Biology subjects

Gazumyan, A.

Publications and source records attributed to Gazumyan, A..

At least 19 recordsLinked to original sources

bioRxiv2026

Biophysical properties of IgD determine thresholds for self-tolerance and selection into germinal centers

Immunoglobulin D (IgD) is among the most conserved antibody isotypes, found in virtually all jawed vertebrates1. Unlike other isotypes, IgD contains an unusually long hinge region of up to 160 amino acids that connects the constant and variable regions. Its expression pattern is also conserved; IgD is co-expressed with IgM on transitional and mature naive B cells. However, the function of IgD has remained enigmatic since its discovery in 19652,3. Here we present and test a biophysical model positing that IgD increases the entropic cost of bivalent antigen binding. Single-molecule measurements revealed that the antigen-binding arms of IgD are substantially more dynamic than those of IgM, suggesting that cell surface IgD would be energetically penalized in bivalent antigen binding. Consistent with the model and biophysical data, we find that the long hinge compromises antigen capture by IgD B cell receptors (BCRs) compared to IgM BCRs. To determine how the difference in antigen binding impacts immunity, we produced mice that express only IgM and IgD, exclusively IgM or IgD, or IgD with a truncated hinge region. The data indicate that the increased entropic cost of antigen binding imposed by the IgD hinge attenuates negative selection by self-antigen while increasing the affinity-based threshold for positive selection into the germinal center (GC). Together the results indicate that IgD functions physiologically to desensitize B cells to antigen, thereby expanding the B cell repertoire while optimizing affinity-based selection into the GC.

immunology↗

bioRxiv2026

Fc receptor dependent and independent mechanisms of antibody-mediatedenhancement of immune responses

Immune memory responses are rapid and qualitatively distinct from primary responses. They typically develop in the presence of antigen-experienced memory T and B cells and pre-existing antibodies. Although the contribution of T and B cells to recall responses is well defined, the contribution of antibody "memory" and the mechanisms by which pre-existing antibodies modulate the development of germinal center and plasma cell responses is not precisely understood. Here we report on mechanisms that mediate antibody enhancement of germinal center (GC) and plasmablast (PB) compartments, and the parallel process by which they change the affinity threshold for B cell recruitment into immune responses. The data indicate that antibody-mediated enhancement of GC and PB responses is Fc gamma receptor (Fc{gamma}R) dependent and largely complement receptor 1 and 2 (CR1/2) independent. In contrast, the reduction in the affinity threshold for GC entry is independent of both Fc{gamma}Rs and CR1/2. SummaryCipolla et al. show that antibody can modulate immune responses via both Fc gamma receptor dependent and independent mechanisms. These mechanisms influence both the magnitude and composition of the germinal center response.

immunology↗

bioRxiv2026

B Lymphocyte Protein Factories produced by Hematopoietic Stem Cell Gene Editing

Long-term in vivo production of therapeutic proteins and development of vaccines that elicit protective levels of broadly neutralizing antibodies (bNAbs) against major pathogens face challenges. Here we report on an alternative gene-editing approach using small numbers of hematopoietic stem and progenitor cells (HSPCs) to direct long-term, high-level expression of antibodies or cargo proteins. Edited B lymphocyte offspring can be activated by cognate antigen to undergo clonal expansion and develop into specific antibody or cargo protein-synthesizing plasma cells. These cells produce long-lasting, therapeutic levels of serum antibody against HIV-1 or malaria and an anti-influenza virus bNAb that mediated universal protection from heterologous lethal challenge. Our data provide a paradigm for cell therapy approaches to prevent or treat disease using self-amplifying B cell protein factories.

immunology↗

bioRxiv2025

Antibody Mediated Diversification of Primary and Secondary Immune Responses

Humoral immune responses are characterized by increasing antibody affinity and diversity over time. Increased affinity is mediated by a combination of immunoglobulin gene somatic mutation and iterative cycles of selection in germinal centers. Less is understood about how diversity increases. Here we examine the role of antibody feedback in diversifying immune responses in mice that produce B cells that are incapable of secreting antibodies. To this end, we produced two strains of mice, one that expresses only membrane and secreted forms of IgM, and a second that produces only the membrane bound form of IgM. Analysis of primary and secondary immune responses show that antibody feedback significantly diversifies both primary and secondary immune responses even when antibodies are present at levels that are 10-30 fold lower than physiologic. The data have significant implication for sequential vaccination approaches aimed at shepherding immunity to produce broadly neutralizing antibodies to highly diversified pathogens such as HIV-1 and Influenza. SummaryHumoral immune responses diversify over time but whether secreted antibodies influence this process is unknown. Using antibody secretion-deficient mice this study shows a profound impact of secreted antibodies on the evolution of B cell diversity after vaccination.

immunology↗

bioRxiv2025

B lymphocytes that enter the germinal center late preferentially differentiate into memory cells that recognize subdominant epitopes

Immune responses to pathogens and effective vaccines elicit germinal center (GC) responses wherein B cells undergo affinity maturation and develop into plasma cells (PCs) and memory B cells (MBCs). The GC reaction is initially seeded by a limited group of founder B cells, and subsequently further diversified by continual entry of naive B cells that compete with GC founder cells for antigen and T cell help. Whether these later-arriving invaders contribute to the development of PCs or MBCs is not known. To investigate the fate of GC invaders we developed a dual-recombinase reporter approach that enables pre- and post-GC B cell lineage tracing and used it to examine immune responses to vaccination and influenza infection. Notably, fate-mapped invaders preferentially give rise to MBCs as opposed to PCs. Moreover, antibodies expressed by invader-derived MBCs harbor fewer somatic mutations, exhibit lower affinity, and their antibodies bind to subdominant antigenic epitopes relative to founder MBCs. Our findings indicate that invader GC B cells are an important source of humoral immune memory diversification after infection or vaccination.

immunology↗

bioRxiv2025

Memory B cell Development in Response to mRNA SARS-CoV-2 and Nanoparticle Immunization in Mice

Nanoparticle immunogens excel at rapidly inducing high levels of circulating antibodies and are being deployed as part of several novel vaccines. However, their ability to elicit memory B cell responses is less well understood. Here we compared serologic and memory B cell responses to prime boost vaccination with either SARS-CoV-2 Wuhan-Hu-1 mRNA vaccine, or protein nanoparticles: SARS-CoV-2 B.1.351 homotypic containing a single receptor binding domain (RBD); (homotypic beta) or a combination of different Sarbecovirus RBDs (mosaic 8b), respectively. The memory B cells elicited by the 3 vaccine regimens showed closely related antibody sequences, similar levels of somatic mutation and clonal diversity. The breadth of serologic responses elicited by the mosaic nanoparticles were comparable to the homotypic nanoparticle and superior to the mRNA vaccine for some mismatched strains. However, serum neutralizing titers to SARS-CoV-2 were highest after mRNA vaccination. The three vaccines elicited memory B cells that produced antibodies specific to a broad range of epitopes on the RBD that differed in a way that may reflect epitope masking. Monoclonal antibodies derived from memory B cells elicited by the mosaic 8b nanoparticle showed greater breadth against a panel of SARS-CoV-2 variants and SARS-CoV. Significance StatementNanoparticle vaccines are promising next-generation vaccine candidates, yet their capacity to generate durable memory B cell responses remains incompletely understood. We compared immune responses following SARS-CoV-2 mRNA, homotypic beta nanoparticle, or mosaic 8b nanoparticle vaccination in mice. Serum antibody neutralizing responses against a panel of SARS-CoV-2 variants elicited by an mRNA vaccine were equivalent or superior to those elicited by mosaic 8b nanoparticle vaccines. However, the monoclonal antibodies derived from memory B cells elicited by the mosaic 8b nanoparticle showed better neutralizing breadth against heterologous pseudoviruses. These findings highlight individual strengths of mRNA and nanoparticle vaccines and show that mosaic 8b nanoparticle immunogens can enhance the breadth of memory B cell-derived antibodies.

immunology↗

bioRxiv2025

Clonal Expansion and Diversification of Germinal Center and Memory B Cell Responses to Booster Immunization in Primates

Effective vaccines elicit B cell clonal expansion in germinal centers (GCs) that produce memory B cells and antibody secreting plasma cells. Studies in mice indicate that, whereas the plasma cell compartment is enriched for cells producing high affinity antibodies, the memory pool is more diverse and contains only a relatively small proportion of higher affinity cells. Upon boosting, murine memory B cells producing high affinity antibodies tend to develop into plasma cells but few if any re-enter GCs. However, mice live for only a few weeks in nature, and in keeping with the rather limited requirement for immune memory, this compartment comprises only 1-2% of all B cells. In contrast, memory accounts for nearly 50% of all B cells in primates. Here we examine memory and GC B cell responses in rhesus macaques immunized and boosted ipsilaterally or contralaterally with an mRNA vaccine encoding severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Spike protein. The neutralizing activity of antibodies cloned from the memory compartment, and the size of the compartment, was independent of the site of boosting. Moreover, in primates, memory B cells enter and undergo iterative expansion in newly developing GCs when boosting is at a site distal to the site of priming. Thus, in primates, high affinity memory B cells constitute a reservoir that actively participates in further development of immunity irrespective of the anatomical site of vaccine boosting. Highlights- Clonal overlap between primate memory and germinal center B cell compartments following booster immunization. - Neutralization activity of the memory and germinal center compartments are independent of the boost site. - Relationship between site of booster immunization (ipsilateral versus contralateral) and development of memory and germinal center (GC) responses in primates

immunology↗

bioRxiv2024

Affinity maturation of antibody responses is mediated by differential plasma cell proliferation

Increased antibody affinity over time after vaccination, known as affinity maturation, is a prototypical feature of immune responses. Recent studies have shown that a diverse collection of B cells, producing antibodies with a wide spectrum of different affinities, are selected into the plasma cell (PC) pathway. How affinity-permissive selection enables PC affinity maturation remains unknown. Here we report that PC precursors (prePC) expressing high affinity antibodies receive higher levels of T follicular helper (Tfh)-derived help and divide at higher rates than their lower affinity counterparts once they leave the GC. Thus, differential cell division by selected prePCs accounts for how diverse precursors develop into a PC compartment that mediates serological affinity maturation.

immunology↗

bioRxiv2023

SARS-CoV-2 spike glycosylation affects function and neutralization sensitivity

The glycosylation of viral envelope proteins can play important roles in virus biology and immune evasion. The spike (S) glycoprotein of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) includes 22 N-linked glycosylation sequons and 17 O-linked glycosites. Here, we investigated the effect of individual glycosylation sites on SARS-CoV-2 S function in pseudotyped virus infection assays and on sensitivity to monoclonal and polyclonal neutralizing antibodies. In most cases, removal of individual glycosylation sites decreased the infectiousness of the pseudotyped virus. For glycosylation mutants in the N-terminal domain (NTD) and the receptor binding domain (RBD), reduction in pseudotype infectivity was predicted by a commensurate reduction in the level of virion-incorporated spike protein. Notably, the presence of a glycan at position N343 within the RBD had diverse effects on neutralization by RBD-specific monoclonal antibodies (mAbs) cloned from convalescent individuals. The N343 glycan reduced overall sensitivity to polyclonal antibodies in plasma from COVID-19 convalescent individuals, suggesting a role for SARS-CoV-2 spike glycosylation in immune evasion. However, vaccination of convalescent individuals produced neutralizing activity that was resilient to the inhibitory effect of the N343 glycan.

microbiology↗

bioRxiv2022

CD4-binding site immunogens elicit heterologous anti-HIV-1 neutralizing antibodies in transgenic and wildtype animals

Passive transfer of broadly neutralizing anti-HIV-1 antibodies (bNAbs) protects against infection, and therefore eliciting bNAbs by vaccination is a major goal of HIV-1 vaccine efforts. bNAbs that target the CD4-binding site (CD4bs) on HIV-1 Env are among the most broadly active, but to date, responses elicited against this epitope in vaccinated animals have lacked potency and breadth. We hypothesized that CD4bs bNAbs resembling the antibody IOMA might be easier to elicit than other CD4bs antibodies that exhibit higher somatic mutation rates, a difficult-to-achieve mechanism to accommodate Envs N276gp120 N-glycan, and rare 5-residue light chain complementarity determining region 3s (CDRL3s). As an initial test of this idea, we developed IOMA germline-targeting Env immunogens and evaluated a sequential immunization regimen in transgenic mice expressing germline-reverted IOMA. These mice developed CD4bs epitope-specific responses with heterologous neutralization, and cloned antibodies overcame neutralization roadblocks including accommodating the N276gp120 glycan, with some neutralizing selected HIV-1 strains more potently than IOMA. The immunization regimen also elicited CD4bs-specific responses in animals containing polyclonal antibody repertoires. Thus, germline-targeting of IOMA-class antibody precursors represents a potential vaccine strategy to induce CD4bs bNAbs.

immunology↗

bioRxiv2022

Memory B cell responses to Omicron subvariants after SARS-CoV-2 mRNA breakthrough infection

Individuals that receive a 3rd mRNA vaccine dose show enhanced protection against severe COVID19 but little is known about the impact of breakthrough infections on memory responses. Here, we examine the memory antibodies that develop after a 3rd or 4th antigenic exposure by Delta or Omicron BA.1 infection, respectively. A 3rd exposure to antigen by Delta breakthrough increases the number of memory B cells that produce antibodies with comparable potency and breadth to a 3rd mRNA vaccine dose. A 4th antigenic exposure with Omicron BA.1 infection increased variant specific plasma antibody and memory B cell responses. However, the 4th exposure did not increase the overall frequency of memory B cells or their general potency or breadth compared to a 3rd mRNA vaccine dose. In conclusion, a 3rd antigenic exposure by Delta infection elicits strain-specific memory responses and increases in the overall potency and breadth of the memory B cells. In contrast, the effects of a 4th antigenic exposure with Omicron BA.1 is limited to increased strain specific memory with little effect on the potency or breadth of memory B cell antibodies. The results suggest that the effect of strain-specific boosting on memory B cell compartment may be limited.

immunology↗

bioRxiv2022

Humoral immunity to SARS-CoV-2 elicited by combination COVID-19 vaccination regimens

The SARS-CoV-2 pandemic prompted a global vaccination effort and the development of numerous COVID-19 vaccines at an unprecedented scale and pace. As a result, current COVID- 19 vaccination regimens comprise diverse vaccine modalities, immunogen combinations and dosing intervals. Here, we compare vaccine-specific antibody and memory B cell responses following two-dose mRNA, single-dose Ad26.COV2.S and two-dose ChAdOx1 or combination ChAdOx1/mRNA vaccination. Plasma neutralizing activity as well as the magnitude, clonal composition and antibody maturation of the RBD-specific memory B cell compartment showed substantial differences between the vaccination regimens. While individual monoclonal antibodies derived from memory B cells exhibited similar binding affinities and neutralizing potency against Wuhan-Hu-1 SARS-CoV-2, there were significant differences in epitope specificity and neutralizing breadth against viral variants of concern. Although the ChAdOx1 vaccine was inferior to mRNA and Ad26.COV2.S in several respects, biochemical and structural analyses revealed enrichment in a subgroup of memory B cell neutralizing antibodies with distinct RBD-binding properties resulting in remarkable potency and breadth.

immunology↗

bioRxiv2022

Antibody evolution to SARS-CoV-2 after single-dose Ad26.COV2.S vaccine

The single dose Ad.26.COV.2 (Janssen) vaccine elicits lower levels of neutralizing antibodies and shows more limited efficacy in protection against infection than either of the available mRNA vaccines. In addition, the Ad.26.COV.2 has been less effective in protection against severe disease during the Omicron surge. Here, we examined the memory B cell response to single dose Ad.26.COV.2 vaccination. Compared to mRNA vaccines, Ad.26.COV.2 recipients had significantly lower numbers of RBD-specific memory B cells 1.5 or 6 months after vaccination. Memory antibodies elicited by both vaccine types show comparable neutralizing potency against SARS-CoV-2 and Delta. However, the number of memory cells producing Omicron neutralizing antibodies was somewhat lower after Ad.26.COV.2 than mRNA vaccination. The data help explain why boosting Ad.26.COV.2 vaccine recipients with mRNA vaccines is effective, and why the Janssen vaccine appears to have been less protective against severe disease during the Omicron surge than the mRNA vaccine. One-Sentence SummaryAd.26.COV.2 vaccine results in lower quantity but comparable quality of protective memory B cells compared to mRNA vaccines.

immunology↗

bioRxiv2022

Increased Potency and Breadth of SARS-CoV-2 Neutralizing Antibodies After a Third mRNA Vaccine Dose

The omicron variant of SARS-CoV-2 infected very large numbers of SARS-CoV-2 vaccinated and convalescent individuals1-3. The penetrance of this variant in the antigen experienced human population can be explained in part by the relatively low levels of plasma neutralizing activity against Omicron in people who were infected or vaccinated with the original Wuhan-Hu-1 strain4-7. The 3rd mRNA vaccine dose produces an initial increase in circulating anti-Omicron neutralizing antibodies, but titers remain 10-20-fold lower than against Wuhan-Hu-1 and are, in many cases, insufficient to prevent infection7. Despite the reduced protection from infection, individuals that received 3 doses of an mRNA vaccine were highly protected from the more serious consequences of infection8. Here we examine the memory B cell repertoire in a longitudinal cohort of individuals receiving 3 mRNA vaccine doses9,10. We find that the 3rd dose is accompanied by an increase in, and evolution of, anti-receptor binding domain specific memory B cells. The increase is due to expansion of memory B cell clones that were present after the 2nd vaccine dose as well as the emergence of new clones. The antibodies encoded by these cells showed significantly increased potency and breadth when compared to antibodies obtained after the 2nd vaccine dose. Notably, the increase in potency was especially evident among newly developing clones of memory cells that differed from the persisting clones in targeting more conserved regions of the RBD. Overall, more than 50% of the analyzed neutralizing antibodies in the memory compartment obtained from individuals receiving a 3rd mRNA vaccine dose neutralized Omicron. Thus, individuals receiving 3 doses of an mRNA vaccine encoding Wuhan-Hu-1, have a diverse memory B cell repertoire that can respond rapidly and produce antibodies capable of clearing even diversified variants such as Omicron. These data help explain why a 3rd dose of an mRNA vaccine that was not specifically designed to protect against variants is effective against variant-induced serious disease.

immunology↗

bioRxiv2022

Conserved Neutralizing Epitopes on the N-Terminal Domain of Variant SARS-CoV-2 Spike Proteins

SARS-CoV-2 infection or vaccination produces neutralizing antibody responses that contribute to better clinical outcomes. The receptor binding domain (RBD) and the N-terminal domain (NTD) of the spike trimer (S) constitute the two major neutralizing targets for the antibody system. Neutralizing antibodies targeting the RBD bind to several different sites on this domain. In contrast, most neutralizing antibodies to NTD characterized to date bind to a single supersite, however these antibodies were obtained by methods that were not NTD specific. Here we use NTD specific probes to focus on anti-NTD memory B cells in a cohort of pre-omicron infected individuals some of which were also vaccinated. Of 275 NTD binding antibodies tested 103 neutralized at least one of three tested strains: Wuhan-Hu-1, Gamma, or PMS20, a synthetic variant which is extensively mutated in the NTD supersite. Among the 43 neutralizing antibodies that were further characterized, we found 6 complementation groups based on competition binding experiments. 58% targeted epitopes outside the NTD supersite, and 58% neutralized either Gamma or Omicron, but only 14% were broad neutralizers. Three of the broad neutralizers were characterized structurally. C1520 and C1791 recognize epitopes on opposite faces of the NTD with a distinct binding pose relative to previously described antibodies allowing for greater potency and cross-reactivity with 7 different variants including Beta, Delta, Gamma and Omicron. Antibody C1717 represents a previously uncharacterized class of NTD-directed antibodies that recognizes the viral membrane proximal side of the NTD and SD2 domain, leading to cross-neutralization of Beta, Gamma and Omicron. We conclude SARS-CoV-2 infection and/or Wuhan-Hu-1 mRNA vaccination produces a diverse collection of memory B cells that produce anti-NTD antibodies some of which can neutralize variants of concern. Rapid recruitment of these cells into the antibody secreting plasma cell compartment upon re-infection likely contributes to the relatively benign course of subsequent infections with SARS-CoV-2 variants including omicron.

immunology↗

bioRxiv2021

Longitudinal clonal dynamics of HIV-1 latent reservoirs measured by combination quadruplex polymerase chain reaction and sequencing

HIV-1 infection produces a long-lived reservoir of latently infected CD4+ T cells that represents the major barrier to HIV-1 cure. The reservoir contains both intact and defective proviruses, but only the proviruses that are intact can re-initiate infection upon cessation of antiretroviral therapy (ART). Here we combine 4 color quantitative polymerase chain reaction and next-generation sequencing (Q4PCR) to distinguish intact and defective proviruses and measure reservoir content longitudinally in 12 infected individuals. Q4PCR differs from other PCR based methods in that the amplified proviruses are sequence verified as intact or defective. Samples were collected systematically over the course of up to 10 years beginning shortly after the initiation of ART. The size of the defective reservoir was relatively stable with minimal decay during the 10-year observation period. In contrast, the intact proviral reservoir decayed with estimated half-life of 4.9 years. Nevertheless, both intact and defective proviral reservoirs are dynamic. As a result, the fraction of intact proviruses found in expanded clones of CD4+ T cells increases overtime with a concomitant decrease in overall reservoir complexity. Thus, reservoir decay measurements by Q4PCR are quantitatively similar to viral outgrowth (VOA) and intact proviral DNA PCR (IPDA) with the addition of sequence information that distinguishes intact and defective proviruses and informs reservoir dynamics. The data is consistent with the notion that intact and defective proviruses are under distinct selective pressure, and that the intact proviral reservoir is progressively enriched in expanded clones of CD4+ T cells resulting in diminishing complexity over time. SignificanceHIV-1 infection requires lifelong treatment with antiretroviral therapy (ART) due to viral rebound of a latent reservoir of intact, transcriptionally silent provirus found to persist in the genome of CD4+ T cells. One of the major challenges to understanding the nature of the latent reservoir is accurately characterizing the measuring the size of the reservoir. Herein, we use quadruplex polymerase chain reaction (Q4PCR) to assess the dynamics of the latent reservoir in HIV+ individuals who have been on long-term ART for up to 10 years. Our results show that Q4PCR can be used to accurately measure the latent reservoir, while providing the added benefit of assessing the genetic diversity of the reservoir to better understand changes to clonal dynamics overtime.

immunology↗

bioRxiv2021

Antibody Evolution after SARS-CoV-2 mRNA Vaccination

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection produces B-cell responses that continue to evolve for at least one year. During that time, memory B cells express increasingly broad and potent antibodies that are resistant to mutations found in variants of concern1. As a result, vaccination of coronavirus disease 2019 (COVID-19) convalescent individuals with currently available mRNA vaccines produces high levels of plasma neutralizing activity against all variants tested1, 2. Here, we examine memory B cell evolution 5 months after vaccination with either Moderna (mRNA-1273) or Pfizer- BioNTech (BNT162b2) mRNA vaccines in a cohort of SARS-CoV-2 naive individuals. Between prime and boost, memory B cells produce antibodies that evolve increased neutralizing activity, but there is no further increase in potency or breadth thereafter. Instead, memory B cells that emerge 5 months after vaccination of naive individuals express antibodies that are similar to those that dominate the initial response. While individual memory antibodies selected over time by natural infection have greater potency and breadth than antibodies elicited by vaccination, the overall neutralizing potency of plasma is greater following vaccination. These results suggest that boosting vaccinated individuals with currently available mRNA vaccines will increase plasma neutralizing activity but may not produce antibodies with breadth equivalent to those obtained by vaccinating convalescent individuals.

immunology↗

bioRxiv2021

Vaccination boosts naturally enhanced neutralizing breadth to SARS-CoV-2 one year after infection

Over one year after its inception, the coronavirus disease-2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) remains difficult to control despite the availability of several excellent vaccines. Progress in controlling the pandemic is slowed by the emergence of variants that appear to be more transmissible and more resistant to antibodies1,2. Here we report on a cohort of 63 COVID-19-convalescent individuals assessed at 1.3, 6.2 and 12 months after infection, 41% of whom also received mRNA vaccines3,4. In the absence of vaccination antibody reactivity to the receptor binding domain (RBD) of SARS-CoV-2, neutralizing activity and the number of RBD-specific memory B cells remain relatively stable from 6 to 12 months. Vaccination increases all components of the humoral response, and as expected, results in serum neutralizing activities against variants of concern that are comparable to or greater than neutralizing activity against the original Wuhan Hu-1 achieved by vaccination of naive individuals2,5-8. The mechanism underlying these broad-based responses involves ongoing antibody somatic mutation, memory B cell clonal turnover, and development of monoclonal antibodies that are exceptionally resistant to SARS-CoV-2 RBD mutations, including those found in variants of concern4,9. In addition, B cell clones expressing broad and potent antibodies are selectively retained in the repertoire over time and expand dramatically after vaccination. The data suggest that immunity in convalescent individuals will be very long lasting and that convalescent individuals who receive available mRNA vaccines will produce antibodies and memory B cells that should be protective against circulating SARS-CoV-2 variants.

immunology↗