The adaptive immune responses to SARS-CoV-2 as a recall response susceptible to immune imprinting

Background The antibody response to SARS-CoV-2 does not follow the immunoglobulin isotype pattern expected in a primary response and is inconsistent with the current interpretation of COVID-19 immunopathology as the result of a primary infection. To better understand the immune response to SARS-CoV-2, it is essential to determine whether it is primary or secondary (or recall). The analysis of highly granular immunological variable trajectories of a homogeneous cohort of patients receiving standardised medical care should discern between primary and secondary responses. Methods This is a prospective cohort study of 191 SARS-CoV-2 infection cases and 44 healthy controls from the second wave of COVID-19 in the Barcelona area. The study stratified patients by severity and analysed the trajectories of SARS-CoV-2 antibodies and multiple immune variables for features associated with primary and recall immune responses. Findings Isotype-specific antibody trajectories to SARS-CoV-2 proteins revealed a pattern of recall response in 94·2% of cases. In these cases, the detailed trajectories of plasmablasts, B cells, cTfh high-resolution subsets, and cytokines were consistent with a secondary response. The transcriptomic data indicated that this cohort is strictly comparable to contemporary cohorts. Conclusions In most cases, the immune response to SARS-CoV-2 is a recall response. This opens the possibility that most COVID-19 cases are subjected to immune imprinting by endemic coronavirus, which, in turn, can contribute to severity by interfering with the immune response to SARS-CoV-2 and by antibody-dependent enhancement. Considering the immune responses to SARS-CoV-2 secondary provides a better perspective to interpret COVID-19 pathology. Funding Grants COV20/00416, Cov20/00654, and COV20/00388 from Instituto de Salud Carlos III (ISCIII), Madrid, Spain, co-financed by the European Regional Development Fund (ERDF).