Mixed formulation of mRNA and protein‐based COVID‐19 vaccines triggered superior neutralizing antibody responses

Abstract Integrating different types of vaccines into a singular immunization regimen is an effective and accessible approach to strengthen and broaden the immunogenicity of existing coronavirus disease 2019 (COVID‐19) vaccine candidates. To optimize the immunization strategy of the novel mRNA‐based vaccine and recombinant protein subunit vaccine that attracted much attention in COVID‐19 vaccine development, we evaluated the immunogenicity of different combined regimens with the mRNA vaccine (RNA‐RBD) and protein subunit vaccine (PS‐RBD) in mice. Compared with homologous immunization of RNA‐RBD or PS‐RBD, heterologous prime‐boost strategies for mRNA and protein subunit vaccines failed to simultaneously enhance neutralizing antibody (NAb) and Th1 cellular response in this study, showing modestly higher serum neutralizing activity and antibody‐dependent cell‐mediated cytotoxicity for “PS‐RBD prime, RNA‐RBD boost” and robust Th1 type cellular response for “RNA‐RBD prime, PS‐RBD boost”. Interestingly, immunizing the mice with the mixed formulation of the two aforementioned vaccines in various proportions further significantly enhanced the NAb responses against ancestral, Delta, and Omicron strains and manifested increased Th1‐type responses, suggesting that a mixed formulation of mRNA and protein vaccines might be a more prospective vaccination strategy. This study provides basic research data on the combined vaccination strategies of mRNA and protein‐based COVID‐19 vaccines.