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Review 1: "Characteristics and Functions of Infection-Enhancing Antibodies to the N-Terminal Domain of SARS-CoV-2"

The reviewer suggests further analysis of the diversity of these antibodies and validate the sequencing methods used in the study.

Published onJun 30, 2024
Review 1: "Characteristics and Functions of Infection-Enhancing Antibodies to the N-Terminal Domain of SARS-CoV-2"
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key-enterThis Pub is a Review of
Characteristics and functions of infection-enhancing antibodies to the N-terminal domain of SARS-CoV-2
Characteristics and functions of infection-enhancing antibodies to the N-terminal domain of SARS-CoV-2
Description

ABSTRACT Characterization of functional antibody responses to the N-terminal domain (NTD) of the SARS-CoV-2 spike (S) protein has included identification of both potent neutralizing activity and putative enhancement of infection. Fcγ-receptor (FcγR)-independent enhancement of SARS-CoV-2 infection mediated by NTD-binding monoclonal antibodies (mAbs) has been observed in vitro, but the functional significance of these antibodies in vivo is not clear. Here we studied 1,213 S-binding mAbs derived from longitudinal sampling of B-cells collected from eight COVID-19 convalescent patients and identified 72 (5.9%) mAbs that enhanced infection in a VSV-SARS-CoV-2-S-Wuhan pseudovirus (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 five months post-infection. Enhancement of PV infection by NTD-binding mAbs was not observed using intestinal (Caco-2) and respiratory (Calu-3) epithelial cells as infection targets and was diminished or lost against SARS-CoV-2 variants of concern (VOC). Proteomic deconvolution of the serum antibody repertoire from two of the convalescent subjects identified, for the first time, NTD-binding, infection-enhancing mAbs among the circulating immunoglobulins directly isolated from serum (i.e., functionally secreted antibody). Functional analysis of these mAbs demonstrated robust activation of FcγRIIIa associated with antibody binding to recombinant S proteins. Taken together, these findings suggest functionally active NTD-specific mAbs arise frequently during natural infection and can last as major serum clonotypes during convalescence. These antibodies display diverse attributes that include FcγR activation, and may be selected against by mutations in NTD associated with SARS-CoV-2 VOC.

RR:C19 Evidence Scale rating by reviewer:

  • Strong. The main study claims are very well-justified by the data and analytic methods used. There is little room for doubt that the study produced has very similar results and conclusions as compared with the hypothetical ideal study. The study’s main claims should be considered conclusive and actionable without reservation.

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Review: This study examined the frequency of previously reported (Y. Liu et al. Cell 2021; D. Li et al., Cell 2021) SARS-CoV-2 infection-enhancing antibodies targeting the S protein NTD. The authors independently reproduce several key findings in a new group of patients: (1) that the infection-enhancing antibodies constitute a significant fraction of the BCR repertoire in COVID-19 patients; (2) that the mAbs enhance ACE2 binding and virus infection in Expi293 cells but not in cells with lower ACE2 expression; (3) that bivalent binding to the NTD is required for the enhancing effect in cells. The authors also examined the frequency of infection-enhancing antibodies in the serum and performed de-novo LC/MS/MS antibody sequencing (Ig-seq). Through this line of inquiry they the authors argue that enhancing antibodies might have “protective FcγR-effector functions in vivo”, an intriguing idea that would be consistent with the loss of infection-enhancement in recent Omicron variants of concern.

It would be useful to better understand the diversity of the infection-enhancing antibodies identified by the authors and by previous studies (Y. Liu et al. Cell 2021; D. Li et al., Cell 2021), for example by sequence analysis of the complementarity-determining regions (CDRs). That is, when taken together, how many families of these antibodies are known? In a similar vein, I would like to know if the Ig-seq derived mAb sequences are contained within the repertoire sequencing data. I admit to being a bit skeptical that Ig-seq is a robust method to determine antibody sequences, but overlap with single-cell or bulk repertoire data in the same patients would be convincing.

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