Department of Infectious Diseases, College of Veterinary Medicine, University of Georgia, Athens, GA, United States.
Center for Vaccines and Immunology, College of Veterinary Medicine, University of Georgia, Athens, GA, United States.
Front Immunol. 2022 Aug 8;13:941865. doi: 10.3389/fimmu.2022.941865. eCollection 2022.
Respiratory syncytial virus (RSV) and human metapneumovirus (hMPV) are two leading causes of severe respiratory infections in children, the elderly, and immunocompromised patients. The fusion (F) protein is the major target of neutralizing antibodies. Recent developments in stabilizing the pre-fusion conformation of the F proteins, and identifying immunodominant epitopes that elicit potent neutralizing antibodies have led to the testing of numerous pre-fusion RSV F-based vaccines in clinical trials. We designed and tested the immunogenicity and protective efficacy of a chimeric fusion protein that contains immunodominant epitopes of RSV F and hMPV F (RHMS-1). RHMS-1 has several advantages over vaccination with pre-fusion RSV F or hMPV F, including a focus on recalling B cells to the most important protective epitopes and the ability to induce protection against two viruses with a single antigen. RHMS-1 was generated as a trimeric recombinant protein, and analysis by negative-stain electron microscopy demonstrated the protein resembles the pre-fusion conformation. Probing of RHMS-1 antigenicity using a panel of RSV and hMPV F-specific monoclonal antibodies (mAbs) revealed the protein retains features of both viruses, including the pre-fusion site Ø epitope of RSV F. Mice immunized with RHMS-1 generated neutralizing antibodies to both viruses and were completely protected from RSV or hMPV challenge. Overall, this study demonstrates protection against two viruses with a single antigen and supports testing of RHMS-1 in additional pre-clinical animal models.
呼吸道合胞病毒（RSV）和人偏肺病毒（hMPV）是导致儿童、老年人和免疫功能低下患者严重呼吸道感染的两个主要病原体。融合（F）蛋白是中和抗体的主要靶标。最近在稳定 F 蛋白的预融合构象以及鉴定能够引发强效中和抗体的免疫优势表位方面的进展，导致了许多基于 RSV F 的预融合疫苗在临床试验中的测试。我们设计并测试了一种嵌合融合蛋白（RHMS-1）的免疫原性和保护效力，该蛋白包含 RSV F 和 hMPV F 的免疫优势表位。与 RSV F 或 hMPV F 的疫苗接种相比，RHMS-1 具有几个优势，包括将 B 细胞集中到最重要的保护性表位，以及用单一抗原诱导对两种病毒的保护能力。RHMS-1 作为三聚体重组蛋白生成，负染电子显微镜分析表明该蛋白类似于预融合构象。使用一组 RSV 和 hMPV F 特异性单克隆抗体（mAb）探测 RHMS-1 的抗原性，结果表明该蛋白保留了两种病毒的特征，包括 RSV F 的预融合位点Ø表位。用 RHMS-1 免疫的小鼠产生了针对两种病毒的中和抗体，并完全免受 RSV 或 hMPV 挑战的影响。总的来说，这项研究证明了用单一抗原预防两种病毒，并支持在其他临床前动物模型中测试 RHMS-1。
