ABSTRACT
BackgroundDespite the availability of effective vaccines against coronavirus disease 2019 (Covid-19), the emergence of variant strains and breakthrough infections pose a challenging new reality. Booster vaccinations are needed to maintain vaccine-induced protection. MethodsENSEMBLE2 is an ongoing, randomized, double-blind, placebo-controlled, phase 3 pivotal trial including crossover vaccination after emergency authorization of Covid-19 vaccines. Adults aged [≥]18 years were randomized to receive Ad26.COV2.S or placebo as a primary dose plus a booster dose at two months. The primary endpoint was vaccine efficacy against the first occurrence of molecularly-confirmed moderate to severe-critical Covid-19 with onset [≥]14 days after booster vaccination in the per-protocol population. Key efficacy, safety, and immunogenicity endpoints were also assessed. ResultsThe double-blind phase enrolled 31,300 participants, 14,492 of whom received 2 doses and were evaluable for efficacy (per-protocol set, Ad26.COV2.S n=7484; placebo n=7008). Baseline demographics and characteristics were balanced. Vaccine efficacy was 75.2% (adjusted 95% CI, 54.6-87.3) against moderate to severe-critical Covid-19 and was similar against symptomatic infection (75.6% [55.5-99.9]). Efficacy was consistent across participants with and without comorbidities, and reached 93.7% (58.5-99.9) in the US. Vaccine efficacy against severe-critical Covid-19 was 100% (32.6-100.0; 0 vs 8 cases). The booster vaccine induced robust humoral responses and exhibited an acceptable safety profile. ConclusionsA homologous Ad26.COV2.S booster administered 2 months after primary single-dose vaccination in adults led to high vaccine efficacy, including against any symptomatic infection and SARS-CoV-2 variants prevalent during the study. (Funding: Janssen Research and Development and others; ENSEMBLE2 ClinicalTrials.gov number, NCT04614948.)