SUMMARY OF RESEARCH PROJECT COVID-19 is a global pandemic, the scope of which has not been seen in a century, and there is a critical unmet need for a vaccine to provide herd immunity against SARS-CoV-2. The objective of this proposal is to identify conserved immunodominant MHC class II peptides from the SARS-CoV-2 proteome that may be incorporated into current vaccine design studies. This meets a critical need to design a vaccine that will provide long-term protective immunity against COVID-19. This proposal uses an innovative immunopeptidomics platform to define the human SARS-CoV-2 MHC class II immunopeptidome using tandem mass spectrometry (Aim 1), and to determine CD4+ T cell responses to potentially immunogenic SARS-CoV-2 MHC-II peptides using a humanized mouse model (Aim 2). Robust CD4+ T cell responses to viral peptides are essential for establishing a pool of long-lived memory B cells and cytotoxic T cells. Results from this study will provide valuable insights into CD4+ T cell responses to viral proteins that may be rapidly incorporated into a vaccine design that will provide long-lasting protection from COVID-19.