Analysis of the Human Antibody Response to Old World Alphavirus Infection

Abstract

Mosquito inoculation of humans with arthritogenic alphaviruses results in a febrile syndrome characterized by debilitating musculoskeletal pain and arthritis. Despite an expanding global disease burden, no approved therapies or licensed vaccines exist. Human monoclonal antibodies (mAbs) that bind to and neutralize multiple alphaviruses were generated from donors who experienced natural infection. These mAbs are potently neutralizing and a subset are broadly neutralizing against multiple alphaviruses. The antigenic regions targeted and mechanisms of neutralization were determined, and therapeutic potential was assessed in vivo. MAbs were found to block binding of virus to a recently discovered alphavirus receptor, Mxra8. These mAbs also reduced musculoskeletal disease, viral burden, and death in several mouse challenge models, suggesting that therapeutic administration could mitigate disease burden. Additionally, three cryo-EM structures of a broadly neutralizing mAb in complex with virus were determined, and revealed a conserved epitope on the E2 viral structural glycoprotein. Knowledge of this epitope will contribute to targeted vaccine design against multiple emerging arthritogenic alphavirus infections.