Isotype-Specific Fc Effector Functions Enhance Antibody- Mediated Rift Valley Fever Virus Protection In Vivo

Discovered in 1931, Rift Valley fever virus (RVFV) is an arbovirus that causes disease in humans and livestock. In humans, disease ranges from a self-limiting febrile illness to a more severe hepatitis or encephalitis. There are currently no licensed human therapeutics for RVFV disease. Given the recent advances in the use of monoclonal antibodies (MAbs) for treating infectious disease, a panel of anti-RVFV Gn glycoprotein MAbs was developed and characterized. RVFV MAbs spanned a range of neutralizing abilities and mapped to distinct epitopes along Gn. The contribution of Fc effector functions in providing MAb-mediated protection from RVFV was assessed. IgG2a version MAbs had increased capacity to induce effector functions and conferred better protection from RVFV challenge in a lethal mouse model than IgG1 version MAbs. Overall, this study shows that Fc-mediated functions are a critical component of humoral protection from RVFV. IMPORTANCE Rift Valley fever virus (RVFV) is a mosquito-borne virus found throughout Africa and into the Middle East. It has a substantial disease burden; in areas of endemicity, up to 60% of adults are seropositive. With a case fatality rate of up to 3% and the ability to cause hemorrhagic fever and encephalitis, RVFV poses a serious threat to human health. Despite the known human disease burden and the fact that it is a NIAID category A priority pathogen and a WHO priority disease for research and development, there are no vaccines or therapeutics available for RVF. In this study, we developed and characterized a panel of monoclonal antibodies against the RVFV surface glycoprotein, Gn. We then demonstrated therapeutic efficacy in the prevention of RVF in vivo in an otherwise lethal mouse model. Finally, we revealed a role for Fc-mediated function in augmenting the protection provided by these antibodies.