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Principal Investigator: XIAOWU PANG
Organization: TENGEN BIOMEDICAL CO.
Fiscal Year: 2023
Award: $298,530
Funding agency: National Institute of Allergy and Infectious Diseases
Developing Vertebrate-Specific Replication-Defective Dengue Virus as
a Novel Single-Cycle Dengue Vaccine Candidate
Abstract
With an estimated minimum of 390 million dengue virus (DENV) infections per year, the
DENV epidemic was listed as one of the world's top 10 public health threats by WHO in
2019. At present, there is no specific treatment. A universal vaccine is urgently needed.
DENV vaccine development's unique challenge is that a dengue vaccine must induce
long-term protection against all four serotypes simultaneously. Historically, tetravalent
live attenuated viral vaccines have shown that it is difficult to achieve balanced immunity
to all four serotypes. Also, inactivated virus vaccines can't confer long-term immunity to
prevent potential antibody-dependent enhancement (ADE). Mindful of these obstacles,
we have investigated single-cycle, pseudoinfectious DENVs as vaccine candidates to
induce balanced long-term immunity against all four serotypes. A significant impediment
to this approach is that replicating pseudoinfecious DENVs usually require complicated
and low-efficient packaging cells, making the scale-up production difficult and costly.
Thus, towards the overall goal of developing a safe, effective, and affordable DENV
vaccine, we converted dual-tropic DENVs into artificial insect-specific viruses to
overcome the dependence on packaging cells to produce a single-cycle virus vaccine.
These vertebrate-specific replication-defective DENVs (VSRD-DENV) were generated
by optimizing the furin cleavage site in viral pre-membrane protein (prM). Preliminary
animal experiments with VSRD-DENV1 and VSRD-DENV2 demonstrated that the
VSRD-DENVs induced robust protective immunity with inherent high safety levels in
mice. Based on these highly promising preliminary results and considering the urgent
need for an effective dengue vaccine, Tengen Biomedical Co. and Howard University
have teamed up to accelerate the evaluation of the VSRD-DENVs-based dengue
vaccine. To achieve this goal, we propose to generate and characterize VSRD-DENV3
and VSRD-DENV4 vaccine candidate viruses. We will then perform a comprehensive
analysis of the immunogenicity and protective efficacy of tetravalent VSRD-DENVs in a
sensitive AG129 mouse model. Successful completion of these proposed studies will
enable the dengue vaccine candidate into non-human primate testing and establish a
platform for developing vaccines for other important flaviviruses.
Terms: <0-11 years old><6 year old><6 years of age><Acceleration><Address><Animal Experiments><Animal Model><Animal Models and Related Studies><Antibody-Dependent Enhancement><Arboviral><Arboviruses><Arthropod-Borne Viruses><Attenuated><Attenuated Live Virus Vaccine><Attenuated Vaccines><Blood Serum><Breakbone Fever Virus><Cell Body><Cell Line><Cell Mediated Immunology><Cell-Mediated Immunity><CellLine><Cells><Cellular Immunity><Child><Child Youth><Children (0-21)><Clinical Trials><Complementary DNA><DENV><DENV infection><DENV vaccine><DNA><Data><Defective Hybrids><Defective Interfering Particles><Defective Interfering Viruses><Defective Viruses><Dengue><Dengue Infection><Dengue Vaccine><Dengue Virus><Dengue fever virus><Dengue virus infection><Dengue virus vaccine><Deoxyribonucleic Acid><Dependence><Development><Evaluation><Female><Flavivirus><Formulation><Foundations><Generations><Goals><Group B Arbovirus><Hand><History><Hospital Admission><Hospitalization><Humoral Immunities><Immune response><Immunity><Immunochemical Immunologic><Immunologic><Immunological><Immunological response><Immunologically><Immunologics><Inactivated Vaccines><Inactivated Virus Vaccine><Incomplete Viruses><Incubated><Insecta><Insects><Insects Invertebrates><Investigation><K562 Cells><Killed Vaccines><Licensing><Live-attenuated Vaccine><Membrane Protein Gene><Membrane Proteins><Membrane-Associated Proteins><Mice><Mice Mammals><Modeling><Murine><Mus><Non-Polyadenylated RNA><Persons><Phase><Phenotype><Production><Proteins><Public Health><RNA><RNA Gene Products><Receptor Protein><Recording of previous events><Ribonucleic Acid><Risk><Safety><Serotyping><Serum><Site><Strains Cell Lines><Subunit Vaccines><Surface Proteins><System><T cell response><Testing><Universities><Vaccinated><Vaccines><Viral><Viral Vaccines><Virus><Virus Replication><ZIKV><Zika Virus><access to vaccination><access to vaccines><age 6 years><animal experiment><antibody-based immunity><attenuate><attenuates><cDNA><commercial application><commercial scale manufacturing><cost><cultured cell line><dengue viral infection><develop a vaccine><develop vaccines><development of a vaccine><developmental><epidemic virus><experimental animal><experimental animals><hands><histories><host response><immune system response><immunogenicity><immunoresponse><kids><live vaccine><live vaccines><male><manufacturing ramp-up><manufacturing scale-up><mindfulness><model of animal><mouse model><murine model><non-human primate><nonhuman primate><novel><pathogen><pre-clinical trial><preclinical trial><prevent><preventing><programs><protective efficacy><receptor><reverse genetics><scale up><scale up batch><scale up production><severe dengue><six year old><six years of age><universal vaccine><upscale manufacturing><vaccination access><vaccination availability><vaccination study><vaccination trial><vaccine access><vaccine availability><vaccine candidate><vaccine development><vaccine study><vaccine trial><viral multiplication><viral replication><virus multiplication><youngster><zikav>