Convergent structural features of respiratory syncytial virus neutralizing antibodies and plasticity of the site V epitope on prefusion F

Respiratory syncytial virus (RSV) is a global public health burden for which no licensed vaccine exists. To aid vaccine development via increased understanding of the protective antibody response to RSV prefusion glycoprotein F (PreF), we performed structural and functional studies using the human neutralizing antibody (nAb) RSB1. The crystal structure of PreF complexed with RSB1 reveals a conformational, pre-fusion specific site V epitope with a unique cross-protomer binding mechanism. We identify shared structural features between nAbs RSB1 and CR9501, elucidating for the first time how diverse germlines obtained from different subjects can develop convergent molecular mechanisms for recognition of the same PreF site of vulnerability. Importantly, RSB1-like nAbs were induced upon immunization with PreF in naturally-primed cattle. Together, this work reveals new details underlying the immunogenicity of Site V and further supports PreF-based vaccine development efforts. Author summary Respiratory syncytial virus (RSV) is a persistent, contagious seasonal pathogen and a serious public health threat. While infants are the most at-risk population, with infections potentially leading to bronchiolitis, adults, especially the elderly, are also burdened by RSV-induced respiratory infections. The only treatment currently available for RSV is passive immunization for high-risk infants. Thus, there is a critical need to develop a vaccine for the vast majority of the vulnerable population for which there is no preventative treatment. The RSV fusion protein in its prefusion form (PreF) is the target of the majority of naturally-induced neutralizing antibodies, and several clinical trials are currently evaluating PreF as a promising vaccine candidate. In this study, we solved the X-ray structure of PreF bound to the Fab fragment of a human neutralizing antibody. The structure reveals plasticity of the epitope, as well as a unique molecular signature for antibodies elicited towards this region of PreF. We also find that similar antibodies are induced upon immunization of naturally-primed cattle with a PreF vaccine antigen, suggesting that this epitope is highly immunogenic. These results will help us better understand the human immune response to RSV infection and vaccination, and guide future vaccine-design efforts.