The overall goal of this research proposal is to prepare a multicomponent, recombinant subunit dengue vaccine and, most importantly, study this vaccine in Phase I clinical trials to be performed by CSL Limited in Australia under a U.S. IND. These clinical trials are important to define the optimal vaccine formulation and immunization schedules prior to performing a human challenge study that will be done at the Walter Reed Army Institute for Research and prior to continued Phase II and Phase III clinical trials. All work described in this grant application constitute a collaboration between Hawaii Biotech, Inc. (HBI) and CSL Limited (CSL). Intramuscular administration of the Dengue virus vaccine is indicated for the prevention of disease caused by dengue virus infection. The vaccine contains five recombinant subunit proteins, carboxyl truncated envelope (80E) proteins from each of the four dengue serotypes (DEN 1-4) and NS1 from DEN2. The antigens will be formulated with ISCOMATRIX(r) adjuvant to provide an immunogenic vaccine formulation. The work covered in this application encompasses GMP manufacture of five dengue proteins covering the four dengue serotypes, GMP manufacture of ISCOMATRIX(r) adjuvant, fill/finish of the vaccine API and adjuvant API, formulation development to support mixing of antigen and adjuvant, testing and release of the vaccine API and adjuvant API prior to use in humans, toxicology and safety testing of the vaccine in animal models preparation of U.S. IND to support Phase I clinical trials and execution of Phase I clinical trials in Australia. The vast majority of the work performed must meet Good Laboratory Practice (GLP), Good Manufacturing Practice (GMP) or Good Clinical Practice (GCP). For this reason, either contract research organizations (CRO) and contract manufacturing organizations (CMO), all of which have been audited for regulatory compliance, are being used to carry out much of the work or the work will be performed at CSL's manufacturing and testing facilities. Manufacture of the ISCOMATRIX(r) adjuvant will be performed in CSL's manufacturing facilities (GMP), and CSL will conduct the Phase I clinical trials. HBI and CSL will collaborate closely on all stages of the development and will jointly oversee the activities at contract facilities.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
NIH Challenge Grants and Partnerships Program - Phase II-Coop.Agreement (UC1)
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Special Emphasis Panel (ZAI1-TH-M (M1))
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Repik, Patricia M
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Hawaii Biotech, Inc.
United States
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Manoff, Susan B; George, Sarah L; Bett, Andrew J et al. (2015) Preclinical and clinical development of a dengue recombinant subunit vaccine. Vaccine 33:7126-34
Coller, Beth-Ann G; Clements, David E; Bett, Andrew J et al. (2011) The development of recombinant subunit envelope-based vaccines to protect against dengue virus induced disease. Vaccine 29:7267-75