Early Fc-effector antibody signatures impact COVID-19 disease trajectory

Alba Escalera; Ana S. Gonzalez-Reiche; Sadaf Aslam; Enrique Bernal; Galit Alter; Amaya Rojo-Fernandez; Alexander Rombauts; Gabriela Abelenda-Alonso; Mary Anne Amper; Venugopalan D. Nair; Harm van Bakel; Jordi Carratalà; Adolfo García-Sastre; Teresa Aydillo

Alba Escalera, Ana S Gonzalez-Reiche, Sadaf Aslam, Enrique Bernal, Galit Alter, Amaya Rojo-Fernandez, Alexander Rombauts, Gabriela Abelenda-Alonso, Mary Anne Amper, Venugopalan D Nair, Harm Van Bakel, Jordi Carratalà, Adolfo García-Sastre, Teresa Aydillo

doi:10.64898/2026.02.18.26346542

Why do some individuals develop mild COVID-19 while others progress to severe disease remains a central challenge in SARS-CoV-2 immunology. In this study, we leveraged the BACO Cohorta unique historical cohort of immunologically naïve, hospitalized COVID-19 patients from the first pandemic waveto investigate early immune determinants of clinical disease trajectories. Integrating bulk RNA-seq, Olink proteomics, and systems serology, we identified two fundamentally distinct immune trajectories according to disease phenotypes. Severe patients exhibited upregulation of proinflammatory genes and monocyte-associated transcripts, alongside downregulation of genes related to T cell responses and immune signaling. Notably, an upregulation of inhibitory Fc-receptor-associated gene was also found in severe cases. In contrast, mild cases showed coordinated lymphoid activation and limited inflammation. Building on these findings, we performed a functional profiling of Fc-effector activity in the polyclonal serum of the patients and found that monocyte-mediated phagocytosis was a common feature of mild disease. Interestingly, this response was mainly driven by rapid induction of S1-specific antibodies. Conversely, severe patients tended to generate higher levels of S2-biased antibodies early after infection with poor Fc-effector functionality. Together, these findings demonstrate that .

COMPETING INTERESTS: ACKNOWLEDGEMENTS: We thank the BACO cohort and their families. We also thank Richard DATA AVAILABILITY: All data are available in the manuscript or the supplementary materials.

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DOI record: { "DOI": "10.64898/2026.02.18.26346542", "URL": "http://dx.doi.org/10.64898/2026.02.18.26346542", "abstract": "ABSTRACT\n Why do some individuals develop mild COVID-19 while others progress to severe disease remains a central challenge in SARS-CoV-2 immunology. In this study, we leveraged the BACO Cohort – a unique historical cohort of immunologically naïve, hospitalized COVID-19 patients from the first pandemic wave – to investigate early immune determinants of clinical disease trajectories. Integrating bulk RNA-seq, Olink proteomics, and systems serology, we identified two fundamentally distinct immune trajectories according to disease phenotypes. Severe patients exhibited upregulation of proinflammatory genes and monocyte-associated transcripts, alongside downregulation of genes related to T cell responses and immune signaling. Notably, an upregulation of inhibitory Fc-receptor–associated gene was also found in severe cases. In contrast, mild cases showed coordinated lymphoid activation and limited inflammation. Building on these findings, we performed a functional profiling of Fc-effector activity in the polyclonal serum of the patients and found that monocyte-mediated phagocytosis was a common feature of mild disease. Interestingly, this response was mainly driven by rapid induction of S1-specific antibodies. Conversely, severe patients tended to generate higher levels of S2-biased antibodies early after infection with poor Fc-effector functionality. Together, these findings demonstrate that early S1-directed, Fc-competent humoral immunity is a key determinant of favorable COVID-19 outcomes, while delayed functional maturation and early S2 bias characterized severe disease in the BACO cohort.", "accepted": { "date-parts": [ [ 2026, 2, 19 ] ] }, "author": [ { "ORCID": "https://orcid.org/0000-0003-0061-0768", "affiliation": [ { "name": "Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA" }, { "name": "Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA" } ], "authenticated-orcid": false, "family": "Escalera", "given": "Alba", "sequence": "first" }, { "ORCID": "https://orcid.org/0000-0003-3583-4497", "affiliation": [ { "name": "Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA" } ], "authenticated-orcid": false, "family": "Gonzalez-Reiche", "given": "Ana S.", "sequence": "additional" }, { "affiliation": [ { "name": "Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA" }, { "name": "Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA" }, { "name": "Department of Health Sciences, University of Burgos, 09001 Burgos, Spain" } ], "family": "Aslam", "given": "Sadaf", "sequence": "additional" }, { "affiliation": [ { "name": "Instituto Murciano de Investigación Biosanitaria, Universidad de Murcia, Hospital General Universitario Reina Sofía, 30003 Murcia, Spain" } ], "family": "Bernal", "given": "Enrique", "sequence": "additional" }, { "affiliation": [ { "name": "The Ragon Institute of MGH, MIT and Harvard, Cambridge, MA 02139, USA" } ], "family": "Alter", "given": "Galit", "sequence": "additional" }, { "affiliation": [ { "name": "Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA" }, { "name": "Global Health and 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