---
title: "Baloxavir-Based Combinations Improve Survival and Virologic Control in H5N1-Infected Mice"
id: "cdc-emerging-infectious-diseases-journal-1-comparison-of-baloxavir-based-combinations-and-monotherapies-for-treating"
canonical_url: "https://medichelpline.com/clinical-feed/cdc-emerging-infectious-diseases-journal-1-comparison-of-baloxavir-based-combinations-and-monotherapies-for-treating"
content_type: "clinical_feed_article"
specialty: "Infectious Disease"
source_name: "CDC Emerging Infectious Diseases Journal"
source_url: "https://wwwnc.cdc.gov/eid/article/32/10/26-0186_article"
published_at: "2026-09-22T04:00:00.000Z"
evidence_level: "Agency Feed"
license: "CC-BY-NC-4.0 / Informational Use"
---
# Baloxavir-Based Combinations Improve Survival and Virologic Control in H5N1-Infected Mice
## Provenance & Clinical Metadata
- **Canonical URL:** https://medichelpline.com/clinical-feed/cdc-emerging-infectious-diseases-journal-1-comparison-of-baloxavir-based-combinations-and-monotherapies-for-treating
- **Specialty:** [Infectious Disease](https://medichelpline.com/clinical-feed/infectious-disease.md)
- **Primary Source:** CDC Emerging Infectious Diseases Journal
- **Source URL:** [Original Journal Publication](https://wwwnc.cdc.gov/eid/article/32/10/26-0186_article)
- **Published At:** 2026-09-22T04:00:00.000Z
- **Evidence Rating:** Agency Feed
## Executive GIST (TL;DR)
- The study compared monotherapies and 2-drug combinations of licensed antivirals against highly pathogenic avian influenza **A(H5N1)** clade 2.3.4.4b in a lethal mouse model, assessing survival, weight loss, tissue viral titers, histopathology, and lung transcriptomes. - Drugs tested were **baloxavir** acid (BXA; single subcutaneous dose), oseltamivir phosphate (OSP; oral twice daily), and molnupiravir (MPV; oral twice daily), at low (20–25 mg/kg BXA/OSP/MPV) and higher (50 mg/kg for OSP/MPV) dose pairs. - Mice were intranasally challenged with 5 LD50 of A/mink/Spain/3691–8_22VIR10586–10/2022 and treated beginning 6 hours postinfection; outcomes monitored through 18 days postinfection. - Vehicle-treated mice experienced rapid weight loss and uniform mortality. Low-dose monotherapies provided partial protection (OSP and MPV: 2/7 survival each; single-dose BXA: 4/7 survival) and dose escalation improved but did not fully prevent deaths. - All tested 2-drug combinations improved weight stabilization and survival relative to corresponding monotherapies. **BXA-containing combinations (BXA/OSP and BXA/MPV)** achieved complete protection (7/7 survival) at both tested dose pairs. - OSP/MPV combinations improved outcomes compared with monotherapies but did not uniformly reach complete protection. - Bliss-independence analysis showed positive ΔBliss for BXA-containing combinations, most prominent at the 20/25 mg/kg dose pair, indicating a favorable interaction; ΔBliss values were smaller at higher doses. - Tissue virology mirrored clinical outcomes: BXA monotherapy more consistently reduced lung titers and prevented extrapulmonary dissemination (brain, heart) than OSP or MPV monotherapies. Combination therapy, especially with **baloxavir**, further suppressed lung viral loads and largely abolished systemic spread by 6 dpi. - Histopathology and influenza A nucleoprotein immunostaining at 6 dpi were performed; combination therapy attenuated pathology and antigen detection relative to vehicle and some monotherapies. - Lung RNA sequencing at 6 dpi was conducted to compare transcriptomic perturbations across treatment groups; the source text reports principal component analysis but details of differential pathways and full results are reported in the Appendix. - The authors conclude that **baloxavir-based combination therapy** improved survival, reduced pulmonary viral loads, and prevented extrapulmonary dissemination in this mouse H5N1 model, supporting preparedness strategies. Details of some data and full transcriptomic analyses are in the article Appendix and figures; the article is an early-release version.
## Clinical Analysis & Structured Key Points
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[EID Journal](https://wwwnc.cdc.gov/eid/) 2. [Volume 32](https://wwwnc.cdc.gov/eid/early-release) 3. [Early Release](https://wwwnc.cdc.gov/eid/early-release#issue-1346) 4. [Main Article](https://wwwnc.cdc.gov/eid/article/32/10/26-0186_article) * [Facebook](https://www.facebook.com/sharer/sharer.php?u=%2Feid%2Farticle%2F32%2F10%2F26-0186_article "Share to Facebook") * [Twitter](http://twitter.com/share?url=%2Feid%2Farticle%2F32%2F10%2F26-0186_article&text= "Share to Twitter") * [LinkedIn](https://www.linkedin.com/shareArticle?url=%2Feid%2Farticle%2F32%2F10%2F26-0186_article&title= "Share to LinkedIn") * [Syndicate](https://tools.cdc.gov/medialibrary/index.aspx#/sharecontent//eid/article/32/10/26-0186_article "Embed this Page") [ Emerging Infectious Disease journal ISSN: 1080-6059 ](https://wwwnc.cdc.gov/eid/) _Disclaimer: Early release articles are not considered as final versions. Any changes will be reflected in the online version in the month the article is officially released._ #### Volume 32, Number 10—October 2026 ##### _Dispatch_ ### Comparison of Baloxavir-Based Combinations and Monotherapies for Treating Influenza A(H5N1) Clade 2.3.4.4b Virus Infection in Mice On This Page [The Study](https://wwwnc.cdc.gov/eid/article/32/10/26-0186_article) * * * [Conclusions](https://wwwnc.cdc.gov/eid/article/32/10/26-0186_article) * * * [Suggested Citation](https://wwwnc.cdc.gov/eid/article/32/10/26-0186_article) Figures [Figure 1](https://wwwnc.cdc.gov/eid/article/32/10/26-0186-f1) * * * [Figure 2](https://wwwnc.cdc.gov/eid/article/32/10/26-0186-f2) * * * [Figure 4](https://wwwnc.cdc.gov/eid/article/32/10/26-0186-f3) * * * [Figure 3](https://wwwnc.cdc.gov/eid/article/32/10/26-0186-f4) Downloads [Appendix ](https://wwwnc.cdc.gov/eid/article/32/10/26-0186-app1.pdf) * * * [RIS [TXT - 2 KB] ](https://wwwnc.cdc.gov/eid/article/32/10/26-0186.ris) Article Metrics [Metric Details](https://wwwnc.cdc.gov/eid/article/32/10/26-0186_article) Related Articles [Divergent HPAI H5N1 Clade 2.3.4.4b Virus, Brazil](https://wwwnc.cdc.gov/eid/article/32/10/26-0723_article) * * * [HPAI Clade 2.3.4.4b Virus Infection in Alpacas](https://wwwnc.cdc.gov/eid/article/32/10/26-0491_article) * * * [Highly Pathogenic Avian Influenza Virus Subtype 5 in Cetaceans, Brazil](https://wwwnc.cdc.gov/eid/article/32/10/26-0051_article) * * * [More articles on Influenza](https://wwwnc.cdc.gov/eid/spotlight/influenza) Seong Cheol Min, Ju Ryeong Lee, Beom Kyu Kim, Ji-Hyun Park, Dong Gyu Lee, Gi Chan Lee, Se Hee An, Santosh Chokkakula, Aman Jain, Young Ki Choi, Yun Hee Baek, and Min-Suk Song[![Comments to Author](https://wwwnc.cdc.gov/eid/content/images/icon/email.gif)](https://wwwnc.cdc.gov/eid/article/32/10/26-0186_article#comment) Author affiliation: Chungbuk National University College of Medicine, Chungbuk, South Korea (S.C. Min, J.R. Lee, B.K. Kim, J.-H. Park, D.G. Lee, G.C. Lee, S.H. An, S. Chokkakula, A. Jain, Y.H. Baek, M.-S. Song); Korea Virus Research Institute Yuseong-gu, Daejeon, South Korea (Y.K. Choi) [Suggested citation for this article](https://wwwnc.cdc.gov/eid/article/32/10/26-0186_article#suggestedcitation) ### Abstract Highly pathogenic avian influenza A(H5N1) clade 2.3.4.4b virus continues to cause animal outbreaks and sporadic zoonotic infections. In a mouse model of lethal influenza disease, we compared oseltamivir, baloxavir, and molnupiravir monotherapies with 2-drug combinations. Baloxavir-based combinations improved survival, reduced lung viral loads, and prevented extrapulmonary dissemination, supporting H5N1 preparedness strategies. Highly pathogenic avian influenza A(H5N1) clade 2.3.4.4b virus continues to cause widespread outbreaks and sporadic zoonotic infections, underscoring the need to optimize antiviral strategies ([_1_](https://wwwnc.cdc.gov/eid/article/32/10/26-0186_article#r1 "1")–[ _3_](https://wwwnc.cdc.gov/eid/article/32/10/26-0186_article#r3 "3")). Licensed influenza antiviral drugs can reduce disease severity but might be compromised in severe infections by high viral burdens, treatment delays, and treatment-emergent resistance, motivating evaluation of combination regimens ([_4_](https://wwwnc.cdc.gov/eid/article/32/10/26-0186_article#r4 "4")–[ _7_](https://wwwnc.cdc.gov/eid/article/32/10/26-0186_article#r7 "7")). Recent H5N1 treatment studies using mouse models suggest antiviral performance can vary by exposure route and disease progression ([_8_](https://wwwnc.cdc.gov/eid/article/32/10/26-0186_article#r8 "8")–[ _11_](https://wwwnc.cdc.gov/eid/article/32/10/26-0186_article#r11 "11")). To inform preparedness-oriented selection, we compared direct-acting antiviral drugs from distinct classes in a lethal mouse model. We tested monotherapies and 2-drug combinations of 2 licensed influenza antiviral agents, oseltamivir phosphate (OSP; neuraminidase inhibitor) and baloxavir acid (BXA; cap-dependent endonuclease inhibitor), and molnupiravir (MPV; nucleoside analog) to assess whether combinations provided synergistic benefit. ### The Study Figure 1 ![Therapeutic efficacy of baloxavir-based combinations and monotherapies for treating influenza A\(H5N1\) clade 2.3.4.4b virus infection in mice. Drug names and doses are provided in the keys \(e.g., BXA+MPV 20+25 mg/kg indicates BXA/MPV at a dose of 20/25 mg/kg\). A–C\) Body weight change \(mean +SD; n = 7/group\) through 18 days postinfection: vehicle, MPV 25 mg/kg, OSP 25 mg/kg, and OSP/MPV 25/25 mg/kg \(A\); vehicle, OSP 25 mg/kg, BXA 20 mg/kg, and BXA/OSP 20/25 mg/kg \(B\); vehicle, MPV 25 mg/kg, BXA 20 mg/kg, and BXA/MPV 20/25 mg/kg \(C\). Dots indicate mean; bars indicate 95% CI; red dotted lines indicate humane endpoint thresholds. D–F\) Kaplan–Meier survival \(n = 7/group\) corresponding to panels A–C; MST values shown in each panel. G–I\) Viral titers in lung, brain, and heart at 4 days postinfection \(n = 3/group\). J–L\) Viral titers at 6 dpi \(n = 3/group\). Bars show group means with individual animals overlaid; dashed line denotes assay limit of detection \(1.801 log10 TCID50/mL\). BXA, baloxavir acid; MPV, molnupiravir; MST, median survival time; OSP, oseltamivir phosphate; SD, standard deviation; TCID50, 50% tissue culture infectious dose.](https://wwwnc.cdc.gov/eid/images/26-0186-F1-tn.jpg) [Figure 1](https://wwwnc.cdc.gov/eid/article/32/10/26-0186-f1 "Figure 1"). Therapeutic efficacy of baloxavir-based combinations and monotherapies for treating influenza A(H5N1) clade 2.3.4.4b virus infection in mice. Drug names and doses are provided in the keys (e.g., BXA+MPV 20+25 mg/kg... We challenged 6- to 8-week-old female BALB/c mice intranasally with A/mink/Spain/3691–8_22VIR10586–10/2022 (5 LD50 [50% median lethal dose]) in a 50-µL inoculum (90 TCID50 [50% tissue culture infectious dose]) ([Appendix](https://wwwnc.cdc.gov/eid/article/32/10/26-0186-app1.pdf)). We treated mice at 6 hours postinfection (hpi). We administered OSP and MPV orally twice daily for 5 days and administered BXA once subcutaneously. For the low-dose comparison, mice received OSP 25 mg/kg, MPV 25 mg/kg, or BXA 20 mg/kg, and corresponding 2-drug pairs at the same dosages: OSP/MPV, BXA/OSP, BXA/MPV. We monitored body weight and survival through 18 days postinfection (dpi) (n = 7) and quantified infectious virus titers in lung, brain, and heart by TCID50 assay at 4 and 6 dpi (n = 3/time point) ([Figure 1](https://wwwnc.cdc.gov/eid/article/32/10/26-0186-f1); [Appendix](https://wwwnc.cdc.gov/eid/article/32/10/26-0186-app1.pdf) Tables 1–5). Vehicle-treated mice exhibited rapid weight loss and uniform death. In monotherapy low-dose treatments, OSP or MPV conferred partial protection (2/7 survival each), whereas BXA administered as a single dose was more protective (4/7 survival) and more consistently limited weight loss ([Figure 1](https://wwwnc.cdc.gov/eid/article/32/10/26-0186-f1), panels A–F). Dose-escalation to 50 mg/kg monotherapies also improved outcomes but did not provide 100% protection ([Appendix](https://wwwnc.cdc.gov/eid/article/32/10/26-0186-app1.pdf) Figures 2, 3), consistent with prior reports showing therapeutic benefit of antiviral drugs in H5N1 mouse infection models ([_8_](https://wwwnc.cdc.gov/eid/article/32/10/26-0186_article#r8 "8")–[ _11_](https://wwwnc.cdc.gov/eid/article/32/10/26-0186_article#r11 "11")). Accordingly, we evaluated 2-drug regimens in which BXA was maintained at 20 mg/kg and partnered with OSP or MPV at either 25 or 50 mg/kg. Across all three 2-drug regimens—OSP/MPV (25/25 mg/kg and 50/50 mg/kg), BXA/OSP (20/25 mg/kg and 20/50 mg/kg), and BXA/MPV (20/25 mg/kg and 20/50 mg/kg)—combination treatment stabilized body weight and markedly improved survival relative to the corresponding monotherapies ([Figure 1](https://wwwnc.cdc.gov/eid/article/32/10/26-0186-f1), panels A–F; [Appendix](https://wwwnc.cdc.gov/eid/article/32/10/26-0186-app1.pdf) Figure 3). BXA-containing combinations showed the greatest protection, and no deaths (7/7 survival) occurred through 18 dpi at both dose pairs, whereas OSP/MPV did not show complete protection ([Figure 1](https://wwwnc.cdc.gov/eid/article/32/10/26-0186-f1), panels A–F; [Appendix](https://wwwnc.cdc.gov/eid/article/32/10/26-0186-app1.pdf) Figure 3). Bliss-independence analysis ([_12_](https://wwwnc.cdc.gov/eid/article/32/10/26-0186_article#r12 "12")) of end-of-study survival (18 dpi; n = 7/group) showed positive ΔBliss estimates for BXA-containing combinations, most clearly at the 20/25 mg/kg dose pairs. At the 20/50 mg/kg dose pairs, ΔBliss values remained positive but were smaller, consistent with an attenuated interaction at higher antiviral exposure. OSP/MPV showed a weaker, dose-dependent interaction ([Appendix](https://wwwnc.cdc.gov/eid/article/32/10/26-0186-app1.pdf) Table 6). We observed that clinical benefit paralleled tissue-level virologic control and prevention of extrapulmonary dissemination ([Figure 1](https://wwwnc.cdc.gov/eid/article/32/10/26-0186-f1), panels G–L). At 4 dpi, monotherapy with BXA and OSP, but not MPV, reduced lung titers; brain and heart titers were near or below the limit of detection (LOD), consistent with limited dissemination at that timepoint. By 6 dpi, vehicle-treated mice showed high lung viral loads accompanied by detectable virus in brain and heart. In treated animals, BXA provided the most consistent tissue-level control, keeping viral titers in brain and heart at the LOD; 25 mg/kg OSP or MPV permitted occasional instances of replication in the brain. Combination therapy further inhibited residual dissemination. At 4 dpi, lung titers in combination groups frequently approached the LOD, most prominently for BXA-containing pairs, whereas brain and heart remained at or near the LOD. By 6 dpi, low lung titers were sustained, and systemic spread was largely abolished in BXA-containing groups. In contrast, OSP/MPV combinations showed comparatively weaker lung viral clearance and survival benefit. Nevertheless, those combinations converted partial clinical protection into near-complete or complete survival, reduced pulmonary titers, and prevented neuroinvasion and detectable heart virus that were still observed under some monotherapy conditions. Figure 2 ![Lung and brain histopathology and influenza A nucleoprotein immunoreactivity at 6 dpi after monotherapy or combination therapy in a study of treating influenza A\(H5N1\) clade 2.3.4.4b virus infection in mice. A\) Brain sections; B\) lung sections. Sections from vehicle, OSP, MPV, BXA, OSP/MPV, BXA/OSP, and BXA/MPV groups. For each group, representative hematoxylin and eosin images \(left\) and immunohistochemistry for influenza A nucleoprotein \(right; 3,3′-diaminobenzidine with hematoxylin counterstain\) are shown as whole-section views with corresponding higher-magnification insets \(boxed regions\). Scale bars indicate 1.25 mm for whole-section views; and 100 μm for higher-magnification insets. BXA, baloxavir acid; MPV, molnupiravir; OSP, oseltamivir phosphate.](https://wwwnc.cdc.gov/eid/images/26-0186-F2-tn.jpg) [Figure 2](https://wwwnc.cdc.gov/eid/article/32/10/26-0186-f2 "Figure 2"). Lung and brain histopathology and influenza A nucleoprotein immunoreactivity at 6 dpi after monotherapy or combination therapy in a study of treating influenza A(H5N1) clade 2.3.4.4b virus infection in mice.... Figure 3 ![Lung transcriptomic responses at 6 days postinfection in comparison of baloxavir-based combinations and monotherapies for treating influenza A\(H5N1\) clade 2.3.4.4b virus infection in mice. Responses show treatment-associated separation and attenuation of infection-associated pathway perturbations under combination therapy. RNA sequencing performed on lung harvested at 6 days postinfection from the same experimental groups as Figure 1 \(n = 3/group\). A\) Principal component analysis of transcriptomic profiles for lung; each point represents an individual mouse, and ellipses denote within-group dispersion. Percent variance expl
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