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In this study, we investigated the monoclonal antibody responses elicited by wild-type SARS-CoV-2 inactivated vaccination compared to those elicited by natural infection and mRNA vaccination. The analysis showed that antibodies encoded by biased germline genes were shared between SARS-CoV-2 vaccinated and naturally infected individuals. Among the 35 shared clonotypes identified, besides the well-known IGHV3-53 and IGHV1-58, we identified a class of IGHV4-59 antibodies characterized by rapid response and neutralizing activity, elicited by 3 doses of inactivated vaccine. Members of this lineage exhibited similar sensitivity against wild-type SARS-CoV-2, whereas different neutralizing activities against SARS-CoV-2 variants, especially against various Omicron subvariants, BA.1, BA.2, BA.2.12.1, BA.4\/5, and BA.2.75. Structural analysis of BA.1 spike complexed with VacBB-639 revealed that the IGHV4-59-lineage antibodies belonged to the Class 2\/3 group. Using sequence alignment, site-mutation assays, and functional verification, we identified two substitutions, N60K in HFR3 and S56G in HCDR2, contributing to opposite neutralization changes of IGHV4-59-lineage antibodies against these Omicron subvariants. These results demonstrate the importance of somatic hypermutation in the evolution of prototypical antigen-elicited antibodies in terms of their neutralization breadth and potency against SARS-CoV-2 Omicron variants.<\/jats:p>","DOI":"10.1093\/jimmun\/vkae056","type":"journal-article","created":{"date-parts":[[2025,2,24]],"date-time":"2025-02-24T15:44:47Z","timestamp":1740411887000},"page":"278-289","source":"Crossref","is-referenced-by-count":3,"title":["Rapid clonal expansion and somatic hypermutation contribute to the fate of SARS-CoV-2 broadly neutralizing antibodies"],"prefix":"10.1093","volume":"214","author":[{"given":"Miao","family":"Wang","sequence":"first","affiliation":[{"name":"Institute for Hepatology, National Clinical Research Center for Infectious Disease, Shenzhen Third People\u2019s Hospital, The Second Affiliated Hospital, School of Medicine, Southern University of Science and Technology , Shenzhen, Guangdong 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Hepatology, National Clinical Research Center for Infectious Disease, Shenzhen Third People\u2019s Hospital, The Second Affiliated Hospital, School of Medicine, Southern University of Science and Technology , Shenzhen, Guangdong Province,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shilong","family":"Tang","sequence":"additional","affiliation":[{"name":"Institute for Hepatology, National Clinical Research Center for Infectious Disease, Shenzhen Third People\u2019s Hospital, The Second Affiliated Hospital, School of Medicine, Southern University of Science and Technology , Shenzhen, Guangdong Province,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Huimin","family":"Guo","sequence":"additional","affiliation":[{"name":"Institute for Hepatology, National Clinical Research Center for Infectious Disease, Shenzhen Third People\u2019s Hospital, The Second Affiliated Hospital, School of Medicine, Southern University of Science and Technology , Shenzhen, Guangdong Province,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bing","family":"Zhou","sequence":"additional","affiliation":[{"name":"Institute for Hepatology, National Clinical Research Center for Infectious Disease, Shenzhen Third People\u2019s Hospital, The Second Affiliated Hospital, School of Medicine, Southern University of Science and Technology , Shenzhen, Guangdong Province,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Haiyan","family":"Wang","sequence":"additional","affiliation":[{"name":"Institute for Hepatology, National Clinical Research Center for Infectious Disease, Shenzhen Third People\u2019s Hospital, The Second Affiliated Hospital, School of Medicine, Southern University of Science and Technology , Shenzhen, Guangdong Province,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiangyang","family":"Ge","sequence":"additional","affiliation":[{"name":"Institute for Hepatology, National Clinical Research Center for Infectious Disease, Shenzhen Third People\u2019s Hospital, The Second Affiliated Hospital, School of Medicine, Southern University of Science and Technology , Shenzhen, Guangdong Province,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3544-1389","authenticated-orcid":false,"given":"Zheng","family":"Zhang","sequence":"additional","affiliation":[{"name":"Institute for Hepatology, National Clinical Research Center for Infectious Disease, Shenzhen Third People\u2019s Hospital, The Second Affiliated Hospital, School of Medicine, Southern University of Science and Technology , Shenzhen, Guangdong Province,","place":["China"]},{"name":"Guangdong Key Laboratory for Anti-infection Drug Quality Evaluation , Shenzhen, Guangdong Province,","place":["China"]},{"name":"Shenzhen Research Center for Communicable Disease Diagnosis and Treatment, Chinese Academy of Medical Sciences , Shenzhen, Guangdong Province,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bin","family":"Ju","sequence":"additional","affiliation":[{"name":"Institute for Hepatology, National Clinical Research Center for Infectious Disease, Shenzhen Third People\u2019s Hospital, The Second Affiliated Hospital, School of Medicine, Southern University of Science and Technology , Shenzhen, Guangdong Province,","place":["China"]},{"name":"Guangdong Key Laboratory for Anti-infection Drug Quality Evaluation , Shenzhen, Guangdong 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