable safety profile. The overall frequencies of solicited local and systemic adverse events (evaluated in the safety subset, n=6067) were higher among vaccine recipients than placebo recipients after the primary and booster doses. The frequency of solicited adverse events in the Ad26.COV2.S group were similar following the primary and booster vaccinations (local adverse events, 1676 [55·6%] of 3015 vs 896 [57·5%] of 1559, respectively; systemic adverse events, 1764 [58·5%] of 3015 vs 821 [52·7%] of 1559, respectively). Solicited adverse events were transient and mostly grade 1-2 in severity.

Interpretation: A homologous Ad26.COV2.S booster administered 2 months after primary single-dose vaccination in adults had an acceptable safety profile and was efficacious against moderate to severe-critical COVID-19. Studies assessing efficacy against newer variants and with longer follow-up are needed.

Funding: Janssen Research & Development.

Figure 1

Participant disposition FAS=full analysis set. PPFD=per-protocol first-dose. PP=per-protocol. *These individuals were still being followed up for safety as of the data cutoff date (June 25, 2021). †Of those receiving one vaccination, 1548 in the Ad26.COV2.S group and 2052 in the placebo group were unmasked before the unmasking visit and 148 in the Ad26.COV2.S group and 262 in the placebo group received a COVID-19 vaccine outside the study before unmasking. ‡Of those receiving a booster dose, 2719 in the Ad26.COV2.S group and 2628 in the placebo group were unmasked before the unmasking visit and 46 in the Ad26.COV2.S group and 168 in the placebo group received a COVID-19 vaccine outside the study before unmasking. §Participants could have more than one reason for exclusion. ¶The PPFD and PP sets are partially overlapping subsets of the FAS and do not sum to a total that equals the FAS. ||Risk sets excluded participants who had a positive PCR result between the first vaccination and day 15 (PPFD set) or day 71 (PP set), or who discontinued before 14 days after the first vaccination (PPFD set) or booster (PP set).

Figure 2

Cumulative incidence of first occurrence of molecularly confirmed moderate to severe–critical COVID-19 with onset at least 1 day after booster vaccination (PP population)* (A) Cumulative incidence of molecularly confirmed moderate to severe–critical COVID-19 with onset at least 1 day after booster vaccination in the PP population. (B) Cumulative incidence of molecularly confirmed moderate to severe–critical COVID-19 due to the alpha (B.1.1.7) variant with onset at least 1 day after booster vaccination in the PP population. (C) Cumulative incidence of molecularly confirmed moderate to severe–critical COVID-19 due to the mu (B.1.621) variant in the PP population. *Number in the PP group minus participants who had an event or were censored (because of outside vaccination) before the booster dose. PP=per protocol.

Figure 2

Cumulative incidence of first occurrence of molecularly confirmed moderate to severe–critical COVID-19 with onset at least 1 day after booster vaccination (PP population)* (A) Cumulative incidence of molecularly confirmed moderate to severe–critical COVID-19 with onset at least 1 day after booster vaccination in the PP population. (B) Cumulative incidence of molecularly confirmed moderate to severe–critical COVID-19 due to the alpha (B.1.1.7) variant with onset at least 1 day after booster vaccination in the PP population. (C) Cumulative incidence of molecularly confirmed moderate to severe–critical COVID-19 due to the mu (B.1.621) variant in the PP population. *Number in the PP group minus participants who had an event or were censored (because of outside vaccination) before the booster dose. PP=per protocol.

Figure 3

Solicited local (A) and systemic (B) adverse events following a prime–boost vaccination regimen in adults (safety set) Percentages of participants specifically reporting grade 3 adverse events are shown above each column for the vaccine and placebo groups.