A novel strategy for vaccine-induced protection against maternal-to-fetal transmission of Zika virus
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Principal Investigator: Sujan Shresta Organization: LA JOLLA INSTITUTE FOR IMMUNOLOGY Fiscal Year: 2024 Award: $894,640 Funding agency: National Institute of Allergy and Infectious Diseases Project Summary The long-term goal of this project is to develop a vaccine that confers robust and durable protection against transplacental transmission of Zika virus (ZIKV). Accomplishing this goal may be challenging in that the vaccine may need to induce both antibody and T cell responses to confer highly effective protection against ZIKV at the maternal-fetal interface (MFI). Studies with pregnant women in Brazil have suggested that antibody responses may contribute to pathogenesis of congenital Zika syndrome (CZS) and neutralizing antibody responses may not correlate with protection against CZS. Recent human studies also suggest that the anti-ZIKV antibody response may be less durable than T cell response. However, ongoing ZIKV vaccine development efforts are focused on eliciting mainly antibody responses. Based on our published data demonstrating a critical role for CD8 T cells in protecting against ZIKV infection in multiple mouse models, we will test our central hypothesis that a robust ZIKV vaccine-induced CD8 T cell response in mothers is required to provide strong and durable protection against transplacental transmission of ZIKV. Our replicon RNA vaccine expressing ZIKV premembrane (prM) and envelope (E) or nonstructural protein 3 (NS3) induces robust protection against ZIKV infection in pregnant mice but only partial protection in their fetuses. Therefore, we will use these replicon RNA vaccines and mouse models to achieve the following Specific Aims: 1) Improve vaccine-induced protection against ZIKV infection during pregnancy, and identify the maternal immune responses associated with the most protective and durable vaccines. 2) Test the role of CD8 T cells in vaccine-induced protection, and determine precise features of MFI CD8 T cells elicited by the most protective and durable vaccine. We have expertise in examining flaviviral pathogenesis and immunity using mouse models. We also have a longstanding collaboration with colleagues at our institute and UC San Diego to investigate virus-host interactions using genomics and histopathology-informed approaches. Terms: <(TNF)-α><0-11 years old><2019 novel corona virus><2019 novel coronavirus><2019-nCoV><ATAC sequencing><ATAC-seq><ATACseq><Allogenic><Antibodies><Antibody Response><Antibody titer measurement><Antibody-Dependent Enhancement><Antigens><Assay for Transposase-Accessible Chromatin using sequencing><BALB C Mouse><BALB/c><Biology><Birth><Birth Defects><Blood Serum><Body Tissues><Brazil><Breakbone Fever Virus><CD134><CD4 Cells><CD4 Positive T Lymphocytes><CD4 T cells><CD4 helper T cell><CD4 lymphocyte><CD4+ T-Lymphocyte><CD4-Positive Lymphocytes><CD8 Cell><CD8 T cells><CD8 lymphocyte><CD8+ T cell><CD8+ T-Lymphocyte><CD8-Positive Lymphocytes><CD8-Positive T-Lymphocytes><COVID-19 virus><COVID19 virus><Cachectin><Cell Body><Cell Protection><Cells><Cells Placenta-Tissue><Child><Child Youth><Children (0-21)><CoV-2><CoV2><Cognitive deficits><Collaborations><Congenital Abnormality><Congenital Anatomical Abnormality><Congenital Defects><Congenital Deformity><Congenital Malformation><Cytoprotection><DENV><DENV vaccine><Data><Dengue Vaccine><Dengue Virus><Dengue fever virus><Dengue virus vaccine><ELISA><Enzyme-Linked Immunosorbent Assay><Epidemic><Exhibits><Exposure to><Female><Fetal Body Weight><Fetal Weight><Fetomaternal Transmission><Fetus><Flavivirus><Genomics><Gestation><Goals><Granzyme><Group B Arbovirus><Haplotypes><Height><Histopathology><Human><Humoral Immunities><Immune response><Immunity><Immunization><Immunological response><Inbred BALB C Mice><Incidence><Individual><Infection><Learning><Life><Live Birth><Longitudinal Studies><Macrophage-Derived TNF><Maternal-Fetal Exchange><Maternal-Fetal Transmission><Mediating><Membrane><Mice><Mice Mammals><Modeling><Modern Man><Molecular Fingerprinting><Molecular Profiling><Monocyte-Derived TNF><Mothers><Murine><Mus><Neurodevelopmental Impairment><Neutralization Tests><Non-structural Protein><Nonstructural Protein><Normal Placentoma><OX40><Orthoflavivirus><Parturition><Pathogenesis><Pathology><Pathway interactions><Persons><Placenta><Placenta Embryonic Tissue><Placentome><Pregnancy><Pregnant Women><Protocol><Protocols documentation><Public Health><Publishing><RNA vaccine><RNA-based vaccine><Replication Unit><Replicon><Reporting><Risk Factors><Role><SARS corona virus 2><SARS-CO-V2><SARS-COVID-2><SARS-CoV-2><SARS-CoV2><SARS-associated corona virus 2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-related corona virus 2><SARS-related coronavirus 2><SARSCoV2><Safety><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-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 related corona virus 2><T cell response><T-Cell Depletion><T-Cells><T-Lymphocyte><T-cell depletion therapy><T-lymphocyte depletion therapy><T4 Cells><T4 Lymphocytes><T8 Cells><T8 Lymphocytes><TNF><TNF A><TNF Alpha><TNF gene><TNF-α><TNFA><TNFα><Testing><Tissues><Transmission><Transplacental Exposure><Tumor Necrosis Factor><Tumor Necrosis Factor-alpha><Vaccinated><Vaccination acquired immunity><Vaccination induced immunity><Vaccine Antigen><Vaccines><Viral><Viral Burden><Viral Diseases><Viral Load><Viral Load result><Virus Diseases><Wuhan coronavirus><ZIKV><ZIKV infected><ZIKV infection><ZIKV positive><ZIKV vaccine><Zika Virus><Zika vaccine><Zika virus infection><Zika virus vaccine><antibody neutralization test><antibody titering><antibody-based immunity><assay for transposase accessible chromatin followed by sequencing><assay for transposase accessible chromatin seq><assay for transposase accessible chromatin sequencing><assay for transposase-accessible chromatin with 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profile><molecular signature><motor deficit><mouse model><murine model><nCoV2><neonate><neutralizing antibody><new approaches><novel><novel approaches><novel strategies><novel strategy><pathway><perforin><pregnant><pregnant mothers><scRNA-seq><serious COVID><serious COVID-19><serious SARS-CoV-2><serious coronavirus disease><serious coronavirus disease 2019><serious severe acute respiratory syndrome coronavirus 2><severe COVID><severe COVID-19><severe COVID19><severe SARS-CoV-2><severe coronavirus disease><severe coronavirus disease 19><severe coronavirus disease 2019><severe severe acute respiratory syndrome coronavirus 2><single cell RNA-seq><single cell RNAseq><single cell expression profiling><single cell transcriptomic profiling><single-cell RNA sequencing><social role><thymus derived lymphocyte><transmission during pregnancy><transmission process><vaccination protocol><vaccine acquired immunity><vaccine against DENV><vaccine against ZIKV><vaccine against Zika><vaccine against dengue><vaccine associated immunity><vaccine candidate against dengue><vaccine development><vaccine efficacy><vaccine protocol><vaccine-induced immunity><vaccine-induced protection><viral infection><virus host interaction><virus infection><virus-induced disease><youngster><zika infected><zika infection><zika viral infection><zikav>