Requirement for Fc effector function is overcome by binding potency for broadly reactive anti-alphavirus antibodies

Alphaviruses are emerging public health threats. Broadly reactive anti-alphavirus monoclonal antibodies (mAbs) have been shown to be protective in mouse models of infection. However, the mechanism of Fc-dependent or Fc-independent heterologous protection remains ill-defined in vivo. Here, we used two vaccine-elicited, broadly reactive, anti-alphavirus mAbs, SKT05 and SKT20, to establish correlates of mAb-mediated protection during Venezuelan equine encephalitis virus (VEEV) challenge. SKT20 required Fc effector functions to prevent lethality. In contrast, SKT05-mediated survival was independent of Fc effector functions, which is likely linked to early viral control through potent egress inhibition. However, control of virus replication and spread with SKT05 was Fc-dependent; these findings extended to additional in vivo models with alternative VEEV subtypes and chikungunya virus. During therapeutic delivery of SKT05, Fc effector functions were only required at 3 days post-infection. The necessity of Fc effector functions for SKT20 was related to mAb binding avidity rather than epitope and could be overcome by increasing the dose of SKT20 relative to the functional avidity of SKT05. Collectively, this study identified antibody avidity as a correlate for in vivo efficacy and associated Fc-dependent mechanisms that can be leveraged for therapeutic development of monoclonal antibodies against alphaviruses.