Characteristics and Functions of Infection-enhancing Antibodies to  the N-terminal Domain of SARS-CoV-2

Ruth Connor; Mrunal Sakharkar; Garrett Rappazzo; Chengzi Kaku; Nicholas Curtis; Seungmin Shin; Wendy Wieland-Alter; Jordan Wentworth; Daniel Mielcarz; Joshua Weiner; Margaret Ackerman; Laura Walker; Jiwon Lee; Peter Wright

doi:10.20411/pai.v9i2.679

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Published: Jun 18, 2024

DOI: https://doi.org/10.20411/pai.v9i2.679

Keywords:

SARS-CoV-2, COVID-19, antibodies, serum clonotypes, infection enhancement, FcR activation, variants of concern

Ruth I. Connor

Department of Pediatrics, Geisel School of Medicine, Dartmouth Health, Lebanon; Department of Microbiology and Immunology, Geisel School of Medicine, Dartmouth College, Hanover, New Hampshire

Mrunal Sakharkar

Adimab LLC, Lebanon, New Hampshire

C. Garrett Rappazzo

Adimab LLC, Lebanon, New Hampshire

Chengzi I. Kaku

Adimab LLC, Lebanon, New Hampshire; Scripps Research, La Jolla, CA

Nicholas C. Curtis

Thayer School of Engineering, Dartmouth College, Hanover, New Hampshire

Seungmin Shin

Thayer School of Engineering, Dartmouth College, Hanover, New Hampshire

Wendy F. Wieland-Alter

Department of Pediatrics, Geisel School of Medicine, Dartmouth Health, Lebanon, New Hampshir

Jordan Wentworth

DartLab, Dartmouth Cancer Center, Geisel School of Medicine, Lebanon, New Hampshire

Daniel W. Mielcarz

DartLab, Dartmouth Cancer Center, Geisel School of Medicine, Lebanon, New Hampshire

Joshua A. Weiner

Thayer School of Engineering, Dartmouth College, Hanover, New Hampshire

Margaret E. Ackerman

Department of Microbiology and Immunology, Geisel School of Medicine, Dartmouth College, Hanover; Thayer School of Engineering, Dartmouth College, Hanover, New Hampshire

Laura M. Walker

Adimab LLC, Lebanon, New Hampshire; Moderna, Inc., Cambridge, Massachusetts

Jiwon Lee

Thayer School of Engineering, Dartmouth College, Hanover, New Hampshire

Peter F. Wright

Department of Pediatrics, Geisel School of Medicine, Dartmouth Health, Lebanon, New Hampshire

Abstract

Background: Fcγ-receptor (FcγR)-independent enhancement of SARS-CoV-2 infection mediated by N-terminal domain (NTD)-binding monoclonal antibodies (mAbs) has been observed in vitro, but the functional significance of these antibodies in vivo is less clear.

Methods: We characterized 1,213 SARS-CoV-2 spike (S)-binding mAbs derived from COVID-19 convalescent patients for binding specificity to the SARS-CoV-2 S protein, VH germ-line usage, and affinity maturation. Infection enhancement in a vesicular stomatitis virus (VSV)-SARS-CoV-2 S pseudovirus (PV) assay was characterized in respiratory and intestinal epithelial cell lines, and against SARS-CoV-2 variants of concern (VOC). Proteomic deconvolution of the serum antibody repertoire was used to determine functional attributes of secreted NTD-binding mAbs.

Results: We identified 72/1213 (5.9%) mAbs that enhanced SARS-CoV-2 infection in a PV assay. The majority (68%) of these mAbs recognized the NTD, were identified in patients with mild and severe disease, and persisted for at least 5 months post-infection. Infection enhancement by NTD-binding mAbs was not observed in intestinal and respiratory epithelial cell lines and was diminished or lost against SARS-CoV-2 VOC. Proteomic deconvolution of the serum antibody repertoire from 2 of the convalescent patients identified, for the first time, NTD-binding, infection-enhancing mAbs among the circulating immunoglobulins directly isolated from serum. Functional analysis of these mAbs demonstrated robust activation of FcγRIIIa associated with antibody binding to recombinant S proteins.

Conclusions: Functionally active NTD-specific mAbs arise frequently during natural infection and can last as major serum clonotypes during convalescence. These antibodies display functional attributes that include FcγR activation, and may be selected against by mutations in NTD associated with SARS-CoV-2 VOC.

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