Combination of adenovirus vector and subunit protein elicits a robust immune response against the SARS-CoV-2 Omicron variant

The rapid and ongoing emergence of SARS-CoV-2 variants has progressively reduced the protection offered by current vaccines, underscoring the urgent need for novel vaccine strategies. In this study, we designed a two-component vaccine in which one component is an adenoviral vector encoding the Omicron XBB.1.5 spike protein (Ad5_XBB.1.5), and the other component is a self-assembling trimeric receptor-binding domain protein (RBD_XBB.1.5-HR or RBD_JN.1-HR). This platform integrates the complementary advantages of subunit protein and adenoviral vector vaccines, elicits robust humoral and cellular immunity in mice after intramuscular administration. Durable IgG responses induced by this two-component vaccine were maintained for over six months post-immunization in mice, attributed to their ability to generate memory B cells and long-lived plasma cells responses. Furthermore, in a heterologous booster setting following mRNA (mRNA_BA.4 and mRNA_XBB.1.5) priming, the two-component vaccine can be severed as a boost shot to rescue the neutralization against emerging variants, such as JN.1. These findings indicate that the two-component vaccine system can act effectively on its own and also serve as a heterologous booster that enhances protection against antigenically evolved variants. Furthermore, the modularity of this platform suggests broad applicability for rapid adaptation to future SARS-CoV-2 strains and for vaccine development against other fast-evolving respiratory viruses. Collectively, this study provides a generalizable framework for next-generation COVID-19 vaccine design and supports the translational relevance of two-component vaccines in the context of continual viral diversification.