A Pan-Pneumovirus vaccine based on immunodominant epitopes of the fusion protein

Abstract

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.

Keywords: RSV (respiratory syncytial virus); epitope; fusion protein; human metapneumovirus (hMPV); neutralizing antibodies; structure-based vaccine design; vaccine.