Heterologous saRNA prime – multivalent protein boost strategy induces broad and durable immunity against SARS-CoV-2 and MERS-CoV

The continuing emergence of SARS- and MERS-related coronaviruses underscores the urgent need for pan-SARBECo vaccines capable of eliciting broad and durable protective immune responses across divergent lineages (Cankat et al. in Cell. Mol. Immunol. 21(2):103–118, 2024). We present a heterologous prime-boost vaccination strategy combining a modified dendrimer nanoparticle (DNP)-encapsulated self-amplifying (saRNA) prime with an alum-adjuvanted multivalent protein booster containing receptor-binding domains (RBDs) from SARS-CoV-2 (Wuhan-Hu-1 and B.1.351) and MERS-CoV. This approach leverages the potent immunogenicity of RNA priming together with the breadth and safety of protein subunit boosting (Bruno et al. in Npj Vaccines 10(1):108, 2025; Kim et al. in Vaccines 13(8):797, 2025) to expand coronavirus coverage. In preclinical mouse and hamster models, the heterologous RNA-protein regimen elicited robust antibody responses with markedly enhanced magnitude, durability, and cross-variant breadth compared with homologous RNA or protein vaccination alone. Inclusion of the MERS-CoV RBD in the booster broadened the response without compromising SARS-CoV-2 immunity. These findings establish a versatile and scalable vaccination strategy with potential to inform the development of next-generation, broadly protective vaccines against emerging coronaviruses.