Novel dengue serotype 4 live virus human challenge: a phase 1 dose optimisation and homologous rechallenge study

Dengue live virus human challenges (LVHCs) are key in dengue vaccine and pharmacological development, to down-select candidates and provide a useful platform for understanding viral-host immunology in a controlled setting. The primary aim of this study was to assess the safety, reactogenicity, and immunogenicity of a newly derived underattenuated dengue virus serotype-4-LVHC (DENV-4-LVHC) strain intended for future dengue challenge studies.

We conducted a first-in-human, phase 1, non-randomised, open-label study that evaluated the safety and optimised dose of the DENV-4-LVHC strain H-241 in flavivirus-naive healthy adult volunteers. The trial was conducted between April 28, 2022, and Dec 18, 2023, at the University of Maryland (Baltimore, MD, USA) and included a dose-optimisation study in which participants were enrolled into staggered-start, dose-ranging cohorts, beginning with the lowest dose, and homologous rechallenge substudy in which willing, primary-infected participants were rechallenged with the optimised dose of DENV-4 at least 12 months from the primary challenge. Successful challenge was defined as more than 90% participants developing self-limiting mild-to-moderate dengue symptoms with detectable RNAemia. Participants were analysed on the basis of the treatment group (primary infection vs rechallenge). This trial is registered with ClinicalTrials.gov (Identifier: NCT05268302).

14 healthy adult participants were enrolled between March 31, 2022, and June 9, 2022 (dose optimisation), and were challenged with a subcutaneous dose of DENV-4-LVHC on June 12, 2023 (rechallenge). The majority were men (11 [79%] of 14), and almost half were non-White (6 [43%]). The mean participant age was 33·6 years (range 20-48). All 14 participants developed viraemia and symptoms consistent with self-limited, mild-to-moderate dengue at an optimised dose of 95 plaque-forming units (low dose). Six (60%) participants (of the original ten from the 2022 cohort) were rechallenged using the optimised 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 challenge studies, to evaluate vaccine and therapeutic candidates. Immunity from previous DENV-4-LVHC infection conferred protection following homologous rechallenge 1 year after primary exposure.

Military Infectious Disease Research Program; Medical Technology Enterprise Consortium.