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: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:The SARS-CoV-2 Omicron (B.1.1.529) variant possesses numerous spike (S) mutations particularly in the S receptor-binding domain (S-RBD) that significantly improve transmissibility and evasion of neutralizing antibodies. But exactly how the mutations in the Omicron variant enhance viral escape from immunological protection remains to be understood. The S-RBD remains the principal target for neutralizing antibodies and therapeutics, thus new structural insights into the Omicron S-RBD and characterization of the post-translational glycosylation changes can inform rational design of vaccines and therapeutics. Here we report the molecular variations and O-glycoform changes of the Omicron S-RBD variant as compared to wild-type (WA1/2020) and Delta (B.1.617.2) variants using high-resolution top-down mass spectrometry (MS). A novel O-glycosite (Thr376) unique to the Omicron variant is identified. Moreover, we have directly quantified the Core 1 and Core 2 O-glycan structures and characterized the O-glycoform structural heterogeneity of the three variants. Our findings reveal high resolution detail of Omicron O-glycoforms and their utilization to provide direct molecular evidence of proteoform alterations in the Omicron variant which could shed light on how this variant escapes immunological protection.
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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:The recent SARS-CoV-2 omicron variant presented significant challenges to the global effort to counter the pandemic. SARS-CoV-2 is predicted to remain prevalent in the coming months, making the ability to identify SARS-CoV-2 variants imperative in understanding and controlling the pandemic. The predominant variant discovery method, genome sequencing, is time-consuming, insensitive, and expensive. Liquid chromatography-mass spectrometry (LC-MS) offers an exciting alternative detection modality provided that variant-containing peptide markers become well-established. This study demonstrates the potential to establish SARS-CoV-2 peptide markers by examining amino-acid variant-containing tryptic peptides, their MS fragmentation intensities, and their detection sensitivity in MS experiments. We have synthesized model tryptic peptides from of SARS-CoV-2 variants beta, gamma, delta, and omicron and evaluated their signal intensity, HCD spectra, and reverse phase retention time.
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Project description:SARS-CoV-2 Omicron infection results in a milder clinical feature compared to the Delta strain. The development of Omicron specific vaccine has also been hampered due to the low immunogenicity. By reverse-mutating the amino acids in the Omicron receptor binding domain (RBD), we identified that the mutation from Phenylalanine 375 (F375) in the Omicron spike to Serine 375 (S375) in Delta and other early strains significantly enhances the immune response in the manner of vaccines. Interestingly, the new evolution of the 371FAPF375FAF sequence in Omicron exhibited a potent inhibitory effect on macrophage uptake of the RBD nanoparticle or spike-pseudovirus particles. Omicron RBD enhances binding to Siglec-9 on macrophages to reduce the immunogenicity and increase the immune evasion, which could be abrogated by Serine 375 mutation. Based upon these observations, we further developed a bivalent Omicron RBD with S375 mutation and Delta RBD nanoparticle vaccine, which elicited potent and broad neutralizing antibodies in mice, rabbits, and rhesus macaques. Our research suggests that manipulating the Siglec-9 pathway could be a promising approach to enhancing vaccine response. Importantly, our findings suggest that Omicron subvariants have developed a new strategy to evade immune surveillance by impairing the phagocytosis and antigen presentation processes of macrophages.
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