Differential serological immune imprinting following SARS-CoV-2 infection, vaccination, and breakthrough infection

• DOI: 10.4049/jimmunol.208.supp.112.09
• Publication Date: 2023-01-03T04:31:14Z
• Authors: William Voss; Yimin Huang; Jeffrey Marchioni; Allison Seeger; Chelsea Paresi; Jessica Kain; Douglas Townsend; Jenny Munt; Ralph Baric; George Georgiou; Jason Lavinder; Gregory Ippolito
• Keywords: 0303 health sciences; 03 medical and health sciences; 3. Good health

Abstract Extensive efforts have been made to study the human immune response following SARS-CoV-2 infection. Recent work by our lab provided insights into the molecular-level composition of the circulating IgG antibody repertoire evoked by SARS-CoV-2 primary infection and revealed key properties of the spike-directed antibodies and the epitopes they target in convalescent plasma (Voss et al., Science 2021). We showed that the antibody response in mild SARS-CoV-2 infection is directed to epitopes outside the RBD and primarily to the S2 domain of the spike glycoprotein. The continual emergence of globally circulating SARS-CoV-2 variants underscores the need for an ongoing study of the long-term evolution of our adaptive immune response to this virus. Collective knowledge about the molecular composition of human serological IgG memory to SARS-CoV-2 is limited. Our research uses single-cell sequencing and plasma IgG proteomics to better understand the evolving plasma antibody response to infection, vaccination, and breakthrough infection. In volunteers with a primary infection prior to vaccination, we can identify the serological recall of somatically mutated, pre-existing IgG antibodies targeting the S2 domain of the SARS-CoV-2 spike that cross-react with conserved epitopes expressed by endemic β-coronaviruses, indicating the existence of serological immune imprinting by prior infections. In contrast, in volunteers who received a full vaccine regimen and then had a breakthrough infection, the serological recall is markedly different—as shall be discussed. Collectively, these data reveal that the molecular nature of serological IgG recall appears to depend on the sequence and mode of exposure to SARS-CoV-2 spike antigen. Supported by NIH NCI COVID-19 SeroNet grant U54-CA260543 (R.S.B.)