» Articles » PMID: 38793718

The D Gene in CDR H3 Determines a Public Class of Human Antibodies to SARS-CoV-2

Overview
Date 2024 May 25
PMID 38793718
Authors
Affiliations
Soon will be listed here.
Abstract

Public antibody responses have been found against many infectious agents. Structural convergence of public antibodies is usually determined by immunoglobulin V genes. Recently, a human antibody public class against SARS-CoV-2 was reported, where the D gene (IGHD3-22) encodes a common YYDxxG motif in heavy-chain complementarity-determining region 3 (CDR H3), which determines specificity for the receptor-binding domain (RBD). In this review, we discuss the isolation, structural characterization, and genetic analyses of this class of antibodies, which have been isolated from various cohorts of COVID-19 convalescents and vaccinees. All eleven YYDxxG antibodies with available structures target the SARS-CoV-2 RBD in a similar binding mode, where the CDR H3 dominates the interaction with antigen. The antibodies target a conserved site on the RBD that does not overlap with the receptor-binding site, but their particular angle of approach results in direct steric hindrance to receptor binding, which enables both neutralization potency and breadth. We also review the properties of CDR H3-dominant antibodies that target other human viruses. Overall, unlike most public antibodies, which are identified by their V gene usage, this newly discovered public class of YYDxxG antibodies is dominated by a D-gene-encoded motif and uncovers further opportunities for germline-targeting vaccine design.

Citing Articles

Retrospective SARS-CoV-2 human antibody development trajectories are largely sparse and permissive.

Kirby M, Petersen B, Faris J, Kells S, Sprenger K, Whitehead T Proc Natl Acad Sci U S A. 2025; 122(4):e2412787122.

PMID: 39841142 PMC: 11789010. DOI: 10.1073/pnas.2412787122.


Cross-reactive sarbecovirus antibodies induced by mosaic RBD-nanoparticles.

Fan C, Keeffe J, Malecek K, Cohen A, West A, West Jr A bioRxiv. 2025; .

PMID: 39803445 PMC: 11722225. DOI: 10.1101/2025.01.02.631145.


Structural Immunology of SARS-CoV-2.

Yuan M, Wilson I Immunol Rev. 2024; 329(1):e13431.

PMID: 39731211 PMC: 11727448. DOI: 10.1111/imr.13431.

References
1.
Barba-Spaeth G, Dejnirattisai W, Rouvinski A, Vaney M, Medits I, Sharma A . Structural basis of potent Zika-dengue virus antibody cross-neutralization. Nature. 2016; 536(7614):48-53. DOI: 10.1038/nature18938. View

2.
Stadlbauer D, Zhu X, McMahon M, Turner J, Wohlbold T, Schmitz A . Broadly protective human antibodies that target the active site of influenza virus neuraminidase. Science. 2019; 366(6464):499-504. PMC: 7105897. DOI: 10.1126/science.aay0678. View

3.
Liu L, Iketani S, Guo Y, Reddem E, Casner R, Nair M . An antibody class with a common CDRH3 motif broadly neutralizes sarbecoviruses. Sci Transl Med. 2022; 14(646):eabn6859. PMC: 9017343. DOI: 10.1126/scitranslmed.abn6859. View

4.
Ekiert D, Kashyap A, Steel J, Rubrum A, Bhabha G, Khayat R . Cross-neutralization of influenza A viruses mediated by a single antibody loop. Nature. 2012; 489(7417):526-32. PMC: 3538848. DOI: 10.1038/nature11414. View

5.
Sakharkar M, Rappazzo C, Wieland-Alter W, Hsieh C, Wrapp D, Esterman E . Prolonged evolution of the human B cell response to SARS-CoV-2 infection. Sci Immunol. 2021; 6(56). PMC: 8128290. DOI: 10.1126/sciimmunol.abg6916. View