Additionally, Fc-modified 3G9 that had lost their in vitro ADE activity showed enhanced therapeutic potency in vivo and competed strongly with an ADE-prone antibody in vitro. Administration of this antibody significantly prolonged the survival of interferon-О±/ОІ/Оі receptor knockout C57BL/6 mice after a lethal DENV challenge. However, one of the HuMAbs, 3G9, exhibited strong neutralization (NT 50 < 0.1 Ојg/ml) and possessed a high somatic hyper-mutation rate of the variable region, indicating affinity-maturation. These HuMAbs exhibited the typical characteristics of weak neutralizing antibodies including high cross-reactivity with other flaviviruses and targeting of the fusion loop epitope (FLE). Here, we generated eight HuMAb clones from an Indonesian patient infected with DENV. Human monoclonal antibodies (HuMAb) can be used to elucidate the mechanisms of neutralization and antibody-dependent enhancement (ADE) of DENV infections, leading to the development of a vaccine or therapeutic antibodies. These results show that an epitope-specific vaccine against conserved regions of NS1 could be a promising approach for DENV vaccines or therapeutics to bind circulating NS1 protein.Дengue virus (DENV), from the genus flavivirus of the family flaviviridae, causes serious health problems globally. We found that two of the candidate vaccines elicited antibodies that bound to recombinant NS1, and one candidate vaccine elicited antibodies that bound to DENV-infected cells. Mice were immunized two times with the candidate vaccines and sera were tested for the presence of antibodies that bound to the cognate peptide, recombinant NS1 from all four DENV serotypes, and DENV-2-infected cells. We generated synthetic peptides to these regions and chemically conjugated them to bacteriophage QОІ virus-like particles (VLPs). We identified highly conserved regions of NS1 from all four DENV serotypes. Immunizing against NS1 could elicit antibodies that block NS1 function and also target NS1-infected cells for antibody-dependent cell cytotoxicity. NS1 causes disruption of endothelial cell barriers, resulting in plasma leakage and hemorrhage. NS1 is present in DENV-infected cells as well as secreted into the blood of infected individuals. Here, we describe efforts to engineer epitope-based vaccines against DENV non-structural protein 1 (NS1). Despite over 60 years of efforts, no licensed vaccine suitable for population-based immunization against DENV is available. Our findings demonstrate the feasibility of using structure-based design to produce subunit vaccines for dengue and other flaviviruses.Дengue virus (DENV) is a major global health problem, with over half of the worldвЂ™s population at risk of infection. Mice immunized with the stabilized dimers developed antibodies that bind to E dimers and not monomers and elicited higher levels of DENV2-neutralizing antibodies compared to mice immunized with WT E antigen. Cross-dimer epitope antibodies bind to the stabilized dimers, and a crystal structure resembles the wild-type (WT) E protein bound to a dimer epitope antibody. Using molecular modeling, we found DENV2 E protein mutations that induce dimerization at low concentrations (<100 pM) and enhance production yield by more than 50-fold. However, recombinantly expressed soluble E proteins are monomers under vaccination conditions and do not present these quaternary epitopes, partly explaining their limited success as vaccine antigens. Neutralizing antibodies bind to quaternary epitopes on DENV envelope (E) protein homodimers. Dengue virus (DENV) is a worldwide health burden, and a safe vaccine is needed.

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