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Principal Investigator: WEN-YUAN E HSIEH
Organization: UNIVERSITY OF COLORADO DENVER
Fiscal Year: 2022
Award: $621,860
Funding agency: National Institute of Allergy and Infectious Diseases
PROJECT SUMMARY
Emergence of the highly transmissible SARS-CoV-2 B.1.617.2 (Delta) variant and return to in-person learning is rapidly increasing the COVID-19 disease incidence and transmission rate in children. Therefore, it is critical to protect younger children. Toward this goal, ongoing COVID-19 vaccine clinical trials aim to reach those as young as 6 months old. Because pediatric trials involve fewer participants and children have a lower rate of symptomatic infection, pediatric vaccine efficacy will be initially based on in vitro immunological parameters virus neutralization and antibodies to the receptor-binding domain (RBD) or S1 fragment of the SARS-CoV-2 spike protein. However, whether these same metrics reflect an effective vaccine response in a developing immune system (<5 years old) remains to be determined. Immune responses to vaccines are influenced by age-associated physiological changes, particularly in the first 5 years of life when changes occur in B and T cell differentiation and effector functions, affinity maturation of B cell responses, and myeloid subpopulations and their cytokine production. Additionally, in very young children mucosal lgA rapidly reach adult levels, while serum lgA only reaches adult levels in adolescence. This difference may account for the disparate COVID-19 disease incidence, transmission, and severity in children. How evolving changes in pediatric mucosal and systemic immune ontogeny affect SARS-CoV-2 infection- and mRNA vaccination-elicited immune responses are incompletely understood. The overall obiective here is to define mucosal and systemic SARS-CoV-2 infection- and mRNA vaccine- elicited molecular and immune cellular responses in healthy pediatric maturing immune systems and in pathological B cell states (inborn or acquired).
In a Pfizer-vaccinated adult cohort, compared to healthy adults, we have found that B cell depleted adult multiple sclerosis patients exhibited a significantly increased RBD-specific CD8 T cell response, despite negligible production of anti-RBD lgG. Interestingly, in children homeostatic and induced lgA levels are minimally affected by B cell depleting therapies. Our central hypothesis is that mRNA vaccination within the pediatric population augments mucosal (IFN and lgA) and CD8 T cellular immune parameters in the youngest children (<5yo) relative to older children (>5yo). We predict that such immune profile will i) correlate with vaccine- and infection-elicited responses, supporting their limited infection pathology (Aim 1); and ii) become enhanced in those children with B cell deficiencies (Aim 2). To test this hypothesis and its predictions, we will i) establish a prospective longitudinal cohort of SARS-CoV-2 infected/vaccinated healthy and B cell deficient children across age groups; and ii) apply transcriptomic, immune phenotypic, and antigen-specific humoral and cellular studies to compare SARS-CoV-2 vaccine- and infection-elicited molecular and cellular signatures in healthy children and those with inborn and acquired B cell defects. Resulting insights will define metrics of infection/vaccine immunity, constituting an initial step toward establishing correlates of protection in immunocompetent/B deficient children.
Terms: <0-11 years old><12-20 years old><2019 novel corona virus><2019 novel coronavirus><2019-nCoV><2019-nCoV S protein><2019-nCoV spike glycoprotein><2019-nCoV spike protein><2019-nCoV vaccine><21+ years old><5 year old><5 years of age><7S Gamma Globulin><Adolescence><Adult><Adult Human><Affect><Affinity><Age><Antigens><B blood cells><B cell><B cells><B-Cell Deficiency><B-Cells><B-Lymphocytes><B-cell><B.1.617.2><Blood Serum><CD8><CD8 Cell><CD8 T cells><CD8 lymphocyte><CD8+ T cell><CD8+ T-Lymphocyte><CD8-Positive Lymphocytes><CD8-Positive T-Lymphocytes><CD8B><CD8B1><CD8B1 gene><CK8><COVID disparity><COVID related disparity><COVID-19><COVID-19 S protein><COVID-19 disparity><COVID-19 induced disparity><COVID-19 infection><COVID-19 related disparity><COVID-19 spike glycoprotein><COVID-19 spike protein><COVID-19 vaccination><COVID-19 vaccine><COVID-19 virus><COVID19><COVID19 S protein><COVID19 disparity><COVID19 infection><COVID19 spike glycoprotein><COVID19 spike protein><COVID19 vaccination><COVID19 vaccine><COVID19 virus><CV-19><CV19><Child><Child Youth><Childhood><Children (0-21)><CoV-2><CoV2><Cytokeratin-8 Staining Method><Defect><Delta variant><Disease><Disorder><Exhibits><Future><Generalized Growth><Genetic><Goals><Growth><IFN><IgA><IgG><Immune><Immune response><Immune system><Immunes><Immunity><Immunochemical Immunologic><Immunocompetent><Immunoglobulin A><Immunoglobulin G><Immunologic><Immunological><Immunological response><Immunologically><Immunologics><In Vitro><Incidence><Infection><Interferons><Knowledge><LYT3><Learning><Life><Long-term cohort><Longitudinal cohort><Longterm cohort><MS patient><Mission><Molecular><Morbidity><Morbidity - disease rate><Mucosa><Mucosal Tissue><Mucous Membrane><Myelogenous><Myeloid><NIH><National Institutes of Health><Participant><Pathologic><Pathology><Persons><Phenotype><Physiologic><Physiological><Population><Production><Public Health><RNA immunization><RNA vaccination><RNA vaccine><RNA-based vaccine><Research><SARS corona virus 2><SARS-CO-V2><SARS-COVID-2><SARS-CoV-2><SARS-CoV-2 B.1.617.2><SARS-CoV-2 S protein><SARS-CoV-2 delta><SARS-CoV-2 infection><SARS-CoV-2 spike glycoprotein><SARS-CoV-2 spike protein><SARS-CoV-2 vaccination><SARS-CoV-2 vaccine><SARS-CoV2><SARS-CoV2 S protein><SARS-CoV2 infection><SARS-CoV2 spike glycoprotein><SARS-CoV2 spike protein><SARS-CoV2 vaccine><SARS-associated corona virus 2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-coronavirus-2 vaccine><SARS-related corona virus 2><SARS-related coronavirus 2><SARSCoV2><Serum><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 CoV 2 vaccine><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 corona virus 2><Severe acute respiratory syndrome coronavirus 2><Severe acute respiratory syndrome coronavirus 2 S protein><Severe acute respiratory syndrome coronavirus 2 infection><Severe acute respiratory syndrome coronavirus 2 spike glycoprotein><Severe acute respiratory syndrome coronavirus 2 spike protein><Severe acute respiratory syndrome coronavirus 2 vaccination><Severe acute respiratory syndrome coronavirus 2 vaccine><Severe acute respiratory syndrome related corona virus 2><Severities><T cell differentiation><T cell response><T8 Cells><T8 Lymphocytes><Testing><Tissue Growth><Transmission><United States National Institutes of Health><Vaccinated><Vaccination><Vaccine Clinical Trial><Vaccines><Virus><Work><Wuhan coronavirus><adaptive immune response><adolescence (12-20)><adulthood><age 5 years><age group><ages><allergic/immunologic body system><allergic/immunologic organ system><base><cohort><corona virus disease 2019><corona virus disease 2019 vaccine><coronavirus disease 2019><coronavirus disease 2019 S protein><coronavirus disease 2019 disparity><coronavirus disease 2019 infection><coronavirus disease 2019 spike glycoprotein><coronavirus disease 2019 spike protein><coronavirus disease 2019 vaccination><coronavirus disease 2019 vaccine><coronavirus disease 2019 virus><coronavirus disease-19><coronavirus disease-19 vaccine><coronavirus disease-19 virus><coronavirus infectious disease-19><cytokine><disparities in COVID><disparities in COVID-19><disparity due to COVID-19><five year old><five years of age><hCoV19><host response><humoral immunity deficiency><immune competent><immune system response><immunization strategy><immunogen><immunoresponse><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><mRNA immunization><mRNA vaccination><mRNA vaccine><mRNA-based vaccine><mortality><multiple sclerosis patient><nCoV2><neutralizing antibody><ontogeny><patients with MS><patients with multiple sclerosis><pediatric><prospective><receptor binding><receptor bound><response><severe acute respiratory syndrome coronavirus 2 B.1.617.2><stem><transcriptomics><transmission process><vaccinate against COVID-19><vaccinate against COVID19><vaccinate against SARS-CoV-2><vaccinate against coronavirus disease 2019><vaccinate against severe acute respiratory syndrome coronavirus 2><vaccination against COVID-19><vaccination against COVID19><vaccination against SARS-CoV-2><vaccination against Severe acute respiratory syndrome coronavirus 2><vaccination against coronavirus disease 2019><vaccination strategy><vaccine against 2019-nCov><vaccine against SARS-CoV-2><vaccine against SARS-CoV2><vaccine against SARS-coronavirus-2><vaccine against Severe Acute Respiratory Syndrome CoV 2><vaccine against Severe acute respiratory syndrome coronavirus 2><vaccine efficacy><vaccine for novel coronavirus><vaccine response><vaccine responsiveness><vaccine-induced response><youngster>