Department of Pathology, Microbiology and Immunology, Vanderbilt University, Nashville, TN 37232, USA.
The Center for Vaccine Research, University of Pittsburgh, Pittsburgh, PA 165261, USA.
Cell. 2020 Dec 23;183(7):1884-1900.e23. doi: 10.1016/j.cell.2020.11.011. Epub 2020 Dec 9.
Eastern equine encephalitis virus (EEEV) is one of the most virulent viruses endemic to North America. No licensed vaccines or antiviral therapeutics are available to combat this infection, which has recently shown an increase in human cases. Here, we characterize human monoclonal antibodies (mAbs) isolated from a survivor of natural EEEV infection with potent (<20 pM) inhibitory activity of EEEV. Cryo-electron microscopy reconstructions of two highly neutralizing mAbs, EEEV-33 and EEEV-143, were solved in complex with chimeric Sindbis/EEEV virions to 7.2 Å and 8.3 Å, respectively. The mAbs recognize two distinct antigenic sites that are critical for inhibiting viral entry into cells. EEEV-33 and EEEV-143 protect against disease following stringent lethal aerosol challenge of mice with highly pathogenic EEEV. These studies provide insight into the molecular basis for the neutralizing human antibody response against EEEV and can facilitate development of vaccines and candidate antibody therapeutics.
东部马脑炎病毒（EEEV）是北美地方性最强的病毒之一。目前尚无针对这种感染的许可疫苗或抗病毒疗法，而最近人类感染病例有所增加。在这里，我们从自然 EEEV 感染幸存者中分离出具有强效（<20 pM）抑制 EEEV 活性的人源单克隆抗体（mAbs）进行了表征。两种高度中和的 mAb，即 EEEV-33 和 EEEV-143，与嵌合辛德毕斯/EEEV 病毒粒子的冷冻电镜重构分别解析至 7.2 Å 和 8.3 Å。这些 mAb 识别两个对抑制病毒进入细胞至关重要的独特抗原位点。在对小鼠进行严格致死性气溶胶挑战高致病性 EEEV 后，EEEV-33 和 EEEV-143 可预防疾病。这些研究为针对 EEEV 的中和人抗体反应的分子基础提供了深入了解，并有助于疫苗和候选抗体疗法的开发。
