Document text
Principal Investigator: JULIE M. OVERBAUGH
Organization: FRED HUTCHINSON CANCER RESEARCH CENTER
Fiscal Year: 2020
Award: $355,912
Funding agency: National Institute of Allergy and Infectious Diseases
ABSTRACT
The greatest hope for an end to the COVID19 pandemic caused by SARS-CoV-2 is a vaccine and/or
antibody therapy. At this point, we know little about protective immunity to SARS-CoV-2, including which
epitopes are the major target of the antibody response to this virus and whether antibodies to specific epitopes
impact outcome. Advancing our understanding of SARS-CoV-2 immunity is critical not only for informing
vaccine design, but also for understanding the epidemiology and spread of SARS-CoV-2, including among
asymptomatic individuals. There is considerable focus on targeting the region of the Spike protein that interacts
with the receptor, which has also been a focus of HIV vaccine efforts for more than three decades with limited
success to-date. Thus, given the urgency due to this pandemic, multiple approaches are warranted to
complement this approach. We propose comprehensive profiling of the antibody response to SARS-CoV-2,
which has the potential to detect both neutralizing and non-neutralizing antibody responses to all the proteins
in the virus. For this purpose, we will develop novel methods based on creating custom Coronavirus (CoV)
phage display peptide libraries and using immunoprecipitation and deep sequencing to comprehensively
examine the antibody response to SARS-CoV-2 in a high-throughput manner. Using this platform, we will
develop and test custom libraries that encode all seven CoV clades, including genetic circulating variants and
peptides spanning all viral proteins. This method will allow us to simultaneously detect antibodies to all CoVs in
a person’s plasma, enabling the detection of the specific responses to SARS CoV-2 infection as well as
providing insights on any interactions between common CoV and SARS-CoV-2 infections, be they protective or
enhancing. We will also develop libraries of SARS-CoV-2 proteins that have mutations to all possible amino
acids at every possible amino acid using an approach we pioneered called Phage-DMS. We have validated
Phage-DMS as a tool to define key amino acids residues of epitopes and pathways of escape from antibodies.
We propose to collect and compare convalescent plasma from verified cases of SARS-CoV-2, including those
with severe symptoms, moderate symptoms and very mild symptoms as well as uninfected controls. The
information gained from these studies will help identify the peptide sequences that define the epitopes targeted
by antibodies in response to SARS-CoV-2 infection and those that distinguish SARS-CoV-2 infection from
other CoV infections. We also hope to identify the antibody responses across the entire CoV genomes that
correlate with outcome, including specific responses to SARS-CoV-2 as well as any interacting effects of
responses to other CoVs.
Terms: <2019 novel coronavirus><2019-nCoV><AIDS Virus><Ab response><Acquired Immune Deficiency Syndrome Virus><Acquired Immunodeficiency Syndrome Virus><Amino Acid Sequence><Amino Acids><Antibodies><Antibody Formation><Antibody Production><Antibody Response><Antibody Therapy><Antigenic Determinants><Assay><Bacteriophages><Binding Determinants><Bioassay><Biologic Assays><Biological Assay><Blood Plasma><COVID-19><COVID-19 epidemic><COVID-19 pandemic><COVID19><COVID19 epidemic><COVID19 pandemic><Clinical><Clinical Treatment Moab><Complement><Complement Proteins><Coronaviridae><Coronaviridae Infections><Coronavirus><Coronavirus Infections><Custom><Detection><Diagnostic><Disease><Disorder><EBOV><Ebola virus><Epidemiology><Epitopes><Genetic><Genetic Alteration><Genetic Change><Genetic defect><Genome><Goals><HIV><HIV Antibodies><HIV vaccine><HIV-Associated Antibodies><HIV/AIDS Vaccines><HTLV-III Antibodies><HTLV-III-LAV Antibodies><Human Immunodeficiency Viruses><Human T-Lymphotropic Virus Type III Antibodies><Immune><Immune Precipitation><Immunes><Immunity><Immunoprecipitation><Individual><Infection><Knowledge><LAV Antibodies><LAV-HTLV-III><Libraries><Lymphadenopathy-Associated Antibodies><Lymphadenopathy-Associated Virus><MERS><MERS coronavirus disease><MERS-CoV disease><Methods><Middle East Respiratory Syndrome><Middle East Respiratory Syndrome CoV disease><Middle East Respiratory Syndrome coronavirus disease><Middle Eastern Respiratory Syndrome><Middle Eastern Respiratory Syndrome CoV disease><Middle Eastern Respiratory Syndrome coronavirus disease><Monoclonal Antibodies><Mutation><Outcome><Pathogenesis><Pathway interactions><Peptide Library><Peptide Phage Display Library><Peptides><Persons><Phage Display><Phages><Plasma><Plasma Serum><Population><Primary Protein Structure><Proteins><Receptor Protein><Resolution><Reticuloendothelial System, Serum, Plasma><SARS><SARS coronavirus disease><SARS-CoV disease><SARS-CoV-2><SARS-CoV2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-related coronavirus 2><Sampling><Severe Acute Respiratory Syndrome><Severe Acute Respiratory Syndrome CoV disease><Severe Acute Respiratory Syndrome coronavirus disease><Severe acute respiratory syndrome coronavirus 2><Symptoms><Testing><VAC-TX><Vaccine Design><Vaccine Therapy><Vaccines><Variant><Variation><Viral Gene Products><Viral Gene Proteins><Viral Proteins><Virus><Virus-HIV><Work><Wuhan coronavirus><aminoacid><antibody based therapies><antibody biosynthesis><antibody treatment><antibody-based therapeutics><antibody-based treatment><bacterial virus><base><corona virus><corona virus disease 2019><corona virus disease 2019 epidemic><corona virus disease 2019 pandemic><coronavirus disease 2019><coronavirus disease 2019 epidemic><coronavirus disease 2019 pandemic><cross reactivity><deep sequencing><design><designing><develop a vaccine><development of a vaccine><ebolavirus><epidemiologic><epidemiological><genome mutation><human immunodeficiency virus vaccine><immunoglobulin biosynthesis><infection risk><insight><mAbs><mutation scanning><mutation screening><neutralizing antibody><novel><optimism><pandemic><pandemic disease><pathway><peptide aminoacid sequence><peptide sequence><postiive attitude><protein aminoacid sequence><protein sequence><rapid method><rapid technique><receptor><receptor binding><receptor bound><response><success><therapeutic vaccination><tool><vaccine development><vaccine formulation><virus protein>