Investigating features of dengue immunity that drive enhancement versus protection 2307730

Abstract Introduction Secondary dengue virus (DENV) infection can lead to severe disease through antibody-dependent enhancement (ADE). However, after recovery, individuals develop broad immunity to all four DENV serotypes, DENV1-4. Methods To investigate the features of natural DENV immunity that drive enhancement versus protection, we evaluated 45 adults who were flavivirus naïve or previously DENV exposed and challenged them with a live DENV3 vaccine (NCT05691530). We measured baseline antibodies using binding and function assays and DENV-specific T cells to evaluate their association with viremia. Results To identify the determinants of viremia, regardless of infection history, we grouped immune participants based on the area under the curve of their viremia using unbiased clustering: those with low viremia had no boost in neutralizing antibodies, consistent with sterilizing immunity (N = 8). Intermediate viremia was of similar magnitude to naïve participants (N = 12), and high viremia was significantly greater than in other groups, as observed during enhanced dengue (N = 11). We found that fold-enhancement of DENV3 infection at a 1:10 serum dilution on a monocytic U937 cell line expressing CD16 (FcγRIII) was the strongest predictor of viremia, while neutralizing antibodies to mature DENV3 and greater neutralization breadth had the strongest protective effects. Neutralization measured using partially immature virus was not directly protective and instead showed non-linear associations with viremia. Sera that competed with a broadly neutralizing antibody for binding to the quaternary envelope-dimer epitope on DENV3 also had lower viremia, while binding responses to other serotypes were not protective. IFN-γ—secreting CD8+ T cells correlated with reduced viremia. Conclusion While enhancing antibodies determine susceptibility to viremia, neutralizing antibodies and antiviral CD8+ T cell responses are protective. Our results may help inform evaluation of future dengue vaccines and therapeutics. Funding Source This research was supported by the Intramural Research Program of the National Institutes of Health (NIH) as well as NIH Bench-to-Bedside Program Funds - Award # 994875, the NIH Director’s Challenge Innovation Award, ReVAMPP grant 1 U19 AI181960-01, and P Topic Categories Immune Mechanisms of Human Disease (HUM)