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. While additional vaccination could increase humoral memory, it did not recapitulate the distinct CD4+ T cell cytokine profile in previously naive individuals. Thus, imprinted features of SARS-CoV-2-specific memory lymphocytes define hybrid immunity.Funding: This work was supported by the following funding: L.B.R. and K.B.P (NIH2T32 AI106677); U. Washington Cell Analysis Facility, Symphony A3 NIH 1S10OD024979- 01A1; D.J.C. and P.A.M. (NIH R01AI127726, NIH U19AI125378-S1) and M.P. (NIH U01AI142001-02S1; R01AI118803); BWF #1018486 and COVID Pilot grant to M.P.; and Emergent Ventures Fast Grant to M.P.Declaration of Interests: M.P. is a member of the Scientific Advisory Board of VaxArt and NeoLeukin Inc.Ethics Approval Statement: Participants were enrolled in the Hospitalized or Ambulatory Adults with Respiratory Viral Infections (HAARVI) study (STUDY00000959), Healthy Adult Specimen Repository study (STUDY00002929) or COVID-19/SARS-CoV-2 Prevalence and Antibody Therapy Development study (Gale Lab, STUDY00009810). All studies are approved by the University of Washington Human Subjects Division Institutional Review Board. Informed consent was obtained from all enrolled participants.