A NOVEL ADENOVIRUS-BASED TETRAVALENT DENGUE VACCINE

DESCRIPTION (provided by applicant): The deliberate attempts to infect political figures and high profile members of the 'the media' with anthrax after the attacks of Sept. 11, 2001 highlight the need for an effective strategy to deal with bioterrorism. The threat of bioterrorism is no longer just a threat. There are a large number of disease-causing agents that have the potential to be used as weapons and we must be prepared to neutralize their effectiveness whether they are ultimately used or not. For many potential bioweapons, the best defense is preemptive vaccination. Unfortunately, there are more disease-causing agents than there are vaccines. We have chosen to focus our attention on one potential bioweapon: dengue virus. Dengue fever and dengue hemorrhagic fever are incapacitating, potentially lethal diseases that are caused by dengue virus infection. Dengue infection has been problematic for American military personnel stationed in tropical or subtropical countries and there is some concern that the virus could be weaponized in the future. There are four common serotypes of dengue virus and immunity against one serotype can enhance the severity of disease following infection with another serotype. Therefore, an effective dengue virus vaccine must elicit a broad response that is capable of neutralizing all four serotypes. We will use a unique adenovirus-based expression system to create a novel tetravalent dengue virus vaccine. Phase I of this project will focus on subcloning genes from all four dengue virus serotypes into adenovirus vectors and characterizing the vectors with respect to protein expression. Three dengue virus genes, prM, E, and NS1, from each serotype will be inserted into adenovirus vectors. Expression of the dengue virus genes from the adenovirus vectors is expected to elicit both humoral and cellular immune responses. The first generation vaccine will consist of a mixture of two adenovirus vectors - each vector expressing six genes from two dengue virus serotypes.