Imprinted SARS-CoV-2-specific memory lymphocytes define hybrid immunity

Immune memory is tailored by cues that lymphocytes perceive during priming. The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic created a situation in which nascent memory could be tracked through additional antigen exposures. Both SARS-CoV-2 infection and vaccination induce multifaceted, functional immune memory, but together, they engender improved protection from disease, termed hybrid immunity. We therefore investigated how vaccine-induced memory is shaped by previous infection. We found that following vaccination, previously infected individuals generated more SARS-CoV-2 RBD-specific memory B cells and variant-neutralizing antibodies and a distinct population of IFN-γ and IL-10-expressing memory SARS-CoV-2 spike-specific CD4+ T cells than previously naive individuals. Although additional vaccination could increase humoral memory in previously naive individuals, it did not recapitulate the distinct CD4+ T cell cytokine profile observed in previously infected subjects. Thus, imprinted features of SARS-CoV-2-specific memory lymphocytes define hybrid immunity. [Display omitted] •Vaccination elicits robust SARS-CoV-2-specific immune memory regardless of prior infection•Hybrid immunity is associated with more virus-specific memory B cells and Omicron nAb•SARS-CoV-2 infection prior to vaccination elicits a robust CD4+ T Th1/IFN-ɣ response•Infection-induced Th1/IFN-ɣ signature is not reproduced by three vaccinations The strong immunity against SARS-CoV-2 in vaccinated individuals that have previously been infected can be explained by a combination of RBD-specific memory B cells, variant-neutralizing antibodies, and a specific population of CD4+ T cells.