Background

Concomitant administration of COVID-19 and influenza vaccines could reduce burden on health-care systems. We aimed to assess the safety of concomitant administration of ChAdOx1 or BNT162b2 plus an age-appropriate influenza vaccine.

Methods

In this multicentre, randomised, controlled, phase 4 trial, adults in receipt of a single dose of ChAdOx1 or BNT162b2 were enrolled at 12 UK sites and randomly assigned (1:1) to receive concomitant administration of either an age-appropriate influenza vaccine or placebo alongside their second dose of COVID-19 vaccine. 3 weeks later the group who received placebo received the influenza vaccine, and vice versa. Participants were followed up for 6 weeks. The influenza vaccines were three seasonal, inactivated vaccines (trivalent, MF59C adjuvanted or a cellular or recombinant quadrivalent vaccine). Participants and investigators were masked to the allocation. The primary endpoint was one or more participant-reported solicited systemic reactions in the 7 days after first trial vaccination(s), with a difference of less than 25% considered non-inferior. Analyses were done on an intention-to-treat basis. Local and unsolicited systemic reactions and humoral responses were also assessed. The trial is registered with ISRCTN, ISRCTN14391248.

Findings

Between April 1 and June 26, 2021, 679 participants were recruited to one of six cohorts, as follows: 129 ChAdOx1 plus cellular quadrivalent influenza vaccine, 139 BNT162b2 plus cellular quadrivalent influenza vaccine, 146 ChAdOx1 plus MF59C adjuvanted, trivalent influenza vaccine, 79 BNT162b2 plus MF59C adjuvanted, trivalent influenza vaccine, 128 ChAdOx1 plus recombinant quadrivalent influenza vaccine, and 58 BNT162b2 plus recombinant quadrivalent influenza vaccine. 340 participants were assigned to concomitant administration of influenza and a second dose of COVID-19 vaccine at day 0 followed by placebo at day 21, and 339 participants were randomly assigned to concomitant administration of placebo and a second dose of COVID-19 vaccine at day 0 followed by influenza vaccine at day 21. Non-inferiority was indicated in four cohorts, as follows: ChAdOx1 plus cellular quadrivalent influenza vaccine (risk difference for influenza vaccine minus placebos −1·29%, 95% CI −14·7 to 12·1), BNT162b2 plus cellular quadrivalent influenza vaccine (6·17%, −6·27 to 18·6), BNT162b2 plus MF59C adjuvanted, trivalent influenza vaccine (–12·9%, −34·2 to 8·37), and ChAdOx1 plus recombinant quadrivalent influenza vaccine (2·53%, −13·3 to 18·3). In the other two cohorts, the upper limit of the 95% CI exceeded the 0·25 non-inferiority margin (ChAdOx1 plus MF59C adjuvanted, trivalent influenza vaccine 10·3%, −5·44 to 26·0; BNT162b2 plus recombinant quadrivalent influenza vaccine 6·75%, −11·8 to 25·3). Most systemic reactions to vaccination were mild or moderate. Rates of local and unsolicited systemic reactions were similar between the randomly assigned groups. One serious adverse event, hospitalisation with severe headache, was considered related to the trial intervention. Immune responses were not adversely affected.

Interpretation

Concomitant vaccination with ChAdOx1 or BNT162b2 plus an age-appropriate influenza vaccine raises no safety concerns and preserves antibody responses to both vaccines. Concomitant vaccination with both COVID-19 and influenza vaccines over the next immunisation season should reduce the burden on health-care services for vaccine delivery, allowing for timely vaccine administration and protection from COVID-19 and influenza for those in need.

Funding

National Institute for Health Research Policy Research Programme

中文翻译：

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英国成人同时接种 COVID-19 疫苗（ChAdOx1 或 BNT162b2）与季节性流感疫苗 (ComFluCOV) 的安全性和免疫原性：一项多中心、随机、对照、4 期试验

 背景

同时接种 COVID-19 和流感疫苗可以减轻医疗保健系统的负担。我们的目的是评估 ChAdOx1 或 BNT162b2 与适合年龄的流感疫苗同时接种的安全性。

 方法

在这项多中心、随机、对照、4 期试验中，接受单剂 ChAdOx1 或 BNT162b2 的成年人在英国 12 个地点入组，并随机分配 (1:1) 接受同时接种适合年龄的流感疫苗或安慰剂与第二剂 COVID-19 疫苗一起服用。三周后，接受安慰剂的组接种了流感疫苗，反之亦然。参与者接受了为期 6 周的随访。流感疫苗是三种季节性灭活疫苗（三价、MF59C 佐剂或细胞或重组四价疫苗）。参与者和研究人员对分配情况不知情。主要终点是第一次试验疫苗接种后 7 天内一个或多个参与者报告的全身反应，差异小于 25% 视为非劣效。分析是在意向治疗的基础上进行的。还评估了局部和自发的全身反应以及体液反应。该试验已在 ISRCTN 注册，ISRCTN14391248。

 发现

2021年4月1日至6月26日期间，679名参与者被招募到六个队列之一，如下：129名ChAdOx1加细胞四价流感疫苗，139名BNT162b2加细胞四价流感疫苗，146名ChAdOx1加MF59C佐剂三价流感疫苗，79名BNT162b2加 MF59C 佐剂三价流感疫苗、128 ChAdOx1 加重组四价流感疫苗和 58 BNT162b2 加重组四价流感疫苗。 340 名参与者被分配在第 0 天同时接种流感疫苗和第二剂 COVID-19 疫苗，随后在第 21 天接种安慰剂，339 名参与者被随机分配在第 1 天同时接种安慰剂和第二剂 COVID-19 疫苗0，然后在第 21 天接种流感疫苗。四个队列显示非劣效性，如下所示： ChAdOx1 加细胞四价流感疫苗（流感疫苗减去安慰剂的风险差异 -1·29%，95% CI -14·7 至 12 ·1)、BNT162b2 加细胞四价流感疫苗（6·17%、-6·27 至 18·6）、BNT162b2 加 MF59C 佐剂、三价流感疫苗（–12·9%、-34·2 至 8·37） ，和 ChAdOx1 加重组四价流感疫苗（2·53%，-13·3 至 18·3）。在另外两个队列中，95% CI 的上限超过了 0·25 非劣效性界限（ChAdOx1 加 MF59C 佐剂，三价流感疫苗 10·3%，-5·44 至 26·0；BNT162b2 加重组四价）流感疫苗 6·75%，-11·8 至 25·3)。大多数疫苗接种的全身反应是轻度或中度。随机分配的组之间局部反应和主动全身反应的发生率相似。一项严重不良事件，即因严重头痛而住院，被认为与试验干预有关。 免疫反应没有受到不利影响。

 解释

同时接种 ChAdOx1 或 BNT162b2 以及适合年龄的流感疫苗不会引起安全问题，并保留对两种疫苗的抗体反应。在下一个免疫季节同时接种 COVID-19 和流感疫苗应该会减轻医疗保健服务提供疫苗的负担，从而能够及时接种疫苗，并为有需要的人提供针对 COVID-19 和流感的保护。

 资金

国家卫生研究院政策研究计划