{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,2,21]],"date-time":"2026-02-21T17:07:19Z","timestamp":1771693639912,"version":"3.50.1"},"posted":{"date-parts":[[2026,2,19]]},"group-title":"Infectious Diseases (except HIV\/AIDS)","reference-count":100,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,2,19]],"date-time":"2026-02-19T00:00:00Z","timestamp":1771459200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,2,19]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:p>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 \u2013 a unique historical cohort of immunologically na\u00efve, hospitalized COVID-19 patients from the first pandemic wave \u2013 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\u2013associated 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.<\/jats:p>","DOI":"10.64898\/2026.02.18.26346542","type":"posted-content","created":{"date-parts":[[2026,2,20]],"date-time":"2026-02-20T03:15:13Z","timestamp":1771557313000},"source":"Crossref","is-referenced-by-count":0,"title":["Early Fc-effector antibody signatures impact COVID-19 disease trajectory"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0061-0768","authenticated-orcid":false,"given":"Alba","family":"Escalera","sequence":"first","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, 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