Abstract
Developing both rapid- and long-acting antiviral drugs for single-dose administration can improve medication adherence and protect people at risk of infection. To provide proof of this concept, here, we designed multimerized form of viral receptor-binding domains (RBDs) to immediately occupy viral receptors to block infection and subsequently induce virus-specific protective immunity. We engineered SARS-CoV-2 RBD, enhancing its affinity to ACE2 and immunogenicity through multimerization and Fc modification. A single administration of 4RBD-Fc not only effectively blocked ACE2-dependent SARS-CoV-2 infections but also elicited robust virus-specific mucosal and systemic immunity in the absence of adjuvants, providing superior early and long-lasting protection compared to adjuvanted vaccines in mice. These findings demonstrate the feasibility and efficacy of engineered viral RBD as immediate-acting and long-lasting single-dose antiviral drugs through rapid receptor blocking and ensuing adaptive immunity induction.