B cell convergence to distinct broadly reactive epitopes following vaccination with chimeric influenza virus hemagglutinins
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PROVIDER: PRJNA940845 | ENA |
REPOSITORIES: ENA
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Project description:In a phase I clinical trial, a chimeric hemagglutinin (cHA) immunogen induced antibody responses against the conserved HA stalk domain as designed. Here, we determined the specificity, function, and subsets of B cells induced by cHA vaccination by pairing single cell RNA-sequencing and B cell receptor repertoire sequencing. We have shown that the cHA inactivated vaccine with a squalene-based adjuvant induced a robust activated B cell and memory B cell (MBC) phenotype against two broadly neutralizing epitopes in the stalk domain. The overall specificities of the acute plasmablast (PB) and MBC responses clonally overlapped, suggesting B cell convergence to these broadly protective epitopes. At one-year post-immunization, we identified that cHA vaccination reshaped the HA-specific MBC pool to enrich for stalk-binding B cells. Altogether, these data indicate the cHA vaccine induced robust and durable B cell responses against broadly protective epitopes of the HA stalk domain, in line with serological data.
2025-03-04 | GSE260836 | GEO
Project description:In a phase I clinical trial, a chimeric hemagglutinin (cHA) immunogen induced antibody responses against the conserved HA stalk domain as designed. Here, we determined the specificity, function, and subsets of B cells induced by cHA vaccination by pairing single cell RNA-sequencing and B cell receptor repertoire sequencing. We have shown that the cHA inactivated vaccine with a squalene-based adjuvant induced a robust activated B cell and memory B cell (MBC) phenotype against two broadly neutralizing epitopes in the stalk domain. The overall specificities of the acute plasmablast (PB) and MBC responses clonally overlapped, suggesting B cell convergence to these broadly protective epitopes. At one-year post-immunization, we identified that cHA vaccination reshaped the HA-specific MBC pool to enrich for stalk-binding B cells. Altogether, these data indicate the cHA vaccine induced robust and durable B cell responses against broadly protective epitopes of the HA stalk domain, in line with serological data.
2025-03-04 | GSE260941 | GEO
Project description:In a phase I clinical trial, the chimeric hemagglutinin (cHA) immunogen induced antibody responses against the conserved HA stalk domain. However, the landscape of the B cell specificities and subsets induced by this vaccine remain undetermined. Here, we paired single cell RNA-sequencing and B cell receptor repertoire sequencing to analyze the relationship between transcriptome and B cell specificity following cHA immunization. We show that the cHA inactivated vaccine with a squalene-based adjuvant induced a robust activated B cell and memory B cell phenotype against two broadly neutralizing epitopes of the stalk domain. The overall specificities of the acute plasmablast and memory B cell responses were distinct, with the plasmablast compartment largely targeting non-neutralizing epitopes of the HA stalk. Altogether, these data indicate the B cell landscape following cHA vaccination includes diverse B cell subsets that are differentially induced by distinct vaccine formulations, including memory and de novo B cell responses against diverse broadly conserved epitopes.
2025-03-04 | GSE226633 | GEO
Project description:Long-lasting B cell convergence to distinct broadly reactive epitopes following vaccination with chimeric influenza virus hemagglutinins
| PRJNA1083594 | ENA
Project description:Long-lasting B cell convergence to distinct broadly reactive epitopes following vaccination with chimeric influenza virus hemagglutinins II
| PRJNA1084081 | ENA
Project description:Infection and vaccination repeatedly expose individuals to antigens that are conserved between influenza virus subtypes. Nevertheless, antibodies recognizing conserved influenza epitopes greatly outnumber antibodies reactive against variable epitopes. Elucidating factors contributing to the paucity of broadly reactive influenza antibodies remains a major obstacle for developing a universal influenza vaccine. Here, we report that inducing broadly reactive influenza antibodies increases autoreactive antibodies in humans and mice and exacerbates disease in four distinct models of autoimmune disease. Importantly, transferring broadly reactive influenza antibodies augments disease in the presence of inflammation or autoimmune susceptibility. Further, broadly reactive influenza antibodies spontaneously arise in mice with defects in B cell tolerance. Together, these data suggest that self-tolerance mechanisms limit the prevalence of broadly reactive influenza antibodies, which can exacerbate disease in the context of additional risk factors.
2022-02-09 | GSE196366 | GEO
Project description:Epitope mapping studies aim to identify the binding sites of antibody-antigen interactions to enhance the development of vaccines, diagnostics and immunotherapeutic compounds. However, mapping is a laborious process employing time- and resource-consuming M-bM-^@M-^Xwet benchM-bM-^@M-^Y techniques or epitope prediction software that are still in their infancy. For polymorphic antigens, another challenge is characterizing cross-reactivity between epitopes, teasing out distinctions between broadly cross-reactive responses, limited cross-reactions among variants and the truly type-specific responses. A refined understanding of cross-reactive antibody binding could guide the selection of the most informative subsets of variants for diagnostics and multivalent subunit vaccines. We explored the antibody binding reactivity of sera from human patients and Peromyscus leucopus rodents infected with Borrelia burgdorferi to the polymorphic outer surface protein C (OspC), an attractive candidate antigen for vaccine and improved diagnostics for Lyme disease. We constructed a protein microarray displaying 23 natural variants of OspC and quantified the degree of cross-reactive antibody binding between all pairs of variants, using Pearson correlation calculated on the reactivity values using three independent transforms of the raw data: (1) logarithmic, (2) rank, and (3) binary indicators. We observed that the global amino acid sequence identity between OspC pairs was a poor predictor of cross-reactive antibody binding. Then we asked if specific regions of the protein would better explain the observed cross-reactive binding and performed in silico screening of the linear sequence and 3-dimensional structure of OspC. This analysis pointed to the C-terminal helix of the structure as a major determinant of type-specific cross-reactive antibody binding. We developed bioinformatics methods to systematically analyze the relationship between local sequence/structure variation and cross-reactive antibody binding patterns among variants of a polymorphic antigen, and this method can be applied to other polymorphic antigens for which immune response data is available for multiple variants. Antibody profiling was performed on sera from Borrelia burgdorferi infected and non-infected humans and Peromyscus leucopus rodents against 23 variants of the surface protein OspC . For infected human serum samples, the OspC type of the infecting B. burgdorferi strain is unknown; for experimentally-infected P. leucopus serum samples, it is known. Of human serum samples, 55 were from infected individuals and 25 from naive controls. Of P. leucopus serum samples, 23 were from infected individuals and 7 were from naive controls.
2013-04-12 | E-GEOD-45996 | biostudies-arrayexpress
Project description:Epitope mapping studies aim to identify the binding sites of antibody-antigen interactions to enhance the development of vaccines, diagnostics and immunotherapeutic compounds. However, mapping is a laborious process employing time- and resource-consuming ‘wet bench’ techniques or epitope prediction software that are still in their infancy. For polymorphic antigens, another challenge is characterizing cross-reactivity between epitopes, teasing out distinctions between broadly cross-reactive responses, limited cross-reactions among variants and the truly type-specific responses. A refined understanding of cross-reactive antibody binding could guide the selection of the most informative subsets of variants for diagnostics and multivalent subunit vaccines. We explored the antibody binding reactivity of sera from human patients and Peromyscus leucopus rodents infected with Borrelia burgdorferi to the polymorphic outer surface protein C (OspC), an attractive candidate antigen for vaccine and improved diagnostics for Lyme disease. We constructed a protein microarray displaying 23 natural variants of OspC and quantified the degree of cross-reactive antibody binding between all pairs of variants, using Pearson correlation calculated on the reactivity values using three independent transforms of the raw data: (1) logarithmic, (2) rank, and (3) binary indicators. We observed that the global amino acid sequence identity between OspC pairs was a poor predictor of cross-reactive antibody binding. Then we asked if specific regions of the protein would better explain the observed cross-reactive binding and performed in silico screening of the linear sequence and 3-dimensional structure of OspC. This analysis pointed to the C-terminal helix of the structure as a major determinant of type-specific cross-reactive antibody binding. We developed bioinformatics methods to systematically analyze the relationship between local sequence/structure variation and cross-reactive antibody binding patterns among variants of a polymorphic antigen, and this method can be applied to other polymorphic antigens for which immune response data is available for multiple variants.
2013-04-12 | GSE45996 | GEO
Project description:Inferring Epitopes of a Polymorphic Antigen Amidst Broadly Cross-Reactive Antibodies Using Protein Microarrays: a Study of OspC Proteins of Borrelia burgdorferi
| PRJNA196868 | ENA
Project description:Influenza hemagglutinin (HA) is the major surface glycoprotein on influenza viruses and mediates viral attachment and subsequent fusion with host cells. The HA is the major target of the immune response, but due to its high level of variability, as evidenced by substantial antigenic diversity, it had been historically considered to elicit only a narrow, strain-specific antibody response. However, a recent explosion in the discovery of broadly neutralizing antibodies (bnAbs) to influenza virus has identified two major supersites of vulnerability on the HA through structural characterization of HA-antibody complexes. These commonly targeted epitopes are involved with receptor binding as well as the fusion machinery and, hence, are functionally conserved and less prone to mutation. These bnAbs can neutralize viruses by blocking infection or the spread of infection by preventing progeny release. Structural analyses of these bnAbs show they exhibit striking similarities and trends in recognition of the HA and use recurring recognition motifs, despite substantial differences in their germline genes. This information can be utilized in design of novel therapeutics as well as in immunogens for improved vaccines with greater breadth and efficacy.
| S-EPMC4358778 | biostudies-literature