Project Summary Two mRNA COVID vaccines that have greater than 90% efficacy in healthy donors have been developed. However the efficacy of these vaccines in PLWH is unknown. PLWH have had suboptimal responses to some prior vaccines potentially because they make limited naïve T cell responses. We and others have shown T cell cross-recognition of spike proteins from SARS-CoV-2 and the common cold coronavirus and demonstrated that these cross-reactive responses are less effective against SARS-CoV-2 than mono- reactive responses. We hypothesize that cross-reactive memory responses will contribute more towards the total SARS-CoV-2 responses in PLWH than in healthy donors and this will result in less effective responses to the mRNA vaccines. We will test this hypothesis by comparing CD4+ T cell and antibody responses in vaccinated healthy donors and PLWH. Our results will have major implications for future policies regarding booster shots for PLWH and the general population