Natural antibodies (Abs) can target host glycans on the surface of pathogens. We studied the evolution of glycan-reactive B cells of rhesus macaques and humans using glycosylated HIV-1 envelope (Env) as a model antigen. 2G12 is a broadly neutralizing Ab (bnAb) that targets a conserved glycan patch on Env of geographically diverse HIV-1 strains using a unique heavy-chain (VH) domain-swapped architecture that results in fragment antigen-binding (Fab) dimerization. Here, we describe HIV-1 Env Fab-dimerized glycan (FDG)-reactive bnAbs without VH-swapped domains from simian-human immunodeficiency virus (SHIV)-infected macaques. FDG Abs also recognized cell-surface glycans on diverse pathogens, including yeast and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike. FDG precursors were expanded by glycan-bearing immunogens in macaques and were abundant in HIV-1-naive humans. Moreover, FDG precursors were predominately mutated IgM+IgD+CD27+, thus suggesting that they originated from a pool of antigen-experienced IgM+ or marginal zone B cells.

Beth Israel Deaconess Medical Center and Harvard Medical School Boston MA 02215 USA

Boston Children's Hospital and Harvard Medical School Boston MA 02115 USA

Department of Chemistry and Biochemistry Swarthmore College Swarthmore PA 19081 USA

Department of Computer Science Duke University Durham NC 27708 USA

Department of Computer Science Duke University Durham NC 27708 USA; Department of Biochemistry Duke University Durham NC 27705 USA; Department of Electrical and Computer Engineering Duke University Durham NC 27708 USA

Department of Medicine Duke University Durham NC 27710 USA

Department of Surgery Duke University Durham NC 27710 USA

Duke Human Vaccine Institute Durham NC 27710 USA

Duke Human Vaccine Institute Durham NC 27710 USA; Department of Immunology Duke University Durham NC 27710 USA

Duke Human Vaccine Institute Durham NC 27710 USA; Department of Immunology Duke University Durham NC 27710 USA; Department of Pediatrics Duke University Durham NC 27710 USA

Duke Human Vaccine Institute Durham NC 27710 USA; Department of Immunology Duke University Durham NC 27710 USA; Department of Surgery Duke University Durham NC 27710 USA

Duke Human Vaccine Institute Durham NC 27710 USA; Department of Medicine Duke University Durham NC 27710 USA

Duke Human Vaccine Institute Durham NC 27710 USA; Department of Medicine Duke University Durham NC 27710 USA; Department of Immunology Duke University Durham NC 27710 USA

Duke Human Vaccine Institute Durham NC 27710 USA; Department of Surgery Duke University Durham NC 27710 USA

Genome Integrity and Structural Biology Laboratory NIEHS NIH Department of Health and Human Services Research Triangle Park NC 27709 USA

Institute of Macromolecular Chemistry Czech Academy of Sciences Prague Czech Republic

Memorial Sloan Kettering Cancer Center New York NY 10065 USA

Perelman School of Medicine University of Pennsylvania Philadelphia PA 19104 USA

Vaccine Research Center NIAID NIH Bethesda MD 20892 USA

Vaccine Research Center NIAID NIH Bethesda MD 20892 USA; Avidea Technologies Inc Baltimore MD USA

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Synthesis and Structure Optimization of Star Copolymers as Tunable Macromolecular Carriers for Minimal Immunogen Vaccine Delivery