Abstract
Introduction. Rabies is currently a rare but deadly viral disease transmitted through animal bites, mainly dogs. There is no standardized effective therapy for clinically manifest rabies. Patients with developed symptoms are mainly provided with palliative care and intensive therapy. In this regard, the search for new therapeutic solutions for rabies is urgent.
Objective. To analyze current advances in rabies post-exposure prophylaxis (PEP) with emphasis on molecular technologies and their integration into personalized medicine.
Material and methods. Systematic search in PubMed and Scopus databases for 2018–2025 using key terms: rabies, post-exposure prophylaxis, monoclonal antibodies, mRNA vaccine, favipiravir, siRNA, aptamer. Original studies, meta-analyses, systematic reviews, and WHO/CDC guidelines were analyzed.
Results. Rabies maintains nearly 100% fatality rate upon symptom manifestation, causing approximately 59 000 deaths annually, predominantly in Africa and Asia. Standard PEP remains highly effective but is limited by immunoglobulin availability in resource-limited regions. Recent advances include: monoclonal antibodies against rabies virus G-protein (docaravimab/miromavimab) demonstrating favorable safety profile as alternative to human rabies immunoglobulin; mRNA vaccines encoding full-length RABV-G providing complete protection in preclinical studies; nucleoside analogs effective when applied early before CNS penetration; RNA therapeutics (aptamers/siRNA) showing convincing in vitro viral suppression results.
Conclusion. Molecular technologies expand personalized PEP capabilities. Monoclonal antibodies are already entering clinical practice, mRNA vaccines are approaching clinical trials, while RNA therapeutics require solving CNS delivery challenges. Key challenges include proving equivalence to standard therapy, ensuring accessibility in endemic regions, and standardizing combined approaches considering individual risk factors.
Keywords
Authors and affiliations
T.V. Potupchik(1), S.V. Generalov(2), A.V. Akaeva(3), K.S. Shablinskaya(4)
1-Federal State Budgetary Educational Institution of Higher Education “Krasnoyarsk State Medical University
named after Professor V.F. Voyno-Yasenetsky” of the Ministry of Health of the Russian Federation, Partizana Zheleznyaka St., 1,
Krasnoyarsk, 660022, Russian Federation; 2-Federal state scientific institution “Russian research anti-plague institute “Microbe”
of the Federal service for surveillance on consumers rights protection and human well-being, Universitetskaya str., 46, Saratov, 410005, Russian Federation; 3-Federal State Budgetary Educational Institution of Higher Education “Perm State Medical University
named after academician E.A. Wagner” of the Russian Ministry of Health, Petropavlovskaya Str., 26, Perm, 614990, Russian Federation; 4“Institute of Plastic Surgery” LLC, Malyy Sukharevskiy Lane, 10, build. 1, Moscow, 127051, Russian Federation
References
1. WHO. Rabies – Fact sheet. Geneva: World Health Organization; 2024. Available from: https://www.who.int/news-room/fact-sheets/detail/rabies
2. Hampson K., Coudeville L., Lembo T., Sambo M., Kieffer A., Attlan M., Barrat J. et al. Estimating the global burden of endemic canine rabies. PLoS Negl Trop Dis. 2015; 9 (4): e0003709. DOI: 10.1371/journal.pntd.0003709
3. Centers for Disease Control and Prevention (CDC). Rabies post-exposure prophylaxis guidance. Atlanta (GA): CDC; 2025 Jul 15 [cited 2025 Sep 15]. Available from: https://www.cdc.gov/rabies/hcp/clinical-care/post-exposure-prophylaxis.html
4. Fooks A.R., Banyard A.C., Horton D.L., Johnson N., McElhinney L.M., Jackson A.C. et al. Current status of rabies and prospects for elimination. Lancet. 2014; 384 (9951): 1389–99. DOI: 10.1016/S0140-6736(13)62707-5
5. Kiflu A.B. The Immune Escape Strategy of Rabies Virus and Its Pathogenicity Mechanisms. Viruses. 2024; 16 (11): 1774. DOI: 10.3390/v16111774
6. Knobel D.L., Cleaveland S., Coleman P.G., Coleman P.G., Fèvre E.M., Meltzer M.I., Miranda M.E.G. et al. Re-evaluating the burden of rabies in Africa and Asia. Bull World Health Organ. 2005; 83 (5): 360–8.
7. Shantavasinkul P., Wilde H. Postexposure prophylaxis for rabies in resource-limited/poor countries. Adv Virus Res. 2011; 79: 291–307. DOI: 10.1016/B978-0-12-387040-7.00013-5
8. Liu C., Lv X., Liu S., Chen Q., Zhu Z., Yu R., Yin W. et al. Research trends in anti-rabies virus monoclonal antibody: A bibliometric analysis. Hum Vaccin Immunother. 2025; 21 (1): 2508559. DOI: 10.1080/21645515.2025.2508559.
9. Manna A., Kundu A.K., Sarkar B., Maji B., Dutta T., Mahajan M. Real-World Safety of TwinRab, the World’s First Novel Cocktail of Rabies Monoclonal Antibodies, in a Clinical Setting. Cureus. 2024; 16 (1): e52163. DOI: 10.7759/cureus.52163.
10. Gogtay N.J., Thatte U.M., Kshirsagar N.A., Mahendra B.J., Kshirsagar V., Gunale B., Moore S. et al. Comparison of a novel human rabies monoclonal antibody to human rabies immunoglobulin for post-exposure prophylaxis: a phase 2/3 randomized, single-blind, non-inferiority study. Clin Infect Dis. 2018; 66 (3): 387–95. DOI:10.1093/cid/cix791
11. Sparrow E., Torvaldsen S., Newall A.T., Wood J.G., Sheikh M., Kieny M.P., Abela-Ridder B. Recent advances in the development of monoclonal antibodies for rabies post exposure prophylaxis: A review of the current status of the clinical development pipeline. Vaccine. 2019; 37 (1): 132–9. DOI: 10.1016/j.vaccine.2018.11.004.
12. Both L., Banyard A.C., van Dolleweerd C., Wright E., Ma J.K.-C., Fooks A.R. Monoclonal antibodies for prophylactic and therapeutic use against viral infections. Vaccine. 2013; 31 (12): 1553–9. DOI: 10.1016/j.vaccine.2013.01.025
13. Li D., Wang X., Li G., Zhou J., Bian L., Zhao X., Xing L. et al. Optimizing rabies mRNA vaccine efficacy via RABV-G structural domain screening and heterologous prime-boost immunization. NPJ Vaccines. 2025; 10 (1): 43 DOI: 10.1038/s41541-025-01098-w
14. Li J., Yu P., Liu Q., Xu L., Chen Y., Yan Li, Zhang F. et al. Safety and efficacy assessment of an mRNA rabies vaccine in dogs, rodents, and cynomolgus macaques. NPJ Vaccines. 2024; 9 (1): 187. DOI: 10.1038/s41541-024-00925-w
15. Wang Y., Yu T., Zhang S., Li N., Zhao J., Mi L., Cai Y. et al. A lyophilized anti-rabies mRNA-LNP vaccine induces early and robust immune responses from a single-dose subcutaneous administration. Vet Microbiol. 2025; 307: 110612. DOI: 10.1016/j.vetmic.2025.110612.
16. Alberer M., Gnad-Vogt U., Hong H.S., Mehr K.T., Backert L., Finak G., Gottardo R. et al. Safety and immunogenicity of a mRNA rabies vaccine in healthy adults: an open-label, non-randomised, prospective, first-in-human phase 1 clinical trial. Lancet. 2017; 390 (10101): 1511–20. DOI: 10.1016/S0140-6736(17)31665-3
17. Yamada K., Noguchi K., Kimitsuki K., Kaimori R., Saito N., Komeno T., Nakajima N. et al. Reevaluation of the efficacy of favipiravir against rabies virus using in vivo imaging analysis. Antiviral Res. 2019; 172: 104641. DOI: 10.1016/j.antiviral.2019.104641
18. Yamada K., Park C.H., Noguchi K., Kojima D., Kubo T., Komiya N., Matsumoto T. et al. Serial passage of rabies virus in neuroblastoma cells leads to attenuation: potential role of the additional N-glycosylation of a viral glycoprotein in the reduced pathogenicity of street rabies virus. Virus Res. 2012; 165 (1): 34–45. DOI: 10.1016/j.virusres.2012.01.002
19. Jochmans D., Neyts J. A novel class of compounds with potent antiviral activity against rabies. Vaccine. 2019; 37 (33): 4660–2. DOI: 10.1016/j.vaccine.2017.12.051.
20. Jackson A. Current and future approaches to the therapy of human rabies. Antiviral Research. 2013; 99 (1): 61–7. DOI: 10.1016/j.antiviral.2013.01.003
21. Ding Q., Wang C., Wang H., Xiang C., Wang Z., Wang Y., Zhao L. et al. Rabies Virus Targeting NIR-II Phototheranostics. J. Am. Chem Soc. 2025; 147 (19): 16661–73. DOI: 10.1021/jacs.5c04975
22. Blaise A, Gautret P. Current perspectives on rabies postexposure prophylaxis. Infect Disord Drug Targets. 2015; 15 (1): 13–9. DOI: 10.2174/1871526515666150320161630
23. Scott T.P., Nel L.H., Rabies Prophylactic and Treatment Options: An In Vitro Study of siRNA- and Aptamer-Based Therapeutics. 2021; 13 (5): 881. DOI: 10.3390/v13050881.
24. Meshram C.D., Agback P., Shiliaev N., Urakova N., Mobley J.A., Agback T., Frolova E.I. et al. Multiple Host Factors Interact with the Hypervariable Domain of Chikungunya Virus nsP3 and Determine Viral Replication in Cell-Specific Mode. J. Virol. 2018; 92 (16): e00838-18. DOI: 10.1128/JVI.00838-18.
25. Liang H.R., Hu G.Q., Zhao Q., Gai W.-W., Xue X.-H., Hu G.-Q., Wu H.-X. et al. Aptamers targeting rabies virus-infected cells inhibit viral replication both in vitro and in vivo. Virus Res. 2013; 173 (2): 398–403. DOI: 10.1016/j.virusres.2012.12.017.
26. Chen Y., Liu L. Modern methods for delivery of drugs across the blood-brain barrier. Adv Drug Deliv Rev. 2012; 64 (7): 640–65. DOI: 10.1016/j.addr.2011.11.010
27. Kayser V., Ramzan I. Viral vectors and their applications in vaccinology. Hum Vaccin Immunother. 2021; 17 (12): 5255–68. DOI: 10.1080/21645515.2021.1977057.
28. Rupprecht C.E., Briggs D., Brown C.M., Franka R., Katz S.L., Kerr H.D., Lett S M. et al. Use of a reduced (4-dose) vaccine schedule for postexposure prophylaxis to prevent human rabies: recommendations of the advisory committee on immunization practices. MMWR Recomm Rep. 2010; 59 (RR-2): 1–9.
29. Manning S.E., Rupprecht C.E., Fishbein D., Hanlon C.A., Lumlertdacha B., Guerra M., Meltzer M.I. et al. Human rabies prevention--United States, 2008: recommendations of the Advisory Committee on Immunization Practices. MMWR Recomm Rep. 2008; 57 (RR-3): 1–28.
30. Bharti O.K., Madhusudana S.N., Gaunta P.L., Belludi A.Y. Local infiltration of rabies immunoglobulins without systemic intramuscular administration: an alternative cost effective approach for passive immunization against rabies. Hum Vaccin Immunother. 2016; 12 (3): 837–42. DOI: 10.1080/21645515.2015.1085142
31. Wilde H., Khawplod P., Khamoltham T., Hemachudha T., Tepsumethanon V., Lumlerdacha B., Mitmoonpitak C. et al. Rabies control in South and Southeast Asia. Vaccine. 2005; 23 (17–18): 2284–9. DOI: 10.1016/j.vaccine.2005.01.030
32. Warrell M.J., Warrell D.A. Rabies and other lyssavirus diseases. Lancet. 2004; 363 (9413): 959–69. DOI: 10.1016/S0140-6736(04)15792-9
33. Jackson A.C. Demise of the Milwaukee protocol for rabies. Clin Infect Dis. 2025; ciaf157. DOI: 10.1093/cid/ciaf157
34. Hemachudha T., Ugolini G., Wacharapluesadee S., Sungkarat W., Shuangshoti S., Laothamatas J. Human rabies: neuropathogenesis, diagnosis, and management. Lancet Neurol. 2013; 12 (5): 498–513. DOI: 10.1016/S1474-4422(13)70038-3.
35. National Medical Products Administration. Technical Guidelines for Clinical Trials of Monoclonal Antibodies Against Rabies Virus. Beijing: NMPA, 2024.
36. World Health Organization. WHO Expert Consultation on Rabies: third report. Geneva: WHO Press, 2018. WHO Technical Report Series, No. 1012.
37. Fisher C.R., Streicker D.G., Schnell M.J. The spread and evolution of rabies virus: conquering new frontiers. Nat Rev Microbiol. 2018; 16 (4): 241–55. DOI: 10.1038/nrmicro.2018.11
38. Shwiff S.A., Hampson K., Anderson A. Potential economic benefits of eliminating canine rabies. Antiviral Res. 2013; 98 (2): 352–6. DOI: 10.1016/j.antiviral.2013.03.004
39. Hampson K., Dobson A., Kaare M., Dushoff J., Magoto M., Sindoya E., Cleaveland S. et al. Rabies exposures, post-exposure prophylaxis and deaths in a region of endemic canine rabies. PLoS Negl Trop Dis. 2008; 2 (11): e339. DOI: 10.1371/journal.pntd.0000339
40. Fitzpatrick M.C., Shah H.A., Pandey A., Bilinski A.M., Kakkar M., Clark A.D., Townsend J.P. et al. One Health approach to cost-effective rabies control in India. Proc Natl Acad Sci USA. 2016; 113 (51): 14574–81. DOI: 10.1073/pnas.1604975113