Detection of envelope-dimer epitope-like broadly protective antibodies in dengue-immune children in the Philippines following vaccination and natural infection

Abstract

The dengue vaccine, Dengvaxia, has been described as eliciting antibody-dependent enhancement (ADE) in dengue-naive individuals. There is an urgent need to develop an effective dengue virus (DENV) vaccine that elicits protective, cross-reactive (CR) neutralizing antibodies (NAbs), which are capable of neutralizing DENV1–4 without triggering ADE such as EDE Abs.Here, we investigated the CRNAbs profile following DENV natural infection versus vaccination in children with prior DENV infection (n=2,996) from a longitudinal vaccine (study) cohort in Cebu, Philippines. In total, 1,214 of these children remained unvaccinated while 1,782 children received a single dose of Dengvaxia in June of 2017 during a mass vaccination campaign. Serum samples were collected one month before and one year after the vaccine campaign.To measure baseline status and change in CRNAbs level following vaccination versus natural infection, we ran Focus Reduction Neutralizing Test (FRNT) using mature DENV1–4 virions and Blockade of binding (B0B) assay against EDE Abs on a random subset of these DENV-immune children’s samples (n=231). Furthermore, we also measured IgG binding against the DENV1–4 E protein monomer and DENV2 E protein dimer.Both vaccinated and naturally infected groups elicit CRNAbs that recognize the quaternary epitopes of EDE antibodies. We also see a significant increase in antibody response in both groups, but CRNAbs had a stronger correlation to mature FRNT in naturally infected compared to vaccinated populations, indicating differences in antibody quality. These results highlight the presence of EDE-like broadly NAbs that could possibly protect against the four DENV serotypes and provide an insight for future vaccine candidates.This work was supported by the Intramural Research Program (DIR) of the National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health, the Philippine Department of Health and the University of North Carolina (PO1: P01AI106695).