Developing Vertebrate-Specific Replication-Defective Dengue Virus as a Novel Single-Cycle Dengue Vaccine Candidate 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.
Public Health Relevance Statement: Narrative: The proposal addresses the urgent need for a safe, effective, and affordable tetravalent dengue vaccine. We have developed unique means to convert dual-tropic dengue virus (DENV) into vertebrate-specific replication defective DENVs (VSRD-DENV) as a novel single-cycle DENV vaccine, which potentially induces balanced long-term immunity against four serotypes in tetravalent formulation. In the proposed project, a tetravalent VSRD-DENV-based dengue vaccine will be developed and comprehensively investigated in AG129 mice model.
Project Terms: Arboviruses; Arboviral; Arthropod-Borne Viruses; Complementary DNA; cDNA; Cell Line; CellLine; Strains Cell Lines; cultured cell line; Cells; Cell Body; Child; 0-11 years old; Child Youth; Children (0-21); youngster; Clinical Trials; Defective Viruses; Defective Hybrids; Defective Interfering Particles; Defective Interfering Viruses; Incomplete Viruses; Dengue; Dengue Virus; Breakbone Fever Virus; Dengue fever virus; DNA; Deoxyribonucleic Acid; Epidemic; Female; Flavivirus; Group B Arbovirus; Foundations; Goals; Hand; Recording of previous events; History; Hospitalization; Hospital Admission; Immunity; Cellular Immunity; Cell Mediated Immunology; Cell-Mediated Immunity; Humoral Immunities; antibody-based immunity; Insecta; Insects; Insects Invertebrates; Lead; Pb element; heavy metal Pb; heavy metal lead; male; Membrane Proteins; Membrane Protein Gene; Membrane-Associated Proteins; Surface Proteins; Mus; Mice; Mice Mammals; Murine; Persons; Phenotype; Production; Public Health; Risk; Non-Polyadenylated RNA; RNA Gene Products; Ribonucleic Acid; RNA; Safety; Serotyping; Testing; Universities; Vaccines; Attenuated Vaccines; Live-attenuated Vaccine; live vaccine; live vaccines; Inactivated Vaccines; Inactivated Virus Vaccine; Killed Vaccines; Viral Vaccines; Virus Replication; viral multiplication; viral replication; virus multiplication; Virus; Generations; base; Site; Phase; Animal Experiments; Evaluation; Blood Serum; Serum; non-human primate; nonhuman primate; Antibody-Dependent Enhancement; Immunological response; host response; immune system response; immunoresponse; Immune response; Attenuated; programs; Investigation; Dependence; System; Viral; Receptor Protein; receptor; develop a vaccine; develop vaccines; development of a vaccine; vaccine development; Animal Models and Related Studies; model of animal; model organism; Animal Model; K562 Cells; novel; Modeling; Subunit Vaccines; preventing; prevent; Incubated; Address; Data; Attenuated Live Virus Vaccine; Vaccinated; Immunologics; Immunochemical Immunologic; Immunologic; Immunological; Immunologically; Development; developmental; cost; immunogenicity; scale up; pathogen; 6 year old; 6 years of age; age 6 years; six year old; six years of age; mouse model; murine model; commercial application; mindfulness; vaccine candidate; protective efficacy; phase 1 study; Phase I Study; T cell response; reverse genetics; vaccine trial; vaccination study; vaccination trial; vaccine study; Zika Virus; ZIKV; zikav; Formulation; preclinical trial; pre-clinical trial; Dengue Infection; DENV infection; Dengue virus infection; dengue viral infection; Dengue Vaccine; DENV vaccine; Dengue virus vaccine; universal vaccine; vaccine access; access to vaccination; access to vaccines; vaccination access; vaccination availability; vaccine availability; severe dengue
