Document text
Principal Investigator: Sujan Shresta
Organization: LA JOLLA INSTITUTE FOR IMMUNOLOGY
Fiscal Year: 2024
Award: $721,849
Funding agency: National Institute of Allergy and Infectious Diseases
ABSTRACT
The long-term goal of this project is to develop a dengue-Zika vaccine that provides protection against
the four serotypes of dengue (DENV1-4) and Zika (ZIKV) viruses with maximal safety and efficacy. To
date, flavivirus vaccine development has focused 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, DENV disease 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 an RNA replicon-based vaccine expressing
ZIKV nonstructural protein 3 elicits only T cell but not nAb responses and confers protection against ZIKV
challenge in mice. Thus, we hypothesize that our combinatorial DENV-ZIKV 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 efficacy of a DENV-ZIKV vaccine. 2) To
determine the durability and mechanistic underpinnings of DENV-ZIKV vaccine-induced protective
immunity.
Terms: <0-11 years old><21+ years old><AIDP><Ab response><Acute Autoimmune Neuropathy><Acute Infective Polyneuritis><Acute Inflammatory Demyelinating Polyradiculoneuropathy><Acute Inflammatory Polyneuropathy><Acute Inflammatory Polyradiculoneuropathy><Address><Adoptive Transfer><Adult><Adult Human><Alpha Virus><Alpha-Beta-Omega Interferon Receptor-1><Antibody Formation><Antibody Production><Antibody Response><Antibody-Dependent Enhancement><Antigenic Determinants><Antigens><Antiviral Protein Alpha Type><Avidity><Binding><Binding Determinants><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><CD8 Cell><CD8 T cells><CD8 lymphocyte><CD8+ T cell><CD8+ T-Lymphocyte><CD8-Positive Lymphocytes><CD8-Positive T-Lymphocytes><CD8B><CD8B1><CD8B1 gene><Cell Mediated Immunology><Cell-Mediated Immunity><Cellular Immunity><Child><Child Youth><Children (0-21)><Clinical Trials><Combination Vaccines><Combined Vaccines><DENV><DENV infection><DENV vaccine><Data><Dengue><Dengue Infection><Dengue Vaccine><Dengue Virus><Dengue fever virus><Dengue virus infection><Dengue virus vaccine><Dengvaxia><Development><Disease><Disease Outbreaks><Disorder><Dose><Epidemic><Epitopes><Flavivirus><Frequencies><Goals><Group A Arboviruses><Group B Arbovirus><Guillain Barré Syndrome><Guillaine-Barre Syndrome><Health Care Systems><Healthcare Systems><HuIFN-Alpha-Rec><Human><Humoral Immunities><IFNBR><IFRC><Immune><Immune response><Immunes><Immunity><Immunization><Immunize><Immunological response><Infant><Infection><Interferon Alpha-Beta Receptor Alpha Chain><LYT3><Landry's paralysis><Landry-Guillain-Barre Syndrome><Licensing><Measures><Mediating><Membrane><Mice><Mice Mammals><Modern Man><Molecular Interaction><Morbidity><Morbidity - disease rate><Murine><Mus><Non-Polyadenylated RNA><Non-structural Protein><Nonstructural Protein><Orthoflavivirus><Outbreaks><Pathogenesis><Persons><Phenotype><Population><Proteins><RNA><RNA Gene Products><RNA vaccine><RNA-based vaccine><Replication Unit><Replicon><Ribonucleic Acid><Risk><Safety><Serotyping><Severity of illness><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><Teff cell><Testing><Vaccinated><Vaccination><Vaccines><Virus><Wild Type Mouse><Work><ZIKA><ZIKV><ZIKV infected><ZIKV infection><ZIKV positive><ZIKV vaccine><Zika Virus><Zika vaccine><Zika virus infection><Zika virus vaccine><acute idiopathic polyneuritis><acute post-infectious polyneuropathy><acute postinfectious polyneuropathy><adulthood><antibody biosynthesis><antibody-based immunity><combinatorial><congenital zika syndrome><congenital zika virus syndrome><congenital zikv syndrome><cross immunity><cross protection><cross reactivity><dengue viral infection><design><designing><develop a vaccine><develop vaccines><development of a vaccine><developmental><disease severity><effector T cell><host response><ifnar1 gene product><immune system response><immunogen><immunogenicity><immunoglobulin biosynthesis><immunoresponse><improved><infected with ZIKV><infected with zika><kids><mRNA vaccine><mRNA-based vaccine><membrane structure><mortality><neonate><neutralizing antibody><prevent><preventing><public health priorities><replicon vaccine><response><severe dengue><thymus derived lymphocyte><type I IFN receptor><type I interferon receptor><vaccine against DENV><vaccine against ZIKV><vaccine against Zika><vaccine against dengue><vaccine candidate against dengue><vaccine development><vaccine response><vaccine responsiveness><vaccine strategy><vaccine-induced response><wildtype mouse><youngster><zika infected><zika infection><zika viral infection><zikav>