Production of high-affinity class-switched antibodies is essential for elimination of viruses and immunity elicited by vaccination. Vaccination has led to the eradication of some diseases, but in some settings do not provide sufficient protection, such as in elderly or immunocompromised individuals. Antibody responses are controlled by humoral immunoregulatory pathways, including inhibition by Tfr cells, which suppress B cell effector functions. Aged-related defects in vaccine responses are partially due to enhanced humoral immunoregulation by Tfr cells. Since the COVID19 pandemic disproportionally affects at-risk populations such as the elderly, new vaccine strategies need to be developed to enhance protection for this group. However, a fundamental understanding of how humoral immunoregulation associated with aging alters SARS-CoV-2 vaccine responses is lacking. We hypothesize that augmented humoral immunoregulation by Tfr cells during aging alters SARS-CoV-2 vaccine responses, and that limiting Tfr cells can enhance vaccine efficacy. We also hypothesize that limiting humoral immunoregulation results in production of new and unique therapeutic antibodies. To test these hypotheses, we will use a novel systems-based approach to integrate, on a per cell basis, SARS-CoV-2 antibody specificity, breadth, viral neutralization potential, and antibody sequence/clonality. We will use novel Tfr-deleter mice to assess how humoral immunoregulation alters these responses. Our aims are to 1) determine how augmented humoral immunoregulation in aging alters clonal selection of neutralizing antibodies during SARS-CoV-2 vaccination, and 2) determine how eliminating humoral immunoregulation enhances clonal selection of neutralizing antibodies. Our goals are to determine, in detail, how humoral immunoregulation alters antibody selection to control effector antibody responses after vaccination.