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

Area of Science:

• Virology
• Immunology
• Clinical Trials

Background:

• Human dengue virus infection models are crucial for evaluating vaccines and antivirals.
• A controlled dengue virus 3 (DENV-3) challenge model offers a platform for assessing clinical interventions.

Purpose of the Study:

• To assess the safety and immunogenicity of an attenuated DENV-3 strain (CH53489) in a phase 1 human challenge model.
• To evaluate the DENV-3 challenge model's ability to induce a controlled, mild dengue infection.

Main Methods:

• Nine healthy, flavivirus-seronegative participants received a subcutaneous inoculation of attenuated DENV-3 CH53489.
• Safety was monitored via solicited and unsolicited adverse events, clinical laboratory tests, and self-reported symptoms.
• Immunogenicity was assessed by DENV-3-specific seroconversion and memory T cell responses.
• Viral RNAemia, RNA sequencing, and serum cytokine analysis were performed.

Main Results:

• All participants developed RNAemia within 7 days, with peak titers varying significantly.
• Mild-to-moderate dengue symptoms, including fever, rash, lymphopenia, thrombocytopenia, and myalgia, were observed in all volunteers.
• DENV-3-specific seroconversion and memory T cell responses occurred within 14 days post-inoculation.
• Anti-viral responses, including cytokine production, correlated with viral load.

Conclusions:

• The low-dose DENV-3 challenge model is safe and induces predictable, mild dengue-like symptoms in healthy volunteers.
• The model elicits robust DENV-3-specific adaptive immune responses, including seroconversion and T cell activation.
• This human infection model provides a valuable platform for the early-stage evaluation of dengue vaccines and therapeutics.