The magnitude of the secondary B cell response is primarily defined by antibody feedback inhibition rather than the number of memory B cells present

Abstract Clonal expansion of memory lymphocytes after each antigen encounter is the primary mechanism for amplifying immunity. For most vaccines, boosters are common practice and are expected to stimulate proliferation of pre-existing memory B cells (B mem ), thereby expanding the antigen-specific B mem pool, along with driving their differentiation into antibody-producing plasma cells that replenish antibody titers. It is widely assumed that the number of B mem present in the body prior to administration of a booster vaccination will define the magnitude of the ensuing response. However, due to technical limitations hampering reliable detection of rare antigen-specific B mem in human subjects, the extent to which B mem numbers are actually modulated following a booster vaccination remains unclear. By comparing B mem frequencies and antibody titers in the same individuals after primary and secondary vaccination with SARS-CoV-2 Spike (S-antigen)-encoding mRNA we found that expansion of B mem and the magnitude of the secondary antibody response were not determined by the number of B mem measured before the second vaccine inoculation. Instead, both were inversely correlated with levels of S-antigen-specific serum IgG prior to the secondary antigen exposure. Collectively, the data suggest that secondary B cell responses are constrained by antibody feedback inhibition of B mem , rather than their paucity.