Alphaviruses are emerging, mosquito-transmitted pathogens that cause musculoskeletal and neurological disease in humans. Although neutralizing antibodies that inhibit individual alphaviruses have been described, broadly reactive antibodies that protect against both arthritogenic and encephalitic alphaviruses have not been reported. Here, we identify DC2.112 and DC2.315, two pan-protective yet poorly neutralizing human monoclonal antibodies (mAbs) that avidly bind to viral antigen on the surface of cells infected with arthritogenic and encephalitic alphaviruses. These mAbs engage a conserved epitope in domain II of the E1 protein proximal to and within the fusion peptide. Treatment with DC2.112 or DC2.315 protects mice against infection by both arthritogenic (chikungunya and Mayaro) and encephalitic (Venezuelan, Eastern, and Western equine encephalitis) alphaviruses through multiple mechanisms, including inhibition of viral egress and monocyte-dependent Fc effector functions. These findings define a conserved epitope recognized by weakly neutralizing yet protective antibodies that could be targeted for pan-alphavirus immunotherapy and vaccine design.

甲病毒是新兴的蚊子传播病原体，可导致人类肌肉骨骼和神经系统疾病。尽管已经描述了抑制单个甲病毒的中和抗体，但尚未报道针对致关节炎和脑炎甲病毒的广泛反应性抗体。在这里，我们鉴定了 DC2.112 和 DC2.315，这两种具有泛保护性但中和性较差的人单克隆抗体 (mAb)，它们强烈地与感染致关节炎和脑炎甲病毒的细胞表面的病毒抗原结合。这些 mAb 与 E1 蛋白结构域 II 中靠近融合肽且位于融合肽内的保守表位结合。 DC2.112 或 DC2.315 治疗可通过多种机制保护小鼠免受致关节炎（基孔肯雅热和 Mayaro）和脑炎（委内瑞拉、东部和西部马脑炎）甲病毒的感染，包括抑制病毒排出和单核细胞依赖性 Fc 效应器功能。这些发现定义了一个由弱中和但具有保护性的抗体识别的保守表位，可以作为泛甲病毒免疫治疗和疫苗设计的目标。