Research Article: Pediatric Measles Vaccine Expressing a Dengue Antigen Induces Durable Serotype-specific Neutralizing Antibodies to Dengue Virus

Date Published: December 12, 2007

Publisher: Public Library of Science

Author(s): Samantha Brandler, Marianne Lucas-Hourani, Arnaud Moris, Marie-Pascale Frenkiel, Chantal Combredet, Michèle Février, Hugues Bedouelle, Olivier Schwartz, Philippe Desprès, Frédéric Tangy, Albert Ko

Abstract: Dengue disease is an increasing global health problem that threatens one-third of the world’s population. Despite decades of efforts, no licensed vaccine against dengue is available. With the aim to develop an affordable vaccine that could be used in young populations living in tropical areas, we evaluated a new strategy based on the expression of a minimal dengue antigen by a vector derived from pediatric live-attenuated Schwarz measles vaccine (MV). As a proof-of-concept, we inserted into the MV vector a sequence encoding a minimal combined dengue antigen composed of the envelope domain III (EDIII) fused to the ectodomain of the membrane protein (ectoM) from DV serotype-1. Immunization of mice susceptible to MV resulted in a long-term production of DV1 serotype-specific neutralizing antibodies. The presence of ectoM was critical to the immunogenicity of inserted EDIII. The adjuvant capacity of ectoM correlated with its ability to promote the maturation of dendritic cells and the secretion of proinflammatory and antiviral cytokines and chemokines involved in adaptive immunity. The protective efficacy of this vaccine should be studied in non-human primates. A combined measles–dengue vaccine might provide a one-shot approach to immunize children against both diseases where they co-exist.

Partial Text: Dengue fever is a mosquito-borne viral disease that threatens the health of a third of the world’s population. During the last twenty years, the four serotypes of dengue virus spread throughout the tropics due to the presence of the mosquito vector Aedes aegypti in all urban sites and to the major demographic changes that occurred in these regions. This global re-emergence shows larger epidemics associated with more severe disease [1]. Dengue is a major worldwide public health problem with an estimated 100 million annual cases of dengue fever (DF) and 500,000 annual cases of dengue hemorrhagic fever (DHF), the severe form of the disease, resulting in about 25,000 fatal cases, mainly in children under the age of 15. Although global prevention appears the best strategy to control dengue expansion, there is still no licensed vaccine available.

The objective of this study was to evaluate the immunogenicity of a dengue vaccine candidate based on a pediatric measles vaccine expressing a minimal dengue antigen. This strategy provides a recombinant vaccine that might protect children simultaneously from measles and dengue and that might be affordable to populations through the EPI program in the regions affected both by dengue and measles infections. An efficient pediatric dengue vaccine is supposed to elicit durable protective humoral immune responses against all four dengue serotypes without risk of ADE [46]. Regarding this objective, we assembled covalently the antigenic domain III from the DV1 envelope E glycoprotein and the pro-apoptotic ectodomain of DV-1 M protein to generate a dengue combined antigen, EDIII-ectoM. In the fusion construct, the N-terminal calreticulin peptide signal sequence directs EDIII-ectoM to the secretory pathway. The furin-dependent cleavage site of prM/M which links ectoM to EDIII allows the processing of the antigen by specific proteases throughout the Golgi apparatus. Expressed by recombinant MV vector, the EDIII-ectoM antigen induced in mice susceptible to MV specific antibodies to DV1 EDIII that did not cross-react with other DV serotypes and that neutralized DV1 infection in vitro. Immunization primed a long-term memory that was vigorously boosted when animals were inoculated with live DV.



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