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Clin. Vaccine Immunol. doi:10.1128/CVI.00330-06
Copyright (c) 2006, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

A Complex Adenovirus-Based Dengue Virus Vaccine: Components for a Tetravalent Formulation

Division of Biodefense Vaccines, GenPhar Inc., 871 Lowcountry Blvd., Mount Pleasant, SC 29464; Department of Microbiology and Immunology, Medical University of South Carolina, 173 Ashley Avenue, Charleston, SC, 29403; Naval Medical Research Center, 503 Robert Grant Ave, Building 503, Room 3A14A, Silver Spring, MD 20910-7500; Department of Medicine, Uniformed Services University of Health Sciences, Bethesda, MD 20892

^* To whom correspondence should be addressed. Email: dongj{at}genphar.com.

	Abstract

Dengue virus infections can cause hemorrhagic fever, shock, encephalitis, and even death. Worldwide, approximately 2.5 billion people live in dengue infested regions with about 100 million new cases each year, although many of these infections are believed to be silent. There are four antigenically distinct serotypes of dengue virus, thus immunity from one serotype will not cross-protect from infection with the other three. The difficulties that hamper vaccine development include requirements of the natural conformation of the envelope glycoprotein to induce neutralizing immune responses and the necessity of presenting antigens of all four serotypes. Currently, the only way to meet these requirements is to use a mixture of four serotypes of live attenuated dengue viruses, but safety remains a major problem. In this study, we have developed the basis for a tetravalent dengue vaccine using a novel complex adenovirus platform that is capable of expressing multiple antigens de novo. This dengue vaccine is constructed as a pair of vectors that each expresses the prM and E genes of two different dengue serotypes. Upon vaccination, the vaccine expressed high levels of the dengue antigens in cells to mimic a natural infection, and induced both humoral and cellular immune responses against multiple serotypes of dengue virus in an animal model. Further analyses show the humoral responses were indeed neutralizing against all four serotypes. Our studies demonstrate the concept of mimicking infections to induce immune responses by synthesizing dengue-membrane antigens de novo and the feasibility of developing an effective tetravalent dengue vaccine by vector-mediated expression of glycoproteins of the four serotypes.

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