Ontology highlight
ABSTRACT:
PROVIDER: PRJNA782992 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR17018724_1.fastq.gz | Fastqsanger.gz | |||
| SRR17018724_2.fastq.gz | Fastqsanger.gz | |||
| SRR17018725_1.fastq.gz | Fastqsanger.gz | |||
| SRR17018725_2.fastq.gz | Fastqsanger.gz | |||
| SRR17018726_1.fastq.gz | Fastqsanger.gz |
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Project description:The COVID-19 pandemic prompted an unprecedented effort to develop effective countermeasures against SARS-CoV-2. While efficacious vaccines and certain therapeutic monoclonal antibodies are available, here, we report the development, cryo-EM structures and functional analyses of distinct potent monoclonal antibodies (mAbs) that neutralize SARS-CoV-2 and its variant B.1.351. We established a platform for rapid identification of highly potent and specific SARS-CoV-2-neutralizing antibodies by high-throughput B cell receptor single cell sequencing of spike receptor binding domain immunized animals. We identified two highly potent and specific SARS-CoV-2 neutralizing mAb clones that have single-digit nanomolar affinity and low-picomolar avidity. We also generated a bispecific antibody of these two lead clones. The lead monospecific and bispecific antibodies showed strong neutralization ability against prototypical SARS-CoV-2 and the highly contagious South African variant B.1.351 that post a further risk of reducing the efficacy of currently available therapeutic antibodies and vaccines. The lead mAbs showed potent in vivo efficacy against authentic SARS-CoV-2 in both prophylactic and therapeutic settings. We solved five cryo-EM structures at ~3 resolution of these neutralizing antibodies in complex with the ectodomain of the prefusion spike trimer, and revealed the molecular epitopes, binding patterns and conformations between the antibodies and spike RBD, which are distinct from existing antibodies. Our recently developed antibodies expand the repertoire of the toolbox of COVID-19 countermeasures against the SARS-CoV-2 pathogen and its emerging variants.
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Project description:Delineating the origins and properties of antibodies elicited by SARS-CoV-2 infection and vaccination is critical for understanding their benefits and potential shortcomings. Therefore, we investigated the SARS-CoV-2 spike (S)-reactive B cell repertoire in unexposed individuals by flow cytometry and single-cell sequencing. We found that ~82% of SARS-CoV-2 S-reactive B cells show a naive phenotype, which represents an unusually high fraction of total human naive B cells (~0.1%). Approximately 10% of these naive S-reactive B cells shared an IGHV1-69/IGKV3-11 B cell receptor pairing, an enrichment of 18-fold compared to the complete naive repertoire. Following SARS-CoV-2 infection, we report an average 37-fold enrichment of IGHV1-69/IGKV3-11 B cell receptor pairing in the S-reactive memory B cells compared to the unselected memory repertoire. This class of B cells targets a previously undefined non-neutralizing epitope on the S2 subunit that becomes exposed on S proteins used in approved vaccines when they transition away from the native pre-fusion state because of instability. These findings can help guide the improvement of SARS-CoV-2 vaccines.
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Project description:This project is aimed at characterizing the interactions of SARS-CoV-2 Spike protein and its variants with multiple full-length antibodies and monitoring the accompanying conformational dynamics. Different categories of antibodies are tested that recognize different domains of the Spike protein. The project aims at identifying the effects of weak, moderate and strong neutralizing antibodies on Spike protein and decipher their mechanisms of action. In addition to the direct binding effects, distal allosteric effects are also determined. A range of biophysical experiments, biochemical assays, and molecular dynamics simulations are used as orthogonal approaches. The rationale is to identify regions on the SARS-CoV-2 Spike protein that acts as indicators for antibody binding and use these hotspots to develop better neutralizing antibodies against SARS-CoV-2 and any future viral pandemics.
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Project description:RNA vaccines are efficient preventive measures to combat the SARS-CoV-2 pandemic. High levels of neutralizing SARS-CoV-2-antibodies are an important component of vaccine-induced immunity. Shortly after the initial two mRNA vaccine doses, the IgG response mainly consists of the pro-inflammatory subclasses IgG1 and IgG3. Here, we report that several months after the second vaccination, SARS-CoV-2-specific antibodies were increasingly composed of non-inflammatory IgG4, which were further boosted by a third mRNA vaccination and/or SARS-CoV-2 variant breakthrough infections. IgG4 antibodies among all spike-specific IgG antibodies rose on average from 0.04% shortly after the second vaccination to 19.27% late after the third vaccination. This induction of IgG4 antibodies was not observed after homologous or heterologous SARS-CoV-2 vaccination with adenoviral vectors. Single-cell sequencing and flow cytometry revealed substantial frequencies of IgG4-switched B cells within the spike-binding memory B-cell population (median 14.4%; interquartile range (ICR) 6.7-18.1%) compared to the overall memory B-cell repertoire (median 1.3%; ICR 0.9-2.2%) after three immunizations. Importantly, this class switch was associated with a reduced capacity of the spike-specific antibodies to mediate antibody-dependent cellular phagocytosis and complement deposition. Since Fc-mediated effector functions are critical for antiviral immunity, these findings may have consequences for the choice and timing of vaccination regimens using mRNA vaccines, including future booster immunizations against SARS-CoV-2.
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