Abstract Human respiratory syncytial virus (RSV) is a major cause of lower respiratory infection. Despite more than 60 years of research, there is no licensed vaccine. While B cell response is a major focus for vaccine design, the T cell epitope profile of RSV is also important for vaccine development. Here, we computationally predicted putative T cell epitopes in the Fusion protein (F) and Glycoprotein (G) of RSV wild circulating strains by predicting Major Histocompatibility Complex (MHC) class I and class II binding affinity. We limited our inferences to conserved epitopes in both F and G proteins that have been experimentally validated. We applied multidimensional scaling (MDS) to construct T cell epitope landscapes to investigate the diversity and evolution of T cell profiles across different RSV strains. We find the RSV strains are clustered into three RSV-A groups and two RSV-B groups on this T epitope landscape. These clusters represent divergent RSV strains with potentially different immunogenic profiles. In addition, our results show a greater proportion of F protein T cell epitope content conservation among recent epidemic strains, whereas the G protein T cell epitope content was decreased. Importantly, our results suggest that RSV-A and RSV-B have different patterns of epitope drift and replacement and that RSV-B vaccines may need more frequent updates. Our study provides a novel framework to study RSV T cell epitope evolution. Understanding the patterns of T cell epitope conservation and change may be valuable for vaccine design and assessment. Author Summary Lower respiratory infections caused by human respiratory syncytial virus (RSV) is a global health challenge. B cell epitope immune response has been the major focus of RSV vaccine and therapeutic development. However, T cell epitope induced immunity plays an important role in the resolution of RSV infection. While RSV genetic diversity has been widely reported, few studies focus on RSV T epitope diversity, which can influence vaccine effectiveness. Here, we use computationally predicted T cell epitope profiles of circulating strains to characterize the diversity and evolution of the T cell epitope of RSV A and B. We systematically evaluate the T epitope profile of RSV F and G proteins. We provide a T cell epitope landscape visualization that shows co-circulation of three RSV-A groups and two RSV-B groups, suggesting potentially distinct T cell immunity. Furthermore, our study shows different levels of F and G protein T cell epitope content conservation, which may be important to correlate with duration of vaccine protection. This study provides a novel framework to study RSV T cell epitope evolution, infer RSV T cell immunity at population levels and monitor RSV vaccine effectiveness.

Diversity and Evolution of Computationally Predicted T Cell Epitopes against Human Respiratory Syncytial Virus