Prolonged evolution of the human B cell response to SARS-CoV-2 infection

A comprehensive understanding of the kinetics and evolution of the human B cell response to SARS-CoV-2 infection will facilitate the development of next-generation vaccines and therapies. Here, we longitudinally profiled this response in mild and severe COVID-19 patients over a period of five months. Serum neutralizing antibody (nAb) responses waned rapidly but spike (S)-specific IgG+ memory B cells (MBCs) remained stable or increased over time. Analysis of 1,213 monoclonal antibodies (mAbs) isolated from S-specific MBCs revealed a primarily de novo response that displayed increased somatic hypermutation, binding affinity, and neutralization potency over time, providing evidence for prolonged antibody affinity maturation. B cell immunodominance hierarchies were similar across donor repertoires and remained relatively stable as the immune response progressed. Cross-reactive B cell populations, likely re-called from prior endemic beta-coronavirus exposures, comprised a small but stable fraction of the repertoires and did not contribute to the neutralizing response. The neutralizing antibody response was dominated by public clonotypes that displayed significantly reduced activity against SARS-CoV-2 variants emerging in Brazil and South Africa that harbor mutations at positions 501, 484 and 417 in the S protein. Overall, the results provide insight into the dynamics, durability, and functional properties of the human B cell response to SARS-CoV-2 infection and have implications for the design of immunogens that preferentially stimulate protective B cell responses.

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Longitudinal dynamics of the human B cell response to the yellow fever 17D vaccine

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1921388117 ◽

2020 ◽

Vol 117 (12) ◽

pp. 6675-6685 ◽

Cited By ~ 17

Author(s):

Anna Z. Wec ◽

Denise Haslwanter ◽

Yasmina N. Abdiche ◽

Laila Shehata ◽

Nuria Pedreño-Lopez ◽

...

Keyword(s):

B Cell ◽

Yellow Fever ◽

Cell Response ◽

Affinity Maturation ◽

Immunoglobulin M ◽

Viral Envelope ◽

Cell Responses ◽

B Cell Responses ◽

Human B Cell ◽

B Cell Response

A comprehensive understanding of the development and evolution of human B cell responses induced by pathogen exposure will facilitate the design of next-generation vaccines. Here, we utilized a high-throughput single B cell cloning technology to longitudinally track the human B cell response to the yellow fever virus 17D (YFV-17D) vaccine. The early memory B cell (MBC) response was mediated by both classical immunoglobulin M (IgM) (IgM+CD27+) and switched immunoglobulin (swIg+) MBC populations; however, classical IgM MBCs waned rapidly, whereas swIg+and atypical IgM+and IgD+MBCs were stable over time. Affinity maturation continued for 6 to 9 mo following vaccination, providing evidence for the persistence of germinal center activity long after the period of active viral replication in peripheral blood. Finally, a substantial fraction of the neutralizing antibody response was mediated by public clones that recognize a fusion loop-proximal antigenic site within domain II of the viral envelope glycoprotein. Overall, our findings provide a framework for understanding the dynamics and complexity of human B cell responses elicited by infection and vaccination.

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Phenotypic and Functional Characterisation of Human B-cell Response in Pemphigus

Case Medical Research ◽

10.31525/ct1-nct04117529 ◽

2019 ◽

Author(s):

Keyword(s):

B Cell ◽

Cell Response ◽

Functional Characterisation ◽

Human B Cell ◽

B Cell Response

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The kinetics and phenotype of the human B-cell response following immunization with a heptavalent pneumococcal-CRM197conjugate vaccine

Immunology ◽

10.1111/j.1365-2567.2006.02436.x ◽

2006 ◽

Vol 119 (3) ◽

pp. 328-337 ◽

Cited By ~ 36

Author(s):

Elizabeth A. Clutterbuck ◽

Penny Salt ◽

Sarah Oh ◽

Arnaud Marchant ◽

Peter Beverley ◽

...

Keyword(s):

B Cell ◽

Cell Response ◽

Human B Cell ◽

B Cell Response

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Distinct clonal evolution of B-cells in HIV controllers with neutralizing antibody breadth

eLife ◽

10.7554/elife.62648 ◽

2021 ◽

Vol 10 ◽

Author(s):

Deniz Cizmeci ◽

Giuseppe Lofano ◽

Evan Rossignol ◽

Anne-Sophie Dugast ◽

Dongkyoon Kim ◽

...

Keyword(s):

B Cells ◽

B Cell ◽

Somatic Hypermutation ◽

Clonal Evolution ◽

Neutralizing Antibody ◽

Affinity Maturation ◽

Gene Repertoire ◽

Immunoglobulin Gene ◽

Hiv Controllers ◽

Hiv 1

A minor subset of individuals infected with HIV-1 develop antibody neutralization breadth during the natural course of the infection, often linked to chronic, high-level viremia. Despite significant efforts, vaccination strategies have been unable to induce similar neutralization breadth and the mechanisms underlying neutralizing antibody induction remain largely elusive. Broadly neutralizing antibody responses can also be found in individuals who control HIV to low and even undetectable plasma levels in the absence of antiretroviral therapy, suggesting that high antigen exposure is not a strict requirement for neutralization breadth. We therefore performed an analysis of paired heavy and light chain B-cell receptor (BCR) repertoires in 12,591 HIV-1 envelope-specific single memory B-cells to determine alterations in the BCR immunoglobulin gene repertoire and B-cell clonal expansions that associate with neutralizing antibody breadth in 22 HIV controllers. We found that the frequency of genomic mutations in IGHV and IGLV was directly correlated with serum neutralization breadth. The repertoire of the most mutated antibodies was dominated by a small number of large clones with evolutionary signatures suggesting that these clones had reached peak affinity maturation. These data demonstrate that even in the setting of low plasma HIV antigenemia, similar to what a vaccine can potentially achieve, BCR selection for extended somatic hypermutation and clonal evolution can occur in some individuals suggesting that host-specific factors might be involved that could be targeted with future vaccine strategies.

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SARS-CoV-2 spike-specific memory B cells express higher levels of T-bet and FcRL5 after non-severe COVID-19 as compared to severe disease

PLoS ONE ◽

10.1371/journal.pone.0261656 ◽

2021 ◽

Vol 16 (12) ◽

pp. e0261656

Author(s):

Raphael A. Reyes ◽

Kathleen Clarke ◽

S. Jake Gonzales ◽

Angelene M. Cantwell ◽

Rolando Garza ◽

...

Keyword(s):

B Cells ◽

B Cell ◽

Symptom Onset ◽

Cell Response ◽

Severe Disease ◽

Memory B Cells ◽

Memory B Cell ◽

Specific Memory ◽

Specific Igg ◽

B Cell Response

SARS-CoV-2 infection elicits a robust B cell response, resulting in the generation of long-lived plasma cells and memory B cells. Here, we aimed to determine the effect of COVID-19 severity on the memory B cell response and characterize changes in the memory B cell compartment between recovery and five months post-symptom onset. Using high-parameter spectral flow cytometry, we analyzed the phenotype of memory B cells with reactivity against the SARS-CoV-2 spike protein or the spike receptor binding domain (RBD) in recovered individuals who had been hospitalized with non-severe (n = 8) or severe (n = 5) COVID-19. One month after symptom onset, a substantial proportion of spike-specific IgG+ B cells showed an activated phenotype. In individuals who experienced non-severe disease, spike-specific IgG+ B cells showed increased expression of markers associated with durable B cell memory, including T-bet and FcRL5, as compared to individuals who experienced severe disease. While the frequency of T-bet+ spike-specific IgG+ B cells differed between the two groups, these cells predominantly showed an activated switched memory B cell phenotype in both groups. Five months post-symptom onset, the majority of spike-specific memory B cells had a resting phenotype and the percentage of spike-specific T-bet+ IgG+ memory B cells decreased to baseline levels. Collectively, our results highlight subtle differences in the B cells response after non-severe and severe COVID-19 and suggest that the memory B cell response elicited during non-severe COVID-19 may be of higher quality than the response after severe disease.

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Prolonged evolution of the memory B cell response induced by a replicating adenovirus-influenza H5 vaccine

Science Immunology ◽

10.1126/sciimmunol.aau2710 ◽

2019 ◽

Vol 4 (34) ◽

pp. eaau2710 ◽

Cited By ~ 16

Author(s):

Kenta Matsuda ◽

Jinghe Huang ◽

Tongqing Zhou ◽

Zizhang Sheng ◽

Byong H. Kang ◽

...

Keyword(s):

B Cell ◽

Specific Antibody ◽

Cell Response ◽

Somatic Hypermutation ◽

Adenovirus Type ◽

Antigen Receptors ◽

Active Viral Replication ◽

Boost Vaccine ◽

Induced Immunity ◽

B Cell Response

Induction of an antibody response capable of recognizing highly diverse strains is a major obstacle to the development of vaccines for viruses such as HIV and influenza. Here, we report the dynamics of B cell expansion and evolution at the single-cell level after vaccination with a replication-competent adenovirus type 4 recombinant virus expressing influenza H5 hemagglutinin. Fluorescent H1 or H5 probes were used to quantitate and isolate peripheral blood B cells and their antigen receptors. We observed increases in H5-specific antibody somatic hypermutation and potency for several months beyond the period of active viral replication that was not detectable at the serum level. Individual broad and potent antibodies could be isolated, including one stem-specific antibody that is part of a new multidonor class. These results demonstrate prolonged evolution of the B cell response for months after vaccination and should be considered in efforts to evaluate or boost vaccine-induced immunity.

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