Dengue Fever: Causes, Complications, and Vaccine Strategies

Abstract

Dengue is a highly endemic infectious disease of the tropical countries and is rapidly becoming a global burden. It is caused by any of the 4 serotypes of dengue virus and is transmitted within humans through female Aedes mosquitoes. Dengue disease varies from mild fever to severe conditions of dengue hemorrhagic fever and shock syndrome. Globalization, increased air travel, and unplanned urbanization have led to increase in the rate of infection and helped dengue to expand its geographic and demographic distribution. Dengue vaccine development has been a challenging task due to the existence of four antigenically distinct dengue virus serotypes, each capable of eliciting cross-reactive and disease-enhancing antibody response against the remaining three serotypes. Recently, Sanofi Pasteur's chimeric live-attenuated dengue vaccine candidate has been approved in Mexico, Brazil, and Philippines for usage in adults between 9 and 45 years of age. The impact of its limited application to the public health system needs to be evaluated. Simultaneously, the restricted application of this vaccine candidate warrants continued efforts in developing a dengue vaccine candidate which is additionally efficacious for infants and naïve individuals. In this context, alternative strategies of developing a designed vaccine candidate which does not allow production of enhancing antibodies should be explored, as it may expand the umbrella of efficacy to include infants and naïve individuals.

Figure 1

Genome organization and membrane topology of dengue virus. The viral RNA is translated as a single polyprotein consisting of structural (light brown-C, prM, and E) and nonstructural (dark brown-NS1, 2A, 2B, 3, 4A, 4B, and 5) protein components. Symbols C, prM, E, NS, and PM denote capsid protein, precursor membrane protein, envelope protein, nonstructural proteins, and plasma membrane, respectively. This single polyprotein then gets processed by viral (green arrow) and host (black arrow) proteases. The structural proteins (prM and E) remain anchored on the luminal side of the ER membrane. The C protein is anchored on the cytoplasmic side of ER membrane. prM is later cleaved by furin (red arrow) in the TGN into the pr peptide and M protein. The NS proteins are mainly processed by NS2B-NS3 (viral protease) in the cytoplasm. NS2A/2B and NS4A/4B are transmembrane proteins and thus stay anchored in the ER. The approximate molecular weight (in kDa) of each protein has been indicated in braces.

Figure 2

Organization of E protein on dengue virus surface during its life cycle. The E protein is colored as follows: EDI (red), EDII (yellow), EDIII (blue), and the FL (green). prM and M protein are colored as cyan. (a) Immature virus contains 60 trimeric spikes of E and prM heterodimer. (b) Mature virus contains 90 homodimers of E protein. (c) These homodimers then further undergo reorganization to form fusion active E homotrimers in which fusion loop is exposed. M protein is not shown in the fusion trimer for simplicity. E, C, M, FL, and prM denote envelope, capsid, membrane, fusion loop, and precursor membrane, respectively.

Figure 3

DENV-1, DENV-2, DENV-3, and DENV-4 with EDIII (circled) in red, green, blue, and black, respectively. EDIIIs elicit strongly neutralizing serotype-specific antibodies (antibodies in bold). Owing to homology especially in domains (EDI/II and prM) in yellow, cross-reactive weakly neutralizing antibodies (unbold antibodies) and nonneutralizing enhancing antibodies (dashed antibodies) are elicited in bulk.

Figure 4

Schematic representation of the dengue virus entry process. The dengue virus makes use of membrane receptors and attachment factors on the cell plasma membrane (PM) to find its way to the cytoplasm. The mature virion either gets attached directly to a cellular membrane receptor (a) or uses several attachment factors (b) to finally trigger the endocytic, clathrin dependent pathway. The endocytic vesicle becomes a late endosome, where acidification triggers conformational changes on the E protein dimers to become fusogenic trimers. Finally, pores are formed and the genome of the virus is released into the cytoplasm.

Figure 5

Classification of dengue vaccine candidates.