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Principal Investigator: Justin Richner
Organization: UNIVERSITY OF ILLINOIS AT CHICAGO
Fiscal Year: 2022
Award: $583,700
Funding agency: National Institute of Allergy and Infectious Diseases
Nearly 400 million people are infected with dengue virus (DENV) each year through the bite of infected mosquitos
concentrated in the tropical and subtropical regions of the world. Symptoms can range from febrile illness to
severe dengue that manifests as plasma leakage, sudden loss of blood pressure, organ failure, and shock that
can ultimately lead to death. Severe dengue complications are often associated with a secondary heterotypic
infection of one of the four circulating serotypes. In this scenario, humoral immune responses targeting cross-
reactive, poorly-neutralizing epitopes lead to increased infectivity of susceptible cells via antibody-dependent
enhancement (ADE). Additionally, DENV immunity has been implicated in increased susceptibility to Zika virus
through ADE. Currently there are no available therapeutics to combat DENV disease. Dengvaxia, the only
licensed DENV vaccine, was found to increase hospitalization rates in naïve populations, and thus is not
recommended for a large portion of at-risk individuals. There is an urgent need for a safe and efficacious vaccine
that elicits a robust, balanced, neutralizing response to all four DENV serotypes. We propose to develop a novel
DENV vaccine utilizing an emergent platform: mRNA encoding for viral proteins encapsidated in a lipid
nanoparticle (LNP). mRNA-LNP vaccines elicit robust humoral and cell-mediated immune responses in a safe,
non-infectious platform. Additionally, we can direct the host immune response towards neutralizing epitopes by
mutating the mRNA encoding for the viral protein. We hypothesize that a sequence-engineered tetravalent
mRNA-LNP vaccine will induce a balanced, protective immune response against all four serotypes of
dengue without the potential of causing immune enhancement and ADE. In Aim 1 of this study we will
generate and optimize mRNA constructs encoding for the pre-membrane and envelope viral glycoproteins for all
four serotypes of DENV. We will mutate the poorly-neutralizing, cross-reactive epitopes that drive ADE. In Aim
2 we will characterize the immune response to the vaccines in a mouse model. In addition to quantifying humoral
and cellular immune responses, we will also measure the immune enhancement capacity of all vaccines. In Aim
3, we will evaluate vaccine efficacy and safety in susceptible mouse models, by challenging vaccinated mice
with different DENV serotypes to monitor protection and ADE. We will also determine mechanism of protection
via adoptive transfer experiments. Through this study, we will identify DENV vaccines that demonstrate broad
protection and lack of immune enhancement for further evaluation as candidate human vaccines.
Terms: <Adoptive Transfer><Animal Model><Animal Models and Related Studies><Animals><Antibodies><Antibody Repertoire><Antibody-Dependent Enhancement><Antigenic Determinants><Antigens><B blood cells><B cell><B cells><B-Cells><B-Lymphocytes><B-cell><Binding Determinants><Bite><Bleeding><Blood Plasma><Blood Pressure><Blood Serum><Breakbone Fever Virus><Cell Body><Cells><Cessation of life><Circulatory Collapse><Clinical><Clinical Trials><Contracting Opportunities><Contracts><Culicidae><DENV vaccine><Data><Death><Dengue><Dengue Vaccine><Dengue Virus><Dengue fever virus><Dengue virus vaccine><Dengvaxia><Disease><Disorder><Engineering><Envelope Protein><Epitopes><Evaluation><Extravasation><Fever><Flavivirus><Future><Glycoproteins><Group B Arbovirus><Health><Hemorrhage><Human><Immune><Immune response><Immunes><Immunity><Immunocompetent><Immunological response><Individual><Infection><Lead><Leakage><Maps><Measures><Membrane><Messenger RNA><Mice><Mice Mammals><Modern Man><Monitor><Mosquitoes><Murine><Mus><Mutate><Nucleosides><Organ failure><Pb element><Persons><Plasma><Plasma Serum><Population><Predisposition><Pregnant Women><Primary Infection><Probability><Protein Biosynthesis><Pyrexia><RNA vaccine><RNA-based vaccine><Refractory><Reticuloendothelial System, Serum, Plasma><Ribosomal Peptide Biosynthesis><Ribosomal Protein Biosynthesis><Ribosomal Protein Synthesis><Risk><Serotyping><Serum><Severity of illness><Shock><Spillage><Structure><Surface><Susceptibility><Symptoms><T-Cell Epitopes><T-Cells><T-Lymphocyte><T-Lymphocyte Epitopes><Techniques><Therapeutic><Vaccinated><Vaccination><Vaccinee><Vaccines><Viral><Viral Diseases><Viral Gene Products><Viral Gene Proteins><Viral Proteins><Virion><Virus Diseases><Virus Particle><ZIKV><Zika Virus><blood loss><cell mediated immune response><circulatory shock><combat><cross reactivity><design><designing><disease severity><env Antigens><env Gene Products><env Polyproteins><env Protein><evaluate vaccines><expectant mother><expecting mother><experiment><experimental research><experimental study><febrile><febris><heavy metal Pb><heavy metal lead><hospitalization rates><host response><immune competent><immune system response><immunogen><immunogenicity><immunoresponse><immunosuppressed><in vivo><lipid based nanoparticle><lipid nanoparticle><mRNA><mRNA delivery><mRNA vaccine><mRNA-based vaccine><membrane structure><model of animal><model organism><mouse model><murine model><neutralizing antibody><new vaccines><next generation vaccines><non-human primate><nonhuman primate><novel><novel vaccines><particle><pathogen><polyclonal antibody><pre-clinical><preclinical><pregnant mothers><protective efficacy><protein synthesis><response><secondary infection><severe dengue><thymus derived lymphocyte><vaccinated individual><vaccinated participant><vaccinated patient><vaccinated person><vaccinated subject><vaccine candidate><vaccine efficacy><vaccine evaluation><vaccine formulation><vaccine immune response><vaccine immunogenicity><vaccine safety><vaccine screening><vaccine testing><viral infection><virus infection><virus protein><virus-induced disease><zikav>