Beyond the unpredictable acute illness caused by SARS-CoV-2, one-fifth of infections unpredictably result in long-term persistence of symptoms despite the apparent clearance of infection. Insights into the mechanisms that underlie post-acute sequelae of COVID-19 (PASC) will be critical for the prevention and clinical management of long-term complications of COVID-19. Several hypotheses have been proposed that may account for the development of PASC, including persistence of virus or the dysregulation of immunity. Among the immunological changes noted in PASC, alterations in humoral immunity have been observed in some patient subsets. To begin to determine whether SARS-CoV-2 or other pathogen specific humoral immune responses evolve uniquely in PASC, we performed comprehensive antibody profiling against SARS-CoV-2 and a panel of endemic pathogens or routine vaccine antigens using Systems Serology in a cohort of patients with pre-existing rheumatic disease who either developed or did not develop PASC. A distinct humoral immune response was observed in individuals with PASC. Specifically, individuals with PASC harbored less inflamed and weaker Fc-receptor binding anti-SARS-CoV-2 antibodies and a significantly expanded and more inflamed antibody response against endemic Coronavirus OC43. Individuals with PASC, further, generated more avid IgM responses and developed an expanded inflammatory OC43 S2-specific Fc-receptor binding response, linked to cross reactivity across SARS-CoV-2 and common coronaviruses. These findings implicate previous common Coronavirus imprinting as a marker for the development of PASC.Competing Interest Statement
G.A. is a founder of SeromYx Systems, Inc. and is a member of the scientific advisory board of Sanofi Pasteur. J.S. has received research support from Bristol Myers Squibb and performed consultancy for AbbVie, Amgen, Boehringer Ingelheim, Bristol Myers Squibb, Gilead, Inova Diagnostics, Janssen, Optum, and Pfizer unrelated to this work. Z.W. reports research support from Bristol-Myers Squibb and Principia/Sanofi and consulting fees from Horizon, Sanofi, Viela Bio, Zenas BioPharma, Shionogi, and MedPace. The other authors declare no competing interests.Funding Statement
We thank Nancy Zimmerman, Mark and Lisa Schwartz, an anonymous donor (financial support), Terry and Susan Ragon, and the SAMANA Kay MGH Research Scholars award for their support. We acknowledge support from the Ragon Institute of MGH, MIT and Harvard, the Massachusetts Consortium on Pathogen Readiness (MassCPR), the NIH (3R37AI080289 11S1, R01AI146785, U19AI42790 01, U19AI135995 02, U19AI42790 01, 1U01CA260476 01, CIVIC75N93019C00052, R01 AR077607, P30 AR070253, P30 AR072577, K23AR073334, 1UL1TR002541-01, and R03AR078938), the Gates Foundation, the Global Health Vaccine Accelerator Platform funding (OPP1146996 and INV001650), the Musk Foundation, R. Bruce and Joan M. Mickey Research Scholar Fund, the Rheumatoid Research Foundation, and the Doris Duke Charitable Foundation.Author Declarations
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The details of the IRB/oversight body that provided approval or exemption for the research described are given below:
All participants provided informed consent prior to participation in the study and the clinical study was approved by the Mass General Brigham Institutional Review Board.
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All data produced in the present study are available upon reasonable request to the authors.