Enhanced durability of a Zika virus self-amplifying RNA vaccine through combinatorial OX40 and 4-1BB agonism 2410

Abstract Description The SARS-CoV-2 pandemic has underscored the potential for mRNA vaccines to enable rapid public health responses to emerging pathogens. However, immunity induced by conventional mRNA vaccines wanes quickly and requires frequent booster doses to maintain protection. Next-generation vaccines consisting of self-amplifying RNA (saRNA), which extend antigen exposure via self-replication, offer a promising strategy to induce more durable immune responses. In this study, we developed an saRNA vaccine encoding Zika virus (ZIKV) membrane and envelope proteins (M/E) and evaluated its immunogenicity and protective efficacy in mice. The vaccine elicited strong humoral and cellular immune responses and significantly reduced tissue viral loads after ZIKV challenge. A single dose of vaccine provided robust protection against ZIKV infection after 28 days, but not 84 days. However, administration of a single dose of vaccine and agonist antibodies against the T cell costimulatory molecules OX40 and 4-1BB on consecutive days successfully sustained vaccine protective efficacy to day 84 and markedly boosted ZIKV-specific polyfunctional and cytotoxic CD8+ T cell responses. These findings suggest that agonists targeting members of the tumor necrosis receptor superfamily, such as OX40 and 4-1BB, might enhance the durability of saRNA vaccine-induced antiviral protection and promote sustained CD8+ T cell immunity. Funding Sources NIH R01AI153500, R01AI163188, and R01AI180196 and the Prebys Foundation Topic Categories Vaccines and Immunotherapy (VAC)