Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Germline-Encoded Affinity for Cognate Antigen Enables Vaccine Amplification of a Human Broadly Neutralizing Response Against Influenza Virus

ABSTRACT: Antibodies display antigen-binding loops comprised of a hypervariable CDRH3 and V gene-encoded CDRs, where the latter may harbor gene-endowed or ‘public’ targeting solutions. To test this, we generated transgenic mice containing human CDRH3 diversity but simultaneously constrained to individual human immunoglobulin VH genes, including IGHV1-69, which shows biased usage in human broadly neutralizing antibodies (bnAbs) targeting the hemagglutinin stalk of Group 1 influenza A viruses. We then rank-ordered the VH-contribution to bnAb-epitope targeting following exposure to viral and nanoparticle displays of hemagglutinin. Notably, sequential immunization with a stalk-only hemagglutinin nanoparticle elicited Group 1 bnAbs, but only in IGHV1-69 constrained mice. This response required minimal affinity maturation, could be elicited under pre-existing influenza immunity, and when IGHV1-69 B cells were diluted to match the frequency measured in humans. Thus, encoded CDRs can naturally endow for specific antibody targets, and a rationally designed immunogen may elicit human influenza bnAbs through this principle.

ORGANISM(S): Mus musculus

PROVIDER: GSE135761 | GEO | 2019/08/13

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Allelic Polymorphism Gates Autoreactivity and Vaccine-Elicitation of Human Broadly Neutralizing Antibodies Against Influenza Virus

Project description:Human broadly neutralizing antibodies (bnAbs) targeting the hemagglutinin stalk of group 1 influenza A viruses (IAVs) are biased for IGHV1-69 alleles that use phenylalanine (F54) but not leucine (L54) within their CDRH2 loops. Despite this, we demonstrate that both alleles encode for human IAV bnAbs that employ structurally convergent modes of contact to the same epitope. To resolve differences in lineage-expandability, we compared F54 vs L54 as substrate within humanized mice where antibodies develop with human-like CDRH3 diversity but are restricted to single VH-genes. While both alleles encoded for bnAb precursors, only F54 IGHV1-69 supported elicitation of heterosubtypic serum bnAbs following immunization with a stalk-only nanoparticle vaccine. L54 IGHV1-69 was unproductive, co-encoding for anergic B cells and autoreactive stalk antibodies that were cleared from B cell memory. Moreover, human stalk antibodies also demonstrated L54-dependent autoreactivity. IGHV1-69 polymorphism, which is skewed ethnically, therefore gates tolerance and vaccine-expandability of influenza bnAbs.

2022-07-02 | GSE207054 | GEO

A single human VH gene endows for a broad-spectrum antibody response targeting bacterial lipopolysaccharides in the blood

Project description:B cell receptors (BCRs) display a combination of variable (V) gene-encoded complementarity determining regions (CDRs) and adaptive/hypervariable CDR3 loops to engage antigens. It has long been proposed that the former naturally tune for recognition of pathogens or groups of pathogens. To mechanistically evaluate this within the human antibody repertoire, we performed immune challenges in transgenic mice bearing diverse human CDR3 and light chains, but were constrained to different human VH genes. We found that out of six commonly deployed VH sequences, only those CDRs encoded by IGHV1-2*02 enabled polyclonal antibody responses against bacterial lipopolysaccharide (LPS) when introduced to the bloodstream. LPS was prepared from diverse strains of gram-negative bacteria, and the VH gene-dependent responses were directed against the non-variable and universal saccrolipid substructure of this antigen. This reveals a broad-spectrum anti-LPS response in which germline-encoded CDRs naturally hardwire the human antibody repertoire for recognition of a conserved microbial target.

2020-07-13 | GSE154285 | GEO

Transcriptome signatures preceding the induction of anti-stalk antibodies elicited by a chimeric hemagglutinin-based universal influenza virus vaccine

Project description:A phase 1 clinical trial to test the immunogenicity of a chimeric group 1 HA (cHA) universal influenza virus vaccine targeting the conserved stalk domain of the hemagglutinin of influenza viruses was carried out. Vaccination with adjuvanted-inactivated vaccines induced high anti-stalk antibody titers. We sought to identify gene expression signatures that correlate with such induction. Messenger-RNA sequencing in whole blood was performed on peripheral blood of 53 vaccinees, at early and late time points after priming and boosting. We generated longitudinal data on peripheral blood of 53 volunteers, at early (days 3 and 7) and late (28 days) time points after priming and boosting with cHAs. Differentially expressed gene analysis showed no differences between placebo and live-attenuated vaccine groups. However, an upregulation of genes involved in innate immune responses and type I interferon signaling was found at day 3 after vaccination with inactivated adjuvanted formulations. Cell type deconvolution analysis revealed a significant enrichment for monocyte markers and different subsets of dendritic cells as mediators for optimal B cell responses and significant increase of anti-stalk antibodies in sera. A significant upregulation of immunoglobulin related genes was only observed after administration of adjuvanted vaccines (either as primer or booster) with specific induction of anti-stalk IGVH1-69. This approach informed of specific immune signatures that correlate with robust anti-stalk antibody responses, while also helping to understand regulation of gene expression induced by cHA proteins under different vaccine regimens.

2022-12-13 | GSE217770 | GEO

Influence of immunoglobulin genotypes on the elicitation of SARS CoV-2 neutralizing antibodies

Project description:The human immunoglobulin heavy chain (IGH) locus is exceptionally polymorphic with high allelic diversity of variable (V) genes and structural variation affecting large regions of the locus. Thus, our germline IGHV gene and allele content is highly personal, which may influence how we respond to infections and vaccinations. Here, we coupled individualized IGHV genotyping with the isolation of monoclonal antibodies against the SARS-CoV-2 spike, focusing on the IGHV1-69 and IGHV3-30 group of genes, which were over-represented in spike-specific B cells. These genes are characterized by both allelic and copy number variations, making them ideal for expanding our understanding of inter-individual differences in antigen-specific antibody responses. We found that for the IGHV1-69*20-using CAB-I47 antibody, the allele usage was critical as germline reversion to other, highly similar, IGHV1-69 alleles abolished the neutralizing activity. Our results demonstrate that as little as single nucleotide differences between different alleles can greatly influence the biological response.

2023-03-11 | PXD031945 | Pride

The antibody landscapes against Group 1 and 2 influenza virus hemagglutinin following AS03 and MF59 adjuvanted H5N1 vaccination (probing_2_iga)

Project description:Current seasonal and pre-pandemic influenza vaccines induce short-lived predominantly strain-specific and limited heterosubtypic responses. To better understand how vaccine adjuvants AS03 and MF59 may provide improved antibody responses to vaccination, we interrogated serum from subjects who received 2 doses of inactivated monovalent influenza A/Indonesia/05/2005 vaccine with or without AS03 or MF59 using hemagglutinin (HA) microarrays (NCT01317758 and NCT01317745). The arrays were designed to reflect both full length and globular head HA derived from 17 influenza A subtypes (H1 to H16 and H18) and influenza B strains. We observed significantly increased strain-specific and broad homo- and hetero-subtypic antibody responses with both AS03 and MF59 adjuvanted vaccination with AS03 achieving a higher titer and breadth of IgG responses relative to MF59. Adjuvanted vaccine was also associated with the elicitation of stalk directed antibody. We established good correlation of the array antibody responses to H5 antigens with standard HA inhibition and microneutralization titers.

2022-07-01 | GSE202383 | GEO

The antibody landscapes against Group 1 and 2 influenza virus hemagglutinin following AS03 and MF59 adjuvanted H5N1 vaccination (probing_4_igg)

2022-07-01 | GSE202390 | GEO

The antibody landscapes against Group 1 and 2 influenza virus hemagglutinin following AS03 and MF59 adjuvanted H5N1 vaccination (probing_4_iga)

2022-07-01 | GSE202389 | GEO

The antibody landscapes against Group 1 and 2 influenza virus hemagglutinin following AS03 and MF59 adjuvanted H5N1 vaccination (probing_3_igg)

2022-07-01 | GSE202388 | GEO

The antibody landscapes against Group 1 and 2 influenza virus hemagglutinin following AS03 and MF59 adjuvanted H5N1 vaccination (probing_3_iga)

2022-07-01 | GSE202387 | GEO

The antibody landscapes against Group 1 and 2 influenza virus hemagglutinin following AS03 and MF59 adjuvanted H5N1 vaccination (probing_2_igg)

2022-07-01 | GSE202385 | GEO