The Potential for Antivirals in Dengue Prophylaxis and Treatment

Dengue virus infection, transmitted by the Aedes mosquito and caused by 4 distinct serotypes (DENV- 1-4), has an expanding global incidence and geographic range¹ with locally acquired cases to Europe and the United States.² While its cases are often mild or asymptomatic, dengue has the potential to cause severe illness, including shock and capillary leak syndrome, in both dengue-naive individuals and those with prior infection.

Two vaccines have received worldwide approval for the prevention and long-term protection against reinfection. CYD-TDV (Dengvaxia; Sanofi) is approved for use in certain endemic areas among those aged 9 to 45 years with confirmed prior dengue infection. However, it is not approved for travelers and is being discontinued due to low demand.

TAK-003 (Qdenga; Takeda) is approved in many countries for both seropositive and seronegative people. Despite vaccine development and availability, there are no approved antiviral prophylaxis or treatments against dengue, especially in those who are nonimmune. Mosnodenvir is an orally administered small-molecule agent developed to target dengue viral replication. The drug inhibits the de novo formation of the NS4B-NS3 complex. NS4B is a transmembrane protein in the endoplasmic reticulum, which binds NS3 to enhance NS3 helicase activity and increase viral replication.³ Preclinical studies have shown serotype-independent antiviral activity through in vitro and in vivo models, and recent phase 1 trials have demonstrated an acceptable safety profile.⁴

This FIGURE represents the viral replication complex of Dengue virus and the target of mosnodenvir. The NS4B complex is ER (endoplasmic reticulum) bound.⁵ Durbin and colleagues conducted a phase 2a trial that assessed the antiviral activity and safety of mosnodenvir in healthy participants who received a challenge virus with a hypoattenuated strain of DENV-3.⁶ This was designed as a doubleblind, randomized, placebo-controlled trial at Johns Hopkins University and the University of Vermont, with funding from Johnson & Johnson. Healthy adults aged 18 to 55 years with no prior dengue exposure or endemic travel were enrolled and assigned to mosnodenvir or placebo in a stepwise, dose-escalation design. Participants were randomly assigned 1:1 to receive a 200-mg loading dose of oral mosnodenvir or placebo for the 5 days prior to challenge, and received an inoculation of underattenuated DENV-3 on day 0.

The participants were then enrolled 2:1 into a high-dose cohort to establish safety. Further participants were randomly assigned to a high (100 mg), medium (50 mg), or low (10 mg) dose vs placebo in a 3:3:1 ratio for maintenance from day 1 to day 21. Patients were then followed through day 85. Primary outcomes included a reduction in DENV-3 RNA levels, clinical symptoms of infection, serologic response, and safety. The trial was powered to 85% probability to detect a 30% difference in RNA load between groups. High-dose mosnodenvir was associated with a significant reduction in DENV-3 RNA levels compared with placebo, with a clear dose-dependent antiviral effect regarding reduction in RNA levels and dengue infection–related symptoms. Participants with undetectable viral RNA did not have any detectable neutralizing antibodies, suggesting that successful inhibition of viral replication may prevent the development of humoral immunity. Mosnodenvir was generally well tolerated, with mostly mild to moderate adverse events.

Only 2 severe events were noted: infection with SARS-CoV-2, and severe elevation in lipase and glucose levels. Together, the findings support mosnodenvir as a promising antiviral for dengue prophylaxis against DENV-3 infection, especially at high doses. However, the small sample size, use of a hypoattenuated DENV-3 challenge strain, and controlled timing of exposure limit generalizability to real-world settings with unpredictable exposure and multiple circulating serotypes. There is further work to be done to study those who have already been infected, those living in endemic regions, and the timing of prophylaxis. Despite these encouraging early results, Johnson & Johnson has discontinued further development of mosnodenvir. ⁷ However, other dengue antiviral strategies remain in development, including agents that target antiviral replication by Novartis, which are undergoing a phase 2 trial.⁸ There is also a monoclonal antibody undergoing evaluation.⁹ These show promise for the future of prophylaxis and treatment for dengue virus in the seropositive and seronegative populations.

Paper: 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;393(21):2107-2118. doi:10.1056/NEJMoa2500179

References

1.Childs ML, Lyberger K, Harris M, Burke M, Mordecai EA. Climate warming is expanding dengue burden in the Americas and Asia. medRxiv. Preprint posted online January 9, 2024. doi:10.1101/2024.01.08.24301015 

2. Dengue current year data (2026). Centers for Disease Control and Prevention. Updated February 26, 2026. Accessed February 2, 2026. https://www.cdc.gov/dengue/data-research/facts-stats/current-data.html

3. Goethals O, Kaptein SJF, Kesteleyn B, et al. Blocking NS3–NS4B interaction inhibits dengue virus in non-human primates. Nature. 2023;615(7953):678-686. doi:10.1038/s41586-023-05790-6 

4.Ackaert O, Vanhoutte F, Verpoorten N, et al. Safety, tolerability, and pharmacokinetics of JNJ-1802, a pan-serotype dengue direct antiviral small molecule, in a phase 1, double-blind, randomized, dose-escalation study in healthy volunteers. Clin Infect Dis. 2023;77(6):857-865. doi:10.1093/cid/ciae174 

5.Biering SB, Harris E. A step towards therapeutics for dengue. Nature. 2021;598(7881):420-421. doi:10.1038/d41586-021-02638-9 

6. Durbin, A.P., Van Wesenbeeck, L., Pierce, K.K., Herrera-Taracena, G., Ebone, L., Buelens, A., Lutton, P., Sabundayo, B.P., Van Eygen, V., De Clerck, K. and Fetter, I., 2025. Daily mosnodenvir as dengue prophylaxis in a controlled human infection model. New England Journal of Medicine, 393(21), pp.2107-2118.

7. Johnson & Johnson to discontinue phase 2 field study evaluating investigational antiviral for the prevention of dengue. News release. Johnson & Johnson. October 4, 2024. Accessed February 2, 2026. https://www.jnj.com/media-center/press-releases/johnson-johnson-to-discontinue-phase-2-field-study-evaluating-investigational-antiviral-for-the-prevention-of-dengue

8. A study to assess the efficacy, safety and pharmacokinectics of EYU688 in patients with dengue fever. ClinicalTrials.gov. Updated February 24, 2026. Accessed February 27, 2026. https://clinicaltrials.gov/study/NCT06006559 

9. Dengue monoclonal antibody phase III randomised double-blind clinical trial for the treatment of symptomatic dengue in children and adult participants. ISRCTN. Updated November 11, 2025. Accessed February 2, 2026. https://www.isrctn.com/ISRCTN50970152