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TitleClonotype-enriched somatic hypermutations drive affinity maturation of a public human antibody targeting an occluded sarbecovirus epitope.
Journal, issue, pagesCell Rep, Vol. 44, Issue 8, Page 116122, Year 2025
Publish dateAug 26, 2025
AuthorsVishal N Rao / Iden A Sapse / Hallie Cohn / Duck-Kyun Yoo / Pei Tong / Jordan J Clark / Bailey Bozarth / Yuexing Chen / Komal Srivastava / Gagandeep Singh / Florian Krammer / Viviana Simon / Duane R Wesemann / Goran Bajic / Camila H Coelho /
PubMed AbstractInvestigating public antibodies that recognize conserved epitopes is critical for vaccine development. Identifying somatic hypermutations (SHMs) that enhance antigen affinity in these public ...Investigating public antibodies that recognize conserved epitopes is critical for vaccine development. Identifying somatic hypermutations (SHMs) that enhance antigen affinity in these public antibodies is key to guiding vaccine design for better protection against pathogens. We propose that affinity-enhancing SHMs are selectively enriched in public antibody clonotypes, surpassing the background frequency seen in antibodies carrying the same V genes but with different epitope specificities. Using M15, a human IGHV4-59/IGKV3-20 public antibody as a model, we compare SHM signatures in antibodies that use the same V genes but recognize other epitopes. We identified clonotype-enriched mutations in the light chain of M15 and showed that, in combination, these SHMs enhance binding to a previously uncharacterized Sarbecovirus epitope, with antibody responses to it increasing after sequential vaccination. Our findings identify convergence and clonotype enrichment as features of affinity-enhancing SHMs in public antibodies, which can help guide vaccine design aimed at eliciting such antibodies.
External linksCell Rep / PubMed:40803328 / PubMed Central
MethodsEM (single particle)
Resolution3.37 Å
Structure data

48507

9mpw

EMDB-48507, PDB-9mpw:
SARS-CoV2 Spike S2 Subunit in complex with M15 Antibody Fragment
Method: EM (single particle) / Resolution: 3.37 Å

Chemicals

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose

Source
  • homo sapiens (human)
  • severe acute respiratory syndrome coronavirus 2
KeywordsIMMUNE SYSTEM / antibody / affinity maturation / SARS / fAb

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