Phase 3 Randomized Study Investigating the Safety, Tolerability, and Immunogenicity of a Combination Modified Messenger RNA Vaccine Against Influenza and COVID-19 in Healthy Adults

Background/Objectives: Vaccination remains an important means of protection against influenza and COVID-19. Administering influenza and COVID-19 vaccines as a combined formulation may be advantageous. Methods: This phase 3, randomized study evaluated an investigational combination nucleoside-modified messenger RNA (modRNA) vaccine formulated with monovalent XBB.1.5-adapted BNT162b2 vaccine (BNT162b2) and an investigational influenza modRNA vaccine (hereafter investigational combination modRNA vaccine); we report safety, tolerability, and immunogenicity of the investigational combination modRNA vaccine in healthy 18- to 64-year-olds in two cohorts (2 and 3). Results: In Cohort 2, 3127 participants received the investigational combination modRNA vaccine and 1563 received the concomitant licensed quadrivalent influenza vaccine (QIV) with BNT162b2. In Cohort 3, 1189 participants received the investigational combination modRNA vaccine, 605 received QIV, 607 received the investigational influenza modRNA vaccine, and 1191 received BNT162b2. Prespecified noninferiority criteria of the geometric mean ratio of strain-specific hemagglutination inhibition (HAI) or SARS-CoV-2 Omicron XBB.1.5 neutralizing titers or differences in percentages of participants achieving HAI sero-conversion or Omicron XBB.1.5 seroresponse for investigational combination modRNA vaccine to concomitant QIV and BNT162b2 (or to QIV and BNT162b2 each administered alone in Cohort 3) were met for influenza A and SARS-CoV-2 Omicron XBB.1.5 strains but not for the influenza B strain. The investigational combination modRNA vaccine was well tolerated with an acceptable safety profile. Conclusions: The single-dose investigational combination influenza plus COVID-19 modRNA vaccine elicited robust immune responses against influenza A and SARS-CoV-2 with acceptable safety. Further work is required to optimize influenza B responses. The modRNA platform offers promise and potential advantages for vaccine development. ClinicalTrials.gov Identifier: NCT06178991 (approval date: 20 December 2023).