Introduction
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.
Public health recommendations in many countries include yearly influenza vaccination as a key preventative strategy.
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.
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.
The US Centers for Disease Control (CDC) recommends a 14-day interval between these vaccines.
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.
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.
In this substudy, we aimed to evaluate the safety, immunogenicity, and efficacy of NVX-CoV2373 when co-administered with a licensed seasonal influenza vaccine.
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.
Methods
Study design and participants
Briefly, this main study enrolled participants at 33 sites in the UK beginning in September, 2020. Eligible participants for the main study were men and non-pregnant women aged 18–84 years who were healthy or had stable chronic medical conditions. Health status was assessed at screening and based on medical history, vital signs, and physical examination. Key exclusion criteria included a history of documented COVID-19, treatment with immunosuppressive therapy, or diagnosis with an unstable medical condition. 15 187 participants were randomly allocated to either the vaccine or placebo, with 15 139 participants receiving at least one dose of NVX-CoV2373 or placebo. Full details about the methods and design of the main study are reported elsewhere.
The protocol is available with the full text of this article online.
Regarding this co-administration substudy of the COVID-19 and influenza vaccines, approximately the first 400 participants who met the additional substudy criteria were invited to participate. The additional specific inclusion criteria were as follows: have not already received a 2020–21 seasonal, licensed influenza vaccine and have no previous history of allergy or severe reaction to influenza vaccines. All participants were excluded from receipt of any live vaccine within 4 weeks or any vaccine within 2 weeks of the first dose of study vaccine or placebo co-administered with the influenza vaccine. Substudy enrolment was not randomised (ie, consecutive patients were enrolled into the substudy from the main study before randomisation) or stratified by age (ie, all patients were allocated to the influenza vaccine; therefore, stratification was not applicable).
We obtained written informed consent from all participants before enrolment in the trial. The trial protocol was approved by the North West–Greater Manchester Central Research Ethics Committee (20/NW/03/99) and was performed in accordance with the International Council for Harmonisation Good Clinical Practice guidelines. Safety oversight was performed by an independent safety monitoring committee.
Randomisation and masking
Participants of the seasonal influenza vaccine co-administration substudy were selected before study vaccine randomisation. Approximately 400 consecutive, non-randomised, eligible participants from four study hospitals in the main study were enrolled into the substudy. Participants were then randomly assigned (1:1) via block randomisation to receive either two intramuscular injections (0·5 mL) of NVX-CoV2373 or placebo (normal saline), 21 days apart. Randomisation was stratified by site and by age (≥65 years). Participants in the seasonal influenza vaccine co-administration substudy then received a concomitant dose of seasonal influenza vaccine with the first study injection only. This dose comprised a single intramuscular injection (0·5 mL) of a licensed influenza vaccine in the opposite deltoid to that of the study vaccine or placebo and was given at the same time. Although the main study was observer-blinded, the substudy of the influenza vaccine was administered in an open-label manner.
Procedures
the quadrivalent influenza cell-based vaccine (Flucelvax Quadrivalent; Seqirus UK, Maidenhead) for those aged 18–64 years, and the adjuvanted trivalent influenza vaccine (Fluad; Seqirus UK, Maidenhead) for those 65 years or older (appendix p 7).
For immunogenicity assessments, blood was collected from all trial participants at baseline and at day 21 for those in the influenza substudy and for all trial participants at baseline and day 35 (14 days after the second dose of study vaccine). To assess the possible effect of the study vaccine on the immunogenicity of the influenza vaccine, a haemagglutination inhibition assay antibody was performed in all influenza substudy participants at baseline and at day 21. To assess humoral immune response to the study vaccine, an ELISA for SARS-CoV-2 anti-spike protein IgG was performed at baseline and on day 35 in approximately 900 non-randomised participants from two study sites in the main study (as part of an immunogenicity cohort) as well as in those in the influenza substudy.
Safety, immunogenicity, and efficacy of a COVID-19 vaccine (NVX-CoV2373) co-administered