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.

中文翻译：

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Ad26.COV2.S 疫苗加强方案针对 COVID-19 (ENSEMBLE2) 的功效、安全性和免疫原性：随机、双盲、安慰剂对照的 3 期试验结果

背景

尽管可获得针对 COVID-19 的有效疫苗，但仍需要加强疫苗接种以维持疫苗诱导的针对变异株和突破性感染的保护。本研究旨在调查 Ad26.COV2.S 疫苗 (Janssen) 作为初级疫苗接种加加强剂量的有效性、安全性和免疫原性。

方法

ENSEMBLE2 是一项随机、双盲、安慰剂对照的 3 期试验，包括 COVID-19 疫苗紧急授权后的交叉疫苗接种。在比利时、巴西、哥伦比亚、法国、德国、菲律宾、南非、西班牙、英国和美国的公共和私人医疗机构和医院，年龄至少 18 岁且之前未接种过 COVID-19 疫苗的成年人被随机分配到 1： 1 通过计算机算法接受肌内注射的 Ad26.COV2.S 作为主要剂量加上 2 个月时的加强剂量或间隔 2 个月的两次安慰剂注射。主要终点是疫苗对首次出现经分子证实的中度至重度危重 COVID-19 的有效性，该疫苗在加强疫苗接种后至少 14 天出现，在接受两剂疫苗或安慰剂的参与者中进行了评估，基线 PCR 检测 SARS-CoV-2 以及基线和第 71 天血清学检测呈阴性，没有重大方案偏差，并且有 COVID-19 风险（即没有 PCR 阳性结果或在第 71 天前停止研究71). 对所有参与者的安全性进行了评估；就征求的局部和全身不良事件而言，反应原性被评估为安全子集（约 6000 名随机选择的参与者）中的次要终点。该试验已在 ClinicalTrials.gov 注册，NCT04614948，并且正在进行中。被评估为安全子集中​​的次要终点（约 6000 名随机选择的参与者）。该试验已在 ClinicalTrials.gov 注册，NCT04614948，并且正在进行中。被评估为安全子集中​​的次要终点（约 6000 名随机选择的参与者）。该试验已在 ClinicalTrials.gov 注册，NCT04614948，并且正在进行中。

发现

招募于 2020 年 11 月 16 日开始，主要分析数据截止日期为 2021 年 6 月 25 日。从筛选的 34 571 名参与者中，双盲阶段招募了 31 300 名参与者，其中 14 492 人接受了两剂（Ad26.COV2 中的 7484 人） .S 组和安慰剂组 7008 人），其中 11639 人有资格纳入主要终点评估（Ad26.COV2.S 组 6024 人，安慰剂组 5615 人）。加强疫苗接种后的中位 (IQR) 随访时间为 36·0 (15·0–62·0) 天。疫苗对中度至重度危重 COVID-19 的疗效为 75·2%（调整后的 95% CI 54·6–87·3）（Ad26.COV2.S 组 14 例，安慰剂组 52 例）。大多数情况是由于变体 alpha (B.1.1.7) 和 mu (B.1.621)；主要分析的终点是从 2020 年 11 月 16 日到 2021 年 6 月 25 日，在 delta (B.1.617.2) 或 omicron (B.1.1.529) 的全球主导地位之前。加强疫苗表现出可接受的安全性。在初次接种和加强接种后，疫苗接种者引发的局部和全身不良事件（在安全子集中​​评估，n=6067）的总体频率高于安慰剂接种者。在 Ad26.COV2.S 组中，初次和加强疫苗接种后引发的不良事件频率相似（局部不良事件，3015 人中的 1676 人 [55·6%]分别对比1559 的 896 [57·5%]；系统性不良事件，分别为 3015 人中的 1764 人 [58·5%]和1559 人中的 821 人 [52·7%]）。主动提出的不良事件是短暂的，严重程度大多为 1-2 级。

解释

在成人初次单剂量疫苗接种后 2 个月给予同源 Ad26.COV2.S 加强剂具有可接受的安全性，并且对中度至重度危重 COVID-19 有效。需要研究评估针对较新变体的疗效并进行更长时间的随访。

资金

杨森研发。