2026 / 03

DOI: 10.24075/brsmu.2026.028
Copyright: © 2026 by the authors. Licensee: Pirogov University.
This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution license (CC BY).

ORIGINAL RESEARCH

Assessment of the immunogenicity of classic and self-amplifying RNA-based antiviral therapeutics for influenza

Kunyk DA1 , Mazunina EP2 , Mukasheva EA2 , Ignatieva AV2 , Kirillova ES2 , Kurchenko OM1 , Ivanov RA1 , Gushchin VA2 , Reshetnikov VV1
About authors

1 Sirius University of Science and Technology, Sirius, Russia

2 Gamaleya National Research Center for Epidemiology and Microbiology, Moscow, Russia

Correspondence should be addressed: Vasiliy V. Reshetnikov
Olimpiysky prospekt, 1, Sochi, 354340; Russia; e-mail: ur.hepsuitnalat@vv.vokintehser

About paper

Funding: the study was supported by grant of the state programme of the Sirius Federal District: Scientific and Technological Development of the Sirius Federal District (Agreement No. 3-03 dated 18 February 2025).

Acknowledgements: the authors express their gratitude to O.O. Vasilieva and I.A. Skvortsov from the Sirius University of Science and Technology for the formulation of RNA into lipid nanoparticles.

Author contribution: Kunyk DA, Kurchenko OM, Reshetnikov VV — study design, preparation of mRNA vaccines, data interpretation, manuscript writing; Mazunina EP — planning and conducting animal experiments; Mukasheva EA, Ignatieva AV, Kirillova ES — serological testing (HAI assay); Reshetnikov VV, Ivanov RA, Gushchin VA — manuscript editing.

Compliance with ethical standards: the study was approved by the Ethics Committee of the Gamaleya National Research Center for Epidemiology and Microbiology (protocol No. 94 dated 20 May 2025). All procedures involving animals were compliant with the ethical standards approved by the Order of the Ministry of Health of Russia and with the principles of the International Guide for the Care and Use of Laboratory Animals. Every effort was made to minimize animal suffering and reduce the number of animals used.

Received: 2026-04-10 Accepted: 2026-05-23 Published online: 2026-06-08
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  1. Nuwarda RF, Alharbi AA, Kayser V. An Overview of Influenza Viruses and Vaccines. Vaccines. 2021; 9 (9): 1032. DOI: 10.3390/vaccines9091032.
  2. Taubenberger JK, Kash JC, Morens DM. The 1918 influenza pandemic: 100 years of questions answered and unanswered. Sci Transl Med. 2019; 11 (502): eaau5485. DOI: 10.1126/scitranslmed.aau5485.
  3. Taubenberger JK, Morens DM. Influenza: The Once and Future Pandemic. Public Health Rep. 2010; 125 (3_suppl): 15–26. DOI: 10.1177/00333549101250S305.
  4. Stubbs TM, Te Velthuis AJ. The Rna-Dependent RNA Polymerase of the Influenza a Virus. Future Virol. 2014; 9 (9): 863–76. DOI: 10.2217/fvl.14.66.
  5. Taylor MW. Vaccines Against Viral Infections. В: Viruses and Man: A History of Interactions. Cham: Springer International Publishing, 2014; p. 355–77 [цитируется по 30 март 2026 г.]. Available from: https://link.springer.com/10.1007/978-3-319-07758-1_19 DOI:10.1007/978-3-319-07758-1_19.
  6. Bulgakova VA, Selimzyanova LR, Privalova TE, Yusupova DA. Immunisation of young children against influenza — evidence review. Lechaschi Vrach. 2022; 10 (25). DOI: 10.51793/OS.2022.25.10.009.
  7. Zost SJ, Parkhouse K, Gumina ME, Kim K, Diaz Perez S, Wilson PC, et al. Contemporary H3N2 influenza viruses have a glycosylation site that alters binding of antibodies elicited by eggadapted vaccine strains. Proc Natl Acad Sci USA. 2017; 114 (47): 12578–83. DOI: 10.1073/pnas.1712377114.
  8. Xie H, Wan XF, Ye Z, Plant EP, Zhao Y, Xu Y, et al. H3N2 Mismatch of 2014–15 Northern Hemisphere Influenza Vaccines and Head-to-head Comparison between Human and Ferret Antisera derived Antigenic Maps. Sci Rep. 2015; 5 (1): 15279. DOI: 10.1038/srep15279.
  9. Paules CI, Fauci AS. Influenza Vaccines: Good, but We Can Do Better. The Journal of Infectious Diseases. 2019; 219 (Supplement_1): S1–4. DOI: 10.1093/infdis/jiy633.
  10. Jin L, Zhou Y, Zhang S, Chen SJ. mRNA vaccine sequence and structure design and optimization: Advances and challenges. Journal of Biological Chemistry. 2025; 301 (1): 108015. DOI: 10.1016/j.jbc.2024.108015.
  11. Kunyk D, Plotnikova M, Bespalov M, Shevyrev D, Klotchenko S, Ivanov R, et al. The Interplay Between Therapeutic Self-Amplifying RNA and the Innate Immune System: Balancing Efficiency and Reactogenicity. IJMS. 2025; 26 (18): 8986. DOI: 10.3390/ijms26188986.
  12. Li J, Liu Y, Dai J, Yang L, Xiong F, Xia J, et al. mRNA Vaccines: Current Applications and Future Directions. MedComm. 2025; 6 (11): e70434. DOI: 10.1002/mco2.70434.
  13. Kozlova A, Pateev I, Shepelkova G, Vasileva O, Zakharova N, Yeremeev V, et al. A Cap-Optimized mRNA Encoding Multiepitope Antigen ESAT6 Induces Robust Cellular and Humoral Immune Responses Against Mycobacterium tuberculosis. Vaccines. 2024; 12 (11): 1267. DOI: 10.3390/vaccines12111267.
  14. Ryapolova A, Shevyrev D, Tsvetkova A, Sokolova O, Vasileva O, Andriianov V, et al. Enhanced Antitumor Effect of Oncolytic Virotherapy Combined with mRNA-Encoded Immunoadjuvants in Colorectal Carcinoma (CT26) Tumor Model. Applied Biosciences. 2025; 5 (1): 1. DOI: 10.3390/applbiosci5010001.
  15. FDA. Guidance for Industry: Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics in Adult Healthy Volunteers. 2005.
  16. World Health Organization, редактор. Manual for the laboratory diagnosis and virological surveillance of influenza. Geneva: World Health Organization, 2011; 139 p.
  17. Allen JD, Ross TM. mRNA vaccines encoding computationally optimized hemagglutinin elicit protective antibodies against future antigenically drifted H1N1 and H3N2 influenza viruses isolated between 2018-2020. Front Immunol. 2024; 15: 1334670. DOI: 10.3389/fimmu.2024.1334670.
  18. Cheung M, Chang C, Rathnasinghe R, Rossignol E, Zhang Y, Ferrari A, et al. Self-amplifying mRNA seasonal influenza vaccines elicit mouse neutralizing antibody and cell-mediated immunity and protect ferrets. npj Vaccines. 2023; 8 (1): 150. DOI: 10.1038/s41541-023-00747-2.
  19. Chang C, Music N, Cheung M, Rossignol E, Bedi S, Patel H, et al. Self-amplifying mRNA bicistronic influenza vaccines raise cross-reactive immune responses in mice and prevent infection in ferrets. Molecular Therapy — Methods & Clinical Development. 2022; 27: 195–205. DOI: 10.1016/j.omtm.2022.09.013.
  20. Cao RG, Suarez NM, Obermoser G, Lopez SMC, Flano E, Mertz SE, et al. Differences in Antibody Responses Between Trivalent Inactivated Influenza Vaccine and Live Attenuated Influenza Vaccine Correlate With the Kinetics and Magnitude of Interferon Signaling in Children. The Journal of Infectious Diseases. 2014; 210 (2): 224–33. DOI: 10.1093/infdis/jiu079.
  21. Uno N, Ross TM. Multivalent next generation influenza virus vaccines protect against seasonal and pre-pandemic viruses. Sci Rep. 2024; 14 (1): 1440. DOI: 10.1038/s41598-023-51024-0.
  22. Reneer ZB, Bergeron HC, Reynolds S, Thornhill-Wadolowski E, Feng L, Bugno M, et al. mRNA vaccines encoding influenza virus hemagglutinin (HA) elicits immunity in mice from influenza A virus challenge. Huber VC, редактор. PLoS ONE. 2024; 19 (4): e0297833. DOI: 10.1371/journal.pone.0297833.
  23. Mazunina EP, Gushchin VA, Kleymenov DA, Siniavin AE, Burtseva EI, Shmarov MM, et al. Trivalent mRNA vaccine-candidate against seasonal flu with cross-specific humoral immune response. Front Immunol. 2024; 15: 1381508. DOI: 10.3389/fimmu.2024.1381508.
  24. Vogel AB, Lambert L, Kinnear E, Busse D, Erbar S, Reuter KC, et al. Self-Amplifying RNA Vaccines Give Equivalent Protection against Influenza to mRNA Vaccines but at Much Lower Doses. Molecular Therapy. 2018; 26 (2): 446–55. DOI: 10.1016/j.ymthe.2017.11.017.
  25. Gong Y, Yong D, Liu G, Xu J, Ding J, Jia W. A Novel Self–Amplifying mRNA with Decreased Cytotoxicity and Enhanced Protein Expression by Macrodomain Mutations. Advanced Science. 2024; 11 (43): 2402936. DOI: 10.1002/advs.202402936.
  26. Casmil IC, Friesen JJ, Bathula NV, Strumpel A, Ho CH, Guez I, et al. Divergent Delivery and Expression Kinetics of Lipid and Polymeric Nanoparticles across mRNA Modalities. Advanced Science. 2025; 12 (38): e08907. DOI: 10.1002/advs.202508907.
  27. McGee JE, Kirsch JR, Kenney D, Cerbo F, Chavez EC, Shih TY, et al. Complete substitution with modified nucleotides in self-amplifying RNA suppresses the interferon response and increases potency. Nat Biotechnol. 2025; 43 (5): 720–6. DOI: 10.1038/s41587-024-02306-z.
  28. World Health Organization. Recommended composition of influenza virus vaccines for use in the 2023–2024 northern hemisphere influenza season.