Abstract
The four serotypes of dengue virus (DENV) are the leading cause of arboviral diseases in humans. Decades of efforts have made remarkable progress in dengue vaccine development. Despite the first dengue vaccine (dengvaxia from Sanofi Pasteur), a live-attenuated tetravalent chimeric yellow fever-dengue vaccine, has been licensed by several countries since 2016, its overall moderate efficacy (56.5–60.8%) in the presence of neutralizing antibodies during the Phase 2b and 3 trials, lower efficacy among dengue naïve compared with dengue experienced individuals, and increased risk of hospitalization among young children during the follow-up highlight the need for a better understanding of humoral responses after natural DENV infection. Recent studies of more than 300 human monoclonal antibodies (mAbs) against DENV have led to the discovery of several novel epitopes on the envelope protein recognized by potent neutralizing mAbs. This information together with in-depth studies on polyclonal sera and B-cells following natural DENV infection has tremendous implications for better immunogen design for a safe and effective dengue vaccine. This review outlines the progress in our understanding of mouse mAbs, human mAbs, and polyclonal sera against DENV envelope and precursor membrane proteins, two surface proteins involved in vaccine development, following natural infection; analyses of these discoveries have provided valuable insight into new strategies involving molecular technology to induce more potent neutralizing antibodies and less enhancing antibodies for next-generation dengue vaccine development.
Highlights
The four serotypes of dengue virus (DENV) cause the most common and important arboviral diseases in humans (Guzman and Harris, 2015)
Complexity of Antibodies to Dengue Virus countries since 2016, the moderate efficacy (56.5–60.8%) in the presence of neutralizing antibodies (Abs) during its Phase 2b and 3 trials, lower efficacy among dengue naïve compared with dengue experienced individuals (35.5–43.2 vs. 74.3–83.7%), and increased risk of hospitalization and severe dengue among young children during the follow-up in years 3–6 highlight the need for a better understanding of immunity, in particular humoral responses, after natural DENV infection (Sabchareon et al, 2012; Capeding et al, 2014; Guy et al, 2015; Hadinegoro et al, 2015; Thomas, 2015; Villar et al, 2015; Aguiar et al, 2016; Flasche et al, 2016; Halstead, 2016; Halstead and Russell, 2016; Wilder-Smith et al, 2016)
We have reviewed more than 300 human monoclonal antibodies (mAbs) against DENV E protein and potent neutralizing epitopes reported far, together with human anti-precursor membrane (prM) mAbs and mouse mAbs
Summary
The four serotypes of dengue virus (DENV) cause the most common and important arboviral diseases in humans (Guzman and Harris, 2015). A similar trend was observed in vaccinees following primary and secondary immunization with monovalent live-attenuated DENV vaccines (Figures 2C,D) Together, these observations suggest that cross-reactive anti-E Abs are the major Abs, followed by anti-prM and NS1 Abs. In the genus Flavivirus of the family Flaviviridae, members belonging to different serocomplexes cause significant human diseases, including the four serotypes of DENV in the DENV serocomplex, WNV and JEV in the JEV serocomplex, tickborne encephalitis virus (TBEV) in the TBEV serocomplex, YFV as a single member, and Zika virus (ZIKV) in its serocomplex (Pierson and Diamond, 2013). Based on the binding to recombinant E protein, DIII or DI/II, alanine mutants, yeast library or escape mutants, group-reactive mAbs were found to recognize either residues in fusion loop or both fusion loop and bc loop, a loop next to fusion loop in DII (Costin et al, 2013; Smith et al, 2013a; Tsai et al, 2013), typespecific mAbs recognize epitopes in DIII, interdomain residues, DI/II hinge region or quaternary epitopes on virion (Beltramello et al, 2010; de Alwis et al, 2011, 2012; Teoh et al, 2012; Fibriansah et al, 2014, 2015a,b), and complex-reactive mAbs recognize DIII or E-dimer epitope which involves fusion loop
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