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Principal Investigator: Wayne A. Marasco
Organization: DANA-FARBER CANCER INST
Fiscal Year: 2021
Award: $903,360
Funding agency: National Institute of Allergy and Infectious Diseases
Project Summary
The emergence of the novel human betacoronavirus SARS-CoV2 in Wuhan, China in 2019 has rapidly evolved
into a worldwide pandemic. Over a 100 million people have been infected and there have been several million
deaths. There is also great disparity in the manner in which COVID-19 illness presents, from asymptomatic
infection to death. COVID-19 illness in children is overall more mild or asymptomatic compared to adults. One
hypothesis that may explain this disparity is that children have cross-immunity to SARS-CoV2 due to frequent
early exposure to globally circulating human coronaviruses (HCoVs) that cause a milder respiratory illness.
Whether there is some level of cross-immunity between the endemic HCoVs and SARS-CoV2 that carries into
adulthood and can provide some level of protection from COVID-19 disease is the subject of this R01 application.
Our primary goal is to provide serologic and molecular evidence of anti-HCoV/SARS-CoV2 spike (S) cross-
reactive and neutralizing antibodies that can provide protection against SARS-CoV2 in vivo. We have an IRB-
approved protocol to collect blood samples on 250 COVID-19 individuals. Our COVID cohort is comprised of 5
groups that includes adult and pediatric cancer patients, adult and pediatric healthcare providers and adults
without COVID patient contact. In addition, we will study our pre-pandemic seasonal influenza cohort for
evidence of pre-existing anti-SARS-CoV2 S Abs. In Aim 1 we will quantify the present of anti-S HCoV antibodies
and quantitate their cross-reactivity to SARS-CoV2 S. The studies in subaim 1A will include FACS staining of
S expressing cells and ELISAs of S subdomains for epitope mapping. In subaim 1B, selected plasma samples
within each study group will be used for affinity column purification of plasma IgGs that will be passaged over
and eluted from one of 4 HCoV or SARS-CoV2 spike columns and tested for cross-binding, cross-Fc effector
activity and cross-neutralization activity. In subaim 1C, these purified IgGs will be tested in vivo in hACE2 mice
for cross-protection against SARS-CoV2 challenge. In Aim 2 we will establish the molecular basis by which bi-
directional immunity to among CoVs could provide cross immunity to HCoVs and SARS-CoV2 through common
spike epitope recognition. In subaim 2A, we will perform memory B (mB) cell screening for presence of S cross-
binding. Single mB cells that bind at least one hCoV S protein and SARS-CoV2 S will be isolated by FACS, their
cognate VH/VL genes cloned, expressed as whole IgG1 mAbs and tested for cross-binding, virus neutralization
and Fc effector activity against the different HoCoVs, SARS and SARS-CoV2. In subaim 2B, mAbs with cross-
CoV activity will be tested in mouse and hamster models for protection against SARS-CoV2 challenge. In
subaim 2C, we will adapt the novel LibraSeq technique to capture the single or multi-spike binding specificity,
BCR repertoires and transcriptomes of selected Bm cells to study the potential different evolutionary origins that
may exist between mono-spike and multi-spike binding cells. This R01 grant will provide proof-of-principle
molecular studies of HCoV/SARS-CoV2 Ab cross-immunity that may aid in COVID-19 vaccine design.
Terms: <0-11 years old><19S Gamma Globulin><2019 novel corona virus><2019 novel coronavirus><2019-nCoV><2019-nCoV vaccine><21+ years old><7S Gamma Globulin><ACE2><Ab-mediated immunity><Ab-mediated protection><Address><Adult><Adult Human><Affinity><Antibodies><Antibody Response><Antibody immunity><Antibody protection><Antibody-mediated protection><Antigenic Determinants><Assay><B blood cells><B cell><B cells><B-Cells><B-Lymphocytes><B-cell><Binding><Binding Determinants><Bioassay><Biologic Assays><Biological Assay><Blood Plasma><Blood Plasma Cell><Blood Sample><Blood specimen><CD8 Cell><CD8 T cells><CD8 lymphocyte><CD8+ T cell><CD8+ T-Lymphocyte><CD8-Positive Lymphocytes><CD8-Positive T-Lymphocytes><COVID><COVID infected patient><COVID patient><COVID positive patient><COVID-19><COVID-19 antibody><COVID-19 infected patient><COVID-19 infection><COVID-19 patient><COVID-19 positive patient><COVID-19 vaccine><COVID-19 virus><COVID19><COVID19 infection><COVID19 patient><COVID19 positive patient><COVID19 vaccine><COVID19 virus><CV-19><CV19><Cancer Patient><Cell Body><Cells><Cessation of life><Child><Child Youth><Childhood><Childhood Cancers><Children (0-21)><China><Clinical><Clinical Treatment Moab><CoV disease><CoV-2><CoV2><Coronaviridae><Coronaviridae Infections><Coronavirus><Coronavirus Infections><Cricetinae><Data><Data Bases><Databases><Death><Development><Disease><Disorder><ELISA><Enzyme-Linked Immunosorbent Assay><Epidemic><Epitope Mapping><Epitopes><Exposure to><External Domain><Extracellular Domain><Generations><Goals><Grant><HCoV><Hamsters><Hamsters Mammals><Health Care Providers><Health Personnel><Healthcare Providers><Healthcare worker><History><Human><IRB><IRBs><IgG><IgG1><IgM><Immune system><Immunity><Immunoglobulin G><Immunoglobulin M><Individual><Infection><Inflammatory><Influenza Vaccines><Institutional Review Boards><Knowledge><Lead><Literature><MERS><MERS coronavirus disease><MERS-CoV disease><Mainland China><Malignant Childhood Neoplasm><Malignant Childhood Tumor><Malignant Pediatric Neoplasm><Malignant Pediatric Tumor><Malignant childhood cancer><Memory B Cell><Memory B-Lymphocyte><Mice><Mice Mammals><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><Modeling><Modern Man><Molecular><Molecular Interaction><Monoclonal Antibodies><Murine><Mus><Patients><Pb element><Peptides><Plasma><Plasma Cells><Plasma Serum><Plasmacytes><Population><Principal Investigator><Property><Prophylactic treatment><Prophylaxis><Proteins><Protocol><Protocols documentation><Receptor Protein><Recording of previous events><Research><Reticuloendothelial System, Serum, Plasma><Risk Factors><SARS><SARS Virus><SARS corona virus><SARS corona virus 2><SARS coronavirus><SARS coronavirus disease><SARS-Associated Coronavirus><SARS-CoV><SARS-CoV 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Respiratory Syndrome-associated coronavirus 2><Severe Acute Respiratory Syndrome-related coronavirus 2><Severe acute respiratory syndrome associated corona virus 2><Severe acute respiratory syndrome corona virus 2><Severe acute respiratory syndrome coronavirus 2><Severe acute respiratory syndrome coronavirus 2 infection><Severe acute respiratory syndrome coronavirus 2 vaccine><Severe acute respiratory syndrome related corona virus 2><Specificity><Staining method><Stains><T-Cell Activation><T8 Cells><T8 Lymphocytes><Techniques><Testing><Vaccine Design><Virus><Wuhan coronavirus><adulthood><allergic/immunologic body system><allergic/immunologic organ system><angiotensin converting enzyme 2><angiotensin converting enzyme II><antibody against COVID-19><antibody against SARS-CoV-2><antibody against SARS-CoV2><antibody against coronavirus disease 2019><antibody against severe acute respiratory syndrome coronavirus 2><antibody to COVID-19><antibody to SARS-CoV-2><antibody to 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