Abstract
Eliciting broadly neutralizing antibodies (bNAbs) against the four dengue virus serotypes (DENV1-4) that are spreading into new territories is an important goal of vaccine design. To define bNAb targets, we characterized 28 antibodies belonging to expanded and hypermutated clonal families identified by transcriptomic analysis of single plasmablasts from DENV-infected individuals. Among these, we identified J9 and J8, two somatically related bNAbs that potently neutralized DENV1-4. Mutagenesis studies showed that the major recognition determinants of these bNAbs are in E protein domain I, distinct from the only known class of human bNAbs against DENV with a well-defined epitope. B cell repertoire analysis from acute-phase peripheral blood suggested that J9 and J8 followed divergent somatic hypermutation pathways, and that a limited number of mutations was sufficient for neutralizing activity. Our study suggests multiple B cell evolutionary pathways leading to DENV bNAbs targeting a new epitope that can be exploited for vaccine design.
Highlights
Dengue virus (DENV) is an enveloped, positive-stranded RNA virus belonging to the Flavivirus genus, which includes clinically significant human pathogens such as Yellow Fever virus, Japanese encephalitis virus, West Nile virus (WNV), and Zika virus (ZIKV)
One (013) with secondary DENV4 infection and another (020) with primary DENV1 infection (Table 1), we identified 15 clonal families comprising a total of 38 unique paired heavy (VH) and light (VL) chain IgG1 plasmablast sequences, some of which were hypermutated (1.67% to 10.77% for VH, 0.67% to 7.22% for VL; Figure 1—figure supplement 1)
We detected secreted IgG in the transfection supernatants for 28 of 36 antibodies, which were tested for binding to DENV2 recombinant soluble E protein and reporter virus particles, as well as for neutralizing activity against a panel of reporter flaviviruses, including DENV1-4, ZIKV, and WNV (Figure 1—figure supplement 1)
Summary
Dengue virus (DENV) is an enveloped, positive-stranded RNA virus belonging to the Flavivirus genus, which includes clinically significant human pathogens such as Yellow Fever virus, Japanese encephalitis virus, West Nile virus (WNV), and Zika virus (ZIKV). DENV is transmitted to humans via Aedes mosquitoes, whose global distribution places half of the world’s population at risk for infection (Kraemer et al, 2019; Messina et al, 2019). The four phylogenetically and antigenically distinct DENV serotypes (DENV1-4) cause approximately 400 million infections (Bhatt et al, 2013). Increased global trade, connectivity, and climate change have fueled the expansion of DENV1-4 into new territories (Kraemer et al, 2019; Messina et al, 2014)
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