Germline IGHV3-53-encoded RBD-targeting neutralizing antibodies are commonly present in the antibody repertoires of COVID-19 patients

Yan, Qihong; He, Ping; Huang, Xiaohan; Luo, Kun; Zhang, Yudi; Yi, Haisu; Wang, Qian; Li, Feng; Hou, Ruitian; Fan, Xiaodi; Li, Pingchao; Liu, Xinglong; Liang, Huan; Deng, Yong-Qiang; Chen, Zhaoming; Chen, Yunfei; Mo, Xiaoneng; Feng, Liqiang; Xiong, Xiaoli; Li, Song; Han, Jian; Qu, Linbing; Niu, Xuefeng; Chen, Ling

doi:10.1080/22221751.2021.1925594

Cited by 29 publications

(50 citation statements)

References 67 publications

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“…We also observed a variable IgG PB response against the RBD early during infection, likely influenced by the heterogeneity in presymptomatic incubation period that led to the detection of RBD-reactive IgG PB at earlier sampling visits. Alternatively, it has been shown that human populations are poised to response to RBD based on multiple studies describing the public IGHV3-53 gene segment being overrepresented in convalescent individuals with the remarkable feature of requiring minimal mutation to achieve high affinity binding [39][40][41][42][43]. Our observation on the SARS-CoV-2-reactive MBCs also showed early formation of the RBD-reactive IgG MBCs, consistent with the notion that RBD-reactive B cells can emerge rapidly following exposure.…”

Section: Discussionsupporting

confidence: 88%

Formation and Expansion of Memory B Cells against Coronavirus in Acutely Infected COVID-19 Individuals

Embong

Nguyen-Contant²,

Wang

et al. 2022

Pathogens

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Infection with the β-coronavirus SARS-CoV-2 typically generates strong virus-specific antibody production. Antibody responses against novel features of SARS-CoV-2 proteins require naïve B cell activation, but there is a growing appreciation that conserved regions are recognized by pre-existing memory B cells (MBCs) generated by endemic coronaviruses. The current study investigated the role of pre-existing cross-reactive coronavirus memory in the antibody response to the viral spike (S) and nucleocapsid (N) proteins following SARS-CoV-2 infection. The breadth of reactivity of circulating antibodies, plasmablasts, and MBCs was analyzed. Acutely infected subjects generated strong IgG responses to the S protein, including the novel receptor binding domain, the conserved S2 region, and to the N protein. The response included reactivity to the S of endemic β-coronaviruses and, interestingly, to the N of an endemic α-coronavirus. Both mild and severe infection expanded IgG MBC populations reactive to the S of SARS-CoV-2 and endemic β-coronaviruses. Avidity of S-reactive IgG antibodies and MBCs increased after infection. Overall, findings indicate that the response to the S and N of SARS-CoV-2 involves pre-existing MBC activation and adaptation to novel features of the proteins, along with the potential of imprinting to shape the response to SARS-CoV-2 infection.

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Section: Discussionsupporting

confidence: 88%

Formation and Expansion of Memory B Cells against Coronavirus in Acutely Infected COVID-19 Individuals

Embong

Nguyen-Contant²,

Wang

et al. 2022

Pathogens

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“…For OD values greater than 4, a value of 4 is assigned. Furthermore, we have compared the binding of WT, N501Y and N501Y-E484K RBD with a SARS-CoV-2 human antibody which was produced as previously described with modifications [26] . Briefly, SARS-CoV-2 RBD-specific memory B cells were sorted by multi-laser AriaII sorter (BD Biosciences, New Jersey, USA) from SARS-CoV-2 infected individuals.…”

Section: Methodsmentioning

confidence: 99%

The impact of spike N501Y mutation on neutralizing activity and RBD binding of SARS-CoV-2 convalescent serum

Lu¹,

Chu²,

Zhang³

et al. 2021

eBioMedicine

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Background Several SARS-CoV-2 lineages with spike receptor binding domain (RBD) N501Y mutation have spread globally. We evaluated the impact of N501Y on neutralizing activity of COVID-19 convalescent sera and on anti-RBD IgG assays. Methods The susceptibility to neutralization by COVID-19 patients’ convalescent sera from Hong Kong were compared between two SARS-CoV-2 isolates (B117-1/B117-2) from the α variant with N501Y and 4 non-N501Y isolates. The effect of N501Y on antibody binding was assessed. The performance of commercially-available IgG assays was determined for patients infected with N501Y variants. Findings The microneutralization antibody (MN) titers of convalescent sera from 9 recovered COVID-19 patients against B117-1 (geometric mean titer[GMT],80; 95% CI, 47–136) were similar to those against the non-N501Y viruses. However, MN titer of these serum against B117-2 (GMT, 20; 95% CI, 11–36) was statistically significantly reduced when compared with non-N501Y viruses (P < 0.01; one-way ANOVA). The difference between B117-1 and B117-2 was confirmed by testing 60 additional convalescent sera. B117-1 and B117-2 differ by only 3 amino acids (nsp2-S512Y, nsp13-K460R, spike-A1056V). Enzyme immunoassay using 272 convalescent sera showed reduced binding of anti-RBD IgG to N501Y or N501Y-E484K-K417N when compared with that of wild-type RBD (mean difference: 0.1116 and 0.5613, respectively; one-way ANOVA). Of 7 anti-N-IgG positive sera from patients infected with N501Y variants (collected 9-14 days post symptom onset), 6 (85.7%) tested negative for a commercially-available anti-S1-IgG assay. Interpretation We highlighted the importance of using a panel of viruses within the same lineage to determine the impact of virus variants on neutralization. Furthermore, clinicians should be aware of the potential reduced sensitivity of anti-RBD IgG assays.

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“…The dynamic of antibody responses induced by SARS-CoV-2 infection requires more systematic and in-depth research on a larger cohort over a longer period. Antibodies identified from these shared spike-specific clusters possess binding and neutralizing activities, as demonstrated in our recent report that synthesized a repertoire-deduced IGHV3-53-encoded heavy chain paired with a common IGKV1-9 light chain were successfully expressed in transfected HEK293 cells and showed RBD binding and virus-neutralizing activities ( 82 ).…”

Section: Discussionmentioning

confidence: 82%

“…This study identified 13 shared clusters that were highly relevant with known neutralizing antibodies isolated from COVID-19 patients. Recent reports showed that IGHV3-53 and IGHV3-30 encode convergent antibodies targeting the RBD of spike protein ( 5 , 72 , 80 – 82 ). These results supported that SARS-CoV-2 induced convergent antibody response across different patients, which can be identified by querying antibody sequencing repertoires.…”

Section: Discussionmentioning

confidence: 99%

Analysis of B Cell Receptor Repertoires Reveals Key Signatures of the Systemic B Cell Response after SARS-CoV-2 Infection

Zhang

Yan

Luo

et al. 2022

J Virol

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A comprehensive study of the B cell response against SARS-CoV-2 could be significant for understanding the immune response and developing therapeutical antibodies and vaccines. To define the dynamics and characteristics of the antibody repertoire following SARS-CoV-2 infection, we analyzed the mRNA transcripts of immunoglobulin heavy chain (IgH) repertoires of 24 peripheral blood samples collected between 3 and 111 days after symptom onset from 10 COVID-19 patients. Massive clonal expansion of naïve B cells with limited somatic hypermutation (SHM) was observed in the second week after symptom onset. The proportion of low-SHM IgG clones strongly correlated with spike-specific IgG antibody titers, highlighting the significant activation of naïve B cells in response to a novel virus infection. The antibody isotype switching landscape showed a transient IgA surge in the first week after symptom onset, followed by a sustained IgG elevation that lasted for at least 3 months. SARS-CoV-2 infection elicited poly-germline reactive antibody responses. Interestingly, 17 different IGHV germline genes recombined with IGHJ6 showed significant clonal expansion. By comparing the IgH repertoires that we sequenced with the 774 reported SARS-CoV-2–reactive monoclonal antibodies (mAbs), 13 shared spike-specific IgH clusters were found. These shared spike-specific IgH clusters are derived from the same lineage of several recently published neutralizing mAbs, including CC12.1, CC12.3, C102, REGN10977, and 4A8. Furthermore, identical spike-specific IgH sequences were found in different COVID-19 patients, suggesting a highly convergent antibody response to SARS-CoV-2. Our analysis based on sequencing antibody repertoires from different individuals revealed key signatures of the systemic B cell response induced by SARS-CoV-2 infection. IMPORTANCE Although the canonical delineation of serum antibody responses following SARS-CoV-2 infection has been well established, the dynamics of antibody repertoire at the mRNA transcriptional level has not been well understood, especially the correlation between serum antibody titers and the antibody mRNA transcripts. In this study, we analyzed the IgH transcripts and characterized the B cell clonal expansion and differentiation, isotype switching, and somatic hypermutation in COVID-19 patients. This study provided insights at the repertoire level for the B cell response after SARS-CoV-2 infection.

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Germline IGHV3-53-encoded RBD-targeting neutralizing antibodies are commonly present in the antibody repertoires of COVID-19 patients

Cited by 29 publications

References 67 publications

Formation and Expansion of Memory B Cells against Coronavirus in Acutely Infected COVID-19 Individuals

Formation and Expansion of Memory B Cells against Coronavirus in Acutely Infected COVID-19 Individuals

The impact of spike N501Y mutation on neutralizing activity and RBD binding of SARS-CoV-2 convalescent serum

Analysis of B Cell Receptor Repertoires Reveals Key Signatures of the Systemic B Cell Response after SARS-CoV-2 Infection

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