Ultrapotent neutralizing antibodies against SARS-CoV-2 with a high degree of mutation resistance

Zou, Jia; Li, Li; Zheng, Pengcheng; Liang, Wenhua; Hu, Shengyong; Zhou, Shuaixiang; Wang, Yanqun; Zhao, Jincun; Yuan, Daopeng; Liu, Lu; Wu, Dongdong; Xu, Maotian; Zhang, Fangfang; Zhu, Mengzhu; Wu, Zhihai; Cao, Xia; Ni, Meng; Ling, Xiaomin; Wu, Yuan; Kuang, Zhihui; Hu, Moyan; Li, Jianfeng; Li, Xue; Guo, Xiling; Xu, Tianmin; Jiang, Haiping; Gao, Changshou; Yu, Michael C.; Liu, Junjian; Zhong, Nanshan; Zhou, Jianfeng; Huang, Jian-An; Jin, Tengchuan; He, Jianxing

doi:10.1172/jci154987

Cited by 15 publications

(15 citation statements)

References 59 publications

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“…Although the somatic hypermutation load per SARS-CoV-2 specific sequence numerically increased in primed participants, it was dramatically boosted by the third vaccination ( Figure 4D ). This was especially observed for BCR sequences encoded by the IGHV3-21, IGHV3-23, IGHV3-53 and IGHV3-30-3 genes ( Figure 4E ) which have been already linked to S-reactive antibodies with exceptional neutralizing potency ( 12 , 35 – 39 ). However, IGHV3-23 is generally mutated more often in unselected B cells of vaccinated and unvaccinated controls ( Supplementary Figure 1 ).…”

Section: Resultsmentioning

confidence: 84%

“…Interestingly, the strong mutational activity was essentially restricted to few lineages that were present and mutated already before the third vaccination and therefore likely involved in previously induced memory B cells that were once again recruited to the lymph node’s germinal center for further refinement. Notably, we observed high mutational rates especially in IGHV3-21, IGHV3-23, IGHV3-53 and IGHV3-30-3 genes that were linked to antibodies isolated from elite neutralizers that have previously shown neutralizing potency against variants of concern after infection with the ancestral strain ( 12 , 35 – 39 ). Interestingly, we did not observe any age-restriction for this maturation process indication that also older people benefit from a third vaccination although this needs further validation due to the limited size of the analyzed cohort.…”

Section: Discussionmentioning

confidence: 86%

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Rapid Hypermutation B Cell Trajectory Recruits Previously Primed B Cells Upon Third SARS-Cov-2 mRNA Vaccination

et al. 2022

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The COVID-19 pandemic shows that vaccination strategies building on an ancestral viral strain need to be optimized for the control of potentially emerging viral variants. Therefore, aiming at strong B cell somatic hypermutation to increase antibody affinity to the ancestral strain - not only at high antibody titers - is a priority when utilizing vaccines that are not targeted at individual variants since high affinity may offer some flexibility to compensate for strain-individual mutations. Here, we developed a next-generation sequencing based SARS-CoV-2 B cell tracking protocol to rapidly determine the level of immunoglobulin somatic hypermutation at distinct points during the immunization period. The percentage of somatically hypermutated B cells in the SARS-CoV-2 specific repertoire was low after the primary vaccination series, evolved further over months and increased steeply after boosting. The third vaccination mobilized not only naïve, but also antigen-experienced B cell clones into further rapid somatic hypermutation trajectories indicating increased affinity. Together, the strongly mutated post-booster repertoires and antibodies deriving from this may explain why the third, but not the primary vaccination series, offers some protection against immune-escape variants such as Omicron B.1.1.529.

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Section: Resultsmentioning

confidence: 84%

Section: Discussionmentioning

confidence: 86%

Rapid Hypermutation B Cell Trajectory Recruits Previously Primed B Cells Upon Third SARS-Cov-2 mRNA Vaccination

et al. 2022

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“…Interestingly, the strong mutational activity was essentially restricted to few lineages that were present and mutated already before the third vaccination and therefore likely involved in previously induced memory B cells that were once again recruited to the lymph node's germinal center for further refinement. Notably, we observed high mutational rates especially in IGHV3-21, IGHV3-23, IGHV3-53 and IGHV3-30-3 genes that were linked to antibodies isolated from elite neutralizers that have previously shown neutralizing potency against variants of concern after infection with the ancestral strain (12,(30)(31)(32)(33)(34). Interestingly, we did not observe any age-restriction for this maturation process indication that also older people benefit from a third vaccination although this needs further validation due to the limited size of the analyzed cohort.…”

Section: Maturation Trajectories In the Primary Vaccination Series An...mentioning

confidence: 88%

“…Although the somatic hypermutation load per SARS-CoV-2 specific sequence numerically increased in primed participants, it was dramatically boosted by the third vaccination (Figure 4D). This was especially observed for BCR sequences encoded by the IGHV3-21, IGHV3-23, IGHV3-53 and IGHV3-30-3 genes (Figure 4E) which have been already linked to S-reactive antibodies with exceptional neutralizing potency (12,(30)(31)(32)(33)(34). The amount of hypermutation did not correlate with age (Figure 4F).…”

Section: Sars-cov-2 Specific B Cell Clonotypes Prior To and After Fir...mentioning

confidence: 93%

Rapid hypermutation B cell trajectory recruits previously primed B cells upon third SARS-CoV-2 mRNA vaccination

Paschold

Klee

Gottschick

et al. 2022

Preprint

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High antibody affinity against the ancestral SARS-CoV-2 strain seems to be necessary (but not always sufficient) for the control of emerging immune-escape variants. Therefore, aiming at strong B cell somatic hypermutation - not only at high antibody titers - is a priority when utilizing vaccines that are not targeted at individual variants. Here, we developed a next-generation sequencing based SARS-CoV-2 B cell tracking protocol to rapidly determine the level of immunoglobulin somatic hypermutation at distinct points during the immunization period. The percentage of somatically hypermutated B cells in the SARS-CoV-2 specific repertoire was low after the primary vaccination series, evolved further over months and increased steeply after boosting. The third vaccination mobilized not only naive, but also antigen-experienced B cell clones into further rapid somatic hypermutation trajectories indicating increased affinity. Together, the strongly mutated post-booster repertoires and antibodies deriving from this may explain why the booster, but not the primary vaccination series, offers some protection against immune-escape variants such as Omicron B.1.1.529.

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“…Hexameric IgG via IgM tailpiece fusion or Fc-Fc interface mutations have been shown to increase CDC function, crosslinking ability of cell surface receptors or SARS-CoV-2 virus neutralization ability 14,15 . Our hexameric IgG-Fc structure provides detail information of the Fc-Fc interaction and guidance for further engineering for therapeutic application of IgG hexamer.…”

Section: Discussionmentioning

confidence: 99%

Structure of IgG-Fc hexamer reveals a mutual lock-and-key mode of Fc-Fc interaction

Yuan¹,

Zhou²,

Ni³

et al. 2022

Preprint

Self Cite

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IgG exists mainly as monomer, but recent studies suggest that IgG forms hexamer to mediate antibody functions. Although many structures of IgG monomer and its fragments are determined, there is no IgG hexamer structure at atomic level due to the weak Fc-Fc interactions. Here we engineered a hexameric IgG with IgM tailpiece fusion and determined the structure by cryo-EM. IgG-Fc hexamer forms hexagon symmetry with the six Fcs lie in a plane with Fc-Fc interaction in a mutual lock-and-key mode. This structure provides structural insights into Fc-Fc interaction of IgG and reveals molecular basis for its function.

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Ultrapotent neutralizing antibodies against SARS-CoV-2 with a high degree of mutation resistance

Cited by 15 publications

References 59 publications

Rapid Hypermutation B Cell Trajectory Recruits Previously Primed B Cells Upon Third SARS-Cov-2 mRNA Vaccination

Rapid Hypermutation B Cell Trajectory Recruits Previously Primed B Cells Upon Third SARS-Cov-2 mRNA Vaccination

Rapid hypermutation B cell trajectory recruits previously primed B cells upon third SARS-CoV-2 mRNA vaccination

Structure of IgG-Fc hexamer reveals a mutual lock-and-key mode of Fc-Fc interaction

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