Development of an NS1-based dengue vaccine that protects via non-neutralizing antibodies and evades antibody-dependent enhancement 2249046

Abstract

Abstract Introduction Dengue is a mosquito-borne virus that threatens one half of the global population. While primary infection is usually mild or asymptomatic, secondary infection with another of the four serotypes increases the risk for severe disease due to a phenomenon called antibody-dependent enhancement (ADE). Through ADE, non-neutralizing antibodies that target dengue structural proteins facilitate viral entry and replication and worsen disease severity and outcomes. Current dengue vaccines are live-attenuated and do not eliminate the possibility of ADE upon breakthrough infection. Novel vaccines that do not induce ADE are consequently needed. NS1 is a secreted non-structural protein that contributes to dengue pathogenesis by mediating vascular leakage. NS1 is a promising vaccine target because anti-NS1 antibodies are non-neutralizing, thereby evading ADE, and they have also been shown to protect mice from disease. Methods Here, we are developing a DENV2 NS1 mRNA-LNP vaccine that is safe, highly immunogenic, and effective in mice. Results This DENV2 NS1 mRNA-LNP vaccine induces non-neutralizing antibodies that protect against severe disease and mortality in a lethal challenge model. Conclusion In future directions, this work will investigate the mechanisms of non-neutralizing anti-NS1-based protection, including the involvement of affinity maturation and Fc effector functions. Together, we present a promising dengue vaccine strategy that evades ADE and protects against lethal disease. Funding Source Jordan Polster is supported by the HHMI Gilliam Fellows Program. David Martinez is supported by the HHMI Hanna Gray Fellows Program. Topic Categories Vaccines and Immunotherapy (VAC)