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 protection across divergent lineages. ¹ 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 ^2–3 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 neutralization 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.