Evidence map›Paper›PMID 40909599›Full record

ArticlebioRxiv : the preprint server for biology2025

Affinity Maturation and Light-Chain-Mediated Paratope Diversification Anticipate Viral Evolution.

John Dingus, Duck-Kyun Yoo, Sachin Kumar, Yajuan Wang, Md Golam Kibria, Shahab Saghei, Zahra Allahyari, Jessica W Chen, Natalie M Caputo, Jason Hwang and 2 more

Abstract readPreprint
PubMed Full text at PMC Publisher
In one paragraph

Article in bioRxiv : the preprint server for biology, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.

0numbers the graph read from it
0cells of the map it votes in
0citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

0 citing papers in PubMed.

No citing paper in PubMed yet.

4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

12 authors.

John DingusDepartment of Medicine, Division of Allergy and Clinical Immunology, Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA, Broad Institute of MIT, and Harvard, Cambridge, MA 02139, USA, Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA 02139, USA.
Duck-Kyun YooDepartment of Medicine, Division of Allergy and Clinical Immunology, Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA, Broad Institute of MIT, and Harvard, Cambridge, MA 02139, USA, Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA 02139, USA.
Sachin KumarDepartment of Medicine, Division of Allergy and Clinical Immunology, Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA, Broad Institute of MIT, and Harvard, Cambridge, MA 02139, USA, Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA 02139, USA.
Yajuan WangDivision of Molecular Medicine, Boston Children's Hospital, and Department of Pediatrics, Harvard Medical School, Boston, MA, USA.
Md Golam KibriaDivision of Molecular Medicine, Boston Children's Hospital, and Department of Pediatrics, Harvard Medical School, Boston, MA, USA.
Shahab SagheiDepartment of Medicine, Division of Allergy and Clinical Immunology, Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA, Broad Institute of MIT, and Harvard, Cambridge, MA 02139, USA, Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA 02139, USA.
Zahra AllahyariDepartment of Medicine, Division of Allergy and Clinical Immunology, Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA, Broad Institute of MIT, and Harvard, Cambridge, MA 02139, USA, Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA 02139, USA.
Jessica W ChenDepartment of Medicine, Division of Allergy and Clinical Immunology, Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA, Broad Institute of MIT, and Harvard, Cambridge, MA 02139, USA, Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA 02139, USA.
Natalie M CaputoDepartment of Medicine, Division of Allergy and Clinical Immunology, Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA, Broad Institute of MIT, and Harvard, Cambridge, MA 02139, USA, Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA 02139, USA.
Jason HwangDepartment of Medicine, Division of Allergy and Clinical Immunology, Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA, Broad Institute of MIT, and Harvard, Cambridge, MA 02139, USA, Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA 02139, USA.
Bing ChenDivision of Molecular Medicine, Boston Children's Hospital, and Department of Pediatrics, Harvard Medical School, Boston, MA, USA.
Duane R WesemannDepartment of Medicine, Division of Allergy and Clinical Immunology, Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA, Broad Institute of MIT, and Harvard, Cambridge, MA 02139, USA, Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA 02139, USA.ORCID 0000-0002-6690-944X

Funding

Technology and Computational CoreP01AI165072 · NIAID · BRIGHAM AND WOMEN'S HOSPITAL · PI WESEMANN, DUANE R. · 2021 to 2023
$19.6M
MECHANISMS OF ARTHRITIC &DERMATOLOGY DISORDERST32AR007530 · NIAMS · BRIGHAM AND WOMEN'S HOSPITAL · PI Michael B. Brenner, Ellen M Gravallese · 1986 to 2026
$10.4M
Flipped Germinal CentersR01AI169619 · NIAID · BRIGHAM AND WOMEN'S HOSPITAL · PI WESEMANN, DUANE R. · 2021 to 2025
$3.7M
Antibody Durability DynamicsR01AI170715 · NIAID · BRIGHAM AND WOMEN'S HOSPITAL · PI Duane R. Wesemann · 2022 to 2026
$3.4M
Elucidating Germinal Center-Mediated Antibody EvolutionR01AI139538 · NIAID · BRIGHAM AND WOMEN'S HOSPITAL · PI WESEMANN, DUANE R. · 2019 to 2022
$2.4M
Structural and functional integrity of antigen receptorsF31AI186232 · NIAID · HARVARD MEDICAL SCHOOL · PI Jessica WT Chen · 2024 to 2026
$119k
NIAID NIH HHS F31 AI186232NIAID NIH HHS P01 AI165072NIAID NIH HHS R01 AI139538NIAID NIH HHS R01 AI169619NIAID NIH HHS R01 AI170715NIAMS NIH HHS T32 AR007530
6 · The paper itself

Abstract

A key goal of vaccinology is to train the immune system to combat current pathogens while simultaneously preparing it for future evolved variants. Understanding factors contributing to anticipatory breadth, wherein affinity maturation against an ancestral strain yields neutralization capacity against evolved variants, is therefore of great importance. Here, we investigated the mechanism of anticipatory breadth development in a public antibody family targeting the functionally restricted ACE2 binding site on SARS-CoV-2. IGHV3-53/66 antibodies isolated from memory B cells of infection-naïve individuals vaccinated with the ancestral Wuhan-strain mRNA vaccine frequently neutralized evolved Omicron variants and contained several hallmark mutations previously shown to enhance neutralization breadth. Comparative analyses with antibodies from Omicron breakthrough infections revealed that breadth-associated patterns of somatic hypermutation emerged independently of variant exposure. However, Omicron infection had a marked impact on light chain pairing frequencies, suggestive of variant-imposed selection of favorable light chains. Analysis of available IGHV3-53/66 antibody structures complexed with SARS-CoV-2 receptor binding domain (RBD) clarified these findings; convergent somatic mutations on the heavy chain largely refined contacts with invariant RBD residues, while light chain pairings shifted epitopes to avoid steric challenges posed by Omicron mutations. These findings support a model of anticipatory breadth with three key elements: (1) targeting of a functionally restricted epitope, (2) affinity maturation to establish an affinity buffer, and (3) variable chain pairing to generate paratope diversity. These elements each serve to compensate for a distinct consequence of viral mutagenesis, offering a mechanistic framework for anticipating viral evolution.

Identifiers

PMID40909599
PMCPMC12407817

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.