Highlight
– In a phase 2a, double‑blind controlled human infection model (CHIM), daily high‑dose mosnodenvir reduced DENV‑3 RNA load (AUCD1–29) versus placebo (P<0.001).
– Protective effect was dose‑dependent: 60% of high‑dose recipients (6/10) showed no clinical signs of infection versus 0% with placebo; lower doses had minimal effect.
– No serious adverse events were observed, plasma drug concentrations were maintained during dosing, but treatment was associated with emergence of amino acid changes in the viral NS4B region in all sequenced mosnodenvir recipients (14/14) and none in placebo recipients.
Background and disease burden
Dengue is a mosquito‑borne flaviviral disease with large and growing global impact. Approximately half the world’s population lives in areas at risk of dengue transmission, and the burden of symptomatic disease and severe complications remains substantial in endemic regions and during outbreaks. Current clinical management is supportive; licensed vaccines have important limitations related to baseline serostatus and age, and no approved antiviral prophylactic or therapeutic agents are available for routine clinical use. The unmet need for safe, effective antivirals that can prevent infection or attenuate viremia is therefore substantial and has high public‑health relevance for travelers, outbreak control, and protection of vulnerable populations.
Study design
This phase 2a, randomized, double‑blind, placebo‑controlled trial (NCT05048875) evaluated oral mosnodenvir as prophylaxis in a CHIM using an underattenuated recombinant dengue virus serotype 3 strain (rDEN3Δ30). Healthy adult volunteers were randomized to receive one of three oral mosnodenvir regimens or matched placebo. The dosing strategy used a 5‑day loading period followed by 21 days of maintenance dosing. The regimens were: low dose (40 mg loading then 10 mg maintenance), medium dose (200 mg then 50 mg), or high dose (600 mg then 200 mg). On day 1 (the first maintenance dose day), participants were inoculated subcutaneously with rDEN3Δ30. Participants were followed for clinical, virologic, pharmacokinetic (PK), and serologic outcomes through day 85.
The prespecified primary efficacy endpoint was DENV‑3 RNA load quantified as the log10 area under the concentration‑time curve from day 1 through day 29 (AUCD1–29). The primary comparison was between the high‑dose and placebo groups. Safety, PK, and viral sequencing (focused on NS4B) were secondary and exploratory endpoints.
Key findings
Efficacy — virologic and clinical outcomes
High‑dose mosnodenvir produced a statistically significant reduction in DENV‑3 RNA burden compared with placebo. The tobit analysis of variance for the primary end point (log10 AUCD1–29) showed a two‑sided P<0.001 favoring the high‑dose arm. Clinically, 60% (6 of 10) of participants receiving high‑dose mosnodenvir remained without signs of DENV‑3 infection, compared with 0% (0 of 7) in the placebo group. The medium dose yielded 1 of 6 participants (17%) uninfected, and the low dose yielded no uninfected participants (0 of 6).
These data demonstrate a dose‑response relationship in this CHIM: the high dose was associated with meaningful protection against detectable infection and markedly lower cumulative viremia over the first 29 days after challenge.
Pharmacokinetics and dosing
Plasma concentrations of mosnodenvir rose during the loading phase (day −5 to day 1) and were maintained through the 21‑day maintenance period, consistent with the intended pre‑exposure prophylaxis strategy. The dosing regimen achieved the systemic exposure required for antiviral activity in this model without reported pharmacokinetic accumulation that led to overt toxicity in this small sample.
Safety
No serious adverse events were reported among mosnodenvir recipients in this trial. Adverse events, their severity distribution, and any dose relationships were not associated with safety signals severe enough to halt the study. Larger and longer studies are required to characterize infrequent or delayed toxicities and to define safety in populations with comorbidities, children, pregnant people, and the immunologically diverse residents of dengue‑endemic regions.
Viral evolution under drug pressure — NS4B changes
Perhaps the most clinically and biologically important exploratory observation was the emergence of amino acid variations in the NS4B region of the rDEN3Δ30 genome in all mosnodenvir recipients for whom sequencing was available (14/14), and in none of the sequenced placebo recipients (0/7). NS4B is an integral component of the flavivirus replication complex; drug‑associated polymorphisms in this region raise the possibility that mosnodenvir imposes selective pressure, leading to escape or compensatory mutations.
Interpretation of these variants requires caution. The trial did not report in vitro phenotypic susceptibility testing of the emergent variants (e.g., changes in EC50), nor did it assess whether these mutations alter viral fitness, transmissibility, or clinical virulence. These remain critical next steps: phenotype the variants, define the genetic barrier to resistance, and evaluate whether similar changes arise across serotypes and in field isolates under treatment.
Expert commentary and mechanistic considerations
The CHIM design is a powerful tool for early proof‑of‑concept assessment of antivirals; it allows controlled exposure and dense virologic sampling that can detect modest antiviral effects with relatively small cohorts. In this trial, the clear dose‑dependent virologic effect supports mosnodenvir’s antiviral activity against DENV‑3 in vivo. The absence of serious adverse events in a small, healthy volunteer cohort is reassuring but not definitive for broader safety.
Mechanistically, the clustering of emergent substitutions in NS4B suggests mosnodenvir likely interacts directly or indirectly with the viral replication apparatus involving NS4B, or that inhibition of another target leads to compensatory changes in NS4B. NS4B plays roles in membrane rearrangement and replication complex formation for flaviviruses; prior antiviral programs against flaviviruses have identified NS4B as a resistance locus. It is therefore important to pair clinical data with laboratory virology: map resistance pathways, determine cross‑resistance patterns, and evaluate combination strategies to raise the genetic barrier to resistance.
Limitations and generalizability
Important limitations of the trial include small sample sizes per arm, the use of a single, underattenuated DENV‑3 CHIM strain rather than diverse circulating field strains or other serotypes, and selection of healthy adult volunteers who are not representative of populations at greatest risk (children, pregnant people, or those with prior flavivirus exposures). CHIM strains are by design controlled and may not reproduce the full spectrum of natural infection. The sequencing results were limited to participants with available data; broader sampling and functional testing are needed. Finally, the trial tested pre‑exposure prophylaxis begun before inoculation; the efficacy of mosnodenvir as postexposure prophylaxis or as therapy for established disease remains to be defined.
Clinical and public‑health implications
If replicated in larger, more diverse trials, mosnodenvir could fill a major therapeutic gap as the first antiviral prophylactic for dengue. Potential near‑term applications include targeted pre‑exposure prophylaxis for travelers to endemic areas, protection of healthcare workers or outbreak responders, or ring prophylaxis during localized outbreaks. However, the emergence of treatment‑associated NS4B variants cautions that monotherapy could select for resistant viruses. For broad public‑health deployment—especially in endemic areas—additional data on efficacy across serotypes, safety in vulnerable populations, duration of protection, impact on immune responses (including vaccine interactions), and resistance dynamics will be essential. Combination antiviral strategies or integrating treatment with vector control and vaccination programs may ultimately provide the most durable control.
Next steps and research priorities
Priority actions include larger randomized field trials in endemic settings to assess efficacy against natural exposure across serotypes, systematic in vitro phenotyping of emergent NS4B variants, dose‑optimization studies, PK assessments in children and pregnant people, and evaluations of combination regimens to mitigate resistance. Epidemiologic modeling of prophylaxis strategies (e.g., targeted vs. mass administration) and cost‑effectiveness analyses will inform potential deployment. Continued safety surveillance and investigations into interactions with dengue vaccines are also needed.
Conclusion
This randomized CHIM study provides compelling early evidence that high‑dose daily mosnodenvir lowers DENV‑3 viremia and can prevent clinical infection in a controlled setting without serious short‑term safety signals. However, the universal emergence of NS4B amino acid changes among sequencing‑available mosnodenvir recipients indicates antiviral pressure and the potential for resistance. Mosnodenvir is a promising candidate for dengue prophylaxis, but its path to clinical use will require robust field efficacy trials, resistance characterization, and evaluation in populations representative of those most affected by dengue.
Funding and clinicaltrials.gov
This study was funded by the National Institute of Allergy and Infectious Diseases and Johnson & Johnson. ClinicalTrials.gov identifier: NCT05048875. The primary report: Durbin AP et al., N Engl J Med. 2025;393:2107–2118.
References
1. Durbin AP, Van Wesenbeeck L, Pierce KK, et al. Daily Mosnodenvir as Dengue Prophylaxis in a Controlled Human Infection Model. N Engl J Med. 2025 Nov 27;393(21):2107-2118. doi:10.1056/NEJMoa2500179.
2. Bhatt S, Gething PW, Brady OJ, et al. The global distribution and burden of dengue. Nature. 2013 Apr 25;496(7446):504–507. doi:10.1038/nature12060.
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4. World Health Organization. Dengue and severe dengue. WHO Fact sheet (2024). Available at: https://www.who.int/news-room/fact-sheets/detail/dengue-and-severe-dengue (accessed 2025).
