Document text
Principal Investigator: Gregory Lee Szeto
Organization: SEATTLE CHILDREN'S HOSPITAL
Fiscal Year: 2024
Award: $125,294
Funding agency: National Institute of Allergy and Infectious Diseases
HIPC3 Scientific Project 3: Immune response to SARS-CoV-2 natural infection followed by vaccination
Abstract
This project will characterize the innate and adaptive immune response to SARS-CoV-2 natural infection in the
setting of mild disease and follow-on vaccination. We will define signatures correlating with reduced viral
shedding, progression to PASC or long COVID, and magnitude of adaptive immune responses in
convalescence and after vaccination. Our approach uses cutting-edge multi-omic single-cell technologies to
dissect the innate and adaptive immune response and identify correlates of protection, vaccine response, and
PASC. We will 1. Define the innate immune response during acute infection and test the hypothesis that
interindividual variation in viral shedding duration is partly regulated by differences in innate response. These
analyses will also include diverse participants to identify potential contributions by race/ethnicity. 2. Track the
evolution and kinetics of T cell responses to natural infection and follow-on vaccination. We hypothesize that
specific targeted epitopes and phenotypes will be more protective in short viral shedding, and that vaccines
induce unique, protective T cells that are not found in the convalescent repertoire. These studies will also
identify key helper T cell phenotypes for mounting robust humoral and cellular responses to natural infection
and vaccine. These signatures will also be correlated with innate immune signatures to identify innate-adaptive
coordination events 3. Characterize the immune response throughout infection and convalescence in PASC.
Innate and adaptive immunity will be analyzed from acute infection through convalescence to understand how
inflammation and antiviral response trajectories may differ in PASC compared to successful recovery. These
will enable hypotheses on the causal mechanisms of PASC and therapeutic targets from ongoing pathogenic
mechanisms. These results will enable improved clinical outcomes, treatment of existing PASC patients, and
can guide vaccine developments and boosters. Overall, our longitudinal analysis will associate immune
responses throughout disease to concrete functional outcomes including duration of viral shedding, PASC, and
vaccine response.
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Sequencing><Characteristics><Chronic><Clinical><CoV-2><CoV2><Convalescence><Coronavirus Infectious Disease 2019><Cytometry><Data><Diagnostic><Disease><Disorder><EB virus><EBV><Epitopes><Epstein Barr Virus><Ethnic Origin><Ethnicity><Event><Evolution><Flow Cytofluorometries><Flow Cytofluorometry><Flow Cytometry><Flow Microfluorimetry><Flow Microfluorometry><Future><Goals><HHV-4><HHV4><HIV><Helper Cells><Helper T-Cells><Helper T-Lymphocytes><Helper-Inducer T-Cells><Helper-Inducer T-Lymphocyte><Human Herpesvirus 4><Human Immunodeficiency Viruses><Humoral Immunities><Immune><Immune Mediators><Immune Mediators/Modulators><Immune Regulators><Immune response><Immunes><Immunity><Immunization><Immunochemical Immunologic><Immunologic><Immunological><Immunological response><Immunologically><Immunologics><Inducer Cells><Inducer T-Lymphocytes><Infection><Infectious Mononucleosis Virus><Inflammation><Inflammatory><Innate Immune Response><Innate Immunity><Kinetics><LAV-HTLV-III><Long COVID><Long COVID-19><Long coronavirus disease><Long coronavirus disease 2019><Long-term cohort><Longitudinal cohort><Longterm cohort><Lymphadenopathy-Associated Virus><Malaria><Maps><Molecular><Native Immunity><Natural Immunity><Non-Specific Immunity><Nonspecific Immunity><Outcome><PASC><Paludism><Participant><Pathogenicity><Patients><Peptide-MHC><Peptide-Major Histocompatibility Protein Complex><Peptide/MHC Complex><Phenotype><Plasmodium Infections><Post Acute Sequelae of COVID19><Post Acute Sequelae of SARS-CoV-2><Post Acute Sequelae of SARS-CoV2><Post Acute Sequelae of severe acute respiratory syndrome coronavirus 2><Post-Acute Sequelae of SARS-CoV-2 Infection><Prevalence><Prognostic Marker><Proteomics><RNA vaccine><RNA-based vaccine><Race><Races><Recovery><SARS corona virus 2><SARS-CO-V2><SARS-COVID-2><SARS-CoV-2><SARS-CoV-2 immune response><SARS-CoV-2 infection><SARS-CoV2><SARS-CoV2 infection><SARS-associated corona virus 2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-related 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Intervention><Time><Vaccination><Vaccination acquired immunity><Vaccination induced immunity><Vaccine Design><Vaccines><Variant><Variation><Viral Burden><Viral Load><Viral Load result><Viral Respiratory Tract Infection><Viral Shedding><Virus><Virus Shedding><Virus-HIV><Work><Wuhan coronavirus><active followup><acute COVID-19><acute SARS-CoV-2 infection><acute infection><acute phase of COVID-19><acute phase of SARS-CoV-2 infection><adaptive immune response><adaptive immunity><adverse sequelae of COVID><adverse sequelae of COVID-19><adverse sequelae of coronavirus disease><adverse sequelae of coronavirus disease 2019><ages><analyzing longitudinal><antibody-based immunity><bio-markers><biologic marker><biomarker><burden of disease><burden of illness><cellular indexing of transcriptomes and epitopes by single cell sequencing><chronic COVID><chronic COVID-19><chronic COVID-19 sequelae><chronic novel coronavirus disease 2019><chronic symptom><cohort><coronavirus disease 2019><coronavirus 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syndrome coronavirus 2><long haul COVID><long haul COVID-19><long haul coronavirus disease><long haul coronavirus disease 2019><long haul sequelae of COVID-19><long haul sequelae of coronavirus disease 2019><long-hauler COVID><long-hauler COVID-19><long-hauler coronavirus disease 2019><long-hauler syndrome><long-term COVID><long-term COVID-19><long-term coronavirus disease><long-term coronavirus disease 2019><long-term sequelae of COVID-19><long-term sequelae of SARS-CoV-2><long-term sequelae of coronavirus disease 2019><long-term sequelae of severe acute respiratory syndrome coronavirus 2><longitudinal analysis><longterm COVID><longterm COVID-19><longterm coronavirus disease><longterm coronavirus disease 2019><mRNA vaccine><mRNA-based vaccine><multiomics><multiple omics><nCoV2><new drug target><new druggable target><new pharmacotherapy target><new therapeutic target><new therapy target><novel drug target><novel druggable target><novel pharmacotherapy target><novel therapeutic target><novel therapy target><pMHC><panomics><persistent COVID-19><persistent symptom><post COVID syndrome><post COVID-19 sequelae><post COVID-19 syndrome><post acute COVID syndrome><post acute COVID-19><post acute COVID-19 syndrome><post acute SARS-CoV-2><post acute coronavirus disease 2019><post acute coronavirus disease 2019 syndrome><post acute coronavirus disease syndrome><post acute sequelae following COVID-19><post acute severe acute respiratory syndrome coronavirus 2><post coronavirus disease 2019 syndrome><post coronavirus disease syndrome><post-acute phases of COVID-19><post-acute sequelae following SARS-CoV-2 infection><post-acute sequelae of COVID-19><post-acute sequelae of acute COVID infection><post-acute sequelae of coronavirus disease 2019><predictive biomarkers><predictive marker><predictive molecular biomarker><prognostic biomarker><prolonged COVID-19 symptoms><racial><racial background><racial diversity><racial origin><racially diverse><response><scRNA-seq><serious 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