Publications

Background

Approximately half the worldwide population is at risk for dengue. No antiviral prophylaxis or treatment options are available.

Methods

In a phase 2a, double-blind, randomized trial, we assigned healthy adults to receive oral mosnodenvir once daily as a low dose (40-mg loading dose followed by 10-mg maintenance dose), medium dose (200 mg followed by 50 mg), or high dose (600 mg followed by 200 mg) or matched placebo. Loading doses were given for 5 days and maintenance doses for 21 days. In a controlled human infection model, participants received subcutaneous inoculation of an underattenuated dengue virus serotype 3 (DENV-3) strain (rDEN3Δ30) on the day of the first maintenance dose (day 1). The primary efficacy end point was the DENV-3 RNA load, assessed as the log₁₀ area under the concentration–time curve from day 1 (immediately before inoculation) through day 29 (AUC_D1–29). The high-dose and placebo groups were compared in the primary end-point analysis. Safety, pharmacokinetic features, and virologic and serologic features were evaluated through day 85.

Results

The percentage of participants without signs of DENV-3 infection was 0% (0 of 6 participants) with the low dose of mosnodenvir, 17% (1 of 6) with the medium dose, and 60% (6 of 10) with the high dose, as compared with 0% (0 of 7) with placebo. High-dose mosnodenvir led to a significantly lower DENV-3 RNA load, assessed as the log₁₀ AUC_D1–29, than placebo (two-sided P<0.001 by tobit analysis of variance). In this small trial, mosnodenvir did not result in any serious adverse events. Plasma concentrations of mosnodenvir increased from day −5 to day 1 and were maintained through day 21. Among participants with available NS4B sequencing data, emerging amino acid variations in the NS4B region of the rDEN3Δ30 genome were detected in 14 of 14 mosnodenvir recipients and none of 7 placebo recipients.

Conclusions

In a controlled human infection model, a high daily dose of oral mosnodenvir led to a significantly lower DENV-3 RNA load than placebo. Mosnodenvir did not result in any serious adverse events. (Funded by the National Institute of Allergy and Infectious Diseases and Johnson & Johnson; ClinicalTrials.gov number, NCT05048875.)

Vaccination with the tetravalent live attenuated dengue virus (DENV) vaccines TV003 and TV005 causes a mild, relatively localized erythematous maculopapular skin rash in most dengue-naïve vaccinees. Human challenge model DENV strains, DENV2Δ30 and DENV3Δ30, trigger a confluent skin rash over most of the body in most unvaccinated participants. To determine the etiology of these rashes we performed in situ hybridization for DENV genome and assessed cellular infiltration by hematoxylin/eosin staining in skin biopsies from humans infected with live attenuated dengue vaccine DENV2Δ30 or DENV3Δ30 challenge strains. Sixty-three biopsies from 40 participants were included in the study, of which 43 biopsies from 32 patients contained intact RNA. Of these, one sample taken from a non-erythematous site from a DENV2Δ30-infected participant experiencing a rash, was positive for DENV2 genome. Incidence and severity of lymphocytic infiltration were highest in rash biopsy samples compared to those from non-involved areas in participants experiencing a rash or from those taken from participants not experiencing a rash. These results indicate that the rash associated with infection with live attenuated dengue vaccines or challenge strains is predominantly lymphocyte-driven perivascular dermal inflammation without local concomitant active viral replication.