4. Dengue vaccines

in intravascular coagulation. Finally, although controversial, the role of autoimmunity in the pathogenesis of dengue is mentioned, as autoantibodies resulting in platelet and endothelial cell dysfunction might be involved in severe dengue pathogenesis. Not all cases of DWS+ occur in people who experience a secondary infection, since in some cases the virus' own virulence, added to the characteristics of the host, leads to the complication of the disease [19], which may be due to the presence of antibodies against viral proteins that have crossreactivity with platelets and coagulation factors [18]. Certain nonstructural proteins such as NS1, NS2, and NS3 appear to have a certain structural homology with coagulation factors, platelets, integrins, and adhesins of human endothelial cells, allowing the activation of autoreactive T lymphocytes that participate in the pathology of dengue [16, 20]. Anti-NS1 antibodies correlate with disease severity, and cross-reaction of anti-NS1 antibodies with liver and endothelial cells are also implicated in affecting the integrity of the vascular endothelium and platelets has been proposed to trigger these cells to express nitric oxide and undergo apoptosis [2, 3, 14]. Certain antibodies to some E protein epitopes can bind to human plasminogen and inhibit plasmin activity (see Figure 3). Recently, it has been reported that Tropomyosin (TPM)-1 may play an important role in the pathogenesis of SD. It is plausible that the elevation of TPM-1 in the plasma of SD patients can be due to excessive cell death, thereby releasing TPM into the circulation as DAMPs, and leading to mast cell activation. Moreover, the insulin pathway may play a role in the pathogenesis of SD, hence, regulating the insulin

150 Dengue Fever - a Resilient Threat in the Face of Innovation

Figure 3. A schematic model of autoantibody-mediated immunopathogenesis in DENV infection. Molecular mimicry between platelets, endothelial cells, and coagulatory molecules with NS1, prM, E, and C proteins underlies the crossreactivity of anti-NS1, anti-prM, anti-E, and anti-C Abs, respectively, to host proteins. Abs Z antibodies; C Z capsid protein; DENV Z dengue virus; E Z envelope protein; NS Z nonstructural protein; prM Z precursor membrane protein.

Adapted from Wan et al. [14].

Dengue virus is widespread throughout the tropics, representing an important, rapidly growing public health problem with an estimated 2.5–3.9 billion people at risk of dengue fever and the life-threatening severe dengue disease. Therefore, the need for a safe and effective vaccine for dengue is immediate. Vaccine development has been slowed by fears that immunization might predispose individuals to the severe form of dengue infection [4]. The characteristics and challenges that the ideal vaccine for the dengue virus must have are described in the following.
