SARS-CoV-2 variants evade immunity despite vaccination with prototype COVID-19 vaccines or previous infection. The 2019nCoV-311 (part 2) study is evaluating immune responses after two booster doses of a vaccine containing the omicron BA.5 subvariant spike protein in adults previously vaccinated with a prototype mRNA vaccine. This interim analysis reports on day 28 immunogenicity and safety outcomes after one booster dose. In this phase 3, randomised, observer-blinded study conducted at 35 sites in Australia, medically stable, previously COVID-19-vaccinated (mRNA-based; ≥three doses) adults aged 18 years or older were enrolled and randomly allocated (1:1:1; via an interactive web response system) to receive two doses of bivalent (NVX-CoV2373 + NVX-CoV2540; bivalent group), authorised prototype (NVX-CoV2373; prototype group), or BA.5 (NVX-CoV2540; BA.5 group) vaccine. Only blinded personnel performed study assessments or had participant contact to collect data after study vaccination. Participants received vaccines containing 5 μg SARS-CoV-2 recombinant spike protein and 50 μg Matrix-M adjuvant, administered via a 0·5 mL intramuscular injection (2·5 μg of NVX-CoV2373 plus 2·5 μg of NVX-CoV2540 for the bivalent vaccine, prepared on-site as a 1:1 mixture). The coprimary endpoints include day 28 neutralising antibody geometric mean titre (GMT) ratios (GMTRs) to omicron BA.5 and the ancestral strain, and seroresponse rates to BA.5, in the bivalent and prototype groups. These endpoints were calculated in the per-protocol analysis set, which was defined as participants who had received a vaccine dose, had baseline and day 28 immunogenicity data, and were PCR-negative for SARS-CoV-2, with no major protocol deviations. The primary objective was to determine the primary outcome (antibody responses), which consisted of three comparisons: superiority of the bivalent versus prototype vaccine for neutralising antibody GMT to BA.5 (ie, lower bound of the GMTR 95% CI >1·0); non-inferiority of neutralising antibody seroresponse rate to BA.5 (ie, lower bound of the seroresponse rate 95% CI >–5%); and non-inferiority of neutralising antibody GMT to the ancestral strain (ie, lower bound of GMTR 95% CI >0·67). This trial was registered at , number . Between March 22, 2023 and May 2, 2023, 837 participants were screened for eligibility and 766 were randomly allocated to receive the BA.5 (n=255), prototype (n=252), or bivalent (n=259) vaccine. After accounting for exclusions due to participants being baseline SARS-CoV-2-positive, having previous infection, or protocol deviations, the per-protocol analysis set included 694 participants (236 in BA.5 group, 227 in prototype group, and 231 in bivalent group). In this interim analysis (maximum follow-up 35 days after the first dose), the bivalent group, compared with the prototype group, had superior neutralising antibody responses to BA.5 (GMT 1017·8 [95% CI 891·0–1162·6] 515·1 [450·4–589·0]; GMTR 2·0 [1·69–2·33]) and a non-inferior seroresponse rate to BA.5 at day 28 (39·8% [33·5–46·5] 12·3% [8·4–17·3]; difference 27·5% [19·8–35·0]). The bivalent group also had non-inferior neutralising antibody responses to the ancestral strain (GMTR 1·0 [0·84–1·20]), compared with the prototype group. All vaccines were similarly well tolerated. All three coprimary endpoints were met in part 2 of the ongoing 2019nCoV-311 study. These data support the development of monovalent and/or bivalent vaccines for the most currently circulating variants, to optimise protection. With no new safety findings, further investigation of omicron-based subvariant vaccines is supported by the evidence. Novavax.

中文翻译：

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二价（omicron BA.5 加祖先）SARS-CoV-2 重组刺突蛋白疫苗作为异源加强剂量的免疫原性和安全性：3 期非劣效性随机临床试验的中期分析


尽管接种了原型 COVID-19 疫苗或既往感染过，但 SARS-CoV-2 变体仍能逃避免疫。 2019nCoV-311（第 2 部分）研究正在评估先前接种过原型 mRNA 疫苗的成年人接种两剂含有 omicron BA.5 亚变刺突蛋白的疫苗后的免疫反应。该中期分析报告了一次加强剂量后第 28 天的免疫原性和安全性结果。在这项第 3 阶段研究中，在澳大利亚 35 个地点进行了随机、观察者盲法研究，招募了 18 岁或以上、病情稳定、之前接种过 COVID-19 疫苗（基于 mRNA；≥三剂）的成年人，并随机分配（1： 1:1；通过交互式网络响应系统）接收两剂二价疫苗（NVX-CoV2373 + NVX-CoV2540；二价组）、授权原型（NVX-CoV2373；原型组）或 BA.5（NVX-CoV2540； BA.5组）疫苗。只有盲人人员进行研究评估或在研究疫苗接种后与参与者联系以收集数据。参与者接受了含有 5 μg SARS-CoV-2 重组刺突蛋白和 50 μg Matrix-M 佐剂的疫苗，通过 0·5 mL 肌肉注射给药（2·5 μg NVX-CoV2373 加 2·5 μg NVX-CoV2540二价疫苗，现场配制为 1:1 混合物）。共同主要终点包括第 28 天对 omicron BA.5 和祖先菌株的中和抗体几何平均滴度 (GMT) 比率 (GMTR)，以及二价组和原型组对 BA.5 的血清反应率。这些终点是在符合方案分析集中计算的，该分析集被定义为已接受疫苗剂量、具有基线和第 28 天免疫原性数据、并且 SARS-CoV-2 PCR 阴性、没有重大方案偏差的参与者。 主要目标是确定主要结果（抗体反应），其中包括三个比较： 二价疫苗与原型疫苗在中和抗体 GMT 至 BA.5 方面的优越性（即 GMTR 95% CI 的下限 >1·0 ）；中和抗体血清反应率不劣于 BA.5（即血清反应率下限 95% CI >–5%）；中和抗体GMT相对于祖先菌株的非劣效性（即GMTR 95% CI的下限>0·67）。本次试验注册号为 。 2023 年 3 月 22 日至 2023 年 5 月 2 日期间，对 837 名参与者进行了资格筛查，其中 766 名参与者被随机分配接受 BA.5 (n=255)、原型 (n=252) 或二价 (n=259) 疫苗。在考虑到由于参与者基线 SARS-CoV-2 呈阳性、既往感染或方案偏差而被排除后，符合方案的分析集包括 694 名参与者（BA.5 组 236 名，原型组 227 名，原型组 231 名）。二价基团）。在此中期分析中（首次给药后最长随访 35 天），与原型组相比，二价组对 BA.5 具有优异的中和抗体反应 (GMT 1017·8 [95% CI 891·0–1162 ·6] 515·1 [450·4–589·0]；GMTR 2·0 [1·69–2·33])，第 28 天对 BA.5 的非劣效血清反应率 (39·8% [ 33·5–46·5] 12·3% [8·4–17·3]；差异 27·5% [19·8–35·0]）。与原型组相比，二价组对祖先菌株也有非劣质的中和抗体反应（GMTR 1·0 [0·84–1·20]）。所有疫苗都同样具有良好的耐受性。正在进行的 2019nCoV-311 研究的第二部分达到了所有三个共同主要终点。 这些数据支持针对当前流行的变种开发单价和/或二价疫苗，以优化保护。由于没有新的安全性发现，对基于 omicron 的亚变疫苗的进一步研究得到了证据的支持。诺瓦瓦克斯。