High binding potency overcomes the requirement of Fc effector functions 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 antibody characteristics that promote in vivo efficacy and dependency on Fc effector functions remain ill defined. 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. The necessity of Fc effector functions for SKT20 was dose dependent and related to mAb binding potency and pseudovirus neutralization rather than epitope specificity. In contrast, survival mediated by SKT05 when given prophylactically was independent of Fc effector functions and rather was linked to early viral control through egress inhibition. However, control of virus replication and spread with SKT05 at later time points was Fc dependent. Therapeutic administration of SKT05 required Fc effector functions only at 3 days after infection. These findings extended to additional in vivo infection models with alternative VEEV subtypes and with chikungunya virus. Collectively, this study identified binding potency and pseudoviral neutralization as correlates for in vivo efficacy of mAbs and demonstrated that Fc-dependent mechanisms can be leveraged for development of therapeutic mAbs against emerging alphaviruses.