Monoclonal antibody-mediated control of lyssavirus infection in the CNS requires Fc effector function

Abstract Lyssaviruses are the causative agent for rabies, a disease that is uniformly fatal in humans. Once infection reaches the central nervous system (CNS), currently approved therapies are ineffective. Using luminescence-based longitudinal tracing of lyssavirus infection in a mouse model of lethal rabies disease, we have shown that peripheral administration of a single dose of human monoclonal antibody (mAb) F11 protects animals from lethality, even when virus is already robustly replicating in the CNS. Additionally, behavioral analyses demonstrate improved motor function of the infected mAb-treated animals compared to infected, untreated controls. Interestingly, A6, another huIgG1 mAb that targets the same lyssavirus G epitope and exhibits similar in vitro neutralization efficiency, is inferior to F11 when used for in vivo therapy. Importantly, functional inactivation of the F11 Fc domain significantly impairs protection against mortality. Thus, Fc effector function is a major determinant of mAb in vivo efficacy. Histology and flow cytometry analysis shows that mAb therapy leads to a shift in leukocyte populations that infiltrate the brain, with significant increases in MHCII+ myeloid cells and CD4+ T cells, consistent with our demonstration that CD4+ T cells are essential for mAb efficacy. Collectively, these data suggest that Fc-mediated effector functions in the periphery yield a potent antiviral immune response in the CNS.