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.
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.
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DOI：
10.1016/s1473-3099(22)00506-0
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发表时间：
2022-12
影响因子：
56.3
通讯作者：
Struyf, Frank
中科院分区：
文献类型：
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作者：
Hardt, Karin;Vandebosch, An;Sadoff, Jerald;Le Gars, Mathieu;Truyers, Carla;Lowson, David;Van Dromme, Ilse;Vingerhoets, Johan;Kamphuis, Tobias;Scheper, Gert;Ruiz-Guinazu, Javier;Faust, Saul N.;Spinner, Christoph D.;Schuitemaker, Hanneke;Van Hoof, Johan;Douoguih, Macaya;Struyf, Frank
尽管可获得有效的COVID-19疫苗，但仍需要加强疫苗接种，以维持疫苗诱导的保护，防止变异株和突破性感染。本研究旨在研究Ad26.COV2.S疫苗（杨森）作为初次接种加加强剂量的有效性、安全性和免疫原性。ENSEMBLE 2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、英国和美国的公立和私立医疗机构和医院，至少18岁且既往未接种过COVID-19疫苗的成年人通过计算机算法以1：1的比例随机分配，接受肌肉注射Ad26.COV2.S作为初始剂量加2个月后的加强剂量或间隔2个月的两次安慰剂注射。主要终点是疫苗对首次发生分子学证实的中度至重度危重COVID-19的有效性，该疾病在加强接种后至少14天发作，在接受两剂疫苗或安慰剂的参与者中进行评估，基线时PCR检测SARS-CoV-2阴性，基线和第71天血清学检测阴性，没有重大方案偏离，并且存在COVID-19风险（即，无PCR阳性结果或在第71天前终止研究）。在所有受试者中评估安全性;在安全性子集（约6000例随机选择的受试者）中，将征集性局部和全身不良事件方面的反应原性作为次要终点进行评估。该试验在ClinicalTrials.gov注册，NCT 04614948，目前正在进行中。入组开始于2020年11月16日，主要分析数据截止日期为2021年6月25日。在筛选的34571名受试者中，双盲期入组了31300名受试者，其中14492人接受了两次给药（Ad26.COV2.S组7484人，安慰剂组7008人），其中11639人有资格入选主要终点评估（Ad26.COV2.S组6024人，安慰剂组5615人）。 加强免疫后的中位（IQR）随访时间为36·0（15·0-62·0）天。针对中度至重度危重COVID-19（Ad26.COV2.S组14例，安慰剂组52例）的疫苗有效率为75.2%（调整后的95%CI 54.6 - 87.3）。大多数病例是由于变体alpha（B.1.1.7）和mu（B.1.621）所致;主要分析的终点从2020年11月16日至2021年6月25日，在delta（B.1.617.2）或omicron（B.1.1.529）的全球优势之前。加强疫苗显示出可接受的安全性。初次和加强剂量后，疫苗接种者征集性局部和全身不良事件（在安全性子集中评价，n=6067）的总体频率高于安慰剂接种者。Ad26.COV2.S组初次和加强接种后征集性不良事件的频率相似（局部不良事件，分别为3015例中的1676例[55.6%]和1559例中的896例[57.5%];全身不良事件，分别为3015例中的1764例[58.5%]和1559例中的821例[52.7%]）。征集性不良事件为一过性，严重程度大多为1-2级。在成人中初次单剂疫苗接种后2个月给予同源Ad26.COV2.S加强剂具有可接受的安全性特征，并且对中度至重度危重COVID-19有效。需要进行针对新变体的疗效评估研究，并进行更长时间的随访。杨森研发公司
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. 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. 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. 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. Janssen Research & Development.