Department of Medicine, Washington University School of Medicine, St. Louis, MO.
Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO.
J Exp Med. 2019 Oct 7;216(10):2282-2301. doi: 10.1084/jem.20190736. Epub 2019 Jul 23.
Despite causing outbreaks of fever and arthritis in multiple countries, no countermeasures exist against Mayaro virus (MAYV), an emerging mosquito-transmitted alphavirus. We generated 18 neutralizing mAbs against MAYV, 11 of which had "elite" activity that inhibited infection with EC values of <10 ng/ml. Antibodies with the greatest inhibitory capacity in cell culture mapped to epitopes near the fusion peptide of E1 and in domain B of the E2 glycoproteins. Unexpectedly, many of the elite neutralizing mAbs failed to prevent MAYV infection and disease in vivo. Instead, the most protective mAbs bound viral antigen on the cell surface with high avidity and promoted specific Fc effector functions, including phagocytosis by neutrophils and monocytes. In subclass switching studies, murine IgG2a and humanized IgG1 mAb variants controlled infection better than murine IgG1 and humanized IgG1-N297Q variants. An optimally protective antibody response to MAYV and possibly other alphaviruses may require tandem virus neutralization by the Fab moiety and effector functions of the Fc region.
尽管马亚罗病毒（MAYV）会在多个国家引发发热和关节炎疫情，但目前尚无针对这种新兴蚊媒传播的阿尔法病毒的对策。我们针对 MAYV 生成了 18 种中和单克隆抗体，其中 11 种具有“精英”活性，能以低于 10ng/ml 的 EC 值抑制感染。在细胞培养中具有最大抑制能力的抗体针对 E1 融合肽附近和 E2 糖蛋白结构域 B 中的表位。出乎意料的是，许多精英中和单克隆抗体未能预防 MAYV 在体内感染和发病。相反，最具保护作用的单克隆抗体以高亲和力结合细胞表面上的病毒抗原，并促进特定的 Fc 效应功能，包括中性粒细胞和单核细胞的吞噬作用。在类别转换研究中，鼠源性 IgG2a 和人源化 IgG1 单克隆抗体变体比鼠源性 IgG1 和人源化 IgG1-N297Q 变体更能控制感染。针对 MAYV 甚至其他阿尔法病毒的最佳保护抗体反应可能需要 Fab 片段的串联病毒中和以及 Fc 区域的效应功能。
