Profiling of human monoclonal antibodies targeting SARS-CoV-2 Omicron variant
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA838205 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR19213755_1.fastq.gz | Fastqsanger.gz | |||
| SRR19213755_2.fastq.gz | Fastqsanger.gz | |||
| SRR19213756_1.fastq.gz | Fastqsanger.gz | |||
| SRR19213756_2.fastq.gz | Fastqsanger.gz | |||
| SRR19213757_1.fastq.gz | Fastqsanger.gz |
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Project description:We generated LNP-mRNA encoding B.1.1.529 SARS-CoV-2 spike, and intramuscularly administered it in a human IgG and IgK knock-in mouse. Single cell VDJ-seq unveiled the sequences of human monoclonal antibodies targeting the B.1.1.529 SARS-CoV-2 spike protein.
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Project description:The COVID-19 pandemic was marked by successive waves of SARS-CoV-2 variants with distinct properties. The Omicron variant that emerged in late 2021 showed a major antigenic shift and rapidly spread worldwide. Since then, Omicron-derived variants have maintained their global dominance, for reasons that remain incompletely understood. We report that the original Omicron variant BA.1 evolved several traits that converged in facilitating viral spread. First, Omicron displayed an early replicative advantage over previous variants when grown in a reconstructed nasal epithelium model based on primary human cells. The increase in Omicron replication was more marked at the 33°C temperature characteristic of human nasal passages, resulting in a physiologically relevant advantage. Omicron also caused a decrease in epithelial integrity, as measured by transepithelial electrical resistance and caspase-3 activation. Furthermore, Omicron caused a more marked loss of motile cilia at 33°C than other variants, suggesting a capacity to impair mucociliary clearance. RNAseq analysis showed that Omicron induced a broad transcriptional downregulation of ciliary genes but only a limited upregulation of host innate defense genes at 33°C. The lower production of type I and type III interferons in epithelia infected by Omicron compared to those infected by the Delta variant, at 33°C as well as 37°C, confirmed the increased capacity of Omicron to evade the innate antiviral response. Thus, Omicron combined replication speed, motile cilia impairment, and limited induction of innate antiviral responses when propagated in reconstructed nasal epithelia at physiological temperature. Omicron has the capacity to propagate efficiently but stealthily in the upper respiratory tract, which likely contributed to the evolutionary success of this SARS-CoV-2 variant.
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Project description:SARS-CoV-2 Omicron (B.1.1.529) and its subvariants are currently the most common variants of concern worldwide, featuring numerous mutations in the spike protein and elsewhere that collectively make Omicron more transmissible and more resistant to antibody-mediated neutralization provided by vaccination, previous infections, and monoclonal antibody therapies than its predecessors. We recently reported the creation and characterization of Ig-MS, a new mass spectrometry-based serology platform that can define the repertoire of antibodies against an antigen of interest at single proteoform resolution. Here, we applied Ig-MS to investigate the evolution of plasma antibody repertoires against the receptor-binding domain (RBD) of SARS-CoV-2 in response to the booster shot and natural viral infection. We also assessed the capacity for antibody repertoires generated in response to vaccination and/or infection with the Omicron variant to bind to both Wuhan- and Omicron-RBDs. Our results show that 1) the booster increases antibody titers against both Wuhan- and Omicron- RBDs and elicits an Omicron-specific response and 2) vaccination and infection act synergistically in generating anti-RBD antibody repertoires able to bind both Wuhan- and Omicron-RBDs with variant-specific antibodies.
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Project description:During V(D)J recombination antibody diversity is enhanced by non-templated junctional modifications that generate immensely diverse heavy chain (HC) and light chain (LC) complementarity-determining 3 antigen-contact regions (CDR3s). We previously developed a mouse model that generates diverse antibody repertoires by rearranging a single human VH1-2 and Vk1-33, associated with highly diverse CDR3s generated by V(D)J recombination with mouse Ds and/or Js. Immunization of this model with SARS-CoV-2 D614G spike elicited an antibody that potently neutralized SARS-CoV-2 variants through Omicron BA.2.754. Here, we report a next generation mouse model in which a single VH1-2 rearranges to human D3-3 and JH6, generating diverse HC-CDR3s much longer on average than those of our prior model. Omicron BA.4/.5 spike ferritin nanoparticle-immunization of the new model elicited four highly-related humanized antibodies that potently neutralize downstream Omicron sub-variants. All four antibodies had 12 AA HC-CDR3s with two aromatic amino acids that engage an epitope comprising a hydrophobic patch opened-up by early omicron lineage mutations and conserved in subsequent variants. Immunization of our prior, shorter CDR3-based model, elicited slightly less potent neutralizing antibodies that bound the same Omicron epitope, and were similar in all other aspects to those from the long, fully-human CDR3 model. One tested antibody from each set reduced lung viral titers in a mouse-adapted BQ1.1 challenge. The antibodies we describe are highly related to, but more potent than, recently described antibodies from omicron-infected humans. These studies validate the utility of single human VH- and Vk-rearranging mice for discovering humanized antibodies that neutralize emerging pathogens.
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Project description:Two-component intranasal vaccine against SARS-CoV-2 Omicron variant
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