Abstract
Dengue virus (DENV), a global disease, is divided into four serotypes (DENV1-4). Cross-reactive and non-neutralizing antibodies against envelope (E) protein of DENV bind to the Fcγ receptors (FcγR) of cells, and thereby exacerbate viral infection by heterologous serotypes via antibody-dependent enhancement (ADE). Identification and modification of enhancing epitopes may mitigate enhancement of DENV infection. In this study, we characterized the cross-reactive DB21-6 and DB39-2 monoclonal antibodies (mAbs) against domain I-II of DENV; these antibodies poorly neutralized and potently enhanced DENV infection both in vitro and in vivo. In addition, two enhancing mAbs, DB21-6 and DB39-2, were observed to compete with sera antibodies from patients infected with dengue. The epitopes of these enhancing mAbs were identified using phage display, structural prediction, and mapping of virus-like particle (VLP) mutants. N8, R9, V12, and E13 are the reactive residues of DB21-6, while N8, R9, and E13 are the reactive residues of DB39-2. N8 substitution tends to maintain VLP secretion, and decreases the binding activity of DB21-6 and DB39-2. The immunized sera from N8 substitution (N8R) DNA vaccine exerted greater neutralizing and protective activity than wild-type (WT)-immunized sera, both in vitro and in vivo. Furthermore, treatment with N8R-immunized sera reduced the enhancement of mortality in AG129 mice. These results support identification and substitution of enhancing epitope as a novel strategy for developing safe dengue vaccines.
Highlights
Dengue virus (DENV) is a mosquito-borne virus that causes prevalent, global disease
We found that serum samples from patients with severe dengue disease contain higher levels of antibodies against enhancing epitope
Our results show that substitution of enhancing epitope can increase the immune response against viral infection, while reducing the potential for antibody-dependent enhancement (ADE)
Summary
Dengue virus (DENV) is a mosquito-borne virus that causes prevalent, global disease. Primary infection with DENV provides immunity against the same serotype, subsequent secondary infection with different DENV serotypes has a higher risk for developing severe dengue disease [3,4,5]. The presence of cross-reactive and non-neutralizing antibodies bound to DENV helps viral entry into Fcγ receptor (FcγR)-bearing cells, resulting in increased virus load and/or production of certain cytokines [6]. This phenomenon is termed antibody-dependent enhancement (ADE) [3,7]. At the time of writing, there is no approved vaccine against DENV infection [8]
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