Background
The safety and immunogenicity profile of COVID-19 vaccines when administered concomitantly with seasonal influenza vaccines have not yet been reported. We therefore aimed to report the results of a substudy within a phase 3 UK trial, by evaluating the safety, immunogenicity, and efficacy of NVX-CoV2373 when co-administered with licensed seasonal influenza vaccines.

Methods
We did a planned exploratory substudy as part of the randomised, observer-blinded, placebo-controlled, phase 3 trial of the safety and efficacy of the COVID-19 vaccine (NVX-CoV2373) by co-administrating the influenza vaccine at four study hospitals in the UK. Approximately, the first 400 participants meeting the main study entry criteria—with no contraindications to influenza vaccination—were invited to join the substudy. Participants of the main study were randomly assigned (1:1) to receive two intramuscular injections of either NVX-CoV2373 (5 μg) or placebo (normal saline) 21 days apart; participants enrolled into the substudy were co-vaccinated with a single (0·5 mL) intramuscular, age-appropriate (quadrivalent influenza cell-based vaccine [Flucelvax Quadrivalent; Seqirus UK, Maidenhead] for those aged 18–64 years and adjuvanted trivalent influenza vaccine [Fluad; Seqirus UK, Maidenhead] for those ≥65 years), licensed, influenza vaccine on the opposite deltoid to that of the first study vaccine dose or placebo. The influenza vaccine was administered in an open-label manner and at the same time as the first study injection. Reactogenicity was evaluated via an electronic diary for 7 days after vaccination in addition to monitoring for unsolicited adverse events, medically attended adverse events, and serious adverse events. Immunogenicity was assessed with influenza haemagglutination inhibition and SARS-CoV-2 anti-spike protein IgG assays. Vaccine efficacy against PCR-confirmed, symptomatic COVID-19 was assessed in participants who were seronegative at baseline, received both doses of study vaccine or placebo, had no major protocol deviations affecting the primary endpoint, and had no confirmed cases of symptomatic COVID-19 from the first dose until 6 days after the second dose (per-protocol efficacy population). Immunogenicity was assessed in participants who received scheduled two doses of study vaccine, had a baseline sample and at least one post-vaccination sample, and had no major protocol violations before unmasking (per-protocol immunogenicity population). Reactogenicity was analysed in all participants who received at least one dose of NVX-CoV2373 or placebo and had data collected for reactogenicity events. Safety was analysed in all participants who received at least one dose of NVX-CoV2373 or placebo. Comparisons were made between participants of the substudy and the main study (who were not co-vaccinated for influenza). This study is registered with ClinicalTrials.gov, number NCT04583995.

Findings
Between Sept 28, 2020, and Nov 28, 2020, a total of 15 187 participants were randomised into the main phase 3 trial, of whom 15 139 received treatment (7569 received dose one of NVX-CoV2373 and 7570 received dose one of placebo). 431 participants were co-vaccinated with a seasonal influenza vaccine in the substudy (217 received NVX-CoV2373 plus the influenza vaccine and 214 received placebo plus the influenza vaccine). In general, the substudy participants were younger, more racially diverse, and had fewer comorbid conditions than those in the main study. Reactogenicity events were more common in the co-administration group than in the NVX-CoV2373 alone group: tenderness (113 [64·9%] of 174 vs 592 [53·3%] of 1111) or pain (69 [39·7%] vs 325 [29·3%]) at injection site, fatigue (48 [27·7%] vs 215 [19·4%]), and muscle pain (49 [28·3%] vs 237 [21·4%]). Incidences of unsolicited adverse events, treatment-related medically attended adverse events, and serious adverse events were low and balanced between the co-administration group and the NVX-CoV2373 alone group. No episodes of anaphylaxis or deaths were reported within the substudy. Co-administration resulted in no change to influenza vaccine immune response although a reduction in antibody responses to the NVX-CoV2373 vaccine was noted. NVX-CoV2373 vaccine efficacy in the substudy (ie, participants aged 18 to <65 years) was 87·5% (95% CI −0·2 to 98·4) and in the main study was 89·8% (95% CI 79·7–95·5).

Interpretation
To our knowledge, this substudy is the first to show the safety, immunogenicity, and efficacy profile of a COVID-19 vaccine when co-administered with seasonal influenza vaccines. Our results suggest concomitant vaccination might be a viable immunisation strategy.

Funding
Novavax.

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Introduction
More than a year has passed since the start of the COVID-19 pandemic due to SARS-CoV-2. COVID-19 has been a devastating disease worldwide, with more than 247 million cases and 5 million deaths reported as of Nov 2, 2021.1 Seasonal influenza epidemics also occur globally, and WHO estimates that 290 000–650 000 individuals die from influenza each year, with the highest numbers of death occurring in adults older than 65 years and children younger than 2 years.2 Public health recommendations in many countries include yearly influenza vaccination as a key preventative strategy.3

Global COVID-19 vaccination efforts are now well underway with more than 6·9 billion vaccine doses administered as of Nov 2, 2021.1 This continued mass COVID-19 vaccination programme will certainly coincide with influenza vaccination programmes. With the initiation of booster campaigns and the continuation of primary series vaccination, the timing of such doses would likely overlap with the 2021–22 influenza season in many settings. Currently, no data exist for the co-administration of COVID-19 vaccines with other vaccines, as most phase 3 trials of COVID-19 vaccines either excluded participants with recent or planned receipt of other licensed vaccines or required an interval of at least 1 week between them. In particular, information about the effects of co-administration on immune responses and safety is needed to formulate public health policy in light of simultaneous vaccination programmes. This information is particularly important as immunosenescence might leave older adults more vulnerable to influenza infection, complications, and mortality, as well as reduce their immune responses to standard influenza vaccines.4 Current guidance in the UK is to separate the administration of any deployed COVID-19 and influenza vaccines by at least 7 days to avoid incorrect attribution of potential adverse events.3 The US Centers for Disease Control (CDC) recommends a 14-day interval between these vaccines.5 However, the need for multiple clinic visits might lead to reduced compliance and hence reduced vaccination uptake. To ensure adequate vaccine uptake of both COVID-19 and influenza vaccines, co-administration would encourage the public to take up these vaccines in one visit rather than returning 7 days or more later.

Herein, we report the results of a substudy of a phase 3 UK trial that assessed the safety and efficacy of two doses of NVX-CoV2373 compared with placebo.6 In the main study, a total of 15 187 participants underwent randomisation, of whom 15 139 participants received at least one dose of NVX-CoV2373 (n=7569) or placebo (n=7570), and 14 039 were included in the per-protocol efficacy population. Of the per-protocol efficacy population, 3910 (27·9%) were 65 years or older, and 3117 (44·6%) had coexisting illnesses. A vaccine efficacy of 89·7% (95% CI 80·2–94·6) against symptomatic PCR-proven COVID-19 was observed. The reactogenicity was generally mild and transient, and the incidence of serious adverse events was low and similar in the two groups.6 In this substudy, we aimed to evaluate the safety, immunogenicity, and efficacy of NVX-CoV2373 when co-administered with a licensed seasonal influenza vaccine.

Research in context
Evidence before this study

We searched PubMed for research articles published from Dec 1, 2019, to April 1, 2021, with no language restrictions using the terms “SARS-CoV-2”, “COVID-19”, “vaccine”, “co-administration”, and “immunogenicity”. No peer-reviewed publications describing the simultaneous use of any SARS-CoV-2 vaccine and another vaccine were reported. Several vaccine manufacturers had publications on phase 3 trials SARS-CoV-2 vaccine results (Pfizer/BioNTech, Moderna, AstraZeneca, Janssen, and the Gamaleya Research Institute of Epidemiology and Microbiology). Neither these publications nor their clinical trials' protocols (when publicly available) described co-administration, and they often had trial criteria specifically excluding those with recent or planned vaccination with any licenced vaccine near or at the time of any study injection.

Added value of this study

Immune interference and safety are always a concern when two vaccines are administered at the same time. To our knowledge, this substudy is the first to show the safety and immunogenicity profile and clinical vaccine efficacy of a COVID-19 vaccine when co-administered with a seasonal influenza vaccine.

Implications of all the available evidence

This study provides much needed information to help guide national immunisation policy decision making on the important issue of concomitant use of COVID-19 vaccines with influenza vaccines.