Background

We previously showed that ARCT-154, a self-amplifying mRNA COVID-19 vaccine, had improved immunogenicity and antibody persistence compared with conventional mRNA or adenovirus vector vaccines. In this study, we compared ARCT-2301, a bivalent self-amplifying mRNA vaccine (Asp614Gly and omicron BA.4/5 variant), with the bivalent Comirnaty omicron BA.4-5 vaccine, to determine whether this improved response persisted in bivalent formulations against different SARS-CoV-2 variants.

Methods

This randomised, multicentre, phase 3, observer-masked, active-controlled comparative study was done at nine hospitals in Japan. Eligible participants were healthy Japanese adults, aged at least 18 years, who had previously received a full immunisation series of three to five doses of mRNA COVID-19 vaccines (Comirnaty or Spikevax [Moderna]), with the last dose received at least 3 months before screening for this trial. Participants were randomly assigned (1:1) to either ARCT-2301 or Comirnaty BA.4-5 mRNA vaccine using interactive computer-generated randomisation with a block size of four. Randomisation was stratified by gender (men vs women), age group (<65 years vs ≥65 years), type of vaccine used for last vaccination (bivalent omicron BA.1 vs bivalent omicron BA.4/5), and time since last COVID-19 vaccination (<5 months vs ≥5 months). ARCT-2301 was supplied in vials containing 100 μg lyophilised mRNA, 50 μg mRNA each coding for the full-length spike proteins of the ancestral Asp614Gly SARS-CoV-2 strain and omicron BA.4/5 variant. Immediately before use, each vial was reconstituted with 10 mL saline. The comparator original omicron BA.4/5 mRNA vaccine (Comirnaty BA.4-5) was supplied in ready-to-use vials containing a single dose of 30 μg mRNA in 0·3 mL volume. Both vaccines were administered by intramuscular injection in the deltoid of the non-dominant arm. The primary outcome of the study was to show non-inferiority of immunogenicity of ARCT-2301 versus Comirnaty BA.4-5 at day 29 as neutralising antibody geometric mean titres (GMT) and seroresponse rates against omicron BA.4/5. Primary analyses were done in a per-protocol manner. The trial is registered with the Japan Registry for Clinical Trials, jRCT2031230340.

Findings

Between Sept 29 and Nov 18, 2023, we enrolled 930 participants (451 men and 479 women) to receive a booster dose of ARCT-2301 (n=465) or Comirnaty BA.4-5 (n=465). The primary immunogenicity outcome to show that the antibody response at day 29 against omicron BA.4/5 elicited by ARCT-2301 was non-inferior to that elicited with Comirnaty BA.4-5 was achieved, both by GMT ratio (1·49, 95% CI 1·26–1·76) and difference in seroresponse rate (7·2%, 95% CI 0·6–13·7). Furthermore, the differences in antibody response between the groups showed superiority for ARCT-2301 against Wuhan-Hu-1 using both criteria, with a GMT ratio of 1·45 (95% CI 1·28–1·63) and a difference in seroresponse rate of 12·5% (95% CI 5·9–19·0), and omicron XBB.1.5, with a GMT ratio of 1·63 (95% CI 1·36–1·94) and a seroresponse rate difference of 16·7% (95% CI 10·1–23·2). Both vaccines were well-tolerated with mainly mild, transient solicited adverse events and no causally related severe or serious adverse events.

Interpretation

Boosting mRNA-immunised adults with ARCT-2301 induced superior immunogenicity compared with Comirnaty BA.4-5 against both Wuhan-Hu-1 and omicron BA.4/5 variant COVID-19, and elicited a higher response against omicron XBB.1.5. Both vaccines had similar tolerability profiles. Self-amplifying mRNA vaccines could provide a substantial contribution to pandemic preparedness and response, inducing robust immune responses with a lower dose of mRNA to allow wider and more equitable distribution.

Funding

Japanese Ministry of Health, Labour, and Welfare and Meiji Seika Pharma.

中文翻译：

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二价（Asp614Gly 和 omicron BA.4/5 变体）自扩增 mRNA SARS-CoV-2 加强疫苗加强剂量与 BNT162b2 omicron BA.4/5 mRNA 疫苗的免疫原性：一项随机 3 期试验

 背景

我们之前表明，与传统的 mRNA 或腺病毒载体疫苗相比，ARCT-154 是一种自扩增 mRNA COVID-19 疫苗，具有更好的免疫原性和抗体持久性。在这项研究中，我们将二价自扩增 mRNA 疫苗（Asp614Gly 和 omicron BA.4/5 变体）ARCT-2301 与二价 Comirnaty omicron BA.4-5 疫苗进行了比较，以确定这种改善的反应是否在针对不同 SARS-CoV-2 变体的二价制剂中持续存在。

 方法

这项随机、多中心、3 期、观察者设盲、主动对照的比较研究在日本的 9 家医院进行。符合条件的参与者是年龄至少 18 岁的健康日本成年人，他们之前接受过三至五剂 mRNA COVID-19 疫苗（Comirnaty 或 Spikevax [Moderna]）的完整免疫系列，最后一剂在筛选该试验前至少 3 个月接受。参与者被随机分配 （1：1） 使用 ARCT-2301 或 Comirnaty BA.4-5 mRNA 疫苗，使用交互式计算机生成的随机化，块大小为 4。随机化按性别（男性与女性）、年龄组（<65 岁对 ≥65 岁）、上次接种疫苗使用的疫苗类型（二价奥密克戎 BA.1 与二价奥密克戎 BA.4/5）和自上次 COVID-19 疫苗接种以来的时间（<5 个月对 ≥5 个月）。ARCT-2301 以小瓶形式提供，其中含有 100 μg 冻干 mRNA、50 μg mRNA，每个 mRNA 编码祖先 Asp614Gly SARS-CoV-2 毒株和 omicron BA.4/5 变体的全长刺突蛋白。临用前，将每个样品瓶用 10 mL 生理盐水复溶。对照原始 omicron BA.4/5 mRNA 疫苗 （Comirnaty BA.4-5） 以即用型小瓶形式提供，其中含有单剂量 30 μg mRNA，体积为 0·3 mL。两种疫苗均通过在非优势臂的三角肌中肌肉注射给药。该研究的主要结果是显示 ARCT-2301 与复必泰 BA.4-5 在第 29 天作为中和抗体几何平均滴度 （GMT） 和对 omicron BA.4/5 的血清反应率的非劣效性。主要分析以符合方案的方式进行。该试验已在日本临床试验注册处注册，jRCT2031230340。

 发现

在 2023 年 9 月 29 日至 11 月 18 日期间，我们招募了 930 名参与者（451 名男性和 479 名女性）接受 ARCT-2301 （n=465） 或 Comirnaty BA.4-5 （n=465） 的加强剂量。主要免疫原性结果显示，ARCT-2301 在第 29 天引发的针对 omicron BA.4/5 的抗体反应不劣于复必泰 BA.4-5 引发的抗体反应，均通过 GMT 比率 （1·49,95% CI 1·26-1·76） 和血清反应率差异 （7·2%，95% CI 0·6-13·7）。此外，使用两个标准，两组之间的抗体反应差异显示 ARCT-2301 优于 Wuhan-胡-1，GMT 比值为 1·45（95% CI 1·28–1·63），血清反应率差异为 12·5%（95% CI 5·9–19·0），以及 omicron XBB.1.5，GMT 比值为 1·63（95% CI 1·36–1·94），血清反应率差异为 16·7%（95% CI 10·1–23·2）. 两种疫苗都具有良好的耐受性，主要是轻度、短暂的诱发性不良事件，没有因果相关的严重或严重不良事件。

 解释

与 Comirnaty BA.4-5 相比，用 ARCT-2301 加强 mRNA 免疫的成人对 Wuhan-胡-1 和 omicron BA.4/5 变体 COVID-19 诱导了更高的免疫原性，并引发了对 omicron XBB.1.5 的更高反应。两种疫苗具有相似的耐受性。自我扩增的 mRNA 疫苗可以为大流行的准备和应对做出重大贡献，以较低剂量的 mRNA 诱导强大的免疫反应，从而实现更广泛、更公平的分配。

 资金

日本厚生劳动省和明治精果制药。