There are approximately 390 million cases of dengue fever each year, with 2.5 billion people at risk, mostly in low income countries. There are four serotypes of dengue fever virus (DENV), and in its uncomplicated form, the disease is worthy of its indigenous name, "break-bone fever". An individual may suffer sequential infections with multiple DENV serotypes, and a second infection is associated with increased risk of dengue hemorrhagic fever/dengue shock syndrome (DHF/DSS), a much more serious and potentially fatal disease. Altravax, Inc. (AVI), has developed a particulate, single molecule, tetravalent immunogen capable of inducing neutralizing antibodies directed against all four serotypes of DENV. Global Vaccines, Inc. (GVI), a not-for-profit vaccine company, has developed a novel adjuvant, which is not only capable of promoting neutralizing antibody responses induced by other DENV immunogens, but also catalyzing the induction of cell mediated immunity. As recent evidence suggests that both arms of the immune response contribute to protection against DENV, these two companies will collaborate to determine the effect of combining their respective technologies in an improved DENV vaccine. The AVI immunogen will be tested in two forms. First, the protein immunogen will be produced in 293F cells and purified. It then will be administered to 129/Sv mice, either alone, with the GVI adjuvant or with alum as a positive adjuvant control. In a second approach, the gene for the AVI immunogen will be cloned into a Venezuelan equine encephalitis virus replicon particle (VRP), and the VRP will be administered to 129/Sv mice for in vivo expression of the immunogen. These formulations will be evaluated for induction of neutralizing antibodies and T cells to each of the four DENV serotypes. The polyclonal sera also will be evaluated to determine whether the antibodies induced by the AVI tetravalent immunogen are directed to serotype specific neutralizing epitopes or to a neutralizing epitope(s) that is (are) conserved in each of the four serotypes. The best of the formulations will be used to immunize 129/Sv mice. Serum, T cells or a mixture of the two from the fully immunocompetent 129/Sv mice will be transferred to na¿ve AG129 mice, a congenic DENV sensitive mouse model, to assess the ability of the induced immune responses to protect against challenge with each of the four DENV serotypes. These experiments are the first to combine these two promising vaccine technologies, and represent an important step in the preclinical development of a safe DENV vaccine candidate which induces both protective humoral and cellular responses and is appropriately inexpensive for the majority of persons at risk.
Public Health Relevance Statement: Public Health Relevance: One-third of the world's population is at risk for dengue fever virus infection. Altravax, Inc. and Global Vaccines, Inc., a not for profit company, will merge ther respective technologies in a new dengue vaccine candidate utilizing a single immunogen and a novel adjuvant to induce protective humoral and cellular immunity to all four dengue virus serotypes. The overall goal is to advance this safe, effective and inexpensive dengue vaccine approach through pre-clinical studies and ultimately, to clinical trials.
Project Terms: 129/Sv Mouse; Adjuvant; Adolescent; Adoption; Adult; aluminum sulfate; Animal Model; Antibodies; Antibody Formation; Antigens; Antiviral Therapy; Arboviruses; arm; Attenuated Live Virus Vaccine; bone; Cells; Cellular Immunity; Centers for Disease Control and Prevention (U.S.); Clinical Trials; Code; cohort; Confidence Intervals; congenic; Country; demographics; Dengue; Dengue Hemorrhagic Fever; Dengue Shock Syndrome; Dengue Virus; Development; Disease; Drug Formulations; E protein; economic cost; Economics; Epitopes; Fever; Florida; Genes; Goals; Hawaii; Human; Humoral Immunities; Immune response; Immunity; Immunocompetent; immunogenicity; improved; In Vitro; in vivo; Indigenous; Individual; Infant; Infection; Licensing; Low income; Maternal antibody; Measures; Mediating; mouse model; Mus; Names; neutralizing antibody; Nonstructural Protein; novel; Palliative Care; pandemic disease; particle; Particulate; Persons; Phase; Placebos; Population; pre-clinical; preclinical study; prevent; protective efficacy; Proteins; public health relevance; Puerto Rico; Replicon; research study; response; Risk; Schools; Serotyping; Serum; single molecule; Small Business Technology Transfer Research; South Texas; Staging; System; T cell response; T-Lymphocyte; Technology; Testing; Vaccinated; Vaccination; vaccine candidate; vaccine development; Vaccines; Venezuelan Equine Encephalitis Virus; Virion; Virus; Virus Diseases; Work
