Efficacy, safety, and immunogenicity of the AS01E-adjuvanted respiratory syncytial virus prefusion F protein vaccine (RSVPreF3 OA) in older adults over three respiratory syncytial virus seasons (AReSVi-006): a multicentre, randomised, observer-blinded, placebo-controlled, phase 3 trial.

This study aimed to evaluate efficacy and safety over three RSV seasons of the AS01E-adjuvanted RSV prefusion F protein-based vaccine (RSVPreF3 OA) against RSV-related lower respiratory tract disease (RSV-LRTD) in older adults.

本研究旨在评估AS01E佐剂RSV前融合F蛋白疫苗（RSVPreF3 OA）在三个RSV季节内对老年人RSV相关下呼吸道疾病（RSV-LRTD）的有效性和安全性。

Methods

In this randomised, observer-blind, placebo-controlled, phase 3 trial (AReSVi-006), participants aged 60 years or older in 275 centres (ie, GP practices and clinical research sites) across 17 countries in Africa, Asia, Oceania, Europe, and North America were randomly assigned (1:1) to receive RSVPreF3 OA or placebo before RSV season one.

在这项随机、观察者盲法、安慰剂对照的III期试验（AReSVi-006）中，60岁及以上的参与者在非洲、亚洲、大洋洲、欧洲和北美的17个国家的275个中心（即全科诊所和临床研究场所）被随机分配（1:1）在RSV季节前接受RSVPreF3 OA或安慰剂。

RSVPreF3 OA recipients were re-randomly assigned (1:1) before RSV season two to receive a second RSVPreF3 OA dose (RSV revaccination group) or placebo (RSV single-dose group).

RSVPreF3 OA的接受者在第二个RSV季节前被重新随机分配（1:1）接受第二剂RSVPreF3 OA（RSV再接种组）或安慰剂（RSV单剂组）。

Recipients of placebo before RSV season one also received placebo before season two (placebo group).

在RSV季节一之前接受安慰剂的受试者，在季节二之前也接受了安慰剂（安慰剂组）

The primary objective (efficacy against first occurrence of RSV-LRTD over one RSV season) was reported previously.

主要目标（一个RSV季节内首次发生RSV-LRTD的疗效）之前已经报告过。

Confirmatory secondary objectives were to demonstrate efficacy over three RSV seasons of a single RSVPreF3 OA dose and of a first dose followed by revaccination 1 year later, against RSV-LRTD, overall and by RSV subtype (success criteria: lower limits of two-sided CIs around efficacy estimates >20% [RSV-LRTD] and >0% [RSV-LRTD by RSV subtype]).

次要确认性终点是证明在三个RSV季节内，单剂量RSVPreF3 OA和首次剂量后1年再接种的疫苗对RSV-LRTD的疗效，总体和按RSV亚型分层（成功标准：疗效估计值的双侧置信区间下限>20% [RSV-LRTD] 和>0% [按RSV亚型的RSV-LRTD]）。

This study is registered with ClinicalTrials.gov, NCT04886596, and is complete.

该研究已在ClinicalTrials.gov上注册，编号为NCT04886596，并已完成。

Results

Participants were enrolled between May 25, 2021, and Jan 31, 2022.

参与者在2021年5月25日至2022年1月31日期间被纳入研究。

Efficacy analyses included 12 468 RSVPreF3 OA recipients and 12 498 placebo recipients.

疗效分析包括12,468名RSVPreF3 OA受试者和12,498名安慰剂受试者。

Cumulative efficacy over three seasons of one RSVPreF3 OA dose was 62·9% (97·5% CI 46·7-74·8) against RSV-LRTD, 69·8% (42·2-85·7) against RSV A-related LRTD, and 58·6% (35·9-74·1) against RSV B-related LRTD (median follow-up from day 15 post-dose one 30·6 months [IQR 26·2-32·0]).

单剂RSVPreF3 OA疫苗在三个季节中的累积效果为：对RSV-LRTD的总保护率为62.9%（97.5%置信区间46.7-74.8），对RSV A相关LRTD的总保护率为69.8%（42.2-85.7），对RSV B相关LRTD的总保护率为58.6%（35.9-74.1）（从第一剂接种后第15天起的中位随访时间为30.6个月，四分位数间距为26.2-32.0）。

Efficacy was observed over three seasons among participants aged 60-69 years, participants aged 70-79 years, pre-frail participants (ie, those with a walking speed of 0·4-0·99 m/s in a gait speed test), and participants with pre-existing conditions that increase the RSV-LRTD risk.

在三个季节中观察到60-69岁、70-79岁参与者，以及步速为0.4-0.99 m/s的前虚弱参与者（即在步速测试中）和有增加RSV-LRTD风险的现有疾病的参与者中，疫苗效果显著。

Efficacy against RSV-LRTD decreased over time.

针对呼吸道合胞病毒引起的下呼吸道感染的疗效随时间降低。

A first RSVPreF3 OA dose followed by revaccination 1 year later had an efficacy that was within the same range as that of one dose.

首次接种RSVPreF3 OA疫苗后，一年后进行加强接种的疗效与单次接种的疗效范围相同。

RSVPreF3 OA showed a clinically acceptable safety profile.

RSVPreF3 OA显示出临床可接受的安全性特征。

Between dose one and trial end, eight (<1%) participants in the RSV single-dose group, 12 (<1%) in the RSV revaccination group, and 12 (<1%) in the placebo group had a serious adverse eventconsidered to be related to the trial intervention by the investigator.

在第一剂和试验结束之间，RSV单剂组有8例（<1%）参与者，RSV再接种组有12例（<1%），安慰剂组有12例（<1%）发生了被认为是与试验干预相关的严重不良事件。

Five deaths were assessed as related to the trial intervention by the investigator: three in the vaccine groups (cardiopulmonary failure, cardiac arrest, and left ventricular failure) and two in the placebo group (death of unknown cause and pulmonary embolism).

研究者评估了五例与试验干预相关的死亡：疫苗组中有三例（心肺衰竭、心脏骤停和左心室衰竭），安慰剂组中有两例（一例原因不明的死亡和一例肺栓塞）。

interpretation

A single RSVPreF3 OA dose was efficacious against RSV-LRTD over three RSV seasons in people aged 60 years or older, despite a decrease in efficacy over time.

在60岁或60岁以上的老年人中，单剂量的RSVPreF3 OA在三个呼吸道合胞病毒（RSV）季节内对RSV引起的下呼吸道疾病（LRTD）是有效的，尽管随着时间的推移疗效有所下降。

Further research is needed to establish the optimal revaccination strategy.

需要进一步研究以确定最佳的加强免疫策略。

These results support the favourable benefit-risk profile of RSVPreF3 OA to help protect against RSV-LRTD for at least three RSV seasons.

这些结果支持RSVPreF3 OA良好的效益-风险比，有助于至少在三个呼吸道合胞病毒（RSV）季节内保护免受RSV下呼吸道疾病（LRTD）的影响。

funding

GSK.

葛兰素史克。