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Principal Investigator: Sujan Shresta
Organization: LA JOLLA INSTITUTE FOR IMMUNOLOGY
Fiscal Year: 2020
Award: $761,992
Funding agency: National Institute of Allergy and Infectious Diseases
ABSTRACT
The long-term goal of this project is to develop a mRNA replicon-based vaccine that provides long-lived
protection against the four serotypes of dengue (DENV1-4) and Zika (ZIKV) viruses. To date, flavivirus
vaccine development has focused almost exclusively on the induction of neutralizing antibodies (nAbs),
as they have been assumed to be the key mechanism for protection against natural infection. However,
DENV and perhaps ZIKV are unusual in that weak Ab responses to vaccination or prior infection can
induce antibody-dependent enhancement (ADE) of infection and pathogenesis during subsequent
reinfections. In fact, ADE with severe sequalae has been documented in children given the only currently
licensed DENV vaccine. Thus, the primary objective of this application is to develop an effective vaccine
against DENV and ZIKV that cannot mediate ADE. We hypothesize that this vaccine will need to elicit
both strong nAb responses and strong T cell effector responses that will counterbalance the presence of
any ADE-mediating Abs, based on our work investigating the interplay between Ab and T cell responses
to DENV and ZIKV. In particular, we have shown that CD8 T cells mediate cross-protection against
heterotypic DENV and ZIKV infections, and that DENV vaccine-elicited CD8 T cells can prevent ADE. In
addition, our preliminary data show that a mRNA replicon-based vaccine expressing ZIKV nonstructural
protein 3 elicits only T cell but not Ab responses and confers protection against ZIKV challenge in mice.
Thus, we hypothesize that our pan-flavivirus mRNA replicon-based vaccine expressing both Ab- and T
cell-targeting proteins of DENV1-4 and ZIKV will produce humoral and cellular immune responses that
provide robust, long-term protection against all five viruses. We will test this hypothesis by achieving the
following Specific Aims: 1: To evaluate immunogenicity and protective efficacy of a pan-flavivirus vaccine
against DENV1-4 and ZIKV designed to elicit CD8 T cell and Ab responses in wild-type mice. 2: To
assess durability and immune mechanisms underlying the pan-flavivirus vaccine-induced protective
immunity and ADE in mice. 3: To assess the immune response and protection induced by the pan-
flavivirus vaccine in nonhuman primates.
Terms: <0-11 years old><Ab response><Alpha Virus><Alpha-Beta-Omega Interferon Receptor-1><Alphavirus><Animal Model><Animal Models and Related Studies><Antibody Formation><Antibody Production><Antibody Response><Antibody-Dependent Enhancement><Antisera><Antiviral Protein Alpha Type><Breakbone Fever Virus><C57BL/6 Mouse><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><Child><Child Youth><Children (0-21)><Clinic><Clinical Virology><DENV infection><DENV vaccine><Data><Dengue><Dengue Infection><Dengue Vaccine><Dengue Virus><Dengue fever virus><Dengue virus infection><Dengue virus vaccine><Development><Disease><Disorder><Dose><Flavivirus><Goals><Group A Arboviruses><Group B Arbovirus><HuIFN-Alpha-Rec><IFNBR><IFRC><Immune><Immune Sera><Immune response><Immunes><Immunity><Immunization><Immunize><Immunochemical Immunologic><Immunologic><Immunologic Sensitization><Immunologic Stimulation><Immunological><Immunological Sensitization><Immunological Stimulation><Immunological response><Immunologically><Immunologics><Immunostimulation><Infection><Infusion><Infusion procedures><Interferon Alpha-Beta Receptor Alpha Chain><M mulatta><M. mulatta><Macaca><Macaca mulatta><Macaque><Measures><Mediating><Messenger RNA><Mice><Mice Mammals><Morbidity><Morbidity - disease rate><Murine><Mus><Names><Non-Polyadenylated RNA><Non-structural Protein><Nonstructural Protein><Outcome><Pathogenesis><Persons><Phenotype><Population><Proteins><RNA><RNA Gene Products><RNA vaccine><Replication Unit><Replicon><Rhesus Macaque><Rhesus Monkey><Ribonucleic Acid><Risk><Serotyping><Severity of illness><T cell based therapeutics><T cell based therapy><T cell response><T cell targeted therapeutics><T cell therapy><T-Cell Depletion><T-Cells><T-Lymphocyte><T-cell depletion therapy><T-lymphocyte depletion therapy><T4 Cells><T4 Lymphocytes><T8 Cells><T8 Lymphocytes><Testing><Time><Vaccinated><Vaccination><Vaccine Design><Vaccines><Viral><Viral Antigens><Viral Diseases><Virus><Virus Diseases><Virus Replication><Wild Type Mouse><Work><ZIKA><ZIKV><ZIKV infection><ZIKV positive><ZIKV vaccine><Zika Virus><Zika vaccine><Zika virus infection><Zika virus vaccine><adoptive T cell transfer><adoptive T-cell therapy><antibody biosynthesis><arm><base><children><childrens'><cross reactivity><dengue viral infection><design><designing><develop a vaccine><development of a vaccine><developmental><disease severity><effector T cell><host response><ifnar1 gene product><immune serum><immunogenicity><immunoglobulin biosynthesis><immunoresponse><mRNA><mRNA vaccine><model of animal><model organism><mortality><neutralizing antibody><non-human primate><nonhuman primate><novel><prevent><preventing><protective efficacy><public health priorities><response><therapeutic T-cell platform><thymus derived lymphocyte><type I IFN receptor><type I interferon receptor><universal vaccine><vaccine candidate><vaccine development><vaccine formulation><viral infection><viral multiplication><viral replication><virus antigen><virus infection><virus multiplication><virus-induced disease><wildtype mouse><youngster><zika infection><zika viral infection><zikav>