Dengue (DEN) is the most important arthropod-borne viral infection of humans with about 100 million cases and 25,000 deaths annually, threatening over 3.5 billion people worldwide. The dengue viruses cause dengue fever (DF), dengue hemorrhagic fever (DHF), and dengue shock syndrome (DSS), and are endemic throughout the world's subtropical and tropical regions. To date, there is no effective vaccine to prevent against DF and no drug treatment for the disease. Dengue infection is caused by one of four different RNA viruses: dengue type 1 (DEN-1), DEN-2, DEN-3 and DEN-4. For a dengue vaccine to be safe and effective, it must be capable of neutralizing all four of the dengue viruses. Inviragen's tetravalent DEN vaccine (DENVax) consists of the live attenuated DEN-2 PDK-53 virus and three chimeras expressing the structural genes (prM and E) from DEN-1, DEN-3 and DEN-4, and retaining the genetic alterations responsible for the safety of the original DEN-2 vaccine. We have demonstrated the safety and efficacy of DENVax in AG129 mice and monkeys. In these studies we have identified tetravalent formulations that induce neutralizing antibodies to all four DENV serotypes. However, the responses to DENVax-4 were limited by interference from the other, more robust chimeras. In this proposal, we will test the hypothesis that the immune responses to the DENVax-4 vaccine construct can be further optimized through genetic manipulation of the DENVax-4 infectious clone. We propose to design and characterize a new chimeric DEN2/4 vaccine, and test the safety and efficacy of this vaccine in mice and monkeys. This proposal uniquely utilizes resources, facilities and reagents available at Inviragen Inc, CDC, and the University of Wisconsin-Madison. The development of an effective dengue vaccine represents an important approach to the prevention and control of this global emerging disease. Inviragen's long term goal is to develop a safe and effective dengue vaccine.
Public Health Relevance: Dengue virus (DEN), a mosquito-borne RNA virus, is the most important arthropod-borne viral infection of humans with about 100 million cases and 25,000 deaths annually. We are developing a safe and effective tetravalent dengue vaccine that will protect against all four dengue serotypes. Such a vaccine would protect U.S. travelers from dengue infection, and significantly improve global public health as dengue threatens over 3.5 billion people worldwide.
Public Health Relevance Statement: Project Narrative Dengue virus (DEN), a mosquito-borne RNA virus, is the most important arthropod- borne viral infection of humans with about 100 million cases and 25,000 deaths annually. We are developing a safe and effective tetravalent dengue vaccine that will protect against all four dengue serotypes. Such a vaccine would protect U.S. travelers from dengue infection, and significantly improve global public health as dengue threatens over 3.5 billion people worldwide.
NIH Spending Category: Biodefense; Biotechnology; Emerging Infectious Diseases; Genetics; Immunization; Infectious Diseases; Orphan Drug; Prevention; Vaccine Related; Vector-Borne Diseases
Project Terms: 0-6 weeks old; 21+ years old; Adult; Amino Acid Sequence; Animals; Antibody Formation; Antibody Production; Antibody Response; Approaches to prevention; Arthropoda; Arthropods; Attenuated; Biosynthetic Proteins; Breakbone Fever Virus; CDC; Capsid; Cell Culture Techniques; Centers for Disease Control; Centers for Disease Control (U.S.); Centers for Disease Control and Prevention; Centers for Disease Control and Prevention (U.S.); Cessation of life; Chimera; Chimera organism; Clinical Trials, Phase II; Complementary DNA; Country; Culicidae; DNA, Complementary; Death; Dengue; Dengue Fever; Dengue Hemorrhagic Fever; Dengue Shock Syndrome; Dengue Virus; Development; Disease; Disorder; Dose; Drug Formulations; Drugs; Egypt 101 virus; Engineering; Engineerings; Formulation; Formulations, Drug; Gene Products, RNA; Generations; Genes; Genes, Structural; Genetic; Genetic Alteration; Genetic Change; Genetic defect; Genomics; Goals; Hawaii; Human; Human, Adult; Human, General; Immune response; Immunization; Immunization Schedule; Immunologic Stimulation; Immunological Stimulation; Immunostimulation; Inbred ICR Mice; Infant, Newborn; Infection; Life; Mammalian Cell; Mammals, Mice; Man (Taxonomy); Man, Modern; Medication; Mice; Mice, Inbred ICR; Monkeys; Mosquitoes; Mouse, ICR; Murine; Mus; Mutation; NIH; National Institutes of Health; National Institutes of Health (U.S.); New Guinea; Newborn Infant; Newborns; Pharmaceutic Preparations; Pharmaceutical Preparations; Phase 2 Clinical Trials; Phase II Clinical Trials; Polyproteins; Prevention approach; Protein Structure, Primary; Public Health; RNA; RNA Splicing; RNA Viruses; RNA, Non-Polyadenylated; Reagent; Recombinant Proteins; Relative; Relative (related person); Research; Research Resources; Resources; Ribonucleic Acid; Safety; Sensitization, Immunologic; Sensitization, Immunological; Serologic; Serological; Serotyping; Site; Spinal Column; Spine; Splicing; Structural Genes; Structural Protein; Technology; Temperature; Testing; Transfection; Translating; Translatings; United States Centers for Disease Control; United States Centers for Disease Control and Prevention; United States National Institutes of Health; Universities; Vaccines; Variant; Variation; Vero Cells; Vertebral column; Viral; Viral Diseases; Viremia; Virus; Virus Diseases; Viruses, General; WNV; West Nile; West Nile virus; Wisconsin; adult human (21+); antibody biosynthesis; attenuation; backbone; base; breakbone fever; cDNA; coat (nonenveloped virus); design; designing; disease/disorder; drug/agent; experience; genetic manipulation; genome mutation; host response; immunogenic; immunogenicity; immunoglobulin biosynthesis; immunoresponse; improved; intraperitoneal; language translation; monolayer; neurovirulence; neutralizing antibody; newborn human (0-6 weeks); non-human primate; nonhuman primate; phase 2 study; phase 2 trial; phase II trial; prevent; preventing; protective efficacy; protein sequence; protocol, phase II; public health medicine (field); public health relevance; response; safety testing; study, phase II; trait; vaccine efficacy; vaccine evaluation; vaccine screening; vaccine testing; viraemia; viral infection; viral sepsis; virus infection; virusemia
