Dengue virus is a category A priority pathogen, as also the most important arbovirus causing human disease. Four distinct serotypes of dengue viruses cause widespread dengue fever (DF) and the more serious dengue hemorrhagic fever/dengue shock syndrome (DHF/DSS). It is estimated that over 100 million dengue infections occur worldwide each year, and a vaccine to prevent dengue disease is a public health priority. A natural dengue infection results only in homotypic immunity against the infecting serotype. Epidemiologic observation that DHF/DSS is mostly associated with secondary heterologous infections, have lead to the hypothesis of antibody dependent enhancement of disease in secondary infections. A dengue vaccine, therefore must provide immunity against all four dengue serotypes. Our long term objective is to produce a licensed tetravalent dengue vaccine based on recombinant adenovirus vectors. This objective is supported by the extensive pre-clinical testing of this candidate vaccine which is described under 'Preliminary Results'.
Specific aims for this proposal are the IND-enabling activities that include (a): scale-up and production of vaccine components under GLP and cGMP guidelines, (b): safety and toxicology studies in animals, and (c): IND application for a Phase-l clinical trial. We are working in close collaboration with Genphar Inc of South Carolina, whose 2nd generation complex adenovirus vector platform forms the basis for the proposed dengue vaccine. We will leverage Genphar's vast experience with this platform and use their state of the art facilities to produce the vaccine lots required for safety and toxicology testing. This will result in considerable cost saving compared to commercial manufacture. After proving the safety of the dengue vaccine, we will invest in cGMP manufacture of the vaccine. Finally, we will develop a phase I clinical trial protocol and collate documentation from manufacturing and safety study to produce a IND application. We anticipate that at the end of this proposal funding, we will have a cGMP certified vaccine lot and an FDA approved IND enabling us to begin a phase I clinical trial of this promising dengue vaccine under separate funding.
