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Principal Investigator: Ralph S Baric
Organization: UNIV OF NORTH CAROLINA CHAPEL HILL
Fiscal Year: 2024
Award: $136,800
Funding agency: National Cancer Institute
Abstract
Zoonotic coronaviruses (CoV) are responsible for three major epidemics/pandemics in the 21st century, including
Severe Acute Respiratory Coronavirus (SARS-CoV) in 2003 and the Middle East Respiratory coronavirus
(MERS-CoV) in 2012. In Dec 2019, a third novel CoV designated SARS-CoV-2 emerged in Wuhan China and
has caused over 13 million cases, >570,000 deaths in >220 countries. In the expanding US epidemic, SARS-
CoV2 has caused >137,000 deaths and significantly more severe infections characterized by pneumonia, severe
acute respiratory distress syndrome (ARDS), coagulopathies, and inflammatory disorders. Incredibly, careful
analyses of zoonotic bat CoV has revealed the presence of numerous group 2b SARS-like, group 2c MERS-like
and remarkably, group 1 strains that replicate efficiently in primary human airway or gut enteroid cultures. To
prepare for future CoV calamities, defined diagnostic assays and serologic investigations are essential for
tracking current and future outbreaks and evaluate type specific and broad serologic immunity associated with
population immunity. The goal of this U54 Center Program is to develop novel type- and group-specific serologic
and neutralization assays (Project 1-Baric, Project 2-, Core B and C) designed to characterize the serological
repertoire and to identify key domain-specific mucosal and systemic neutralizing and non-neutralizing antibodies
after SARS-CoV-2 infection. One key underlying hypothesis is that IgA and IgG repertoires are different across
mucosal and systemic compartments and target unique and overlapping epitope domains in the SARS-CoV2 S
glycoprotein. Another underlying hypothesis is that intervention strategies can altered the memory B cell and
antibody repertoires in mucosal and serologic compartments. Finally the program develops novel mouse models
of human disease designed to mechanistically address fundamental immune innate and adaptive interactions
associated with protective immunity. The Project uses novel technologies, basic and applied strategies to build
a portfolio of reagents that map, track and treat SARS-CoV2 and other SARS-like group 2b CoV of the future.
In Aim 1, we evaluate the kinetics, magnitude, durability of type specific neutralizing antibody responses after
infection. Aim 2 characterizes the breadth of the mucosal and systemic serologic repertoires across
Sarbecoviruses. In Aim 3, we characterize the antibodies in the mucosal and serum serologic repertoires using
a variety of in vitro and in vivo platforms, designed to reveal correlates associated with protective immunity. To
achieve our goals, the project interfaces closely with other projects and cores within the Center.
Terms: <2019 novel corona virus><2019 novel coronavirus><2019-nCoV><2019-nCoV S protein><2019-nCoV spike glycoprotein><2019-nCoV spike protein><7S Gamma Globulin><ARDS><Ab response><Acute Respiratory Distress><Acute Respiratory Distress Syndrome><Address><Adult ARDS><Adult RDS><Adult Respiratory Distress Syndrome><Antibodies><Antibody Formation><Antibody Production><Antibody Repertoire><Antibody Response><Antibody Therapy><Antibody-Dependent Enhancement><Antigenic Determinants><Applied Research><Applied Science><Assay><Bats><Binding Determinants><Bioassay><Biological Assay><Blood Coagulation Disorders><Blood Serum><COVID assay><COVID crisis><COVID epidemic><COVID infected patient><COVID pandemic><COVID patient><COVID positive patient><COVID-19><COVID-19 S protein><COVID-19 assay><COVID-19 crisis><COVID-19 epidemic><COVID-19 era><COVID-19 exposure><COVID-19 global health crisis><COVID-19 global pandemic><COVID-19 health crisis><COVID-19 immunity><COVID-19 infected patient><COVID-19 infection><COVID-19 pandemic><COVID-19 patient><COVID-19 period><COVID-19 positive patient><COVID-19 public health crisis><COVID-19 spike><COVID-19 spike glycoprotein><COVID-19 spike protein><COVID-19 therapy><COVID-19 treatment><COVID-19 virus><COVID-19 virus infection><COVID-19 years><COVID19 assay><COVID19 infection><COVID19 patient><COVID19 positive patient><COVID19 virus><CV-19><Cessation of life><China><Chiroptera><Clinical Immunology><CoV emergence><CoV-2><CoV2><Coagulation Disorder><Coagulopathy><Collaborations><Collection><Coronaviridae><Coronaviridae Infections><Coronavirus><Coronavirus Infections><Coronavirus Infectious Disease 2019><Country><Da Nang Lung><Data><Death><Diagnostic Reagent><Disease><Disorder><Epidemic><Epitopes><Future><Glycoproteins><Goals><Human><IgA><IgG><Immune><Immunes><Immunity><Immunoglobulin A><Immunoglobulin G><Immunology><In Vitro><Infection><Inflammatory><Intervention><Intervention Strategies><Investigation><Kinetics><Lentivirinae><Lentivirus><MERS><MERS corona virus><MERS coronavirus><MERS coronavirus disease><MERS virus><MERS-CoV><MERS-CoV disease><Mainland China><Maps><Measures><Memory B Cell><Memory B-Lymphocyte><Middle East Respiratory Syndrome><Middle East Respiratory Syndrome CoV disease><Middle East Respiratory Syndrome Corona Virus><Middle East Respiratory Syndrome Coronavirus><Middle East Respiratory Syndrome Virus><Middle East Respiratory Syndrome coronavirus disease><Middle East Respiratory Syndrome-CoV><Middle East Respiratory Virus><Middle East Respiratory coronavirus><Middle Eastern Respiratory Syndrome><Middle Eastern Respiratory Syndrome CoV disease><Middle Eastern Respiratory Syndrome Corona virus><Middle Eastern Respiratory Syndrome Coronavirus><Middle Eastern Respiratory Syndrome Virus><Middle Eastern Respiratory Syndrome coronavirus disease><Middle Eastern Respiratory Syndrome-CoV><Modeling><Modern Man><Mucosa><Mucosal Immunity><Mucosal Tissue><Mucous Membrane><North Carolina><Outcome><Pathogenicity><Persons><Play><Pneumonia><Population><Public Health><Reagent><Recombinants><Role><SARS><SARS Virus><SARS corona virus><SARS corona virus 2><SARS coronavirus><SARS coronavirus disease><SARS-Associated Coronavirus><SARS-CO-V2><SARS-COVID-2><SARS-CoV><SARS-CoV disease><SARS-CoV-1><SARS-CoV-2><SARS-CoV-2 S><SARS-CoV-2 S protein><SARS-CoV-2 assay><SARS-CoV-2 epidemic><SARS-CoV-2 exposure><SARS-CoV-2 global health crisis><SARS-CoV-2 global pandemic><SARS-CoV-2 immunity><SARS-CoV-2 infected patient><SARS-CoV-2 infection><SARS-CoV-2 pandemic><SARS-CoV-2 patient><SARS-CoV-2 positive patient><SARS-CoV-2 spike><SARS-CoV-2 spike glycoprotein><SARS-CoV-2 spike protein><SARS-CoV-2 therapy><SARS-CoV-2 treatment><SARS-CoV2><SARS-CoV2 exposure><SARS-CoV2 infection><SARS-Related Coronavirus><SARS-associated corona virus 2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-coronavirus-2 epidemic><SARS-coronavirus-2 pandemic><SARS-related corona virus 2><SARS-related coronavirus 2><SARSCoV2><Sampling><Sarbecovirus><Serodiagnoses><Serological Diagnosis><Serology><Serum><Severe Acute Respiratory Coronavirus><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><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 disease><Severe Acute Respiratory Syndrome Virus><Severe Acute Respiratory Syndrome corona virus><Severe Acute Respiratory Syndrome coronavirus><Severe Acute Respiratory Syndrome coronavirus disease><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 S protein><Severe acute respiratory syndrome coronavirus 2 epidemic><Severe acute respiratory syndrome coronavirus 2 exposure><Severe acute respiratory syndrome coronavirus 2 immunity><Severe acute respiratory syndrome coronavirus 2 infection><Severe acute respiratory syndrome coronavirus 2 pandemic><Severe acute respiratory syndrome coronavirus 2 spike glycoprotein><Severe acute respiratory syndrome coronavirus 2 spike protein><Severe acute respiratory syndrome related corona virus 2><Shock Lung><Specificity><Stiff lung><Study models><Technology><Texas><Therapeutic antibodies><Time><Translational Research><Translational Science><Treatment Protocols><Treatment Regimen><Treatment Schedule><Vaccination><Viral><Virus><Work><Wuhan coronavirus><Zoonoses><Zoonotic><Zoonotic Infection><after COVID-19 infection><after SARS-CoV-2 infection><after SARS-CoV2 infection><after infection by SARS-CoV-2><after severe acute respiratory distress syndrome CoV-2 infection><aged mice><aged mouse><antibody based therapies><antibody biosynthesis><antibody treatment><antibody-based therapeutics><antibody-based treatment><bleeding disorder><clinical care><clotting disorder><cohort><convalescent plasma><corona virus><corona virus emergence><coronavirus disease 2019><coronavirus disease 2019 S protein><coronavirus disease 2019 assay><coronavirus disease 2019 crisis><coronavirus disease 2019 epidemic><coronavirus disease 2019 exposure><coronavirus disease 2019 global health crisis><coronavirus disease 2019 global pandemic><coronavirus disease 2019 health crisis><coronavirus disease 2019 immunity><coronavirus disease 2019 infected patient><coronavirus disease 2019 infection><coronavirus disease 2019 pandemic><coronavirus disease 2019 patient><coronavirus disease 2019 positive patient><coronavirus disease 2019 public health crisis><coronavirus disease 2019 spike glycoprotein><coronavirus disease 2019 spike protein><coronavirus disease 2019 therapy><coronavirus disease 2019 treatment><coronavirus disease 2019 virus><coronavirus disease assay><coronavirus disease crisis><coronavirus disease epidemic><coronavirus disease infected patient><coronavirus disease pandemic><coronavirus disease patient><coronavirus disease positive patient><coronavirus disease-19><coronavirus disease-19 global pandemic><coronavirus disease-19 pandemic><coronavirus disease-19 patient><coronavirus disease-19 virus><coronavirus emergence><coronavirus infectious disease-19><coronavirus patient><design><designing><diagnostic assay><diagnostic serology><elderly mice><emergent CoV><emergent corona virus><emergent coronavirus><emerging CoV><emerging corona virus><emerging coronavirus><exposure to COVID-19><exposure to SARS-CoV-2><exposure to SARS-CoV2><exposure to Severe acute respiratory syndrome coronavirus 2><exposure to coronavirus disease 2019><following COVID-19 infection><following SARS-CoV-2 infection><following SARS-CoV2 infection><following infection by SARS-CoV-2><following severe acute respiratory distress syndrome CoV-2 infection><future outbreak><hCoV19><human disease><human model><immunity against COVID-19><immunity against SARS-CoV-2><immunity against Severe acute respiratory syndrome coronavirus 2><immunity against coronavirus disease 2019><immunity to COVID-19><immunity to SARS-CoV-2><immunity to Severe acute respiratory syndrome coronavirus 2><immunity to coronavirus disease 2019><immunoglobulin biosynthesis><improved><in vivo><infected with COVID-19><infected with COVID19><infected with SARS-CoV-2><infected with SARS-CoV2><infected with coronavirus disease 2019><infected with severe acute respiratory syndrome coronavirus 2><insight><interventional strategy><model of human><mouse model><murine model><nCoV><nCoV2><neutralizing antibody><new CoV><new corona virus><new coronavirus><new diagnostics><new technology><next generation diagnostics><next outbreak><novel><novel CoV><novel corona virus><novel coronavirus><novel diagnostics><novel technologies><old mice><outbreak in the future><pandemic><pandemic disease><patient infected with COVID><patient infected with COVID-19><patient infected with SARS-CoV-2><patient infected with coronavirus disease><patient infected with coronavirus disease 2019><patient infected with severe acute respiratory syndrome coronavirus 2><patient with COVID><patient with COVID-19><patient with COVID19><patient with SARS-CoV-2><patient with coronavirus disease><patient with coronavirus disease 2019><patient with severe acute respiratory distress syndrome coronavirus 2><post SARS-CoV-2 infection><prevent><preventing><previous COVID-19 infection><previous SARS-CoV-2 infection><previous SARS-CoV2 infection><previous severe acute respiratory distress syndrome CoV-2 infection><prior COVID-19 infection><prior SARS-CoV-2 infection><prior SARS-CoV2 infection><prior severe acute respiratory distress syndrome CoV-2 infection><programs><response><reverse genetics><severe acute respiratory syndrome coronavirus 2 assay><severe acute respiratory syndrome coronavirus 2 global health crisis><severe acute respiratory syndrome coronavirus 2 global pandemic><severe acute respiratory syndrome coronavirus 2 infected patient><severe acute respiratory syndrome coronavirus 2 patient><severe acute respiratory syndrome coronavirus 2 positive patient><severe acute respiratory syndrome coronavirus 2 therapy><severe acute respiratory syndrome coronavirus 2 treatment><severe acute respiratory syndrome-CoV><social role><spike proteins on SARS-CoV-2><time use><translation research><translational investigation><treat COVID-19><treat SARS-CoV-2><treat coronavirus disease 2019><treat severe acute respiratory syndrome coronavirus 2><vaccine candidate><wet lung><zoonotic CoV><zoonotic coronavirus>