ABSTRACT
The creation of safe and effective vaccines that induce potent cellular and humoral immune responses against SARS-CoV-2 is urgently needed to end the global COVID-19 epidemic. Here we developed an alphavirus-derived self-replicating RNA (repRNA)-based vaccine platform encoding the receptor binding domain (RBD) of SARS-CoV-2 spike glycoprotein. The repRNA triggers prolonged antigen expression compared to conventional mRNA due to the replication machinery of repRNA. To improve the delivery and vaccine efficacy of repRNA, we developed a self-assembling liposome-protamine-RNA (LPR) nanoparticle with highly efficient encapsulation and transfection of repRNA. LPR-repRNA vaccines substantially activated type I interferon response and innate immune signaling pathways. Subcutaneous immunization of LPR-repRNA-RBD led to prolonged antigen expression, stimulation of innate immune cells and induction of germinal center response in draining lymph nodes. LPR-repRNA-RBD induced antigen-specific T-cell responses and skewed cellular immunity towards an effector memory CD8+ T cell response. Immunizations with LPR-repRNA-RBD triggered the production of anti-RBD IgG antibodies and induced neutralizing antibody response against SARS-CoV-2 pseudovirus. LPR-repRNA-RBD vaccines reduced SARS-CoV-2 infection and lung inflammation in mice. Altogether, these data suggest that LPR-repRNA platform can be a promising avenue for COVID-19 vaccine development. Graphical Zhang and colleagues develop a LPR nanovaccine platform encapsulating repRNA that encodes the RBD of SARS-CoV-2 spike glycoprotein (LPR-repRNA-RBD). Compared to conventional mRNA vaccines, LPR-repRNA vaccines enhance the magnitude and duration of antigen expression, activate innate immunity, induce antigen-specific cellular and humoral immune responses, and reduce SARS-CoV-2 infection and lung injury.