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Principal Investigator: Sagar D Khare
Organization: RUTGERS, THE STATE UNIV OF N.J.
Fiscal Year: 2024
Award: $187,992
Funding agency: National Institute of Allergy and Infectious Diseases
The ongoing rapid and widespread transmission of SARS-CoV-2 across the world has resulted in myriad viral
strains, but human immunity has been acquired from vaccination against a single (Wuhan-Hu-1) strain and/or
previous infection with a handful of strains. The large number of substitutions present in the recently emerged
Omicron Variant of Concern (VOC) spike (S) protein's receptor-binding domain (RBD) – a key antigenic site –
are associated with immune evasion and a putative broadening of species tropism. Immune evasion may have
serious consequences, potentially leading to increased incidence of infection, reinfection and/or further
enhancing viral fitness during uncontrolled spread around the globe. Omicron has not directly descended from
any of the previously identified VOCs raising the specter of future, highly-substituted immune-evasive VOCs.
Prior knowledge of the space of potential variants may enable the development of active and passive
immunization strategies for blunting the damage caused by novel VOCs. However, the scientific community
currently lacks the tools to prospectively identify novel highly-substituted VOCs capable of immune evasion. In
Aim 1 we propose a pipeline for discovering a diverse set of heavily substituted and immune-evasive RBD
variants. Relatedly, the medical community lacks binding-based therapeutic passive immunization leads against
unknown future variants that can be deployed in the event of a novel VOC outbreak. For example, many
monoclonal antibody therapies that previously received emergency use authorization from FDA no longer
neutralize the Omicron VOC, leading to fewer clinically relevant pharmaceutical interventions. For Aim 2, we
propose to redesign existing small-protein-based therapeutic entities to bind nearly all possible prospectively
identified novel VOCs. Our proposal is enabled by results from the PI and co-I laboratories, in which we
developed high-throughput structure-based computational and experimental approaches for predicting and
characterizing the binding of diverse SARS-CoV-2 RBD variants with the ACE2 and a set of neutralizing
antibodies (nAbs) to effectively recapitulate variant S function and immune evasion properties. We will apply our
technologies to broadly sample heavily substituted (10-20 substitutions) but functional RBD variants and identify
those that are predicted to abrogate binding to a representative set of neutralizing antibodies raised against two
key (Class 1 and Class 2) epitope regions of the RBD. Experimentally validated classes of escape-competent
RBD variants will serve as targets for the design of small protein-based inhibitors. The overall impact of this
project will be the prospective identification of the space of possible variation in Class 1 and Class 2 epitopes
that can still be recognized by the prevalent immune response. This will aid therapeutic intervention and identify
candidate RBD variant immunogens for inclusion in next-generation vaccines. This project will also provide
potent inhibitors of the diverse highly substituted RBD variants. With further clinical development, these may
serve as off-the-shelf therapeutics for effectively stopping a new VOC in its tracks.
Terms: <2019 novel corona virus><2019 novel coronavirus><2019-nCoV><2019-nCoV variant><2019-nCoV variant forms><2019-nCoV variant strains><ACE2><Active Immunization><Active vaccination><Aerosols><Algorithm Design><Algorithmic Design><Algorithmic Engineering><Antibodies><Antigenic Determinants><Antigens><Assay><B.1.1.529><Binding><Binding Determinants><Bioassay><Biological Assay><Biotech><Biotechnology><COVID-19 transmission><COVID-19 variant><COVID-19 variant forms><COVID-19 variant strains><COVID-19 virus><COVID-19 virus transmission><COVID19 virus><CoV-2><CoV2><Communities><Development><Directed Molecular Evolution><Drug Kinetics><Epitopes><Event><FDA EUA><FDA Emergency Use Authorization><Food and Drug Administration EUA><Food and Drug Administration Emergency Use Authorization><Future><Human><Immune Evasion><Immune response><Immunity><Immunological response><Incidence><Infection><Intervention><Intervention Strategies><Knowledge><Laboratories><Libraries><Lung><Lung Respiratory System><Machine Learning><Medical><Modern Man><Molecular Interaction><Molecular Modeling Nucleic Acid Biochemistry><Molecular Modeling Protein/Amino Acid Biochemistry><Molecular Models><Monoclonal Antibody Therapy><Omicron variant><Passive Immunization><Peptide Domain><Pharmaceutical Agent><Pharmaceuticals><Pharmacokinetics><Pharmacologic Substance><Pharmacological Substance><Property><Protein Domains><Protein Engineering><Proteins><Reagent><Receptor Protein><SARS corona virus 2><SARS-CO-V2><SARS-COVID-2><SARS-CoV-2><SARS-CoV-2 B.1.1.529><SARS-CoV-2 inhibitor><SARS-CoV-2 omicron><SARS-CoV-2 omicron variant><SARS-CoV-2 transmission><SARS-CoV-2 variant><SARS-CoV-2 variant forms><SARS-CoV-2 variant strains><SARS-CoV2><SARS-associated corona virus 2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-related corona virus 2><SARS-related coronavirus 2><SARSCoV2><Sampling><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-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 inhibitor><Severe acute respiratory syndrome related corona virus 2><Site><Structure><Surface><Technology><Tertiary Protein Structure><Testing><Therapeutic><Therapeutic Intervention><Tropism><Vaccination><Vaccines><Variant><Variation><Viral><Wuhan coronavirus><Yeasts><algorithm engineering><algorithmic composition><angiotensin converting enzyme 2><angiotensin converting enzyme II><block SARS-CoV-2><block severe acute respiratory syndrome coronavirus 2><candidate identification><clinical development><clinical relevance><clinically relevant><coronavirus disease 2019 transmission><coronavirus disease 2019 variant><coronavirus disease 2019 variant forms><coronavirus disease 2019 variant strains><coronavirus disease 2019 virus><coronavirus disease 2019 virus transmission><coronavirus disease-19 virus><data to train><dataset to train><design><designing><developmental><directed evolution><emergency use authorization><genetic protein engineering><hCoV19><host response><immune evasive><immune system response><immunization strategy><immunogen><immunoresponse><inhibit SARS-CoV-2><inhibit severe acute respiratory syndrome coronavirus 2><inhibitor><intervention therapy><interventional strategy><mAB-based therapy><mAb therapy><mAb-based therapeutics><machine based learning><molecular modeling><mutation scanning><mutation screening><nCoV2><neutralizing antibody><new vaccines><next generation><next generation vaccines><novel><novel vaccines><omicron variant of COVID-19><omicron variant of SARS-CoV-2><outbreak concern><outbreak potential><outbreak risk><outbreak threat><parallel computation><parallel computer><parallel computing><passive vaccination><pharmaceutical><prospective><protein design><pulmonary><receptor><receptor binding><receptor bound><severe acute respiratory syndrome coronavirus 2 B.1.1.529><severe acute respiratory syndrome coronavirus 2 transmission><severe acute respiratory syndrome coronavirus 2 variant><severe acute respiratory syndrome coronavirus 2 variant forms><severe acute respiratory syndrome coronavirus 2 variant strains><therapeutically effective><tool><training data><transmitted COVID-19><transmitted SARS-CoV-2><transmitted coronavirus disease 2019><transmitted severe acute respiratory syndrome coronavirus 2><vaccination strategy><variants of concern><viral fitness>