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Principal Investigator: FENGWEI BAI
Organization: UNIVERSITY OF SOUTHERN MISSISSIPPI
Fiscal Year: 2023
Award: $444,000
Funding agency: National Institute of Allergy and Infectious Diseases
Summary
Zika virus (ZIKV) is a mosquito-transmitted flavivirus that has caused devastating congenital Zika syndromes
(CZS), including microcephaly, congenital malformation, and fetal demise in human newborns in the 2015 - 2016
epidemics. In addition, ZIKV infection can cause Guillain-Barré syndrome (GBS) and meningoencephalitis in
adults. Currently, ZIKV pathogenesis is incompletely understood, and there is no approved therapeutic or
vaccine available. Although the number of human Zika cases has dropped since 2017, ZIKV will likely become
endemic, and a vaccine that can prevent CZS and adult Zika diseases remains urgently needed to prepare for
future outbreaks. Our research group recently developed a new live-attenuated ZIKV strain (named Z7) by
inserting a 50-RNA-nucleotides (nt) hairpin into the 5’ untranslated region (UTR) of a pre-epidemic ZIKV
Cambodian strain, FSS13025, which is attenuated in neurovirulence, immune antagonism, and mosquito
infectivity compared with the American epidemic isolates. Our preliminary data demonstrate that Z7 replicates
efficiently and produces high titers in Vero cells without causing apparent cytopathic effects (CPE) or losing the
insert sequence even after ten consecutive passages. Interestingly, we identified a mutation S1417A in NS2B
protein in Z7 after the 7th passage, indicating Z7 may have adapted a fitness mutation through the passaging.
Importantly, Z7 induces sterilizing immunity that completely prevents viremia after a challenge with a high dose
of an American epidemic strain (PRVABC59) in mice. These results suggest that modification of ZIKV 5’UTR is
a novel strategy to develop live-attenuated vaccine candidates for ZIKV and potentially for other flaviviruses. In
this application, we will first characterize Z7-induced humoral and cell-mediated immunity in a mouse model
(Specific Aim 1), and then evaluate the safety features of Z7 in mice (Specific Aim 2). In Specific Aim 3, we will
determine the mechanisms of action of Z7 attenuation. We believe that this project is highly significant because
it will characterize the immunity and safety of a novel live-attenuated ZIKV vaccine candidate, Z7, which was
developed for the first time by introducing a hairpin loop into a viral 5’ UTR. In addition, this R15 project will also
provide a valuable and unique training opportunity to both undergraduate and graduate students at the University
of Southern Mississippi.
Terms: <0-4 weeks old><21+ years old><3' Untranslated Regions><3'UTR><5' Untranslated Regions><5'UTR><AIDP><Acute Autoimmune Neuropathy><Acute Infective Polyneuritis><Acute Inflammatory Demyelinating Polyradiculoneuropathy><Acute Inflammatory Polyneuropathy><Acute Inflammatory Polyradiculoneuropathy><Adult><Adult Human><Affect><Alpha-Beta-Omega Interferon Receptor-1><American><Antibodies><Antiviral Protein Alpha Type><Attenuated><Attenuated Vaccines><Birth><Birth Defects><Body Tissues><Body Weight decreased><CD8 Cell><CD8 T cells><CD8 lymphocyte><CD8+ T cell><CD8+ T-Lymphocyte><CD8-Positive Lymphocytes><CD8-Positive T-Lymphocytes><CNS Nervous System><Cambodian><Capsid><Categories><Cell Body><Cell Mediated Immunology><Cell-Mediated Immunity><Cells><Cellular Immunity><Central Nervous System><Cerebromeningitis><Clinical><Congenital Abnormality><Congenital Anatomic Abnormality><Congenital Anatomical Abnormality><Congenital Defects><Congenital Deformity><Congenital Malformation><Contracting Opportunities><Contracts><Culicidae><Data><Defect><Dose><Drops><Effectiveness><Encephalomeningitis><Enzyme Gene><Enzymes><Epidemic><Esteroproteases><Exhibits><Female><Flavivirus><Genetic Alteration><Genetic Change><Genetic defect><Genome><Gestation><Goals><Group B Arbovirus><Guillain Barré Syndrome><Guillaine-Barre Syndrome><HuIFN-Alpha-Rec><Human><Human Bites><IFNBR><IFRC><Immune><Immunes><Immunity><Immunization><Inactivated Vaccines><Inactivated Virus Vaccine><Interferon Alpha-Beta Receptor Alpha Chain><Killed Vaccines><Landry's paralysis><Landry-Guillain-Barre Syndrome><Live-attenuated Vaccine><Liver><Measures><Membrane><Meningoencephalitis><Mice><Mice Mammals><Microcephaly><Mississippi><Modern Man><Modification><Molecular><Mosquitoes><Murine><Mus><Mutation><Names><Nerve Cells><Nerve Unit><Neural Cell><Neuraxis><Neurocyte><Neurons><Newborn Infant><Newborns><Non-Polyadenylated RNA><Non-structural Protein><Nonstructural Protein><Nucleotides><ORFs><Open Reading Frames><Organ><Parturition><Pathogenesis><Pathogenicity><Peptidases><Peptide Hydrolases><Peripheral><Polyproteins><Pregnancy><Production><Protease Gene><Proteases><Protein Coding Region><Proteinases><Proteins><Proteolytic Enzymes><Public Health><RNA><RNA Gene Products><Research><Ribonucleic Acid><Safety><Spleen><Spleen Reticuloendothelial System><Structure><Subunit Vaccines><Survival Rate><T cell response><T8 Cells><T8 Lymphocytes><Teff cell><Testicles><Testis><Therapeutic><Time><Tissues><Translating><Translations><Transmission><Universities><Vaccines><Vagina><Vaginal><Vero Cells><Viral><Viral Burden><Viral Genome><Viral Load><Viral Load result><Viremia><Weight Loss><Weight Reduction><ZIKA><ZIKV><ZIKV disease><ZIKV infected><ZIKV infection><ZIKV positive><ZIKV vaccine><Zika Virus><Zika vaccine><Zika virus disease><Zika virus infection><Zika virus vaccine><access to vaccination><access to vaccines><acute idiopathic polyneuritis><acute post-infectious polyneuropathy><acute postinfectious polyneuropathy><adult youth><adulthood><antagonism><antagonist><assess effectiveness><attenuate><attenuates><attenuation><base><bases><body weight loss><congenital zika syndrome><congenital zika virus syndrome><congenital zikv syndrome><determine effectiveness><effectiveness assessment><effectiveness evaluation><effector T cell><evaluate effectiveness><examine effectiveness><fetal><fitness><future outbreak><genetic approach><genetic strategy><genome mutation><graduate student><hepatic body system><hepatic organ system><ifnar1 gene product><infected with ZIKV><infected with zika><insight><live vaccine><live vaccines><mRNA Leader Sequences><male><membrane structure><micrencephaly><microencephaly><mouse model><murine model><name><named><naming><neuronal><neurovirulence><new approaches><newborn child><newborn children><next outbreak><novel><novel approaches><novel strategies><novel strategy><postnatal><prevent><preventing><response><reverse genetics><safety assessment><training opportunity><translation><transmission process><type I IFN receptor><type I interferon receptor><undergrad><undergraduate><undergraduate student><vaccination access><vaccination availability><vaccine access><vaccine availability><vaccine candidate><viraemia><viral sepsis><virus genome><virusemia><wt-loss><young adult><young adulthood><zika disease><zika infected><zika infection><zika viral infection><zikav>