1. Introduction

Dengue is a mosquito-borne viral disease caused by four types of dengue viruses, which, in the recent years, has rapidly become widespread worldwide. Dengue virus transmission is attributed to female mosquitoes of the species Aedes aegypti, in the majority of cases, as well as Ae. albopictus to a lesser extent. Other diseases that are transmitted by this mosquito include chikungunya, yellow fever, and Zika infection [1]. Dengue is a very rapidly growing public health problem being currently faced by approximately 40% of the global population living in more than a hundred tropical and subtropical countries [2]. Dengue is widespread throughout the tropics, with local variations in risk influenced by rainfall, temperature as consequence of climate change, unplanned rapid urbanization, unprecedented population growth, increasing

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and eproduction in any medium, provided the original work is properly cited. © 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

movement of people (and consequently viruses), international travel and breakdown in public health infrastructure, and vector control programs. The actual numbers of dengue cases are underreported and many cases are misclassified. The prevalence of dengue is estimated at 3.9 billion people who are at risk of infection in 128 tropical and subtropical countries, mainly southeast and south Asia, Central and South America, and the Caribbean. A recent estimate indicates 390 million dengue infections per year (95% credible interval 284–528 million), of which 96 million (67–136 million) manifest clinically (with any severity of disease), with an estimated 500,000 cases each year of life-threatening disease in the form of severe dengue—including dengue hemorrhagic fever and dengue shock syndrome mostly in the pediatric population, with about 20,000 succumbing to it, and is the leading cause of childhood death in many countries [1– 3]. Dengue is associated with considerable social, economic, and political consequences caused by urban epidemics, such as those seen in Delhi (1996), Cuba (1977–1979 and 1997), Taiwan (2002), and Brazil (2008). Furthermore, Dengue is currently also a major cause of morbidity in American and European travelers and military personnel [4]. This disease places a high economic burden on both governments and individuals; for instance, in America, Dengue illness costs US\$2.1 billion per year on average, excluding vector control, exceeding costs of other viral illnesses. In addition, in Southeast Asia, there is an estimate of 2.9 million dengue episodes and 5906 deaths annually, with an annual economic burden of \$950 million [3].

when an increase in capillary permeability accompanied by increased hematocrit can occur, leading to hypovolemic shock that can result in organ impairment, metabolic acidosis, disseminated intravascular coagulation, and severe hemorrhage. If untreated, mortality can be as high as 20%, whereas appropriate case management and intravenous rehydration can reduce mortality to less than 1% [3]. SD usually affects children younger than 15 years of age, although it can occur in adults. SD is characterized by a transient increase in vascular permeability resulting in plasma leakage with high fever, bleeding, thrombocytopenia, and hemoconcentration, which can lead to shock [5]. Two factors, namely, antibody-dependentenhancement (ADE) and inherent virulence of the DEN viruses, appear to contribute the most

Current Status of Vaccines against Dengue Virus http://dx.doi.org/10.5772/intechopen.80820 147

The pathophysiological basis for severe dengue is multifactorial, resulting from a complex interaction between the virus, the host, and, at least in part, immune-mediated mechanisms. Individuals with primary Dengue virus infection induce a lifelong protective immunity to the infecting serotype, accompanied by a short-term cross-immunity against other serotypes and development only leads to self-limited dengue fever characterized by high fever and debilitating joint pain, recovery from infection by one provides lifelong immunity against that serotype. However, subsequent infection with a different dengue serotype is more likely to cause DWS+/SD, and cross-immunity to the other serotypes after recovery is only partial and temporary. Epidemiological data suggest an increased risk of DWS+/SD in people with preexisting heterotypic dengue virus antibodies, and this has led to research in dengue pathogenesis focusing on the subsequent infections by other serotypes and an increased risk of developing severe dengue. Accordingly, antibodies against a given serotype can cross-react with, but not cross-protect against, the remaining three virus serotypes [4] during secondary infections. Immunopathological mechanisms have been proposed, such as the immune system improvement phenomenon (immunopotentiation), which contribute to the increased risk of DWS+ or SD. It is widely accepted that these cross-reactive antibodies can promote enhanced uptake of the heterologous virus into host cells, precipitating a hyperimmune reaction resulting in blood vessel leakage and potentially fatal hypovolemic shock [1, 2]. This increase occurs when nonneutralizing antibodies resulting from the primary infection favor the invasion of the second virus with a different serotype into the target cells, a phenomenon known as antibody-dependent amplification or antibody-dependent enhancement (ADE) [8, 9]. Subsequent infection with a different dengue serotype is more likely to cause DWS+/SD [8, 9]. According to the ADE hypothesis, a primary infection with DENV produces an insufficient concentration of antibodies or avidity to neutralize a secondary infection by DENV of a different serotype that differs in its amino acid sequence by 30–35%; and these sub-neutralizing antibody concentrations can promote infection in such cells by facilitating Fc-receptor-mediated entry [10]. These concentrations could be enough to opsonize the secondary virus and target it for Fc-receptormediated endocytosis into myeloid cells such as monocytes and macrophages (which constitute the main site of DENV replication) and in this manner promote higher viral loads. ADE can be observed in vitro and has also been proven to drive higher viral loads of DENV in animal models [11]. The following findings support the hypothesis of the antibody-dependent

to disease pathogenesis [2].

3. Pathogenesis of Dengue virus infection
