Skip to content
2000
image of Evaluating the Protective Immunity of 5’-Cap Altered Rabies mRNA Vaccines in a Mouse Model

Abstract

Introduction

Rabies Virus (RV or RABV) is a neurophilic pathogen predominantly transmitted to humans through bites, scratches, or wounds. Upon entering the central nervous system, the virus can cause severe symptoms, including acute encephalitis and paralysis, ultimately leading to death with an almost 100% mortality rate. Hence, it is essential to develop an effective oral rabies vaccine.

Methods

We designed and synthesized three modified 5'-cap mRNA vaccines (RV-01(CAP-01), RV-01(CAP-02) and RV-01(CAP-03)) encoding rabies virus glycoproteins in vitro and evaluated their immunogenicity and protective effect in mice.

Results

The modified 5'-cap vaccine was successfully constructed and could be effectively expressed in HEK293 cells. The antibody detection results revealed the abundance of RABV-G in RV-01(CAP-01), RV-01(CAP-02) and RV-01(CAP-03). ELISPOT assays indicated that these variants promoted the production of immune-related cytokines. Furthermore, the modified 5'-cap vaccines could reduce the rabies viral load of mice and effectively prolong their survival.

Discussion

The rabies mRNA vaccine had high efficacy and safety in preventing rabies, suggesting the great potential of mRNA as a promising candidate for RABV vaccines. However, the potential causes of the differences in the performance of the three modified 5'-cap rabies mRNA vaccines and the clinical application of 5’-Cap altered rabies mRNA vaccines need to be explored.

Conclusion

Hence, these results demonstrated that the modified 5’-cap mRNA vaccine was effective in inducing immune responses, which might be considered a promising prophylactic strategy for rabies.

Loading

Article metrics loading...

/content/journals/cpb/10.2174/0113892010396404250903044326
2025-09-30
2025-11-07
Loading full text...

Full text loading...

References

  1. Knobel D.L. Jackson A.C. Bingham J. Ertl H.C.J. Gibson A.D. Hughes D. Joubert K. Mani R.S. Mohr B.J. Moore S.M. Rivett-Carnac H. Tordo N. Yeates J.W. Zambelli A.B. Rupprecht C.E. A one medicine mission for an effective rabies therapy. Front. Vet. Sci. 2022 9 867382 10.3389/fvets.2022.867382 35372555
    [Google Scholar]
  2. Pattanaik A. Mani R.S. WHO’s new rabies recommendations: Implications for high incidence countries. Curr. Opin. Infect. Dis. 2019 32 5 401 406 10.1097/QCO.0000000000000578 31305491
    [Google Scholar]
  3. Lushasi K. Steenson R. Bernard J. Changalucha J.J. Govella N.J. Haydon D.T. Hoffu H. Lankester F. Magoti F. Mpolya E.A. Mtema Z. Nonga H. Hampson K. One health in practice: Using integrated bite case management to increase detection of rabid animals in tanzania. Front. Public Health 2020 8 13 10.3389/fpubh.2020.00013 32117850
    [Google Scholar]
  4. 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 10.1016/S1474‑4422(13)70038‑3 23602163
    [Google Scholar]
  5. Guo Y. Duan M. Wang X. Gao J. Guan Z. Zhang M. Early events in rabies virus infection—Attachment, entry, and intracellular trafficking. Virus Res. 2019 263 217 225 10.1016/j.virusres.2019.02.006 30772332
    [Google Scholar]
  6. Ng W.M. Fedosyuk S. English S. Augusto G. Berg A. Thorley L. Haselon A.S. Segireddy R.R. Bowden T.A. Douglas A.D. Structure of trimeric pre-fusion rabies virus glycoprotein in complex with two protective antibodies. Cell Host Microbe 2022 30 9 1219 1230.e7 10.1016/j.chom.2022.07.014 35985336
    [Google Scholar]
  7. Stefano M.L. Kream R.M. Stefano G.B. A novel vaccine employing non-replicating rabies virus expressing chimeric sars-cov-2 spike protein domains: Functional inhibition of viral/nicotinic acetylcholine receptor complexes. Med. Sci. Monit. 2020 26 e926016 10.12659/MSM.926016 32463026
    [Google Scholar]
  8. Thoulouze M.I. Lafage M. Schachner M. Hartmann U. Cremer H. Lafon M. The neural cell adhesion molecule is a receptor for rabies virus. J. Virol. 1998 72 9 7181 7190 10.1128/JVI.72.9.7181‑7190.1998 9696812
    [Google Scholar]
  9. Sasaki M. Anindita P.D. Ito N. Sugiyama M. Carr M. Fukuhara H. Ose T. Maenaka K. Takada A. Hall W.W. Orba Y. Sawa H. The role of heparan sulfate proteoglycans as an attachment factor for rabies virus entry and infection. J. Infect. Dis. 2018 217 11 1740 1749 10.1093/infdis/jiy081 29529215
    [Google Scholar]
  10. Alameh M.G. Weissman D. Pardi N. Messenger RNA-based vaccines against infectious diseases. Curr. Top. Microbiol. Immunol. 2020 440 111 145 10.1007/82_2020_202 32300916
    [Google Scholar]
  11. Zhang Y. Mo R. Sun S. Cui Z. Liang B. Li E. Wang T. Feng Y. Yang S. Yan F. Zhao Y. Xia X. Bacillus subtilis vector based oral rabies vaccines induced potent immune response and protective efficacy in mice. Front. Microbiol. 2023 14 1126533 10.3389/fmicb.2023.1126533 36846792
    [Google Scholar]
  12. Heine A. Juranek S. Brossart P. Clinical and immunological effects of mRNA vaccines in malignant diseases. Mol. Cancer 2021 20 1 52 10.1186/s12943‑021‑01339‑1 33722265
    [Google Scholar]
  13. Wang Y. Zhang Z. Luo J. Han X. Wei Y. Wei X. mRNA vaccine: A potential therapeutic strategy. Mol. Cancer 2021 20 1 33 10.1186/s12943‑021‑01311‑z 33593376
    [Google Scholar]
  14. Sabnis S. Kumarasinghe E.S. Salerno T. Mihai C. Ketova T. Senn J.J. Lynn A. Bulychev A. McFadyen I. Chan J. Almarsson Ö. Stanton M.G. Benenato K.E. A novel amino lipid series for mrna delivery: Improved endosomal escape and sustained pharmacology and safety in non-human primates. Mol. Ther. 2018 26 6 1509 1519 10.1016/j.ymthe.2018.03.010 29653760
    [Google Scholar]
  15. Li J. Liu Q. Liu J. Wu X. Lei Y. Li S. Zhao D. Li Z. Luo L. Peng S. Ou Y. Yang H. Jin J. Li Y. Peng Y. An mRNA-based rabies vaccine induces strong protective immune responses in mice and dogs. Virol. J. 2022 19 1 184 10.1186/s12985‑022‑01919‑7 36371169
    [Google Scholar]
  16. Bai S. Yang T. Zhu C. Feng M. Zhang L. Zhang Z. Wang X. Yu R. Pan X. Zhao C. Xu J. Zhang X. A single vaccination of nucleoside-modified Rabies mRNA vaccine induces prolonged highly protective immune responses in mice. Front. Immunol. 2023 13 1099991 10.3389/fimmu.2022.1099991 36761167
    [Google Scholar]
  17. Kim J. Eygeris Y. Gupta M. Sahay G. Self-assembled mRNA vaccines. Adv. Drug Deliv. Rev. 2021 170 83 112 10.1016/j.addr.2020.12.014 33400957
    [Google Scholar]
  18. Pardi N. Tuyishime S. Muramatsu H. Kariko K. Mui B.L. Tam Y.K. Madden T.D. Hope M.J. Weissman D. Expression kinetics of nucleoside-modified mrna delivered in lipid nanoparticles to mice by various routes. J. Control. Release 2015 217 345 351 10.1016/j.jconrel.2015.08.007 26264835
    [Google Scholar]
  19. Lazzaro S. Giovani C. Mangiavacchi S. Magini D. Maione D. Baudner B. Geall A.J. De Gregorio E. D’Oro U. Buonsanti C. CD 8 T‐cell priming upon mRNA vaccination is restricted to bone‐marrow‐derived antigen‐presenting cells and may involve antigen transfer from myocytes. Immunology 2015 146 2 312 326 10.1111/imm.12505 26173587
    [Google Scholar]
  20. Liang F. Lindgren G. Lin A. Thompson E.A. Ols S. Röhss J. John S. Hassett K. Yuzhakov O. Bahl K. Brito L.A. Salter H. Ciaramella G. Loré K. Efficient targeting and activation of antigen-presenting cells in vivo after modified mrna vaccine administration in rhesus macaques. Mol. Ther. 2017 25 12 2635 2647 10.1016/j.ymthe.2017.08.006 28958578
    [Google Scholar]
  21. Lindsay K.E. Bhosle S.M. Zurla C. Beyersdorf J. Rogers K.A. Vanover D. Xiao P. Araínga M. Shirreff L.M. Pitard B. Baumhof P. Villinger F. Santangelo P.J. Visualization of early events in mRNA vaccine delivery in non-human primates via PET–CT and near-infrared imaging. Nat. Biomed. Eng. 2019 3 5 371 380 10.1038/s41551‑019‑0378‑3 30936432
    [Google Scholar]
  22. Oberli M.A. Reichmuth A.M. Dorkin J.R. Mitchell M.J. Fenton O.S. Jaklenec A. Anderson D.G. Langer R. Blankschtein D. Lipid nanoparticle assisted mRNA delivery for potent cancer immunotherapy. Nano Lett. 2017 17 3 1326 1335 10.1021/acs.nanolett.6b03329 28273716
    [Google Scholar]
  23. Firdessa-Fite R. Creusot R.J. Nanoparticles versus dendritic cells as vehicles to deliver mRNA encoding multiple epitopes for immunotherapy. Mol. Ther. Methods Clin. Dev. 2020 16 50 62 10.1016/j.omtm.2019.10.015 31871957
    [Google Scholar]
  24. Semple S.C. Akinc A. Chen J. Sandhu A.P. Mui B.L. Cho C.K. Sah D.W.Y. Stebbing D. Crosley E.J. Yaworski E. Hafez I.M. Dorkin J.R. Qin J. Lam K. Rajeev K.G. Wong K.F. Jeffs L.B. Nechev L. Eisenhardt M.L. Jayaraman M. Kazem M. Maier M.A. Srinivasulu M. Weinstein M.J. Chen Q. Alvarez R. Barros S.A. De S. Klimuk S.K. Borland T. Kosovrasti V. Cantley W.L. Tam Y.K. Manoharan M. Ciufolini M.A. Tracy M.A. de Fougerolles A. MacLachlan I. Cullis P.R. Madden T.D. Hope M.J. Rational design of cationic lipids for siRNA delivery. Nat. Biotechnol. 2010 28 2 172 176 10.1038/nbt.1602 20081866
    [Google Scholar]
  25. Varkouhi A.K. Scholte M. Storm G. Haisma H.J. Endosomal escape pathways for delivery of biologicals. J. Control. Release 2011 151 3 220 228 10.1016/j.jconrel.2010.11.004 21078351
    [Google Scholar]
  26. Selby L.I. Cortez-Jugo C.M. Such G.K. Johnston A.P.R. Nanoescapology: Progress toward understanding the endosomal escape of polymeric nanoparticles. Wiley Interdiscip. Rev. Nanomed. Nanobiotechnol. 2017 9 5 e1452 10.1002/wnan.1452 28160452
    [Google Scholar]
  27. Klöcker N. Weissenboeck F.P. van Dülmen M. Špaček P. Hüwel S. Rentmeister A. Photocaged 5′ cap analogues for optical control of mRNA translation in cells. Nat. Chem. 2022 14 8 905 913 10.1038/s41557‑022‑00972‑7 35725774
    [Google Scholar]
  28. Schnee M. Vogel A.B. Voss D. Petsch B. Baumhof P. Kramps T. Stitz L. An mRNA vaccine encoding rabies virus glycoprotein induces protection against lethal infection in mice and correlates of protection in adult and newborn pigs. PLoS Negl. Trop. Dis. 2016 10 6 e0004746 10.1371/journal.pntd.0004746 27336830
    [Google Scholar]
/content/journals/cpb/10.2174/0113892010396404250903044326
Loading
/content/journals/cpb/10.2174/0113892010396404250903044326
Loading

Data & Media loading...


  • Article Type:
    Research Article
Keywords: rabies virus ; modified 5’ -cap ; immunization ; mRNA vaccines
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error
Please enter a valid_number test