Once-Weekly Mosnodenvir Prevents Dengue Infection in 83% of Participants in Early Human Challenge Trial

Introduction

Dengue remains a major global public health challenge, particularly in tropical and subtropical regions. Effective antiviral treatments are lacking, highlighting the need for new preventive strategies.

Mosnodenvir is an investigational antiviral agent with activity against dengue virus. Previous phase 2a research demonstrated antiviral activity with daily administration in a controlled human infection model. Findings published online on 14 October 2026 extend this investigation to once-weekly dosing.

How was the study conducted?

This was a phase 2a, double-blind, randomised, placebo-controlled human infection study. The new report describes Cohort 2, building on previously published Cohort 1 findings. Twenty-four participants were allocated equally to four groups. All underwent controlled subcutaneous exposure to the underattenuated DENV-3 strain rDEN3Δ30 on day 1.

This experimental model differs from studying prevention of dengue after natural mosquito-borne exposure.

What dosing regimens were investigated?

Loading doses were given twice daily for two days (days −2 and −1), followed by daily or weekly maintenance treatment beginning on day 1.

The shorter two-day loading schedule was a notable change from the previously investigated five-day loading period.

What were the main results?

The key finding was the proportion without evidence of DENV-3 infection, assessed using undetectable viral RNA and absence of anti-DENV IgM, IgG and neutralising antibodies.

These daily-dose findings were broadly consistent with Cohort 1, in which 60% (6/10) receiving daily high-dose mosnodenvir had no evidence of infection. The trial was too small to establish equivalence between weekly regimens or superiority over daily dosing. The correspondence did not provide formal comparative efficacy estimates or confidence intervals.

What did the viral load analysis demonstrate?

Figure 1B reports DENV-3 RNA viral load area under the curve from days 1 to 29. Observed viral RNA exposure was lower in mosnodenvir groups than in placebo recipients, and several treated participants had undetectable viral RNA throughout the assessment period. These findings provide virological support for the observed prophylactic activity. Importantly, the small number of participants and absence of detailed statistical comparisons limit the precision of conclusions about differences between treatment regimens.

Were adequate drug concentrations maintained with weekly dosing?

Plasma mosnodenvir concentrations increased rapidly following loading doses and were maintained during the maintenance phase. These findings support the pharmacokinetic feasibility of weekly dosing, but no validated plasma concentration threshold guaranteeing protection was established.

Were there concerns about antiviral resistance?

Among mosnodenvir recipients with breakthrough infections and available sequencing data, NS4B amino acid variations were identified in four of four participants: A19L, V91G, L94F and Y99H. Variations were also found in two of six placebo recipients with breakthrough infections. The study does not establish whether these variations caused treatment failure or confer clinically meaningful resistance.

What did the study show about safety?

The investigators reported no clinically significant safety concerns. Nevertheless, only 18 participants in Cohort 2 received active mosnodenvir, and follow-up lasted up to 120 days. Uncommon adverse events, delayed toxicity and long-term safety cannot be reliably assessed from this small study.

What are the major limitations?

The endpoint was absence of detectable infection after an experimental challenge—not prevention of symptomatic dengue, hospitalisation or severe dengue in natural transmission settings.

What could these findings mean for clinical practice?

These results provide early evidence that a once-weekly oral antiviral regimen may be feasible for dengue prophylaxis. If effectiveness is confirmed in larger trials involving natural exposure, it could have future relevance in high-transmission settings or during outbreaks. Several questions remain unanswered:

• Can mosnodenvir prevent naturally acquired symptomatic dengue?
• Is its antiviral activity maintained against DENV-1, DENV-2 and DENV-4?
• How long does protection persist after the last dose?
• What is the optimal loading and maintenance regimen?
• What are the implications of NS4B variations for antiviral resistance?
• Is repeated or prolonged administration safe in broader populations?

Mosnodenvir remains investigational and is not established for routine dengue prophylaxis.

Clinical takeaway

Once-weekly mosnodenvir demonstrated substantial antiviral activity in a small controlled DENV-3 human infection study, with five of six participants in each weekly-dose group showing no evidence of infection. Larger trials evaluating naturally acquired dengue, multiple serotypes, clinically important outcomes and longer-term safety are essential before routine preventive use can be considered.

Full reference

Van Wesenbeeck L, Rasschaert F, Pierce KK, et al. Once-Weekly Mosnodenvir as Dengue Prophylaxis in a Human Infection Model. N Engl J Med. 2026;395(15):1553–1555. https://doi.org/10.1056/NEJMc2516395