A single-blind, phase IV UK multi-centre randomised controlled trial to determine reactogenicity and immunogenicity of COVID-19 vaccines administered concomitantly with seasonal influenza vaccines

Background The COVID-19 outbreak was declared a public health emergency in January 2020. Globally, by October 2020, there had been 40,890,712 confirmed cases of COVID-19, including 1,126,351 deaths. Vaccines effective against SARS-CoV-2 have now been developed. The Pfizer/BioNTech BNT162b2 and Oxford/AstraZeneca ChAdOx1 nCOV-19 vaccines are approved for use in the UK.

While rates of COVID-19 have been decreasing, there is concern that there could be increased transmission over the winter period and it is likely that the COVID-19 vaccine schedule will be extended to include a booster dose for some age and at-risk groups and could potentially become an annual vaccination.

This time period for vaccination would coincide with the usual time period for influenza vaccination, therefore to manage both vaccination programmes it would be preferable to permit administration of both vaccines at the same appointment.

This trial will determine the safety and immunogenicity of concomitant immunisation with currently available COVID-19 and influenza vaccines.

Aims and objectives The trial aims to evaluate whether the reactogenicity of concomitant administration of COVID-19 and influenza vaccine is no worse than COVID-19 vaccine alone.

Specific objectives of the trial are to evaluate: Difference in reactogenicity of concomitant administration of COVID-19 and influenza vaccine and COVID-19 vaccine alone (primary outcome) Difference in i) severity of solicited local and systemic reactions, ii) unsolicited reactions and iii) safety between concomitant administration of COVID-19 and influenza vaccine and COVID-19 vaccine alone Immunogenicity of second dose of COVID-19 vaccine given alone or concomitantly with influenza vaccine Immunogenicity of influenza vaccine concomitantly with COVID-19 vaccine or 3 weeks after COVID-19 vaccine Methods Multicentre, single-blind phase-IV randomised controlled trial in 6 hospitals. 504 adults who have received their first Astra-Zeneca/Oxford or Pfizer COVID-19 vaccine and are due their second vaccine will be eligible.

Equal numbers of participants aged under 65 and 65+ years receiving each COVID-19 vaccine will be recruited.

Participants will be randomised (1:1) to receive either an age-appropriate influenza vaccine or placebo (saline) at the same time as the second COVID-19 vaccine (visit 1). At the second visit (visit 2) those who received the influenza vaccine will receive the placebo and vice versa. Participants and outcome assessors will be blinded.

Participants will have 3 study visits, 3 weeks apart. The primary outcome is one or more solicited systemic reaction in the 7 days following the COVID-19 vaccination.

Secondary outcomes include: type and severity of primary outcome events; unsolicited adverse reactions, medically attended events or serious adverse events during trial participation, anti-spike protein immunoglobulins and neutralising antibodies against SARS-CoV-2 measured from blood samples taken at visits 1 and 2, haemagglutination inhibition assay (from blood) and mucosal immune responses to COVID-19 vaccines (from saliva) taken at each visit, success of blinding, participant willingness to receive concomitant influenza and COVID-19 vaccinations in future, days off work.

Timeline 6-month project Anticipated impact and dissemination The trial will provide preliminary data on the safety of administering concomitant influenza and COVID-19 vaccinations, which will inform government policy to support resource management and planning.