Novel srRNA vectors for customizable vaccine development

Recent approvals of self-replicating RNA (srRNA) vaccines have shown the advantages of this platform technology, including generation of durable and comprehensive immune responses at clinical doses approximately 10-fold lower than conventional mRNA. This is in part due to the viral origin of synthetic srRNA vectors which include a replicase that amplifies the co-encoded transgene (i.e. vaccine antigen), allowing for dose-sparing, and adjuvantation of immune responses for vaccines. Interestingly, two approved srRNA vaccines for SARS-CoV-2, as well as many others in late-stage development, share the same base vector derived from the alphavirus Venezuelan Equine Encephalitis virus (VEEV). As with traditional viral vectors, the context in which the host sees an antigen can shape downstream immune responses. Thus, we evaluated if a panel of VEEV and non-VEEV alphaviral vectors result in differential humoral and cell-mediated immunity. Here, we show that although VEEV is advantaged for generation of antibody responses to a viral glycoprotein, a novel, non-VEEV-based srRNA vector can be advantaged for the generation of T cell responses to the same antigen. Thus, similar to traditional viral vectors, we propose that srRNA vectors can also bias downstream immune responses and allow for customizable vaccine design.