Bivalent fusion protein vaccine induces protective immunity against SARS-CoV-2 and Staphylococcus aureus

Viral-bacterial co-infections pose significant global health challenges. Currently, there are limited vaccines that target both viral and bacterial pathogens simultaneously. In this study, we present HRBD, a novel fusion protein vaccine combining the receptor-binding domain (RBD) of SARS-CoV-2 and a detoxified α-hemolysin mutant (Hla^H35A) from S.aureus. When tested in mice, HRBD induced robust IgG1-dominated antibody responses against both antigens, leading to neutralizing effects against SARS-CoV-2 pseudovirus (NT₅₀ ∼ 10³) and S. aureus hemolytic activity (NT₅₀ ∼ 10²). HRBD promoted a Th2 immune response with increased IL-4 levels, while also boosting IFN-γ production. Importantly, HRBD showed dose-sparing efficacy, achieving similar immune responses as high-dose single or mixed-antigen vaccines with half the antigen amount. Functional tests confirmed that HRBD sera could neutralize Hla-induced cell lysis and block SARS-CoV-2 entry and syncytium formation. HRBD vaccination protected hACE2 transgenic mice against the co-infection of SARS-CoV-2 pseudovirus and S. aureus. These results suggest that HRBD is a promising candidate for preventing SARS-CoV-2 and S. aureus co-infections.