[Dengue fever: from disease to vaccination]

Dengue is a tropical disease affecting 110 countries throughout the world and placing over 3 billion people at risk of infection. According the World Health Organization 70 to 500 million persons are infected every year including 2 million who develop hemorrhagic form and 20,000 who die. Children are at highest risk for death. Due to the absence of specialized laboratories in most endemic regions and to the lack of specifici clinical presentation, the incidence of dengue and its economic costs are certainly underestimated. Dengue iscaused by an arbovirus belonging to the Flavivirus genus of the family Flaviviridae. There are four dengue virus serotypes and no cross protection between them. The disease is transmitted through the bites of mosquitoes belonging to the Aedes genus, mainly Aedes aegypti. However A. albopictus has played an important role in the spread of the disease and other species may be involved in specific locations (e.g., A. polynesiensis in the South Pacific). There is no specific treatment for dengue. Management of severe forms depends on symptomatic treatment of hemorrhagic complications and hypovolemic shock. Prevention requires control of vector mosquitoes that is difficult to implement and maintain. Dengue is a major emerging infectious disease with a heavy impact on public health. The high human and economic costs as well as the absence of specific preventive measures underscore the need to develop a vaccine. However finding and distributing such a vaccine to populations at risk is hampered by numerous obstacles. The most notable challenges standing in the way of development of a candidate vaccine are as follows: absence of an animal model, which has important implications for the preclinical development strategy; need to develop a live attenuated vaccine; existence of 4 antigenically distinct serotypes with the resulting risk of competition between vaccine strains; immunologic risks related to antibody-dependent enhancement that has been hypothesized to be the cause of severe forms of the illness; absence of a well defined correlate of protection and preexisting vaccine, which will require the organization of large-scale pre-clinical trials to demonstrate the efficacy of the virus; complexity associated with industrial production of a tetravalent vaccine. Development and production of a safe and reliable vaccine are only the first steps to ensuring protection of the populations at risk, It twill also be necessary to identify and take into account a variety of geographic, economic, regulatory, and logistic factors: The epidemiological profile of dengue is variable. For example the age at which the likelihood of developing the disease is highest is not the same in Asia and Latin America. Vaccination programs must be tailored to regional and national epidemiological specificities. Introduction of dengue vaccination in the national immunization programs must take into account the special features of each country without jeopardizing the existing vaccines already in use. The need for an additional visit can represent a hardship both economically and logistically. Alternative funding will be needed to finance vaccination programs in some countries located in endemic zones, Long-term phase 4 effectiveness and tolerance field studies must be planned in collaboration with national authorities. All these challenges and obstacles have been taken into account in the development of Sanofi Pasteur's live attenuated tetravalent vaccine. Research for development of a dengue vaccine began during the 1990s. Clinical studies with the most promising tetravalent vaccine were started in the 2000s. A trial carried out in adults in the United States has shown that administration of three doses of the tetravalent candidate vaccine was 100% successful in inducing an antibody response capable of neutralizing all four dengue virus serotypes. Phase II clinical trials are now under way in children and adults in Mexico, Peru, and the Philippines. The first efficacy trial in children began in Thailand in February 2009. The purpose is to evaluate the efficacy of the tetravalent dengue vaccine in children. The study is being conducted in the Ratchaburi province in collaboration with the University of Mahidol and the Thai Ministry of Health as well as the Pediatric Dengue Vaccine Initiative (PDVI). This efficacy trial will be an important step for successful development of a live attenuated tetravalent vaccine.