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1.
Immunity ; 2021 Oct 29.
Article in English | MEDLINE | ID: covidwho-1521063

ABSTRACT

Viral mutations are an emerging concern in reducing SARS-CoV-2 vaccination efficacy. Second-generation vaccines will need to elicit neutralizing antibodies against sites that are evolutionarily conserved across the sarbecovirus subgenus. Here, we immunized mice containing a human antibody repertoire with diverse sarbecovirus receptor-binding domains (RBDs) to identify antibodies targeting conserved sites of vulnerability. Antibodies with broad reactivity against diverse clade B RBDs targeting the conserved class 4 epitope, with recurring IGHV/IGKV pairs, were readily elicited but were non-neutralizing. However, rare class 4 antibodies binding this conserved RBD supersite showed potent neutralization of SARS-CoV-2 and all variants of concern. Structural analysis revealed that the neutralizing ability of cross-reactive antibodies was reserved only for those with an elongated CDRH3 that extends the antiparallel beta-sheet RBD core and orients the antibody light chain to obstruct ACE2-RBD interactions. These results identify a structurally defined pathway for vaccine strategies eliciting escape-resistant SARS-CoV-2 neutralizing antibodies.

2.
Non-conventional in English | [Unspecified Source], Grey literature | ID: grc-750507

ABSTRACT

During virus infection B cells are critical for the production of antibodies and protective immunity. Here we show that the human B cell compartment in patients with diagnostically confirmed SARS-CoV-2 and clinical COVID-19 is rapidly altered with the early recruitment of B cells expressing a limited subset of IGHV genes, progressing to a highly polyclonal response of B cells with broader IGHV gene usage and extensive class switching to IgG and IgA subclasses with limited somatic hypermutation in the initial weeks of infection. We identify extensive convergence of antibody sequences across SARS-CoV-2 patients, highlighting stereotyped naive responses to this virus. Notably, sequence-based detection in COVID-19 patients of convergent B cell clonotypes previously reported in SARS-CoV infection predicts the presence of SARS-CoV/SARS-CoV-2 cross-reactive antibody titers specific for the receptor-binding domain. These findings offer molecular insights into shared features of human B cell responses to SARS-CoV-2 and other zoonotic spillover coronaviruses.

3.
Immunity ; 2021.
Article in English | EuropePMC | ID: covidwho-1489418

ABSTRACT

Viral mutations are an emerging concern in reducing SARS-CoV-2 vaccination efficacy. Burnett et al. immunized humanized mice with different diverse sarbecovirus RBDs to elicit antibodies targeting conserved sites. Non-neutralizing cross-reactive antibodies targeting the conserved class 4 epitope were readily elicited. Neutralizing ability was reserved only for antibodies binding this conserved supersite through an elongated CDRH3 that obstructed ACE2-RBD interactions.

4.
Science ; 372(6543): 738-741, 2021 05 14.
Article in English | MEDLINE | ID: covidwho-1180894

ABSTRACT

Vaccination and infection promote the formation, tissue distribution, and clonal evolution of B cells, which encode humoral immune memory. We evaluated pediatric and adult blood and deceased adult organ donor tissues to determine convergent antigen-specific antibody genes of similar sequences shared between individuals. B cell memory varied for different pathogens. Polysaccharide antigen-specific clones were not exclusive to the spleen. Adults had higher clone frequencies and greater class switching in lymphoid tissues than blood, while pediatric blood had abundant class-switched convergent clones. Consistent with reported serology, prepandemic children had class-switched convergent clones to severe acute respiratory syndrome coronavirus 2 with weak cross-reactivity to other coronaviruses, while adult blood or tissues showed few such clones. These results highlight the prominence of early childhood B cell clonal expansions and cross-reactivity for future responses to novel pathogens.


Subject(s)
Antibodies, Viral/immunology , B-Lymphocytes/immunology , Coronavirus/immunology , Immunologic Memory , SARS-CoV-2/immunology , Adolescent , Adult , Aged , Aged, 80 and over , Aging , Child, Preschool , Cross Reactions , Ebolavirus/immunology , Female , Fetal Blood/immunology , Genes, Immunoglobulin , Humans , Immunoglobulin Class Switching , Immunoglobulin D/genetics , Immunoglobulin D/immunology , Immunoglobulin Heavy Chains/immunology , Immunoglobulin M/genetics , Immunoglobulin M/immunology , Infant , Lymph Nodes/immunology , Male , Middle Aged , Receptors, Antigen, B-Cell/immunology , Somatic Hypermutation, Immunoglobulin , Spleen/immunology , Young Adult
5.
Nat Med ; 27(1): 125-135, 2021 01.
Article in English | MEDLINE | ID: covidwho-1023963

ABSTRACT

Most of what we know about adaptive immunity has come from inbred mouse studies, using methods that are often difficult or impossible to confirm in humans. In addition, vaccine responses in mice are often poorly predictive of responses to those same vaccines in humans. Here we use human tonsils, readily available lymphoid organs, to develop a functional organotypic system that recapitulates key germinal center features in vitro, including the production of antigen-specific antibodies, somatic hypermutation and affinity maturation, plasmablast differentiation and class-switch recombination. We use this system to define the essential cellular components necessary to produce an influenza vaccine response. We also show that it can be used to evaluate humoral immune responses to two priming antigens, rabies vaccine and an adenovirus-based severe acute respiratory syndrome coronavirus 2 vaccine, and to assess the effects of different adjuvants. This system should prove useful for studying critical mechanisms underlying adaptive immunity in much greater depth than previously possible and to rapidly test vaccine candidates and adjuvants in an entirely human system.


Subject(s)
Influenza Vaccines/immunology , Palatine Tonsil/immunology , Adjuvants, Immunologic , B-Lymphocytes/cytology , B-Lymphocytes/immunology , COVID-19 Vaccines/immunology , Germinal Center/cytology , Hemagglutinin Glycoproteins, Influenza Virus , Humans , In Vitro Techniques , Lymphoid Tissue/immunology , Measles-Mumps-Rubella Vaccine/immunology , Organoids/cytology , Organoids/immunology , Rabies Vaccines/immunology , T-Lymphocytes/immunology
6.
Res Sq ; 2020 May 06.
Article in English | MEDLINE | ID: covidwho-829290

ABSTRACT

During virus infection B cells are critical for the production of antibodies and protective immunity. Establishment of a diverse antibody repertoire occurs by rearrangement of germline DNA at the immunoglobulin heavy and light chain loci to encode the membrane-bound form of antibodies, the B cell antigen receptor. Little is known about the B cells and antigen receptors stimulated by the novel human coronavirus SARS-CoV-2. Here we show that the human B cell compartment in patients with diagnostically confirmed SARS-CoV-2 and clinical COVID-19 is rapidly altered with the early recruitment of B cells expressing a limited subset of V genes, and extensive activation of IgG and IgA subclasses without significant somatic mutation. We detect expansion of B cell clones as well as convergent antibodies with highly similar sequences across SARS-CoV-2 patients, highlighting stereotyped naïve responses to this virus. A shared convergent B cell clonotype in SARS-CoV-2 infected patients was previously seen in patients with SARS. These findings offer molecular insights into shared features of human B cell responses to SARS-CoV-2 and other zoonotic spillover coronaviruses.

7.
Cell Host Microbe ; 28(4): 516-525.e5, 2020 10 07.
Article in English | MEDLINE | ID: covidwho-743914

ABSTRACT

B cells are critical for the production of antibodies and protective immunity to viruses. Here we show that patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) who develop coronavirus disease 2019 (COVID-19) display early recruitment of B cells expressing a limited subset of IGHV genes, progressing to a highly polyclonal response of B cells with broader IGHV gene usage and extensive class switching to IgG and IgA subclasses with limited somatic hypermutation in the initial weeks of infection. We identify convergence of antibody sequences across SARS-CoV-2-infected patients, highlighting stereotyped naive responses to this virus. Notably, sequence-based detection in COVID-19 patients of convergent B cell clonotypes previously reported in SARS-CoV infection predicts the presence of SARS-CoV/SARS-CoV-2 cross-reactive antibody titers specific for the receptor-binding domain. These findings offer molecular insights into shared features of human B cell responses to SARS-CoV-2 and SARS-CoV.


Subject(s)
Antibodies, Viral/immunology , B-Lymphocytes/immunology , Betacoronavirus/immunology , Coronavirus Infections/immunology , Coronavirus Infections/virology , Pneumonia, Viral/immunology , Pneumonia, Viral/virology , Adult , Aged , Aged, 80 and over , Antibodies, Viral/blood , Antibodies, Viral/genetics , Antibody Formation , Betacoronavirus/genetics , COVID-19 , Female , HEK293 Cells , Humans , Immunogenetics , Immunoglobulin A/genetics , Immunoglobulin A/immunology , Immunoglobulin G/genetics , Immunoglobulin G/immunology , Male , Middle Aged , Pandemics , SARS-CoV-2 , Sequence Analysis , Spike Glycoprotein, Coronavirus/immunology
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