Low-dose dengue virus 3 human challenge model: a phase 1 open-label study

Adam T Waickman; Krista Newell; Joseph Q Lu; HengSheng Fang; Mitchell Waldran; Chad Gebo; Jeffrey R Currier; Heather Friberg; Richard G Jarman; Michelle D Klick; Lisa A Ware; Timothy P Endy; Stephen J Thomas

doi:10.1038/s41564-024-01668-z

Low-dose dengue virus 3 human challenge model: a phase 1 open-label study

Nat Microbiol. 2024 Apr 1. doi: 10.1038/s41564-024-01668-z. Online ahead of print.

Authors

Adam T Waickman^{1

2}, Krista Newell³, Joseph Q Lu^{3

4}, HengSheng Fang³, Mitchell Waldran³, Chad Gebo³, Jeffrey R Currier⁵, Heather Friberg⁵, Richard G Jarman⁵, Michelle D Klick⁴, Lisa A Ware⁴, Timothy P Endy³, Stephen J Thomas^{6

7}

Affiliations

¹ Department of Microbiology and Immunology, State University of New York Upstate Medical University, Syracuse, NY, USA. waickmaa@upstate.edu.
² Institute for Global Health and Translational Sciences, State University of New York Upstate Medical University, Syracuse, NY, USA. waickmaa@upstate.edu.
³ Department of Microbiology and Immunology, State University of New York Upstate Medical University, Syracuse, NY, USA.
⁴ Institute for Global Health and Translational Sciences, State University of New York Upstate Medical University, Syracuse, NY, USA.
⁵ Viral Diseases Branch, Walter Reed Army Institute of Research, Silver Spring, MD, USA.
⁶ Department of Microbiology and Immunology, State University of New York Upstate Medical University, Syracuse, NY, USA. ThomStep@upstate.edu.
⁷ Institute for Global Health and Translational Sciences, State University of New York Upstate Medical University, Syracuse, NY, USA. ThomStep@upstate.edu.

PMID: 38561497
DOI: 10.1038/s41564-024-01668-z

Abstract

Dengue human infection models present an opportunity to explore the potential of a vaccine, anti-viral or immuno-compound for clinical benefit in a controlled setting. Here we report the outcome of a phase 1 open-label assessment of a low-dose dengue virus 3 (DENV-3) challenge model (NCT04298138), in which nine participants received a subcutaneous inoculation with 0.5 ml of a 1.4 × 10³ plaque-forming unit per ml suspension of the attenuated DENV-3 strain CH53489. The primary and secondary endpoints of the study were to assess the safety of this DENV-3 strain in healthy flavivirus-seronegative individuals. All participants developed RNAaemia within 7 days after inoculation with peak titre ranging from 3.13 × 10⁴ to 7.02 × 10⁸ genome equivalents per ml. Solicited symptoms such as fever and rash, clinical laboratory abnormalities such as lymphopenia and thrombocytopenia, and self-reported symptoms such as myalgia were consistent with mild-to-moderate dengue in all volunteers. DENV-3-specific seroconversion and memory T cell responses were observed within 14 days after inoculation as assessed by enzyme-linked immunosorbent assay and interferon-gamma-based enzyme-linked immunospot. RNA sequencing and serum cytokine analysis revealed anti-viral responses that overlapped with the period of viraemia. The magnitude and frequency of clinical and immunologic endpoints correlated with an individual's peak viral titre.