biostudies-literatureLebedin MEuropean Research CouncilDeutsche ForschungsgemeinschaftHelmholtz Association of German Research CentresEU Framework Programme for Research and Innovation Marie Skłodowska-Curie ActionsBMBF BerlinEuropean CommissionBerlin Institute of Health at Charité109330https://www.ebi.ac.uk/biostudies/studies/S-EPMC10940809biostudies-literatureUnknown27(3)Identifying immune modulators that impact neutralizing antibody responses against severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) is of great relevance. We postulated that high serum concentrations of soluble angiotensin-converting enzyme 2 (sACE2) might mask the spike and interfere with antibody maturation toward the SARS-CoV-2-receptor-binding motif (RBM). We tested 717 longitudinal samples from 295 COVID-19 patients and showed a 2- to 10-fold increase of enzymatically active sACE2 (a-sACE2), with up to 1 μg/mL total sACE2 in moderate and severe patients. Fifty percent of COVID-19 sera inhibited ACE2 activity, in contrast to 1.3% of healthy donors and 4% of non-COVID-19 pneumonia patients. A mild inverse correlation of a-sACE2 with RBM-directed serum antibodies was observed. <i>In silico</i>, we show that sACE2 concentrations measured in COVID-19 sera can disrupt germinal center formation and inhibit timely production of high-affinity antibodies. We suggest that sACE2 is a biomarker for COVID-19 and that soluble receptors may contribute to immune suppression informing vaccine design.iScienceSoluble ACE2 correlates with severe COVID-19 and can impair antibody responses.PMC10940809948464Spatt LGarg AStubbemann Pde la Rosa KGarcia CVObermayer BRatswohl CLebedin MWeiner JThibeault CKurth FPischon TVelasquez IMWitzenrath MMeyer-Hermann MGerhard CSchips MHanitsch LGSander LEfalseSoluble ACE2 correlates with severe COVID-19 and can impair antibody responses.Identifying immune modulators that impact neutralizing antibody responses against severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) is of great relevance. We postulated that high serum concentrations of soluble angiotensin-converting enzyme 2 (sACE2) might mask the spike and interfere with antibody maturation toward the SARS-CoV-2-receptor-binding motif (RBM). We tested 717 longitudinal samples from 295 COVID-19 patients and showed a 2- to 10-fold increase of enzymatically active sACE2 (a-sACE2), with up to 1 μg/mL total sACE2 in moderate and severe patients. Fifty percent of COVID-19 sera inhibited ACE2 activity, in contrast to 1.3% of healthy donors and 4% of non-COVID-19 pneumonia patients. A mild inverse correlation of a-sACE2 with RBM-directed serum antibodies was observed. <i>In silico</i>, we show that sACE2 concentrations measured in COVID-19 sera can disrupt germinal center formation and inhibit timely production of high-affinity antibodies. We suggest that sACE2 is a biomarker for COVID-19 and that soluble receptors may contribute to immune suppression informing vaccine design.2024-01-01T00:00:00Z2024 Mar2026-07-01T03:21:29.427Z2025-02-19T04:36:17.329ZS-EPMC109408093849629610.1016/j.isci.2024.109330