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1.
Front Immunol ; 12: 710263, 2021.
Article in English | MEDLINE | ID: covidwho-1315952

ABSTRACT

The unprecedented global demand for SARS-CoV-2 vaccines has demonstrated the need for highly effective vaccine candidates that are thermostable and amenable to large-scale manufacturing. Nanoparticle immunogens presenting the receptor-binding domain (RBD) of the SARS-CoV-2 Spike protein (S) in repetitive arrays are being advanced as second-generation vaccine candidates, as they feature robust manufacturing characteristics and have shown promising immunogenicity in preclinical models. Here, we used previously reported deep mutational scanning (DMS) data to guide the design of stabilized variants of the RBD. The selected mutations fill a cavity in the RBD that has been identified as a linoleic acid binding pocket. Screening of several designs led to the selection of two lead candidates that expressed at higher yields than the wild-type RBD. These stabilized RBDs possess enhanced thermal stability and resistance to aggregation, particularly when incorporated into an icosahedral nanoparticle immunogen that maintained its integrity and antigenicity for 28 days at 35-40°C, while corresponding immunogens displaying the wild-type RBD experienced aggregation and loss of antigenicity. The stabilized immunogens preserved the potent immunogenicity of the original nanoparticle immunogen, which is currently being evaluated in a Phase I/II clinical trial. Our findings may improve the scalability and stability of RBD-based coronavirus vaccines in any format and more generally highlight the utility of comprehensive DMS data in guiding vaccine design.


Subject(s)
COVID-19 Vaccines/administration & dosage , COVID-19/prevention & control , Immunization Schedule , Immunogenicity, Vaccine , Mutation , Protein Domains/genetics , Protein Domains/immunology , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus/immunology , Animals , Antibodies, Neutralizing/blood , Antibodies, Neutralizing/immunology , Antibodies, Viral/blood , Antibodies, Viral/immunology , COVID-19/blood , COVID-19/virology , COVID-19 Vaccines/immunology , Chlorocebus aethiops , Female , HEK293 Cells , Humans , Linoleic Acids , Mice , Mice, Inbred BALB C , Nanoparticles/chemistry , Spike Glycoprotein, Coronavirus/chemistry , Treatment Outcome , Vero Cells
2.
Emerg Med Australas ; 33(1): 152-154, 2021 02.
Article in English | MEDLINE | ID: covidwho-894717

ABSTRACT

OBJECTIVE: To review the impact of COVID-19 social restrictions on trauma presentations in South Australia. METHODS: Retrospective database review. RESULTS: During the period of social restrictions, there was a reduction in presentations of trauma and major trauma by 17% and 33%, respectively. The reduction in presentation rates was due to a large decrease in those aged over 40, with an increase in presentations in those younger than 40. Review by mechanism and location of injury revealed a reduction in road trauma, yet an increase in pedestrian trauma and trauma at home. CONCLUSION: Social restrictions alter the characteristics of trauma presentations.


Subject(s)
Quarantine , Wounds and Injuries/epidemiology , Adolescent , Adult , Age Factors , COVID-19/epidemiology , COVID-19/prevention & control , Female , Humans , Male , Middle Aged , Quarantine/statistics & numerical data , Retrospective Studies , South Australia/epidemiology , Young Adult
3.
Cell ; 182(5): 1295-1310.e20, 2020 09 03.
Article in English | MEDLINE | ID: covidwho-709109

ABSTRACT

The receptor binding domain (RBD) of the SARS-CoV-2 spike glycoprotein mediates viral attachment to ACE2 receptor and is a major determinant of host range and a dominant target of neutralizing antibodies. Here, we experimentally measure how all amino acid mutations to the RBD affect expression of folded protein and its affinity for ACE2. Most mutations are deleterious for RBD expression and ACE2 binding, and we identify constrained regions on the RBD's surface that may be desirable targets for vaccines and antibody-based therapeutics. But a substantial number of mutations are well tolerated or even enhance ACE2 binding, including at ACE2 interface residues that vary across SARS-related coronaviruses. However, we find no evidence that these ACE2-affinity-enhancing mutations have been selected in current SARS-CoV-2 pandemic isolates. We present an interactive visualization and open analysis pipeline to facilitate use of our dataset for vaccine design and functional annotation of mutations observed during viral surveillance.


Subject(s)
Molecular Docking Simulation , Mutation , Peptidyl-Dipeptidase A/metabolism , Spike Glycoprotein, Coronavirus/genetics , Angiotensin-Converting Enzyme 2 , Binding Sites , HEK293 Cells , Humans , Peptidyl-Dipeptidase A/chemistry , Phenotype , Protein Binding , Protein Folding , Saccharomyces cerevisiae , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/metabolism
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