A5012916588- SARS-CoV-2 and COVID-19 Research
- Animal Virus Infections Studies
- vaccines and immunoinformatics approaches
- Viral gastroenteritis research and epidemiology
- CRISPR and Genetic Engineering
- Viral Infections and Immunology Research
- Monoclonal and Polyclonal Antibodies Research
- COVID-19 Clinical Research Studies
- Evolution and Genetic Dynamics
- Virus-based gene therapy research
- RNA and protein synthesis mechanisms
- Immunotherapy and Immune Responses
- Protein Structure and Dynamics
- SARS-CoV-2 detection and testing
- RNA modifications and cancer
- Viral Infections and Outbreaks Research
- Bacillus and Francisella bacterial research
- Heat shock proteins research
- T-cell and B-cell Immunology
- Genomics and Phylogenetic Studies
- Computational Drug Discovery Methods
- Transgenic Plants and Applications
- Animal Genetics and Reproduction
- Microbial Metabolic Engineering and Bioproduction
- interferon and immune responses
University of Utah
2022-2025
University of Chicago
2016-2024
Cape Town HVTN Immunology Laboratory / Hutchinson Centre Research Institute of South Africa
2021-2023
Fred Hutch Cancer Center
2020-2023
Cancer Research Center
2021-2023
Howard Hughes Medical Institute
2021-2023
University of Washington
2022
Seattle University
2021-2022
Willamette University
2012
State Street (United States)
2012
The receptor binding domain (RBD) of the SARS-CoV-2 spike glycoprotein mediates viral attachment to ACE2 and is a major determinant host range dominant target neutralizing antibodies. Here, we experimentally measure how all amino acid mutations RBD affect expression folded protein its affinity for ACE2. Most are deleterious binding, identify constrained regions on RBD's surface that may be desirable targets vaccines antibody-based therapeutics. But substantial number well tolerated or even...
Antibodies targeting the SARS-CoV-2 spike receptor-binding domain (RBD) are being developed as therapeutics and a major contributor to neutralizing antibody responses elicited by infection. Here, we describe deep mutational scanning method map how all amino-acid mutations in RBD affect binding apply this 10 human monoclonal antibodies. The escape cluster on several surfaces of that broadly correspond structurally defined epitopes. However, even antibodies same surface often have distinct...
Mapping antibody escape in SARS-CoV-2 Several antibodies are use or under development as therapies to treat COVID-19. As new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants emerge, it is important predict whether they will remain susceptible treatment. Starr et al. used a yeast library that covers all mutations the receptor-binding domain do not strongly disrupt binding host receptor (ACE2) and mapped how these affect three leading anti–SARS-CoV-2 antibodies. The maps...
An ideal therapeutic anti-SARS-CoV-2 antibody would resist viral escape
Monoclonal antibodies and antibody cocktails are a promising therapeutic prophylaxis for coronavirus disease 2019 (COVID-19). However, ongoing evolution of severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) can render monoclonal ineffective. Here, we completely map all the mutations to SARS-CoV-2 spike receptor-binding domain (RBD) that escape binding by leading antibody, LY-CoV555, its cocktail combination with LY-CoV016. Individual each combined in circulating B.1.351 P.1...
Monoclonal antibodies targeting a variety of epitopes have been isolated from individuals previously infected with SARS-CoV-2, but the relative contributions these different antibody classes to polyclonal response remains unclear. Here we use yeast-display system map all mutations viral spike receptor-binding domain (RBD) that escape binding by representatives three potently neutralizing anti-RBD high-resolution structures. We compare antibody-escape maps similar for convalescent plasmas,...
Understanding the molecular basis for immune recognition of SARS-CoV-2 spike glycoprotein antigenic sites will inform development improved therapeutics. We determined structures two human monoclonal antibodies–AZD8895 and AZD1061–which form investigational antibody cocktail AZD7442, in complex with receptor-binding domain (RBD) to define genetic structural neutralization. AZD8895 forms an 'aromatic cage' at heavy/light chain interface using germ line-encoded residues...
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has evolved variants with substitutions in the spike receptor-binding domain (RBD) that affect its affinity for angiotensin-converting enzyme (ACE2) receptor and recognition by antibodies. These could also shape future evolution modulating effects of mutations at other sites-a phenomenon called epistasis. To investigate this possibility, we performed deep mutational scans to measure on ACE2 binding all single-amino acid Wuhan-Hu-1,...
The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants with mutations in key antibody epitopes has raised concerns that antigenic evolution could erode adaptive immunity elicited by prior infection or vaccination. susceptibility to viral is shaped part the breadth targeted antibodies vaccination natural infection. To investigate how human responses vaccines are influenced mutations, we used deep mutational scanning compare specificity polyclonal either two...
Abstract The evolution of SARS-CoV-2 could impair recognition the virus by human antibody-mediated immunity. To facilitate prospective surveillance for such evolution, we map how convalescent serum antibodies are impacted all mutations to spike’s receptor-binding domain (RBD), main target neutralizing activity. Binding polyclonal is affected in three epitopes RBD, but there substantial variation impact both among individuals and within same individual over time. Despite this inter-...
To combat future severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants and spillovers of SARS-like betacoronaviruses (sarbecoviruses) threatening global health, we designed mosaic nanoparticles that present randomly arranged sarbecovirus spike receptor-binding domains (RBDs) to elicit antibodies against epitopes are conserved relatively occluded rather than variable, immunodominant, exposed. We compared immune responses elicited by mosaic-8 (SARS-CoV-2 seven animal...
Two different sarbecoviruses have caused major human outbreaks in the past two decades
SARS-CoV-2 continues to acquire mutations in the spike receptor-binding domain (RBD) that impact ACE2 receptor binding, folding stability, and antibody recognition. Deep mutational scanning prospectively characterizes impacts of on these biochemical properties, enabling rapid assessment new seen during viral surveillance. However, effects can change as virus evolves, requiring updated deep scans. We determined all single amino acid Omicron BA.1 BA.2 RBDs ACE2-binding affinity, RBD folding,...
Understanding broadly neutralizing sarbecovirus antibody responses is key to developing countermeasures against SARS-CoV-2 variants and future zoonotic sarbecoviruses. We describe the isolation characterization of a human monoclonal antibody, designated S2K146, that neutralizes viruses belonging SARS-CoV- SARS-CoV-2-related clades which use ACE2 as an entry receptor. Structural functional studies show most virus residues directly bind S2K146 are also involved in binding ACE2. This allows...
Abstract A key goal of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) surveillance is to rapidly identify viral variants with mutations that reduce neutralization by polyclonal antibodies elicited vaccination or infection. Unfortunately, direct experimental characterization new lags their sequence-based identification. Here we help address this challenge aggregating deep mutational scanning data into an ‘escape estimator’ estimates the antigenic effects arbitrary combinations...
The Omicron BA.1 variant emerged in late 2021 and quickly spread across the world. Compared to earlier SARS-CoV-2 variants, has many mutations, some of which are known enable antibody escape. Many these antibody-escape mutations individually decrease spike receptor-binding domain (RBD) affinity for ACE2, but still binds ACE2 with high affinity. fitness evolution lineage is therefore driven by combined effects numerous mutations. Here, we systematically map epistatic interactions between 15...
Among the 30 nonsynonymous nucleotide substitutions in Omicron S-gene are 13 that have only rarely been seen other SARS-CoV-2 sequences. These mutations cluster within three functionally important regions of at sites will likely impact (1) interactions between subunits Spike trimer and predisposition to shift from down up configurations, (2) with ACE2 receptors, (3) priming for membrane fusion. We show here that, based on both rarity these intrapatient sequencing reads patterns selection...
New variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continue to arise and prolong the disease 2019 (COVID-19) pandemic. Here, we used a cell-free expression workflow rapidly screen optimize constructs containing multiple computationally designed miniprotein inhibitors SARS-CoV-2. We found broadest efficacy was achieved with homotrimeric version 75-residue angiotensin-converting enzyme (ACE2) mimic AHB2 (TRI2-2) geometrically match trimeric spike architecture....
The Omicron BA.1 variant of SARS-CoV-2 escapes convalescent sera and monoclonal antibodies that are effective against earlier strains the virus. This immune evasion is largely a consequence mutations in receptor binding domain (RBD), major antigenic target SARS-CoV-2. Previous studies have identified several key RBD leading to escape from most antibodies. However, little known about how these interact with each other RBD. Here, we systematically map interactions by measuring affinity all...