First-in-Human Dengue Serotype 4 Live Virus Human Challenge: A Phase 1 Dose Optimization and Homologous Rechallenge Study

Dengue Live Virus Human Challenges (LVHC) are critically needed in dengue vaccine and pharmacologic development to down-select candidates and provides a useful platform for understanding viral-host immunology in a controlled setting. We conducted a first-in-human phase 1 open label study evaluating the safety and optimized dose of an underattenuated dengue virus serotype-4-LVHC (DENV-4-LVHC) strain H-241. The study was divided into a dose optimization study followed by a homologous rechallenge substudy. Fourteen healthy adult participants were enrolled and challenged with a subcutaneous dose of DENV-4-LVHC. All 14 developed viremia and symptoms consistent with self-limited, mild-moderate dengue. Six participants were rechallenged using the optimized dose 1 year after primary challenge, and none developed detectable dengue. Robust antibody responses, plasmablast expansion, and antiviral gene upregulation were seen during primary infection but not after rechallenge. No severe dengue, need for inpatient observation, or dengue challenge-related serious adverse events were observed. DENV-4-LVHC was found to be safe and highly predictable for use in future studies to evaluate vaccine and therapeutic candidates. Immunity from prior DENV-4-LVHC infection conferred protection following homologous rechallenge one year after primary exposure. ClinicalTrial.gov identifier: NCT05268302.