Dengue vaccines: recent developments, ongoing challenges and current candidates

Abstract

Dengue is among the most prevalent and important arbovirus diseases of humans. To effectively control this rapidly spreading disease, control of the vector mosquito and a safe and efficacious vaccine are critical. Despite considerable efforts, the development of a successful vaccine has remained elusive. Multiple factors have complicated the creation of a successful vaccine, not the least of which are the complex, immune-mediated responses against four antigenically distinct serotypes necessitating a tetravalent vaccine providing long-lasting protective immunity. Despite the multiple impediments, there are currently many promising vaccine candidates in preclinical and clinical development. Here, the recent advances in dengue virus vaccine development are reviewed and the challenges associated with the use of these vaccines as a public health tool are briefly discussed.

Figure 1

Organization of the flavivirus genome. A) RNA genome including the 5’ and 3’ untranslated regions (UTR) and coding regions for the structural and non-structural proteins. B) Polyprotein processed by both virus-encoded and host proteases resulting in three structural proteins (capsid (C), membrane (M), and envelope (E)) and seven non-structural (NS) proteins (NS1, NS2A, NS2B, NS3, NS4A, NS4B, and NS5). C) Diagram indicating the alterations to the DENV genome for generation of several live attenuated virus vaccine candidates. See text for a brief description of the vaccines mentioned in this panel.

Figure 2

Potential mechanisms for immune mediated enhancement of DENV infection. A) Immune responses following primary DENV infection include infection of monocytes and other antigen presenting cells which produce cytokines/chemokines and present antigen to lymphocytes. Type-specific and cross-reactive B and T lymphocytes are activated. B lymphocytes produce serotype-specific, neutralizing antibodies as well as cross-reactive, weakly or non-neutralizing antibodies. B) Following secondary heterologous infection, uptake of DENV is facilitated through binding of cross-reactive, non-neutralizing antibodies from a previous infection (or maternally derived antibodies in the case of primary infection in infants). Additionally, there is activation of cross-reactive T cells that produce skewed cytokine responses and demonstrate decreased cytotoxicity for DENV infected cells. Massive quantities of pro-inflammatory cytokines (“cytokine storm”) result in increased vascular permeability and plasma leakage. Furthermore, expression or release of DENV-NS1 by infected cells may mediate complement activation resulting in increased vascular permeability.