Background

Coadministration of a respiratory syncytial virus (RSV) vaccine with seasonal influenza or SARS-CoV-2 vaccines could reduce health-care visits and increase vaccination uptake in older adults who are at high risk for severe respiratory disease. The RSV mRNA-1345 vaccine demonstrated efficacy against RSV disease with acceptable safety in the ConquerRSV trial in adults aged 60 years and older. We aimed to evaluate the safety and immunogenicity of mRNA-1345 coadministered with a seasonal influenza vaccine or SARS-CoV-2 mRNA vaccine.

Methods

We conducted a two-part, phase 3, observer-blinded, placebo-controlled, randomised trial in medically stable adults aged 50 years or older in the USA. In part A, participants were randomly assigned in a 7:10:10 ratio to receive 50 μg mRNA-1345 plus placebo (0·9% sodium chloride) or coadministered with 60 μg of a standard-dose quadrivalent inactivated influenza vaccine (SIIV4), or SIIV4 plus placebo. In part B, participants were randomly assigned in a 1:1:1 ratio to receive 50 μg mRNA-1345 plus placebo or coadministered with 50 μg SARS-CoV-2 mRNA-1273.214 (bivalent [Wuhan-Hu-1 plus omicron BA.1]), or mRNA-1273.214 plus placebo. Random allocation in both parts was stratified by age group (50–59 years, 60–74 years, and ≥75 years) and used interactive response technology. The coprimary objectives in each part were safety in the safety set throughout the study and non-inferiority for six immunogenicity endpoints in the per-protocol set comparing coadministered versus individual vaccines on day 29. Immunogenicity endpoints were geometric mean titre (GMT) ratios (GMRs) of RSV-A neutralising antibodies (nAbs; in parts A and B), GMRs of haemagglutination inhibition (HAI) titres to each of the four influenza strains in SIIV4 (A/Victoria/2570/2019 [H1N1]pdm09-like virus [A/H1N1], A/Cambodia/e0826360/2020 [H3N2]-like virus [A/H3N2], B/Washington/02/2019-like virus [B/Victoria], and B/Phuket/3073/2013-like virus [B/Yamagata]; in part A), GMRs of nAbs against SARS-CoV-2 (ancestral [D614G] and omicron BA.1; part B), and differences in seroresponse rates for nAbs against RSV-A (parts A and B) and SARS-CoV-2 (ancestral [D614G] and omicron BA.1; part B). Non-inferiority was declared when the lower bound of the 95% CI for GMRs was greater than 0·667 and for seroresponse rate differences was greater than −10%. This trial is registered with ClinicalTrials.gov (NCT05330975) and is ongoing.

Findings

Between April 1 and June 9, 2022, 1631 participants were randomly allocated in part A and 1623 received vaccinations on day 1 (685 [42%] received mRNA-1345 plus SIIV4, 249 [15%] mRNA-1345 plus placebo, and 689 [42%] SIIV4 plus placebo). Due to an interactive response technology error, the mRNA-1345 plus placebo group was smaller than planned (249 vs 420 participants). Of the 1623 participants in the safety set, 877 (54%) were female and 746 (46%) were male. Between July 27 and Sept 28, 2022, 1691 participants were randomly allocated in part B and 1681 received vaccinations on day 1 (564 [34%] received mRNA-1345 plus mRNA-1273.214, 558 [33%] mRNA-1345 plus placebo, and 559 [33%] mRNA-1273.214 plus placebo). Among the 1681 participants in the safety set, 924 (55%) were female and 757 (45%) were male. The reactogenicity profiles of the coadministered regimens were generally similar to the profiles when the vaccines were administered alone. As of the 6-month and 7-month follow-up times for parts A and B, respectively, no serious adverse events, adverse events of special interest, discontinuations due to adverse events, or fatal events considered related to study vaccination were reported. In part A, the GMR of nAbs against RSV-A in the mRNA-1345 plus SIIV4 group versus the mRNA-1345 alone group was 0·81 (95% CI 0·67 to 0·97), and the seroresponse rate difference in nAbs against RSV-A between the groups was −11·2% (95% CI −17·9 to −4·1). GMRs of anti-HAI titres in the mRNA-1345 plus SIIV4 versus SIIV4 alone groups were 0·89 (0·77 to 1·03) for A/H1N1, 0·97 (0·86 to 1·09) for A/H3N2, 0·93 (0·82 to 1·05) for B/Victoria, and 0·91 (0·81 to 1·02) for B/Yamagata. In part B, the GMR of nAbs against RSV-A in the mRNA-1345 plus mRNA-1273.214 versus the mRNA-1345 alone groups was 0·80 (95% CI 0·70 to 0·90), and the seroresponse rate difference was –4·4% (95% CI –9·9 to 1·0). Comparing the mRNA-1345 plus mRNA-1273.214 group with the mRNA-1273.214 alone group, the GMR of nAbs was 0·96 (0·87 to 1·06) for the ancestral (D614G) virus and 1·00 (0·89 to 1·14) for omicron BA.1; seroresponse rate differences were 0·2% (95% CI –6·0 to 6·3) for SARS-CoV-2 ancestral and –0·9% (–6·6 to 4·7) for omicron BA.1.

Interpretation

Coadministered mRNA-1345 plus SIIV4 or mRNA-1273.214 vaccines had acceptable safety profiles and elicited mostly non-inferior immune responses compared to individual vaccines in adults aged 50 years or older; only the seroresponse rate difference in nAbs against RSV-A in part A did not meet the non-inferiority criterion. Overall, these data support coadministration of mRNA-1345 with these vaccines in this population; longer-term evaluation continues in this study.

Funding

Moderna.

中文翻译：

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mRNA-1345 RSV 疫苗与 50 岁或以上成人流感或 COVID-19 疫苗联合接种的安全性和免疫原性：一项观察者设盲、安慰剂对照、随机、3 期试验

 背景

呼吸道合胞病毒 （RSV） 疫苗与季节性流感或 SARS-CoV-2 疫苗共同接种可以减少严重呼吸系统疾病高风险老年人的医疗保健就诊并提高疫苗接种率。RSV mRNA-1345 疫苗在 60 岁及以上成年人的 ConquerRSV 试验中显示出对 RSV 疾病的疗效和可接受的安全性。我们旨在评估 mRNA-1345 与季节性流感疫苗或 SARS-CoV-2 mRNA 疫苗联合接种的安全性和免疫原性。

 方法

我们在美国 50 岁或以上的 50 岁或以上身体状况稳定的成年人中进行了一项分为两部分的 3 期、观察者盲法、安慰剂对照、随机试验。在 A 部分，参与者以 7：10：10 的比例随机分配接受 50 μg mRNA-1345 加安慰剂（0·9% 氯化钠）或与 60 μg 标准剂量四价灭活流感疫苗 （SIIV4） 或 SIIV4 加安慰剂。在 B 部分，参与者以 1：1：1 的比例随机分配接受 50 μg mRNA-1345 加安慰剂或与 50 μg SARS-CoV-2 mRNA-1273.214（二价 [Wuhan-胡-1 加 omicron BA.1]）或 mRNA-1273.214 加安慰剂。两个部分的随机分配按年龄组 （50-59 岁、60-74 岁和 ≥75 岁） 分层，并使用交互式响应技术。每个部分的共同主要目标是整个研究过程中安全性集中的安全性，以及在第 29 天比较联合接种与单独疫苗的按方案集中的六个免疫原性终点的非劣效性。免疫原性终点是 RSV-A 中和抗体（nAbs;A 部分和 B 部分）的几何平均滴度 （GMT） 比值 （GMR），血凝抑制 （HAI） 滴度与 SIIV4 中四种流感毒株的 GMR（A/Victoria/2570/2019 [H1N1]pdm09 样病毒 [A/H1N1]、A/Cambodia/e0826360/2020 [H3N2] 样病毒 [A/H3N2]、B/Washington/02/2019 样病毒 [B/Victoria]、 和 B/Phuket/3073/2013 病毒 [B/Yamagata];在 A 部分）、针对 SARS-CoV-2 的 nAb（祖先 [D614G] 和 omicron BA.1;B 部分）的 GMR，以及针对 RSV-A（祖先 [D614G] 和 omicron BA.1;B 部分）的 nAb 血清反应率的差异。 当 GMR 的 95% CI 下限大于 0·667 且血清反应率差异大于 -10% 时，宣布非劣效性。该试验已在 ClinicalTrials.gov （NCT05330975） 注册，并且正在进行中。

 发现

在 2022 年 4 月 1 日至 6 月 9 日期间，1631 名参与者被随机分配到 A 部分，1623 名参与者在第 1 天接受了疫苗接种（685 名 [42%] 接受了 mRNA-1345 加 SIIV4,249 名 [15%] mRNA-1345 加安慰剂，689 名 [42%] SIIV4 加安慰剂）。由于交互式反应技术错误，mRNA-1345 加安慰剂组比计划的要小（249 名对 420 名参与者）。在安全组的 1623 名参与者中，877 名 （54%） 为女性，746 名 （46%） 为男性。在 2022 年 7 月 27 日至 9 月 28 日期间，1691 名参与者被随机分配到 B 部分，1681 名参与者在第 1 天接受了疫苗接种（564 名 [34%] 接受了 mRNA-1345 加 mRNA-1273.214,558 名 [33%] mRNA-1345 加安慰剂，以及 559 名 [33%] mRNA-1273.214 加安慰剂）。在安全组的 1681 名参与者中，924 名 （55%） 为女性，757 名 （45%） 为男性。联合给药方案的反应原性特征通常与单独接种疫苗时的反应原性特征相似。截至 A 部分和 B 部分的 6 个月和 7 个月随访时间，分别未报告严重不良事件、特别关注的不良事件、因不良事件而停药或被认为与研究疫苗接种相关的致命事件。在 A 部分，mRNA-1345 加 SIIV4 组与单独 mRNA-1345 组相比，nAb 对 RSV-A 的 GMR 为 0·81（95% CI 0·67 至 0·97），两组之间 nAb 对 RSV-A 的血清反应率差异为 -11·2%（95% CI -17·9 至 -4·1）。mRNA-1345 联合 SIIV4 与单独 SIIV4 组中抗 HAI 滴度的 GMR 分别为 A/H1N1 为 0·89（0·77 至 1·03），A/H3N2 为 0·97（0·86 至 1·09），B/Victoria 为 0·93（0·82 至 1·05），B/Yamagata 为 0·91（0·81 至 1·02）。在第 B 部分中，nAb 对 mRNA-1345 和 mRNA-1273 中 RSV-A 的 GMR。214 与单独使用 mRNA-1345 组相比为 0·80（95% CI 为 0·70 至 0·90），血清反应率差异为 -4·4%（95% CI 为 -9·9 至 1·0）。将 mRNA-1345 加 mRNA-1273.214 组与单独 mRNA-1273.214 组进行比较，祖先 （D614G） 病毒 nAb 的 GMR 为 0·96（0·87 至 1·06），奥密克戎 BA.1 的 GMR 为 1·00（0·89 至 1·14）;SARS-CoV-2 祖先的血清反应率差异为 0·2%（95% CI -6·0 至 6·3），奥密克戎 BA.1 的血清反应率差异为 -0·9%（-6·6 至 4·7）。

 解释

与 50 岁或以上成人的单独疫苗相比，联合接种 mRNA-1345 加 SIIV4 或 mRNA-1273.214 疫苗具有可接受的安全性，并且与单个疫苗相比，引起了大多数非劣效免疫反应;只有 A 部分 nAb 对 RSV-A 的血清反应率差异不符合非劣效性标准。总体而言，这些数据支持在该人群中将 mRNA-1345 与这些疫苗共同给药;本研究将继续进行长期评估。

 资金

 莫德纳。