Efficacy and Safety of a Booster Regimen of Ad26.COV2.S Vaccine against Covid-19
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Abstract
Background
Despite 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.
Methods
ENSEMBLE2 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.
Results
The 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.
Conclusions
A 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 .)
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SciScore for 10.1101/2022.01.28.22270043: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Ethics IRB: The protocol and amendments were approved by ethics committees and institutional review boards per local regulations.
Consent: All relevant ethical guidelines have been followed, all necessary institutional review board (IRB) and/or ethics committee approvals have been obtained, all necessary patient/participant consent has been obtained, and the appropriate institutional forms archived.Sex as a biological variable not detected. Randomization Trial Design and Oversight: ENSEMBLE2 is an ongoing, randomized, double-blind, placebo-controlled, phase 3 trial (including crossover vaccination after emergency authorization of Covid-19 vaccines) conducted in 10 countries: Belgium, Brazil, … SciScore for 10.1101/2022.01.28.22270043: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Ethics IRB: The protocol and amendments were approved by ethics committees and institutional review boards per local regulations.
Consent: All relevant ethical guidelines have been followed, all necessary institutional review board (IRB) and/or ethics committee approvals have been obtained, all necessary patient/participant consent has been obtained, and the appropriate institutional forms archived.Sex as a biological variable not detected. Randomization Trial Design and Oversight: ENSEMBLE2 is an ongoing, randomized, double-blind, placebo-controlled, phase 3 trial (including crossover vaccination after emergency authorization of Covid-19 vaccines) conducted in 10 countries: Belgium, Brazil, Colombia, France, Germany, The Philippines, South Africa, Spain, the United Kingdom, and the United States. Blinding Participants and sites were blinded to assignment until the unblinding visit (Supplementary Methods). Power Analysis Sample size was based on an assumption of vaccine efficacy of 65% against molecularly-confirmed moderate to severe–critical SARS-CoV-2 infection, a type 1 error rate of 0.025 to evaluate vaccine efficacy, and a 1:1 randomization ratio. Table 2: Resources
No key resources detected.
Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).
Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:There are limitations to this study. As ENSEMBLE2 was conducted at the peak of the Covid-19 wave of early 2021, when Covid-19 vaccines were first made available by EUA, it was no longer ethical to maintain the placebo control, leading to early unblinding. All participants could request unblinding to determine whether they qualified for Covid-19 vaccination outside the study and placebo recipients could receive the open-label crossover vaccination (timing varied by country). Unblinding/crossover reduced participant numbers receiving both doses and planned follow-up time in the double-blind phase and led to limited numbers of Covid-19 cases being available for evaluation of the booster dose; data within subgroups, including by variant, should be interpreted with caution. More participants in the placebo group than the Ad26.COV2.S group terminated prematurely, partly because after unblinding, placebo recipients terminated participation to receive another Covid-19 vaccine outside the study, and possibly due to non-study antibody testing. Most participants nevertheless completed the double-blind phase, and the study power remained strong. The person-years of follow-up in the PP and FAS sets were generally similar, indicating that blinding was properly maintained and bias minimized. Moreover, vaccine efficacy estimation methods accounted for imbalances of follow-up. Given the short follow-up and low numbers for some groups, the exact breadth and incremental protection of the booste...
Results from TrialIdentifier: We found the following clinical trial numbers in your paper:
Identifier Status Title NCT04614948 Active, not recruiting A Study of Ad26.COV2.S for the Prevention of SARS-CoV-2-medi… Results from Barzooka: We did not find any issues relating to the usage of bar graphs.
Results from JetFighter: We did not find any issues relating to colormaps.
Results from rtransparent:- Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
- Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
- No protocol registration statement was detected.
Results from scite Reference Check: We found no unreliable references.
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