Document text
Principal Investigator: Peter M Tessier
Organization: UNIVERSITY OF MICHIGAN AT ANN ARBOR
Fiscal Year: 2023
Award: $185,721
Funding agency: National Institute of Allergy and Infectious Diseases
Emerging SARS-CoV-2 variants are of broad interest because they may be more resistant to current vaccines
and associated immune responses. Toward the long-term goal of understanding how receptor-binding domain
(RBD) mutations impact transmissibility, it is critical to elucidate the impacts of RBD mutations on ACE2 affinity
and antibody escape. This information is important because RBD mutations can strongly modulate ACE2 affinity,
which is linked to changes in viral infectivity, and antibody escape, which is linked to changes in antibody
neutralization potency. Moreover, this information is also important because of the inherent tradeoffs between
ACE2 affinity and antibody escape, as many RBD mutations that strongly increase one property also strongly
decrease the other property, suggesting that evaluating either property in isolation is unlikely to explain how RBD
mutations impact SARS-CoV-2 transmissibility. Therefore, the Tessier lab has developed machine learning
models to describe the impact of single and multisite RBD mutations on ACE2 affinity and antibody escape. This
approach uses large but sparsely sampled experimental datasets that measure the impact of single and multisite
RBD mutations on ACE2 affinity and antibody escape to train machine learning models. Next, the models are
used to predict the impact of vast numbers of additional RBD mutations that are absent in the experimental
datasets. The goal of this proposal is to use machine learning models and multiple experimental techniques to
predict and experimentally evaluate the impacts of additional RBD mutations in Variants of Concern, such as the
Delta variant, on ACE2 affinity and antibody escape. The hypothesis is that the models will be able to identify
additional single and multisite mutations in the RBDs of key Variants of Concern that strongly modulate ACE2
affinity and/or antibody escape. To test this hypothesis, in Aim 1, predictions of the impact of additional single
and multisite mutations in the RBDs of Variants of Concern on ACE2 affinity and infectivity will be tested. This
Aim will involve testing these predictions using i) yeast surface display of RBDs and flow cytometry to measure
ACE2 affinity, and ii) pseudovirus assays to measure infectivity. No live viruses will be generated or tested in
this work. Next, in Aim 2, predictions of the impact of additional single and multisite mutations in the RBDs of
Variants of Concern on antibody escape and neutralization will be tested. The human serum samples that will
be used are from donors that were either infected, vaccinated, or infected and subsequently vaccinated. This
Aim will involve testing the model predictions using i) yeast surface display of RBDs and flow cytometry to
measure antibody binding, and ii) pseudovirus assays to measure antibody neutralization. A key expected
outcome will be the optimization and validation of models that can be used to aid in the rapid identification of the
most threatening emerging SARS-CoV-2 variants. This integrated experimental and computational approach
holds great potential for use in improving vaccine and therapeutic antibody development to address current and
future pandemics.
Terms: <2019 novel corona virus><2019 novel coronavirus><2019-nCoV><2019-nCoV vaccine><2019-nCoV variant><2019-nCoV variant forms><2019-nCoV variant strains><ACE2><Acceleration><Address><Affinity><Antibodies><Assay><B.1.617.2><Binding><Bioassay><Biologic Assays><Biological Assay><Blood Serum><Brazil P.1><Brazil variant><Brazilian variant><COVID crisis><COVID epidemic><COVID pandemic><COVID-19 crisis><COVID-19 epidemic><COVID-19 global health crisis><COVID-19 global pandemic><COVID-19 health crisis><COVID-19 pandemic><COVID-19 public health crisis><COVID-19 vaccine><COVID-19 variant><COVID-19 variant forms><COVID-19 variant strains><COVID-19 virus><COVID19 crisis><COVID19 epidemic><COVID19 global health crisis><COVID19 global pandemic><COVID19 health crisis><COVID19 pandemic><COVID19 public health crisis><COVID19 vaccine><COVID19 virus><CoV-2><CoV2><Computer Models><Computerized Models><Data Set><Delta variant><Development><Evaluation><Flow Cytofluorometries><Flow Cytofluorometry><Flow Cytometry><Flow Microfluorimetry><Flow Microfluorometry><Future><Gamma variant><Genetic Alteration><Genetic Change><Genetic defect><Goals><Human><Humanities><Immune response><Immunological response><Infection><Link><Measures><Modeling><Modern Man><Molecular Interaction><Mutation><Mutation Analysis><Outcome><P.1 strain><P.1 variant><Property><Proteins><Receptor Protein><Research><Resistance><SARS corona virus 2><SARS-CO-V2><SARS-COVID-2><SARS-CoV-2><SARS-CoV-2 B.1.617.2><SARS-CoV-2 P.1><SARS-CoV-2 delta><SARS-CoV-2 epidemic><SARS-CoV-2 global health crisis><SARS-CoV-2 global pandemic><SARS-CoV-2 pandemic><SARS-CoV-2 vaccine><SARS-CoV-2 variant><SARS-CoV-2 variant forms><SARS-CoV-2 variant strains><SARS-CoV2><SARS-CoV2 epidemic><SARS-CoV2 pandemic><SARS-CoV2 vaccine><SARS-associated corona virus 2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-coronavirus-2 epidemic><SARS-coronavirus-2 pandemic><SARS-coronavirus-2 vaccine><SARS-related corona virus 2><SARS-related coronavirus 2><SARSCoV2><Sampling><Serum><Severe Acute Respiratory Coronavirus 2><Severe Acute Respiratory Distress Syndrome CoV 2><Severe Acute Respiratory Distress Syndrome Corona Virus 2><Severe Acute Respiratory Distress Syndrome Coronavirus 2><Severe Acute Respiratory Syndrome CoV 2><Severe Acute Respiratory Syndrome CoV 2 epidemic><Severe Acute Respiratory Syndrome CoV 2 pandemic><Severe Acute Respiratory Syndrome CoV 2 vaccine><Severe Acute Respiratory Syndrome-associated coronavirus 2><Severe Acute Respiratory Syndrome-related coronavirus 2><Severe acute respiratory syndrome associated corona virus 2><Severe acute respiratory syndrome coronavirus 2><Severe acute respiratory syndrome coronavirus 2 epidemic><Severe acute respiratory syndrome coronavirus 2 pandemic><Severe acute respiratory syndrome coronavirus 2 vaccine><Severe acute respiratory syndrome related corona virus 2><Site><Surface><Techniques><Testing><Therapeutic antibodies><Time><Training><Vaccinated><Vaccination><Vaccines><Validation><Variant><Variation><Viral><Virus><Work><Wuhan coronavirus><Yeasts><angiotensin converting enzyme 2><angiotensin converting enzyme II><computational modeling><computational models><computer based models><computer based prediction><computerized modeling><corona virus disease 2019 epidemic><corona virus disease 2019 pandemic><corona virus disease 2019 vaccine><coronavirus disease 2019 crisis><coronavirus disease 2019 epidemic><coronavirus disease 2019 global health crisis><coronavirus disease 2019 global pandemic><coronavirus disease 2019 health crisis><coronavirus disease 2019 pandemic><coronavirus disease 2019 public health crisis><coronavirus disease 2019 vaccine><coronavirus disease 2019 variant><coronavirus disease 2019 variant forms><coronavirus disease 2019 variant strains><coronavirus disease 2019 virus><coronavirus disease crisis><coronavirus disease epidemic><coronavirus disease pandemic><coronavirus disease-19 global pandemic><coronavirus disease-19 pandemic><coronavirus disease-19 vaccine><coronavirus disease-19 virus><current pandemic><deep sequencing><defined contribution><deploy vaccines><developmental><distribute vaccines><flow cytophotometry><future pandemic><genome mutation><hCoV19><host response><immune system response><immunoresponse><improved><interest><machine learning based model><machine learning based prediction model><machine learning based predictive model><machine learning model><machine learning prediction><machine learning prediction model><mutant><nCoV vaccine><nCoV-19 vaccine><nCoV19 vaccine><nCoV2><neutralizing antibody><new approaches><next pandemic><novel><novel approaches><novel strategies><novel strategy><prediction model><predictive modeling><present pandemic><receptor><receptor binding><receptor bound><resistant><response><severe acute respiratory syndrome coronavirus 2 B.1.617.2><severe acute respiratory syndrome coronavirus 2 P.1><severe acute respiratory syndrome coronavirus 2 global health crisis><severe acute respiratory syndrome coronavirus 2 global pandemic><severe acute respiratory syndrome coronavirus 2 variant><severe acute respiratory syndrome coronavirus 2 variant forms><severe acute respiratory syndrome coronavirus 2 variant strains><vaccine against 2019-nCov><vaccine against SARS-CoV-2><vaccine against SARS-CoV2><vaccine against SARS-coronavirus-2><vaccine against Severe Acute Respiratory Syndrome CoV 2><vaccine against Severe acute respiratory syndrome coronavirus 2><vaccine antibodies><vaccine deployment><vaccine distribution><vaccine for novel coronavirus><vaccine induced antibodies><vaccine roll-out><vaccine rollout><vaccine-induced antibodies><validations><variants of concern>