Deep sequencing of B cell receptor repertoires from COVID-19 patients reveals strong convergent immune signatures

Galson, Jacob D.; Schaetzle, Sebastian; Bashford-Rogers, Rachael; Raybould, Matthew I. J.; Kovaltsuk, Aleksandr; Kilpatrick, Gavin J.; Minter, Ralph; Finch, Donna K.; Dias, Jorge Amil; James, Louisa K.; Thomas, Gavin; Lee, Wing-Yiu Jason; Betley, Jason R.; Cavlan, Olivia; Leech, Alex; Deane, Charlotte; Seoane, Joan; Caldas, Carlos; Pennington, D. J.; Pfeffer, Paul; Osbourn, Jane

doi:10.1101/2020.05.20.106294

Cited by 52 publications

(83 citation statements)

References 40 publications

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“…107 Potently neutralising N specific antibodies were isolated in other studies, 73,109 and the potential for antibodies binding to protease cleavage sites as alternatives to RBD isolated from convalescent plasma has also been identified, 114 population. 115 Strong convergence of response emerged across different participants, which was judged to be associated with disease severity, and these findings were consistent with another high quality study. 87…”

Section: Correlation Of Neutralisation With Specific Antibodiessupporting

confidence: 86%

Antibody response to SARS-CoV-2 infection in humans: a systematic review

Post

Eddy

Huntley

et al. 2020

Preprint

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Introduction Progress in characterising the humoral immune response to Severe Acute Respiratory Syndrome 2 (SARS-CoV-2) has been rapid but areas of uncertainty persist. This review comprehensively evaluated evidence describing the antibody response to SARS-CoV-2 published from 01/01/2020-26/06/2020. Methods Systematic review. Keyword-structured searches were carried out in MEDLINE, Embase and COVID-19 Primer. Articles were independently screened on title, abstract and full text by two researchers, with arbitration of disagreements. Data were double-extracted into a pre-designed template, and studies critically appraised using a modified version of the MetaQAT tool, with resolution of disagreements by consensus. Findings were narratively synthesised. Results 150 papers were included. Most studies (75%) were observational in design, and included papers were generally of moderate quality based on hospitalised patients. Few considered mild or asymptomatic infection. Antibody dynamics were well described in the acute phase, and up to around 3 months from disease onset, although inconsistencies remain concerning clinical correlates. Development of neutralising antibodies following SARS-CoV-2 infection is typical, although titres may be low. Specific and potent neutralising antibodies have been isolated from convalescent plasma. Cross reactivity but limited cross neutralisation occurs with other HCoVs. Evidence for protective immunity in vivo is limited to small, short-term animal studies, which show promising initial results in the immediate recovery phase. Interpretation Published literature on immune responses to SARS-CoV-2 is of variable quality with considerable heterogeneity with regard to methods, study participants, outcomes measured and assays used. Antibody dynamics have been evaluated thoroughly in the acute phase but longer follow up and a comprehensive assessment of the role of demographic characteristics and disease severity is needed. The role of protective neutralising antibodies is emerging, with implications for therapeutics and vaccines. Large, cross-national cohort studies using appropriate statistical analysis and standardised serological assays and clinical classifications should be prioritised.

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Section: Correlation Of Neutralisation With Specific Antibodiessupporting

confidence: 86%

Antibody response to SARS-CoV-2 infection in humans: a systematic review

Post

Eddy

Huntley

et al. 2020

Preprint

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“…Concurrent early production of virus-specific IgM and IgG in the response to SARS-CoV-2 infection suggests a response mediated by IgG MBCs as well as naïve B cells (9,(15)(16)(17). This picture is supported by identification of B cell subsets with high and low immunoglobulin V gene mutation frequencies during the response to SARS-CoV-2 infection (18). However, little direct analysis of SARS-CoV-2-reactive MBCs in unexposed subjects has been performed.…”

Section: Sars-cov-2-reactive Memory B Cells (Mbcs) Generated In B Celmentioning

confidence: 99%

S protein-reactive IgG and memory B cell production after human SARS-CoV-2 infection includes broad reactivity to the S2 subunit

Nguyen-Contant

Embong

Kanagaiah

et al. 2020

Preprint

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The high susceptibility of humans to SARS-CoV-2 infection, the cause of COVID-19, reflects the novelty of the virus and limited preexisting B cell immunity. IgG against the SARS-CoV-2 spike (S) protein, which carries the novel receptor binding domain (RBD), is absent or at low levels in unexposed individuals. To better understand the B cell response to SARS-CoV-2 infection, we asked whether virus-reactive memory B cells (MBCs) were present in unexposed subjects and whether MBC generation accompanied virus-specific IgG production in infected subjects. We analyzed sera and PBMCs from non-SARS-CoV-2-exposed healthy donors and COVID-19 convalescent subjects. Serum IgG levels specific for SARS-CoV-2 proteins (S, including the RBD and S2 subunit, and nucleocapsid [N]) and non-SARS-CoV-2 proteins were related to measurements of circulating IgG MBCs. Anti-RBD IgG was absent in unexposed subjects. Most unexposed subjects had anti-S2 IgG and a minority had anti-N IgG, but IgG MBCs with these specificities were not detected, perhaps reflecting low frequencies. Convalescent subjects had high levels of IgG against the RBD, S2, and N, together with large populations of RBD- and S2-reactive IgG MBCs. Notably, IgG titers against the S protein of the human coronavirus OC43 in convalescent subjects were higher than in unexposed subjects and correlated strongly with anti-S2 titers. Our findings indicate cross-reactive B cell responses against the S2 subunit that might enhance broad coronavirus protection. Importantly, our demonstration of MBC induction by SARS-CoV-2 infection suggests that a durable form of B cell immunity is maintained even if circulating antibody levels wane.IMPORTANCERecent rapid worldwide spread of SARS-CoV-2 has established a pandemic of potentially serious disease in the highly susceptible human population. Key questions are whether humans have preexisting immune memory that provides some protection against SARS-CoV-2 and whether SARS-CoV-2 infection generates lasting immune protection against reinfection. Our analysis focused on pre- and post-infection IgG and IgG memory B cells (MBCs) reactive to SARS-CoV-2 proteins. Most importantly, we demonstrate that infection generates both IgG and IgG MBCs against the novel receptor binding domain and the conserved S2 subunit of the SARS-CoV-2 spike protein. Thus, even if antibody levels wane, long-lived MBCs remain to mediate rapid antibody production. Our study also suggests that SARS-CoV-2 infection strengthens preexisting broad coronavirus protection through S2-reactive antibody and MBC formation.

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“…Concurrent early production of virusspecific IgM and IgG in the response to SARS-CoV-2 infection suggests a response mediated by IgG MBCs as well as by naive B cells (10,(15)(16)(17). This picture is supported by identification of B cell subsets with high and low immunoglobulin V gene mutation frequencies during the response to SARS-CoV-2 infection (18). However, little direct analysis of SARS-CoV-2-reactive MBCs in unexposed subjects has been performed.…”

mentioning

confidence: 99%

S Protein-Reactive IgG and Memory B Cell Production after Human SARS-CoV-2 Infection Includes Broad Reactivity to the S2 Subunit

Nguyen-Contant

Embong

Kanagaiah

et al. 2020

mBio

200

174

View full text Add to dashboard Cite

The high susceptibility of humans to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, the cause of coronavirus disease 2019 (COVID-19), reflects the novelty of the virus and limited preexisting B cell immunity. IgG against the SARS-CoV-2 spike (S) protein, which carries the novel receptor binding domain (RBD), is absent or at low levels in unexposed individuals. To better understand the B cell response to SARS-CoV-2 infection, we asked whether virus-reactive memory B cells (MBCs) were present in unexposed subjects and whether MBC generation accompanied virus-specific IgG production in infected subjects. We analyzed sera and peripheral blood mononuclear cells (PBMCs) from non-SARS-CoV-2-exposed healthy donors and COVID-19 convalescent subjects. Serum IgG levels specific for SARS-CoV-2 proteins (S, including the RBD and S2 subunit, and nucleocapsid [N]) and non-SARS-CoV-2 proteins were related to measurements of circulating IgG MBC levels. Anti-RBD IgG was absent in unexposed subjects. Most unexposed subjects had anti-S2 IgG, and a minority had anti-N IgG, but IgG MBCs with these specificities were not detected, perhaps reflecting low frequencies. Convalescent subjects had high levels of IgG against the RBD, S2, and N, together with large populations of RBD- and S2-reactive IgG MBCs. Notably, IgG titers against the S protein of the human coronavirus OC43 were higher in convalescent subjects than in unexposed subjects and correlated strongly with anti-S2 titers. Our findings indicate cross-reactive B cell responses against the S2 subunit that might enhance broad coronavirus protection. Importantly, our demonstration of MBC induction by SARS-CoV-2 infection suggests that a durable form of B cell immunity is maintained even if circulating antibody levels wane. IMPORTANCE The recent rapid worldwide spread of SARS-CoV-2 has established a pandemic of potentially serious disease in the highly susceptible human population. Key issues are whether humans have preexisting immune memory that provides some protection against SARS-CoV-2 and whether SARS-CoV-2 infection generates lasting immune protection against reinfection. Our analysis focused on pre- and postinfection IgG and IgG memory B cells (MBCs) reactive to SARS-CoV-2 proteins. Most importantly, we demonstrate that infection generates both IgG and IgG MBCs against the novel receptor binding domain and the conserved S2 subunit of the SARS-CoV-2 spike protein. Thus, even if antibody levels wane, long-lived MBCs remain to mediate rapid antibody production. Our study results also suggest that SARS-CoV-2 infection strengthens preexisting broad coronavirus protection through S2-reactive antibody and MBC formation.

show abstract

Deep sequencing of B cell receptor repertoires from COVID-19 patients reveals strong convergent immune signatures

Cited by 52 publications

References 40 publications

Antibody response to SARS-CoV-2 infection in humans: a systematic review

Antibody response to SARS-CoV-2 infection in humans: a systematic review

S protein-reactive IgG and memory B cell production after human SARS-CoV-2 infection includes broad reactivity to the S2 subunit

S Protein-Reactive IgG and Memory B Cell Production after Human SARS-CoV-2 Infection Includes Broad Reactivity to the S2 Subunit

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