Safety and immunogenicity of a COVID-19–Influenza Combination nanoparticle vaccine (CIC) containing SARS-CoV-2 recombinant spike and quadrivalent influenza hemagglutinin with Matrix-M® adjuvant: A phase 1/2 clinical trial

Based on viral evolution, increases in seasonal infections, and facilitation of delivery, an annual combination vaccine simultaneously targeting influenza and SARS-CoV-2 would benefit public health. The safety and immunogenicity of a COVID-19-Influenza Combination nanoparticle vaccine (CIC) containing SARS-CoV-2 recombinant spike (rS) to the ancestral strain (Wuhan) and quadrivalent influenza hemagglutinin with a Matrix-M® saponin-based adjuvant were evaluated in a phase 1/2 blinded, randomized trial. The safety, tolerability, and immunogenicity of a CIC two-dose series were assessed and compared with standalone quadrivalent influenza (qNIV) and monovalent COVID-19 (NVX-CoV2373) vaccines. Reactogenicity events, unsolicited adverse events (AEs), antiviral microneutralization responses, hemagglutination-inhibition antibody titers, anti-rS protein immunoglobulin G, and human angiotensin-converting enzyme 2 receptor binding inhibition antibody responses for SARS-CoV-2 were measured. All participants had been previously vaccinated against ancestral SARS-CoV-2. From September 8, 2021, to April 22, 2022, 642 participants were enrolled and randomized into the study; 637 received at least one vaccination. After each dose, CIC formulations induced antibody responses against homologous and heterologous influenza and SARS-CoV-2 strains that were comparable with the references. The CIC vaccine group had similar incidence of solicited and unsolicited AEs as the qNIV and NVX-CoV2373 reference groups. Severe unsolicited AEs only occurred in the CIC group but were infrequent and not considered related to the study vaccine. Overall, CIC formulations displayed reference-comparable safety and immunogenicity and provided data for statistical modeling analyses to optimize influenza hemagglutinin and SARS-CoV-2 rS antigen concentrations for use in phase 2 clinical trials investigating CIC.