Characterization of a novel dengue virus strain and its implication for vaccine development

Abstract

Abstract Dengue virus (DENV) causes up to 390 million infections yearly worldwide. Currently, four serotypes, DENV 1–4, circulate between Aedes mosquitoes and humans and can cause severe dengue, which has been associated with secondary DENV infection by a different serotype. DENV strain DKE-121 was recently isolated from Malaysia and is 12–38% different in its envelope protein from DENV 1–4. While previous studies of DENV genetic variation have described up to 3% amino acid divergence within a serotype, this virus differs by up to 12% from DENV4, suggesting its possible classification as a new serotype. The potential of a new DENV serotype emerging into circulation raises concerns of increased risk of severe dengue and uncertainty of how protective current tetravalent vaccine efforts would be. We tested the ability of serum from mice, non-human primates (NHPs), and humans that were infected or vaccinated with DENV4 and DKE-121 to neutralize infection of DENV4 and DKE-121. NHPs and humans immunized with DENV4 had 2 and 5-fold higher neutralizing titers (EC50 values), respectively, against the homologous DENV4 than DKE-121. However, mice boosted with DENV4 had similar neutralizing titers against DENV4 and DKE-121. In comparison, DKE-121 infection in NHPs and mice elicited 3-fold and up to 21-fold, respectively, higher titers against DKE-121 than DENV4. In addition, DKE-121 was poorly neutralized by type-specific anti-DENV4 monoclonal antibodies (mAbs), and reciprocally neutralizing mAbs against DKE-121 did not inhibit DENV4 infection. Using polyclonal sera and mAbs, DKE-121 and DENV4 show substantive differences in antigenicity. Ongoing studies are aimed at determining how these differences affect antibody-mediated protection in vivo.