tetano
Editor, Senior Moderator
J Immunol
. 2025 Feb 1;214(2):278-289.
doi: 10.1093/jimmun/vkae056. Rapid clonal expansion and somatic hypermutation contribute to the fate of SARS-CoV-2 broadly neutralizing antibodies
Miao Wang[SUP] 1 [/SUP], Congcong Liu[SUP] 1 [/SUP], Qing Fan[SUP] 1 [/SUP], Yuehong Sun[SUP] 1 [/SUP], Shilong Tang[SUP] 1 [/SUP], Huimin Guo[SUP] 1 [/SUP], Bing Zhou[SUP] 1 [/SUP], Haiyan Wang[SUP] 1 [/SUP], Xiangyang Ge[SUP] 1 [/SUP], Zheng Zhang[SUP] 1 2 3 [/SUP], Bin Ju[SUP] 1 2 [/SUP]
Affiliations
Several vaccines and immunization strategies, including inactivated vaccines, have proven effective in eliciting antibodies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), providing an opportunity to characterize the antibody response. 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.
Keywords: IGHV4-59 antibody; SARS-CoV-2; neutralizing activity; rapid clonal expansion; somatic hypermutation.
. 2025 Feb 1;214(2):278-289.
doi: 10.1093/jimmun/vkae056. Rapid clonal expansion and somatic hypermutation contribute to the fate of SARS-CoV-2 broadly neutralizing antibodies
Miao Wang[SUP] 1 [/SUP], Congcong Liu[SUP] 1 [/SUP], Qing Fan[SUP] 1 [/SUP], Yuehong Sun[SUP] 1 [/SUP], Shilong Tang[SUP] 1 [/SUP], Huimin Guo[SUP] 1 [/SUP], Bing Zhou[SUP] 1 [/SUP], Haiyan Wang[SUP] 1 [/SUP], Xiangyang Ge[SUP] 1 [/SUP], Zheng Zhang[SUP] 1 2 3 [/SUP], Bin Ju[SUP] 1 2 [/SUP]
Affiliations
- PMID: 40073246
- DOI: 10.1093/jimmun/vkae056
Several vaccines and immunization strategies, including inactivated vaccines, have proven effective in eliciting antibodies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), providing an opportunity to characterize the antibody response. 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.
Keywords: IGHV4-59 antibody; SARS-CoV-2; neutralizing activity; rapid clonal expansion; somatic hypermutation.