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Principal Investigator: KENNETH D STUART
Organization: SEATTLE CHILDREN'S HOSPITAL
Fiscal Year: 2024
Award: $349,031
Funding agency: National Institute of Allergy and Infectious Diseases
Scientific Project 1: Immune Responses to Pre-erythrocytic Malaria Vaccination or Infection
Abstract
This project will identify and characterize key characteristics of human immune responses to the pre-erythrocytic
(PE) falciparum malaria infection and vaccination that targets this stage with a focus on responses that correlate
with protection or infection. We hypothesize that responses by protected vs. not protected, and infected subjects
will identify the relevant immune constituents and processes. We will use complementary immunological
analyses and systems immunology approaches and characterize responses in the innate and adaptive immune
compartments to identify cellular and humoral responses that correlate with protection or infection. We will: 1.
Define cellular and soluble mediators of early innate responses and test the hypothesis that innate response
variations affect adaptive responses and are predictive of protective immunity development. We will also analyze
the influence of prior malaria exposure on vaccine efficacy. 2. Define the stimulation and temporal programming
of vaccine-elicited protective adaptive immune cells with a focus on the stimulation, signaling, and programming
of T and B cells and which pathways lead to protective phenotypes. We hypothesize that key signaling and
maturation pathways lead to protective adaptive immunity. Details of antigen receptor usage, cell lineages,
transcriptional programming, and phenotypic changes will be integrated with innate signaling events to define
events that shepherd cells through recall and maturation during immunization. 3. Connect protective phenotypes
with adaptive immune functional activity to identify functional characteristics of cellular and humoral
responses that correlate with protection. Antigen specific reactive T cell responses will be analyzed by
cytometric, functional, single-cell sequencing, and multi-omics methods. B functions will be analyzed by
deep multi-parametric analysis of sera and monoclonal antibodies. This will identify key functional characteristics
of cell populations and antibodies that are associated with immune protection. Integration of cell phenotypes and
functional activities of multiple immune compartments will give insights into immune signatures and processes
that define protective responses to malaria vaccines and provide benchmarks to guide vaccine development.
Overall, our integrated immunological and systems biology analyses of samples from malaria vaccine trials will
identify immune signatures during critical stages following vaccination which correlate with protection against
malaria or result from its infection and advance understanding of factors that impact development of elicited
protective immune responses.
Terms: <AIDS Virus><Acquired Immune Deficiency Syndrome Virus><Acquired Immunodeficiency Syndrome Virus><Adaptive Immune System><Affect><Antibodies><Antibody Response><Antigen Receptors><Antigens><Assay><Attenuated><B blood cells><B cell><B cells><B-Cells><B-Lymphocytes><B-cell><Benchmarking><Best Practice Analysis><Bioassay><Biological Assay><Blood Serum><Blood erythrocyte><Blood monocyte><COVID-19 infection><COVID-19 virus infection><COVID19 infection><Cell Body><Cell Communication and Signaling><Cell Function><Cell Lineage><Cell Physiology><Cell Process><Cell Signaling><Cells><Cellular Function><Cellular Physiology><Cellular Process><Characteristics><Clinical Treatment Moab><Development><Erythrocytes><Erythrocytic><Evaluation><Event><Falciparum Malaria><Fingerprint><Future><Gene Transcription><Generations><Genetic><Genetic Algorithm><Genetic Programming><Genetic Transcription><Goals><HIV><Human><Human Characteristics><Human Immunodeficiency Viruses><Human Nature><Immune><Immune response><Immunes><Immunity><Immunization><Immunochemical Immunologic><Immunologic><Immunological><Immunological response><Immunologically><Immunologics><Immunology><Infection><Innate Immune System><Intracellular Communication and Signaling><LAV-HTLV-III><Lead><Lymphadenopathy-Associated Virus><Malaria><Malaria Vaccines><Malarial Vaccines><Marrow erythrocyte><Marrow monocyte><Mediating><Mediator><Methods><Modern Man><Molecular><Monoclonal Antibodies><Multiparametric Analysis><Outcome><P falciparum><P. falciparum><P.falciparum><PBMC><Paludism><Pathway interactions><Pb element><Peptides><Peripheral Blood Mononuclear Cell><Phenotype><Plasmodium Infections><Plasmodium falciparum><Plasmodium falciparum Malaria><Population><Process><RNA Expression><Red Blood Cells><Red Cell><SARS-CoV-2 infection><SARS-CoV2 infection><Sampling><Serum><Severe acute respiratory syndrome coronavirus 2 infection><Signal Transduction><Signal Transduction Systems><Signaling><Single cell seq><Sorting><Sporozoites><Staining method><Stains><Subcellular Process><System><Systems Biology><T cell response><T-Cells><T-Lymphocyte><Testing><Transcription><Vaccination><Vaccines><Variant><Variation><Virus-HIV><acquired immune system><adaptive immunity><attenuate><attenuates><benchmark><biological signal transduction><blood corpuscles><coronavirus disease 2019 infection><cytokine><develop a vaccine><develop therapy><develop vaccines><development of a vaccine><developmental><heavy metal Pb><heavy metal lead><high dimensionality><host response><immune system response><immunogen><immunoresponse><improved><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><intervention development><mAbs><malaria infection><malaria-infected><malarial infection><monoclonal Abs><monocyte><multiomics><multiple omics><panomics><pathway><response><single cell next generation sequencing><single cell sequencing><therapy development><thymus derived lymphocyte><treatment development><vaccination study><vaccination trial><vaccine development><vaccine efficacy><vaccine response><vaccine responsiveness><vaccine study><vaccine trial><vaccine-induced response><vaccines against malaria>