Virologic, clinical, and immunological characteristics of a dengue virus 3 human challenge model

Abstract

Dengue human infection models present an opportunity to explore a vaccine, antiviral, or immuno-compound's potential for clinical benefit in a controlled setting. Herein, we report the outcome of a phase 1, open-label assessment of a DENV-3 challenge model. In this study, 9 participants received a subcutaneous inoculation with 0.5ml of a 1.4x103PFU/ml suspension of the DENV-3 strain CH53489. All subjects developed RNAemia within 7 days of inoculation, with peak titers ranging from 3.13x104to 7.02x108GE/ml. Symptoms and clinical lab abnormalities consistent with mild dengue infection were observed in all subjects. DENV-3 specific seroconversion was observed by 14 days after inoculation, along with DENV-3 specific memory T cell responses. RNAseq and serum cytokine analysis revealed the presence of an antiviral transcriptional and cytokine response to infection that overlapped with the period of viremia. The magnitude and frequency of clinical and immunologic endpoints correlated with an individual's peak viral titer.

TV005 dengue vaccine protects against dengue serotypes 2 and 3 in two controlled human infection studies

“…Both CHIMs are designed as "infection models" with an endpoint of viremia and mild symptoms of dengue infection, including mild-to-moderate rash, transient neutropenia, and mild retro-orbital pain, all prevented by TV005 vaccination. In contrast, CHIM strains under development by other teams are designed as "disease models" and cause signs and symptoms consistent with classic dengue fever including fever and high viremia (19,25,26). We believe the protective effect of TV005 against infection and concomitant symptoms of rDEN2Δ30 and rDEN3Δ30 "infection models" are indicative of protection against WT dengue and safe for human volunteers.…”

“…The opportunities for DENV CHIMs as an integrated component of global dengue vaccine development are still being realized. Additional dengue serotypes and strains from different viral backgrounds have been described (25,26,32,33); each model has distinct features, including various degrees of viral titer (viremia) and clinical signs and symptoms. Of particular interest are opportunities for vaccine CHIMs in dengue-endemic settings in which the documentation of efficacy in populations with varying degrees of baseline immunity would increase confidence before the large-scale introduction of dengue vaccines or phase III efficacy trials in new populations.…”

Magnitude and kinetics of the human immune cell response associated with severe dengue progression by single-cell proteomics

“…Last, future studies are needed to monitor the host response following the mosquito bite and during the first 2 to 3 days of symptoms. Since difficult to capture in natural DENV infection, inoculation studies as those previously conducted (79,80) would be ideal for addressing this knowledge gap.…”