Browse
Submit Data
Databases
API
Help

Dataset Information

15 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Potent and protective IGHV3-53/3-66 public antibodies and their shared escape mutant on the spike of SARS-CoV-2.

ABSTRACT: Neutralizing antibodies (nAbs) to SARS-CoV-2 hold powerful potentials for clinical interventions against COVID-19 disease. However, their common genetic and biologic features remain elusive. Here we interrogate a total of 165 antibodies from eight COVID-19 patients, and find that potent nAbs from different patients have disproportionally high representation of IGHV3-53/3-66 usage, and therefore termed as public antibodies. Crystal structural comparison of these antibodies reveals they share similar angle of approach to RBD, overlap in buried surface and binding residues on RBD, and have substantial spatial clash with receptor angiotensin-converting enzyme-2 (ACE2) in binding to RBD. Site-directed mutagenesis confirms these common binding features although some minor differences are found. One representative antibody, P5A-3C8, demonstrates extraordinarily protective efficacy in a golden Syrian hamster model against SARS-CoV-2 infection. However, virus escape analysis identifies a single natural mutation in RBD, namely K417N found in B.1.351 variant from South Africa, abolished the neutralizing activity of these public antibodies. The discovery of public antibodies and shared escape mutation highlight the intricate relationship between antibody response and SARS-CoV-2, and provide critical reference for the development of antibody and vaccine strategies to overcome the antigenic variation of SARS-CoV-2.

SUBMITTER: Zhang Q

PROVIDER: S-EPMC8270942 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

Sequence signatures of two IGHV3-53/3-66 public clonotypes to SARS-CoV-2 receptor binding domain.

Project description:Since the COVID-19 pandemic onset, the antibody response to SARS-CoV-2 has been extensively characterized. Antibodies to the receptor binding domain (RBD) on the spike protein are frequently encoded by IGHV3-53/3-66 with a short CDR H3. Germline-encoded sequence motifs in CDRs H1 and H2 play a major role, but whether any common motifs are present in CDR H3, which is often critical for binding specificity, have not been elucidated. Here, we identify two public clonotypes of IGHV3-53/3-66 RBD antibodies with a 9-residue CDR H3 that pair with different light chains. Distinct sequence motifs on CDR H3 are present in the two public clonotypes that appear to be related to differential light chain pairing. Additionally, we show that Y58F is a common somatic hypermutation that results in increased binding affinity of IGHV3-53/3-66 RBD antibodies with a short CDR H3. Overall, our results advance fundamental understanding of the antibody response to SARS-CoV-2.

| S-EPMC7852275 | biostudies-literature

Germline variants of IGHV3-53 / V3-66 are determinants of antibody responses to the BNT162b2 mRNA COVID-19 vaccine.

Project description: Not available

| S-EPMC9627529 | biostudies-literature

The prominent role of a CDR1 somatic hypermutation for convergent IGHV3-53/3-66 antibodies in binding to SARS-CoV-2.

Project description:In the fight against severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), monoclonal antibodies (mAbs) serve as key strategies for the rapid prevention and treatment of COVID-19. However, analysis to fully characterize functional SARS-CoV-2 mAbs is still needed. In this study, by interrogating 1,695 published or patented mAbs of human origin and validated SARS-CoV-2-binding potency, we found a highly preferential usage of IGHV3-53/3-66 germline genes that was then revealed as a distinct selectivity of SARS-CoV-2-induced humoral immunity across other coronaviruses. Moreover, among the rare somatic hypermutations, we identified a novel mutation signature of F27 to I, L, or V with high frequency, which was located in the CDR1 region of the heavy chain among IGHV3-53/3-66-encoded antibodies. This convergent mutation contributed to improving SARS-CoV-2 binding affinity and may advance our knowledge of the humoral immunity to SARS-CoV-2.

| S-EPMC9045774 | biostudies-literature

Association of an IGHV3-66 gene variant with Kawasaki disease.

Project description:In a meta-analysis of three GWAS for susceptibility to Kawasaki disease (KD) conducted in Japan, Korea, and Taiwan and follow-up studies with a total of 11,265 subjects (3428 cases and 7837 controls), a significantly associated SNV in the immunoglobulin heavy variable gene (IGHV) cluster in 14q33.32 was identified (rs4774175; OR = 1.20, P = 6.0 × 10-9). Investigation of nonsynonymous SNVs of the IGHV cluster in 9335 Japanese subjects identified the C allele of rs6423677, located in IGHV3-66, as the most significant reproducible association (OR = 1.25, P = 6.8 × 10-10 in 3603 cases and 5731 controls). We observed highly skewed allelic usage of IGHV3-66, wherein the rs6423677 A allele was nearly abolished in the transcripts in peripheral blood mononuclear cells of both KD patients and healthy adults. Association of the high-expression allele with KD strongly indicates some active roles of B-cells or endogenous immunoglobulins in the disease pathogenesis. Considering that significant association of SNVs in the IGHV region with disease susceptibility was previously known only for rheumatic heart disease (RHD), a complication of acute rheumatic fever (ARF), these observations suggest that common B-cell related mechanisms may mediate the symptomology of KD and ARF as well as RHD.

| S-EPMC7585995 | biostudies-literature

An Alternative Binding Mode of IGHV3-53 Antibodies to the SARS-CoV-2 Receptor Binding Domain.

Project description:IGHV3-53-encoded neutralizing antibodies are commonly elicited during SARS-CoV-2 infection and target the receptor-binding domain (RBD) of the spike (S) protein. Such IGHV3-53 antibodies generally have a short CDR H3 because of structural constraints in binding the RBD (mode A). However, a small subset of IGHV3-53 antibodies to the RBD contain a longer CDR H3. Crystal structures of two IGHV3-53 neutralizing antibodies here demonstrate that a longer CDR H3 can be accommodated in a different binding mode (mode B). These two classes of IGHV3-53 antibodies both target the ACE2 receptor binding site, but with very different angles of approach and molecular interactions. Overall, these findings emphasize the versatility of IGHV3-53 in this common antibody response to SARS-CoV-2, where conserved IGHV3-53 germline-encoded features can be combined with very different CDR H3 lengths and light chains for SARS-CoV-2 RBD recognition and virus neutralization.

| S-EPMC7522650 | biostudies-literature

Germline IGHV3-53-encoded RBD-targeting neutralizing antibodies are commonly present in the antibody repertoires of COVID-19 patients.

Project description:Monoclonal antibodies (mAbs) encoded by IGHV3-53 (VH3-53) targeting the spike receptor-binding domain (RBD) have been isolated from different COVID-19 patients. However, the existence and prevalence of shared VH3-53-encoded antibodies in the antibody repertoires is not clear. Using antibody repertoire sequencing, we found that the usage of VH3-53 increased after SARS-CoV-2 infection. A highly shared VH3-53-J6 clonotype was identified in 9 out of 13 COVID-19 patients. This clonotype was derived from convergent gene rearrangements with few somatic hypermutations and was evolutionary conserved. We synthesized 34 repertoire-deduced novel VH3-53-J6 heavy chains and paired with a common IGKV1-9 light chain to produce recombinant mAbs. Most of these recombinant mAbs (23/34) possess RBD binding and virus-neutralizing activities, and recognize ACE2 binding site via the same molecular interface. Our computational analysis, validated by laboratory experiments, revealed that VH3-53 antibodies targeting RBD are commonly present in COVID-19 patients' antibody repertoires, indicating many people have germline-like precursor sequences to rapidly generate SARS-CoV-2 neutralizing antibodies. Moreover, antigen-specific mAbs can be digitally obtained through antibody repertoire sequencing and computational analysis.

| S-EPMC8183521 | biostudies-literature

Medicare Shared Savings Program: public reporting and shared savings distributions.

Project description:To determine if Medicare Shared Savings Program (MSSP) accountable care organizations (ACOs) are meeting public reporting requirements related to shared savings plans, to quantitate the composition of shared savings distribution plans, and to investigate whether early ACO success is associated with specific plan or ACO characteristics.Cross-sectional study.ACO descriptive characteristics and distribution plan details were abstracted from official ACO websites for all 338 active MSSP ACOs launched through January 2014. Publicly available MSSP results from 2012 and 2013 start date ACOs were used to investigate associations with successful shared savings generation.Of current MSSP ACOs, 313 of 338 (93%) maintain a website, 284 of 338 (84%) provided at least a general statement about shared savings distributions, and 176 of 338 (52%) reported detailed allocation percentages to ACO participants. On average, ACOs reporting detailed allocations planned to give 63% (range = 0%-100%; SD = 26.3) to their primary care providers (PCPs), specialists, and/or hospitals, and 33% (range = 0%-100%; SD = 25.6) to infrastructure. ACOs including a hospital planned to give a larger average percentage to participating entities than those without (69% vs 58%; P = .01). ACOs planning to give > 50% to their PCPs and specialists were more likely to have generated savings (P = .001), as were ACOs composed of > 10 participating entities (P = .004).Just over one-half of MSSP ACOs report detailed shared savings distribution plans online, and these plans vary widely. There appears to be no single shared savings distribution plan determinate of ACO success. Continued investigation of predictors for generating savings is needed to inform future shared savings models.

| S-EPMC5578417 | biostudies-literature

SARS-CoV-2 variants, spike mutations and immune escape.

Project description:Although most mutations in the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) genome are expected to be either deleterious and swiftly purged or relatively neutral, a small proportion will affect functional properties and may alter infectivity, disease severity or interactions with host immunity. The emergence of SARS-CoV-2 in late 2019 was followed by a period of relative evolutionary stasis lasting about 11 months. Since late 2020, however, SARS-CoV-2 evolution has been characterized by the emergence of sets of mutations, in the context of 'variants of concern', that impact virus characteristics, including transmissibility and antigenicity, probably in response to the changing immune profile of the human population. There is emerging evidence of reduced neutralization of some SARS-CoV-2 variants by postvaccination serum; however, a greater understanding of correlates of protection is required to evaluate how this may impact vaccine effectiveness. Nonetheless, manufacturers are preparing platforms for a possible update of vaccine sequences, and it is crucial that surveillance of genetic and antigenic changes in the global virus population is done alongside experiments to elucidate the phenotypic impacts of mutations. In this Review, we summarize the literature on mutations of the SARS-CoV-2 spike protein, the primary antigen, focusing on their impacts on antigenicity and contextualizing them in the protein structure, and discuss them in the context of observed mutation frequencies in global sequence datasets.

| S-EPMC8167834 | biostudies-literature

mutated IGHV3-23 CLL

Project description:Expression of stereotyped B cell receptors (BCR), i.e. non-random combinations of immunoglobulin heavy-chain variable (IGHV) genes, complementarity-determining region-3 (HCDR3), and IGV light chains, identifies discrete clusters and represents a peculiar feature of chronic lymphocytic leukemia (CLL). Expression of IGHV3-23 characterized a CLL subset with peculiar molecular and clinical features.

2009-06-13 | GSE16065 | GEO

VH3-53/66-Class RBD-Specific Human Monoclonal Antibody iB20 Displays Cross-Neutralizing Activity against Emerging SARS-CoV-2 Lineages.

Project description:Immune evasion of SARS-CoV-2 undermines current strategies tocounteract the pandemic, with the efficacy of therapeutic virus-neutralizing monoclonal antibodies (nAbs) being affected the most. In this work, we asked whether two previously identified human cross-neutralizing nAbs, iB14 (class VH1-58) and iB20 (class VH3-53/66), are capable of neutralizing the recently emerged Omicron (BA.1) variant. Both nAbs were found to bind the Omicron RBD with a nanomolar affinity, yet they displayed contrasting functional features. When tested against Omicron, the neutralizing activity of iB14 was reduced 50-fold, whereas iB20 displayed a surprising increase in activity. Thus, iB20 is a unique representative of the VH3-53/66-class of nAbs in terms of breadth of neutralization, which establishes it as a candidate for COVID-19 therapy and prophylactics.

| S-EPMC9224930 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data