Toward next-generation rabies vaccines: Innovations and challenges
Rabies continues to pose a significant fatal zoonotic threat, with approximately 59,000 human deaths reported annually, despite the disease being mostly preventable through vaccination. Recently, several notable scientific advancements have been made, including the determination of the pre-fusion conformation of the rabies virus glycoprotein (RABV-G), structure-guided antigen design strategies to enhance immunogenicity, and the development of mRNA-lipid nanoparticle (LNPs) delivery platforms encoding RABV-G. Pre-clinical models have shown that these mRNA-LNPs platforms induce neutralizing antibody titers that are approximately ten-fold higher than those elicited by traditional inactivated vaccines. Heterologous prime-boost vaccination regimens integrating inactivated rabies virus with mRNA boosters have demonstrated synergistic efficacy, achieving 100% protection with evidence of potential durability in non-human primate models. However, several critical knowledge gaps remain, such as the structure of the full-length or ectodomain of pre-fusion RABV-G, the mechanisms underlying pH-driven conformational changes of RABV-G and its fusion process, the binding mechanisms of different viral receptors, and the induction of long-term protection. Future breakthroughs will hinge on integrating technological innovation with global accessibility to achieve the “Zero by 30” rabies elimination initiative. This requires coordinated efforts to translate cutting-edge research into scalable, affordable interventions that address both scientific challenges and public health gaps.
- Amoako YA, El-Duah P, Sylverken AA, et al. Rabies is still a fatal but neglected disease: A case report. J MedCase Rep. 2021;15(1):575. doi: 10.1186/s13256-021-03164-y
- Rupprecht CE, Salahuddin N. Current status of human rabies prevention: Remaining barriers to global biologics accessibility and disease elimination. Expert Rev Vaccines. 2019;18(6):629-640. doi: 10.1080/14760584.2019.1627205
- Ren M, Stone MD, Semedo MH, Nel LH. New global strategic plan to eliminate dog-mediated rabies by 2030. Lancet Glob Health. 2018;6(8):e828-e829. doi: 10.1016/s2214-109x(18)30302-4
- Coetzer A, Scott TP, Amparo AC, Jayme SI, Nel LH. Formation of the Asian rabies control network (ARACON): A common approach towards a global good. Antiviral Res. 2018;157:134-139. doi: 10.1016/j.antiviral.2018.07.018
- Fooks AR, Cliquet F, Finke S, et al. Rabies. Nat Rev Dis Primers. 2017;3(1):17091. doi: 10.1038/nrdp.2017.91
- Yang F, Lin S, Ye F, et al. Structural analysis of rabies virus glycoprotein reveals pH-dependent conformational changes and interactions with a neutralizing antibody. Cell Host Microbe. 2020;27(3):441-453.e7. doi: 10.1016/j.chom.2019.12.012
- You Y, Yang F, Lin S, et al. Rabies Virus Glycoprotein: Structure, Function, and Antivirals. hLife. Indian: In Press; 2025. doi: 10.1016/j.hlife.2025.06.003
- Callaway HM, Zyla D, Larrous F, et al. Structure of the rabies virus glycoprotein trimer bound to a prefusion -specific neutralizing antibody. Sci Adv. 2022;8(24):eabq9151. doi: 10.1126/sciadv.abp9151
- Cao H, Li H, Liu W, et al. A QS21+ CpG-adjuvanted rabies virus g subunit vaccine elicits superior humoral and moderate cellular immunity. Vaccines (Basel). 2025;13(8):887. doi: 10.3390/vaccines13080887
- Kessels J, Tarantola A, Salahuddin N, Blumberg L, Knopf L. Rabies post-exposure prophylaxis: A systematic review on abridged vaccination schedules and the effect of changing administration routes during a single course. Vaccine. 2019;37:A107-A117. doi: 10.1016/j.vaccine.2019.01.041
- Wang L, Li J, Mu Q, et al. Study on immune persistence of the CTN-1V strain rabies vaccine in humans. J Virus Erad. 2024;10(1):100365. doi: 10.1016/j.jve.2024.100365
- Zhang C, Tian Y, Chen C, et al. Virus-like vesicles based on semliki forest virus-containing rabies virus glycoprotein make a safe and efficacious rabies vaccine candidate in a mouse model. J Virol. 2021;95(20):e0079021. doi: 10.1128/jvi.00790-21
- Wang SY, Sun JF, Liu P, et al. Immunogenicity and safety of human diploid cell vaccine (HDCV) vs. Purified Vero cell vaccine (PVRV) vs. Purified chick embryo cell vaccine (PCECV) used in post-exposure prophylaxis: A systematic review and meta-analysis. Hum Vaccin Immunother. 2022;18(1):2027714. doi: 10.1080/21645515.2022.2027714
- Kaye AD, Perilloux DM, Field E, et al. Rabies vaccine for prophylaxis and treatment of rabies: A narrative review. Cureus. 2024;16(6):e62429. doi: 10.7759/cureus.62429
- Astray RM, Jorge SAC, Pereira CA. Rabies vaccine development by expression of recombinant viral glycoprotein. Arch Virol. 2017;162(2):323-332. doi: 10.1007/s00705-016-3128-9
- Pardi N, Hogan MJ, Porter FW, Weissman D. mRNA vaccines - a new era in vaccinology. Nat Rev Drug Discov. 2018;17(4):261-279. doi: 10.1038/nrd.2017.243
- Andrews N, Stowe J, Kirsebom F, et al. Effectiveness of COVID-19 booster vaccines against COVID-19-related symptoms, hospitalization and death in England. Nat Med. 2022;28(4):831-837. doi: 10.1038/s41591-022-01699-1
- Reis BY, Barda N, Leshchinsky M, et al. Effectiveness of BNT162b2 vaccine against delta variant in adolescents. N Engl J Med. 2021;385(22):2101-2103. doi: 10.1056/NEJMc2114290
- Armbruster N, Jasny E, Petsch B. Advances in RNA vaccines for preventive indications: A case study of a vaccine against rabies. Vaccines (Basel). 2019;7(4):132. doi: 10.3390/vaccines7040132
- Li J, Liu Q, Liu J, et al. An mRNA-based rabies vaccine induces strong protective immune responses in mice and dogs. Virol J. 2022;19(1):184. doi: 10.1186/s12985-022-01919-7
- Li M, Fang E, Wang Y, et al. An mRNA vaccine against rabies provides strong and durable protection in mice. Front Immunol. 2023;14:1288879. doi: 10.3389/fimmu.2023.1288879
- Zhang H, Zhang L, Lin A, et al. Algorithm for optimized mRNA design improves stability and immunogenicity. Nature. 2023;621(7978):396-403. doi: 10.1038/s41586-023-06127-z
- Hellgren F, Cagigi A, Arcoverde Cerveira R, et al. Unmodified rabies mRNA vaccine elicits high cross-neutralizing antibody titers and diverse B cell memory responses. Nat Commun. 2023;14(1):3713. doi: 10.1038/s41467-023-39421-510.1038/s41467-023-39421-5
- Saxena S, Sonwane AA, Dahiya SS, et al. Induction of immune responses and protection in mice against rabies using a self-replicating RNA vaccine encoding rabies virus glycoprotein. Vet Microbiol. 2009;136(1-2):36-44. doi: 10.1016/j.vetmic.2008.10.030
- Schnee M, Vogel AB, Voss D, et al. 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. doi: 10.1371/journal.pntd.0004746
- Stitz L, Vogel A, Schnee M, et al. A thermostable messenger RNA based vaccine against rabies. PLoS Negl Trop Dis. 2017;11(12):e0006108. doi: 10.1371/journal.pntd.0006108
- Stokes A, Pion J, Binazon O, et al. Nonclinical safety assessment of repeated administration and biodistribution of a novel rabies self-amplifying mRNA vaccine in rats. Regul Toxicol Pharmacol. 2020;113:104648. doi: 10.1016/j.yrtph.2020.104648
- Donahue DA, Ballesteros C, Maruggi G, et al. Nonclinical safety assessment of lipid nanoparticle-and emulsion-based self-amplifying mRNA vaccines in rats. Int J Toxicol. 2023;42(1):37-49. doi: 10.1177/10915818221138781
- Yu PC, Dan M, He Y, et al. A novel mRNA rabies vaccine as a promising candidate for rabies post-exposure prophylaxis protects animals from different rabies viruses. Microb Pathog. 2023;185:106425. doi: 10.1016/j.micpath.2023.106425
- Bai S, Yang T, Zhu C, et al. A single vaccination of nucleoside-modified Rabies mRNA vaccine induces prolonged highly protective immune responses in mice. Front Immunol. 2023;13:1099991. doi: 10.3389/fimmu.2022.1099991
- Hongtu Q, BoLi L, Jianguo C, Shusheng P, Ming M. Immunogenicity of rabies virus G mRNA formulated with lipid nanoparticles and nucleic acid immunostimulators in mice. Vaccine. 2023;41(48):7129-7137. doi: 10.1016/j.vaccine.2023.10.019
- Long J, Yu C, Cao Y, et al. A rabies mRNA vaccine provides a rapid and long-term immune response in mice. Nano Today. 2023;53:102038. doi: 10.1016/j.nantod.2023.102038
- Wan J, Yang J, Wang Z, et al. A single immunization with core–shell structured lipopolyplex mRNA vaccine against rabies induces potent humoral immunity in mice and dogs. Emerg Microbes Infect. 2023;12(2):2270081. doi: 10.1080/22221751.2023.2270081
- Li J, Yu P, Liu Q, et al. Safety and efficacy assessment of an mRNA rabies vaccine in dogs, rodents, and cynomolgus macaques. NPJ Vaccines. 2024;9(1):130. doi: 10.1038/s41541-024-00925-w
- Cao H, Li H, Luan N, et al. A rabies mRNA vaccine with H270P mutation in its glycoprotein induces strong cellular and humoral immunity. Vaccine. 2024;42(5):1116-1121. doi: 10.1016/j.vaccine.2024.01.057
- Liu J, Sun J, Ding X, et al. A nucleoside-modified mRNA vaccine forming rabies virus-like particle elicits strong cellular and humoral immune responses against rabies virus infection in mice. Emerg Microbes Infect. 2024;13(1):2389115. doi: 10.1080/22221751.2024.2389115
- Wang Y, Wang S, Huang L, et al. A nucleoside-modified rabies mRNA vaccine induces long-lasting and comprehensive immune responses in mice and non-human primates. Mol Ther. 2024;33:548-559. doi: 10.1016/j.ymthe.2024.12.041
- Wan J, Wang Z, Wang L, et al. Circular RNA vaccines with long-term lymph node-targeting delivery stability after lyophilization induce potent and persistent immune responses. MBio. 2024;15(1):e01775-23. doi: 10.1128/mbio.01775-23
- Li D, Wang X, Li G, 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
- Li Q, Bai H, Yu X, Liu Q, Hu R. Immunogenicity of rabies virus g-protein mRNA formulated with muscle-targeting lipid nanoparticles in mice. Vaccines (Basel). 2025;13(3):217. doi: 10.3390/vaccines13030217
- Bai S, Pan X, Yang T, et al. Rabies virus large protein-derived T-cell immunogen facilitates rapid viral clearance and enhances protection against lethal challenge in mice. Commun Med (Lond). 2025;5(1):127. doi: 10.1038/s43856-025-00851-5
- Fisher CR, Streicker DG, Schnell MJ. The spread and evolution of rabies virus: Conquering new frontiers. Nat Rev Microbiol. 2018;16(4):241-255. doi: 10.1038/nrmicro.2018.11
- Ren Q, Chen N, Mu D, et al. Characteristics, post-exposure prophylaxis usage, and clinical features of Chinese human rabies cases, 2016-2020. PLoS Negl Trop Dis. 2025;19(6):e0013089. doi: 10.1371/journal.pntd.0013089
- Yousaf MZ, Qasim M, Zia S, Khan M, Ashfaq UA, Khan S. Rabies molecular virology, diagnosis, prevention and treatment. Virol J. 2012;9:50. doi: 10.1186/1743-422x-9-50
- Ribadeau-Dumas F, Cliquet F, Gautret P, Robardet E, Le Pen C, Bourhy H. Travel-associated rabies in pets and residual rabies risk, Western Europe. Emerg Infect Dis. 2016;22(7):1268-71. doi: 10.3201/eid2207.151733
- Smith JS. New aspects of rabies with emphasis on epidemiology, diagnosis, and prevention of the disease in the United States. Clin Microbiol Rev. 1996;9(2):166-176. doi: 10.1128/CMR.9.2.166
- Belotto A, Leanes LF, Schneider MC, Tamayo H, Correa E. Overview of rabies in the Americas. Virus Res. 2005;111(1): 5-12. doi: 10.1016/j.virusres.2005.03.006
- Rupprecht CE, Hanlon CA, Hemachudha T. Rabies re-examined. Lancet Infect Dis. 2002;2(6):327-343. doi: 10.1016/s1473-3099(02)00287-6
- Nel LH, Rupprecht CE. Emergence of lyssaviruses in the old world: The case of Africa. Curr Top Microbiol Immunol. 2007;315:161-93. doi: 10.1007/978-3-540-70962-6_8
- Hampson K, Coudeville L, Lembo T, et al. Estimating the global burden of endemic canine rabies. PLoS Negl Trop Dis. 2015;9(4):e0003709. doi: 10.1371/journal.pntd.0003709
- Manoj S, Mukherjee A, Johri S, Kumar KVSH. Recovery from rabies, a universally fatal disease. Mil Med Res. 2016;3:21. doi: 10.1186/s40779-016-0089-y
- 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
- Charlton KM, Nadin-Davis S, Casey GA, Wandeler AI. The long incubation period in rabies: Delayed progression of infection in muscle at the site of exposure. Acta Neuropathol. 1997;94(1):73-77. doi: 10.1007/s004010050674
- Brunker K, Mollentze N. Rabies virus. Trends Microbiol. 2018;26(10):886-887. doi: 10.1016/j.tim.2018.07.001
- Scott TP, Nel LH. Lyssaviruses and the fatal encephalitic disease rabies. Mini review. Front Immunol. 2021;12:786953. doi: 10.3389/fimmu.2021.786953
- Hemachudha T, Laothamatas J, Rupprecht CE. Human rabies: A disease of complex neuropathogenetic mechanisms and diagnostic challenges. Lancet Neurol. 2002;1(2): 101-109. doi: 10.1016/s1474-4422(02)00041-8
- Shuangshoti S, Thorner PS, Teerapakpinyo C, et al. Intracellular spread of rabies virus is reduced in the paralytic form of canine rabies compared to the furious form. PLoS Negl Trop Dis. 2016;10(6):e0004748. doi: 10.1371/journal.pntd.0004748
- Lodha L, Ananda AM, Mani RS. Advancing rabies diagnosis: Time for a new “gold standard”? Mol Diagn Ther. 2025;29(2):153-159. doi: 10.1007/s40291-024-00758-2
- Wunner WH, Conzelmann KK. Rabies virus. In: Fooks AR, Jackson AC, editors. Rabies (Fourth Edition). Ch. 2. United States: Academic Press; 2020. p. 43-81.
- Lentz TL, Burrage TG, Smith AL, Crick J, Tignor GH. Is the acetylcholine receptor a rabies virus receptor? Science. 1982;215(4529):182-184. doi: 10.1126/science.7053569
- Thoulouze MI, 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. doi: 10.1128/jvi.72.9.7181-7190.1998
- Tuffereau C, Bénéjean J, Blondel D, Kieffer B, Flamand A. Low-affinity nerve-growth factor receptor (P75NTR) can serve as a receptor for rabies virus. Article. EMBO J. 1998;17(24):7250-7259. doi: 10.1093/emboj/17.24.7250
- Sasaki M, Anindita PD, Ito N, et al. The role of heparan sulfate proteoglycans as an attachment factor for rabies virus entry and infection. J Infect Dis. 2018;217(11):1740-1749. doi: 10.1093/infdis/jiy081
- Wang J, Wang Z, Liu R, et al. Metabotropic glutamate receptor subtype 2 is a cellular receptor for rabies virus. PLOS Pathog. 2018;14(7):e1007189. doi: 10.1371/journal.ppat.1007189
- Coulon P, Ternaux JP, Flamand A, Tuffereau C. An avirulent mutant of rabies virus is unable to infect motoneurons in vivo and in vitro. J Virol. 1998;72(1):273-278. doi: 10.1128/jvi.72.1.273-278.1998
- Piccinotti S, Kirchhausen T, Whelan SP. Uptake of rabies virus into epithelial cells by clathrin-mediated endocytosis depends upon actin. J Virol. 2013;87(21):11637-11647. doi: 10.1128/jvi.01648-13
- Piccinotti S, Whelan SPJ. Rabies internalizes into primary peripheral neurons via clathrin coated pits and requires fusion at the cell body. PLOS Pathog. 2016;12(7):e1005753. doi: 10.1371/journal.ppat.1005753
- Gaudin Y, Tuffereau C, Segretain D, Knossow M, Flamand A. Reversible conformational changes and fusion activity of rabies virus glycoprotein. J Virol. 1991;65(9): 4853-4859. doi: 10.1128/jvi.65.9.4853-4859.1991
- Gaudin Y. Rabies virus-induced membrane fusion pathway. J Cell Biol. 2000;150(3):601-612. doi: 10.1083/jcb.150.3.601
- Tuffereau C, Schmidt K, Langevin C, Lafay F, Dechant G, Koltzenburg M. The rabies virus glycoprotein receptor p75NTR is not essential for rabies virus infection. J Virol. 2007;81(24):13622-13630. doi: 10.1128/JVI.02368-06
- Ng WM, Fedosyuk S, English S, et al. Structure of trimeric pre-fusion rabies virus glycoprotein in complex with two protective antibodies. Cell Host Microbe. 2022;30(9): 1219-1230.e7. doi: 10.1016/j.chom.2022.07.014
- Finke S, Cox JH, Conzelmann KK. Differential transcription attenuation of rabies virus genes by interg enic regions: Generation of recombinant viruses overexpressing the pol ymerase gene. J Virol. 2000;74(16):7261-7269. doi: 10.1128/jvi.74.16.7261-7269.2000
- Whelan SP, Barr JN, Wertz GW. Transcription and replication of nonsegmented negative-strand RNA viruses. Curr Top Microbiol Immunol. 2004;283:61-119. doi: 10.1007/978-3-662-06099-5_3
- Finke S, Mueller-Waldeck R, Conzelmann KK. Rabies virus matrix protein regulates the balance of virus transcription and replication. J Gen Virol. 2003;84(Pt 6):1613-1621. doi: 10.1099/vir.0.19128-0
- Mebatsion T, Weiland F, Conzelmann KK. Matrix protein of rabies virus is responsible for the assembly and budding of bullet-shaped particles and interacts with the transmembrane spike glycoprotein G. J Virol. 1999;73(1):242-250. doi: 10.1128/jvi.73.1.242-250.1999
- Bauer A, Nolden T, Schröter J, et al. Anterograde glycoprotein-dependent transport of newly generated rabies virus in dorsal root ganglion neurons. J Virol. 2014;88(24):14172-14183. doi: 10.1128/jvi.02254-14
- Potratz M, Zaeck LM, Weigel C, et al. Neuroglia infection by rabies virus after anterograde virus spread in peripheral neurons. Acta Neuropathol Commun. 2020;8(1):199. doi: 10.1186/s40478-020-01074-6
- Roche S, Rey FA, Gaudin Y, Bressanelli S. Structure of the prefusion form of the vesicular stomatitis virus glycoprotein G. Science. 2007;315(5813):843-848. doi: 10.1126/science.1135710
- Roche S, Bressanelli S, Rey FA, Gaudin Y. Crystal structure of the low-pH form of the vesicular stomatitis virus glycoprotein G. Science. 2006;313(5784):187-191. doi: 10.1126/science.1127683
- Hellert J, Buchrieser J, Larrous F, et al. Structure of the prefusion-locking broadly neutralizing antibody RVC20 bound to the rabies virus glycoprotein. Nat Commun. 2020;11(1):596. doi: 10.1038/s41467-020-14398-7
- Harrison SC. Viral membrane fusion. Virology. 2015;479- 480:498-507. doi: 10.1016/j.virol.2015.03.043
- Prehaud C, Coulon P, LaFay F, Thiers C, Flamand A. Antigenic site II of the rabies virus glycoprotein: Structure and role in viral virulence. J Virol. 1988;62(1):1-7. doi: 10.1128/jvi.62.1.1-7.1988
- Gaudin Y, Ruigrok RWH, Tuffereau C, Knossow M, Flamand A. Rabies virus glycoprotein is a trimer. Virology. 1992;187(2):627-632. doi: 10.1016/0042-6822(92)90465-2
- Whitt MA, Buonocor L, Prehaud C, Rose JK. Membrane fusion activity, oligomerization, and assembly of the rabies virus glycoprotein. Virology. 1991;185(2):681-688. doi: 10.1016/0042-6822(91)90539-N
- Kedari A, Iheozor-Ejiofor R, Salminen P, et al. Structural insight into rabies virus neutralization revealed by an eng ineered antibody scaffold. Structure. 2024;32(12): 2220-2230.e4. doi: 10.1016/j.str.2024.10.002
- Benmansour A, Leblois H, Coulon P, et al. Antigenicity of rabies virus glycoprotein. J Virol. 1991;65(8):4198-4203. doi: 10.1128/jvi.65.8.4198-4203.1991
- Chen Cx, Wang X, Su W, et al. Changes in the dynamic characteristics of G-protein can alter the immune-protection efficacy of rabies virus vaccine. J Virol. 2025;99(3):e0195424. doi: 10.1128/jvi.01954-24
- Shi C, Sun P, Yang P, et al. Research progress on neutralizing epitopes and antibodies for the Rabi es virus. Infectious Medicine. 2022;1(4):262-271. doi: 10.1016/j.imj.2022.09.003
- Sloan SE, Hanlon C, Weldon W, et al. Identification and characterization of a human monoclonal antibody tha t potently neutralizes a broad panel of rabies virus isolates. Vaccine. 2007;25(15):2800-2810. doi: 10.1016/j.vaccine.2006.12.031
- Kang G, Lakhkar A, Bhamare C, et al. Active safety surveillance of rabies monoclonal antibody and rabies vaccine in patients with category III potential rabies exposure. Lancet Reg Health Southeast Asia. 2023;14:100207. doi: 10.1016/j.lansea.2023.100207
- Wang Y, Rowley KJ, Booth BJ, Sloan SE, Ambrosino DM, Babcock GJ. G glycoprotein amino acid residues required for human monoclonal antib ody RAB1 neutralization are conserved in rabies virus street isolates. Antiv Res. 2011;91(2):187-194. doi: 10.1016/j.antiviral.2011.06.002
- Dietzschold B, Gore M, Marchadier D, et al. Structural and immunological characterization of a linear virus-neutralizing epitope of the rabies virus glycoprotein and its possible use in a synthetic vaccine. J Virol. 1990;64(8): 3804-3809. doi: 10.1128/jvi.64.8.3804-3809.1990
- Van Der Heijden RW, Langedijk JP, Groen J, UytdeHaag FG, Meloen RH, Osterhaus AD. Structural and functional studies on a unique linear neutralizing antigenic site (G5) of the rabies virus glycoprotein. J Gen Virol. 1993;74(Pt8):1539-1545. doi: 10.1099/0022-1317-74-8-1539
- Préhaud C, Lay S, Dietzschold B, Lafon M. Glycoprotein of nonpathogenic rabies viruses is a key determinant of human cell apoptosis. J Virol. 2003;77(19):10537-10547. doi: 10.1128/jvi.77.19.10537-10547.2003
- Zhang Y, Zhang X, Yang X, et al. AP3B1 facilitates PDIA3/ ERP57 function to regulate rabies virus glycoprotein selective degradation and viral entry. Autophagy. 2024;20(12):2785-2803. doi: 10.1080/15548627.2024.2390814
- Mahmood F, Xu R, Awan MUN, et al. PDIA3: Structure, functions and its potential role in viral infections. Biomed Pharmacother. 2021;143:112110. doi: 10.1016/j.biopha.2021.112110
- Gaudin Y. Folding of rabies virus glycoprotein: Epitope acquisition and interact ion with endoplasmic reticulum chaperones. J Virol. 1997;71(5):3742-3750. doi: 10.1128/jvi.71.5.3742-3750.1997
- Ashraf S, Singh PK, Yadav DK, et al. High level expression of surface glycoprotein of rabies virus in tobacco leaves and its immunoprotective activity in mice. J Biotechnol. 2005;119(1):1-14. doi: 10.1016/j.jbiotec.2005.06.009
- Wojczyk BS, Takahashi N, Levy MT, et al. N-glycosylation at one rabies virus glycoprotein sequon influences N-glycan processing at a distant sequon on the same molecule. Glycobiology. 2005;15(6):655-666. doi: 10.1093/glycob/cwi046
- Yamada K, Noguchi K, Nishizono A. Efficient N-glycosylation at position 37, but not at position 146, in the street rabies virus glycoprotein reduces pathogenicity. Virus Res. 2014;179:169-176. doi: 10.1016/j.virusres.2013.10.015
- Gaudin Y, Tuffereau C, Benmansour A, Flamand A. Fatty acylation of rabies virus proteins. Virology. 1991;184(1): 441-444. doi: 10.1016/0042-6822(91)90866-A
- Jackson AC. History of Rabies Research. Rabies. Netherlands: Elsevier; 2013. p. 1-15.
- Tarantola A. Four thousand years of concepts relating to rabies in animals and humans, its prevention and its cure. Trop Med Infect Dis. 2017;2(2):5. doi: 10.3390/tropicalmed2020005
- Natesan K, Isloor S, Vinayagamurthy B, Ramakrishnaiah S, Doddamane R, Fooks AR. Developments in rabies vaccines: The path traversed from pasteur to th e modern era of immunization. Vaccines. 2023;11(4):756. doi: 10.3390/vaccines11040756
- Rappuoli R. Inner Workings: 1885, the first rabies vaccinationin humans. Proc Natl Acad Sci U S A. 2014;111(34):12273. doi: 10.1073/pnas.1414226111
- Giesen A, Gniel D, Malerczyk C. 30 years of rabies vaccination with Rabipur: A summary of clinical data and global experience. Expert Rev Vaccines. 2015;14(3):351-367. doi: 10.1586/14760584.2015.1011134
- Plotkin S. History of vaccination. Proc Natl Acad Sci U S A. 2014;111(34):12283-12287. doi: 10.1073/pnas.1400472111
- Rupprecht CE, Freuling CM, Mani RS, Palacios C, Sabeta CT, Ward M. A history of rabies-the foundation for global canine rabies elimination. In: Fooks AR, Jackson AC, editors. Rabies Fourth Edition. Ch. 1. United States: Academic Press; 2020. p. 1-42.
- Javier RS, Kunishita T, Koike F, Tabira T. Semple rabies vaccine: Presence of myelin basic protein and proteolipid protein and its activity in experimental allergic encephalomyelitis. J Neurol Sci. 1989;93(2-3):221-230. doi: 10.1016/0022-510x(89)90192-5
- Hicks DJ, Fooks AR, Johnson N. Developments in rabies vaccines. Clin Exp Immunol. 2012;169(3):199-204. doi: 10.1111/j.1365-2249.2012.04592.x
- Swaddiwuthipong W, Weniger BG, Wattanasri S, Warrell MJ. A high rate of neurological complications following Semple anti-rabies vaccine. Trans Royal Soc Trop Med Hygiene. 1988;82(3):472-475. doi: 10.1016/0035-9203(88)90167-8
- Fuenzalida E, Palacios R. Un método mejorado en la preparación de la vacuna antirrábica. Bol Inst bact Chile. 1955;8:3-10.
- Fuenzalida E, Palacios R, Borgono JM. Antirabies antibody response in man to vaccine made from infected suckling-mouse brains. Bull World Health Organ. 1964;30(3):431-436.
- Larghi OP, Varela-Diaz VM, Soto E, Imas B, Cuba- Caparo A, Fuenzalida E. Laboratory investigations on neuroparalytic accidents associated with suckling mouse brain rabies vaccine. III. -- Preservation of vaccine potency after elimination of murine brain myelin by centrifugation. Ann Microbiol (Paris). 1976;127b(4):567-572.
- Meslin FX, Kaplan MM, Koprowski H, World Health O. Laboratory Techniques in Rabies. 4th ed. Geneva: World Health Organization; 1996.
- Woodruff AM, Goodpasture EW. The susceptibility of the chorio-allantoic membrane of chick embryos to infection with the fowl-pox virus. Am J Pathol. 1931;7(3):209-222.5.
- Fox JP, Koprowski H, Conwell DP, Black J, Gelfand HM. Study of antirabies immunization of man; Observations with HEP Flury and other vaccines, with and without hyperimmune serum, in primary and recall immunizations. Bull World Health Organ. 1957;17(6):869-904.
- Culbertson CG, Peck FB Jr., Powell HM. Duck-embryo rabies vaccine; study of fixed virus vaccine grown in embryonated duck eggs and killed with beta-propiolactone (BPL). J Am Med Assoc. 1956;162(15):1373-1376. doi: 10.1001/jama.1956.02970320021006
- Kissling RE. Growth of rabies virus in non-nervous tissue culture. Proc Soc Exp Biol Med. 1958;98(2):223-225. doi: 10.3181/00379727-98-23997
- Fenje P. Propagation of rabies virus in cultures of hamster kidney cells. Can J Microbiol. 1960;6(5):479-484. doi: 10.1139/m60-055
- Kissling RE, Reese DR. Anti-rabies vaccine of tissue culture origin. J Immunol. 1963;91(3):362-368. doi: 10.4049/jimmunol.91.3.362
- Wiktor TJ, Plotkin SA, Grella DW. Human cell culture rabies vaccine. Antibody response in man. Jama. 1973;224(8): 1170-1171. doi: 10.1001/jama.1973.03220220072012
- Garner WR, Jones DO, Pratt E. Problems associated with rabies preexposure prophylaxis. JAMA. 1976;235(11): 1131-1132. doi: 10.1001/jama.1976.03260370039029
- Rupprecht CE, Plotkin SA. Rabies vaccines. In: Plotkin SA, Orenstein WA, Offit PA, editors. Vaccines. 6thed. Ch. 29. Netherlands: W.B. Saunders; 2013. p. 646-668.
- Barth R, Gruschkau H, Bijok U, et al. A new inactivated tissue culture rabies vaccine for use in man. Evaluation of PCEC-vaccine by laboratory tests. J Biol Stand. 1984;12(1):29-46. doi: 10.1016/s0092-1157(84)80019-0
- Suntharasamai P, Warrell DA, Looareesuwan S, et al. New purified vero-cell vaccine prevents rabies in patients bitten by rabid animals. Lancet. 1986;328(8499):129-131. doi: 10.1016/S0140-6736(86)91946-X
- Pichon S, Guinet-Morlot F, Minutello M, et al. A serum-free, purified vero cell rabies vaccine is safe and as immunogenic as the reference vaccine Verorab for pre-exposure use in healthy adults: Results from a randomized controlled phase-II trial. Vaccine. 2013;31(18):2295-2301. doi: 10.1016/j.vaccine.2013.02.058
- Toovey S. Preventing rabies with the Verorab vaccine: 1985- 2005 Twenty years of clinical experience. Travel Med Infect Dis. 2007;5(6):327-348. doi: 10.1016/j.tmaid.2007.07.004
- Zhao C, Gao J, Wang Y, et al. A novel rabies vaccine based on a recombinant bovine herpes virus type 1 expressing rabies virus glycoprotein. Front Microbiol. 2022;13:931043. doi: 10.3389/fmicb.2022.931043
- Kieny MP, Lathe R, Drillien R, et al. Expression of rabies virus glycoprotein from a recombinant vaccinia virus. Nature. 1984;312(5990):163-166. doi: 10.1038/312163a0
- Wiktor TJ, Macfarlan RI, Reagan KJ, et al. Protection from rabies by a vaccinia virus recombinant containing the rabies virus glycoprotein gene. Proc Natl Acad Sci U S A. 1984;81(22):7194-7198. doi: 10.1073/pnas.81.22.7194
- World Health Organization. WHO Expert Consultation on Rabies: Third Report. Vol. 1012. Geneva: World Health Organization; 2018.
- Johnson N, Cunningham AF, Fooks AR. The immune response to rabies virus infection and vaccination. Vaccine. 2010;28(23):3896-3901. doi: 10.1016/j.vaccine.2010.03.039
- Estapé Senti M, García Del Valle L, Schiffelers RM. mRNA delivery systems for cancer immunotherapy: Lipid nanoparticles an d beyond. Adv Drug Deliv Rev. 2024;206:115190. doi: 10.1016/j.addr.2024.115190
- Brenner S, Jacob F, Meselson M. An unstable intermediate carrying information from genes to ribosomes for protein synthesis. Nature. 1961;190(4776):576-581. doi: 10.1038/190576a0
- Crunkhorn S. Monkeypox mRNA vaccine protects mice and macaques. Nat Rev Drug Discov. 2024;23(4):251. doi: 10.1038/d41573-024-00038-y
- Elliott L, Foster T, Castillo P, Mendez-Gomez H, Sayour EJ. Therapeutic mRNA vaccine applications in oncology. Mol Ther. 2025;33(6):2610-2618. doi: 10.1016/j.ymthe.2025.04.044
- Lockard RE, Lingrel JB. The synthesis of mouse hemoglobin chains in a rabbit reticulocyte cell-free system programmed with mouse reticulocyte 9S RNA. Biochem Biophys Res Commun. 1969;37(2):204-212. doi: 10.1016/0006-291X(69)90720-7
- Krieg PA, Melton D. Functional messenger RNAs are produced by SP6 in vitro transcription of cloned cDNAs. Nucleic Acids Res. 1984;12(18):7057-7070. doi: 10.1093/nar/12.18.7057
- Malone RW, Felgner PL, Verma IM. Cationic liposome-mediated RNA transfection. Proc Natl Acad Sci. 1989;86(16):6077-6081. doi: 10.1073/pnas.86.16.6077
- Martinon F, Krishnan S, Lenzen G, et al. Induction of virusuillet JG, G, ationic liposome-medin vivo by liposomeof virusuillet JGEur J Immunol. 1993;23(7):1719-1722. doi: 10.1002/eji.1830230749
- Karikó K, Ni H, Capodici J, Lamphier M, Weissman D. mRNA is an endogenous ligand for Toll-like receptor 3. J Biol Chem. 2004;279(13):12542-12550. doi: 10.1074/jbc.M310175200
- Diebold SS, Kaisho T, Hemmi H, Akira S, Reis e Sousa C. Innate antiviral responses by means of TLR7- mediated recognition of single-stranded RNA. Science. 2004;303(5663):1529-1531. doi: 10.1126/science.1093616
- Karikó K, Buckstein M, Ni H, Weissman D. Suppression of RNA recognition by Toll-like receptors: The impact of nucleoside modification and the evolutionary origin of RNA. Immunity. 2005;23(2):165-175. doi: 10.1016/j.immuni.2005.06.008
- Hoy SM. Patisiran: First global approval. Drugs. 2018;78(15):1625-1631. doi: 10.1007/s40265-018-0983-6
- El Sahly HM, Baden LR, Essink B, et al. Efficacy of the mRNA-1273 SARS-CoV-2 vaccine at completion of blinded phase. N Engl J Med. 2021;385(19):1774-1785. doi: 10.1056/NEJMoa2113017
- Chaudhary N, Weissman D, Whitehead KA. mRNA vaccines for infectious diseases: Principles, delivery and clinical translation. Nat Rev Drug Discov. 2021;20(11):817-838. doi: 10.1038/s41573-021-00283-5
- Buschmann MD, Carrasco MJ, Alishetty S, Paige M, Alameh MG, Weissman D. Nanomaterial delivery systems for mRNA vaccines. Vaccines (Basel). 2021;9(1):65. doi: 10.3390/vaccines9010065
- Kim J, Eygeris Y, Gupta M, Sahay G. Self-assembled mRNA vaccines. Adv Drug Deliv Rev. 2021;170:83-112. doi: 10.1016/j.addr.2020.12.014
- Hou X, Zaks T, Langer R, Dong Y. Lipid nanoparticles for mRNA delivery. Nat Rev Mater. 2021;6(12):1078-1094. doi: 10.1038/s41578-021-00358-0
- Schoenmaker L, Witzigmann D, Kulkarni JA, et al. mRNA-lipid nanoparticle COVID-19 vaccines: Structure and stability. Int J Pharm. 2021;601:120586. doi: 10.1016/j.ijpharm.2021.120586
- Zhang NN, Zhang RR, Zhang YF, et al. Rapid development of an updated mRNA vaccine against the SARS-CoV-2 Omicron variant. Cell Res. 2022;32(4):401-403. doi: 10.1038/s41422-022-00626-w
- Sayour EJ, Boczkowski D, Mitchell DA, Nair SK. Cancer mRNA vaccines: Clinical advances and future opportunities. Nat Rev Clin Oncol. 2024;21(7):489-500. doi: 10.1038/s41571-024-00902-1
- Qu L, Yi Z, Shen Y, et al. Circular RNA vaccines against SARS-CoV-2 and emerging variants. Cell. 2022;185(10):1728- 1744.e16. doi: 10.1016/j.cell.2022.03.044
- Niu D, Wu Y, Lian J. Circular RNA vaccine in disease prevention and treatment. Signal Transduct Target Ther. 2023;8(1):341. doi: 10.1038/s41392-023-01561-x
- Liu X, Wang S, Sun Y, et al. Unlocking the potential of circular RNA vaccines: A bioinformatics and computational biology perspective. EBioMedicine. 2025;114:105638. doi: 10.1016/j.ebiom.2025.105638
- Liu X, Zhang Y, Zhou S, Dain L, Mei L, Zhu G. Circular RNA: An emerging frontier in RNA therapeutic targets, RNA the rapeutics, and mRNA vaccines. J Control Release. 2022;348:84-94. doi: 10.1016/j.jconrel.2022.05.043
- Blakney AK, McKay PF, Shattock RJ. Structural components for amplification of positive and negative stran d VEEV splitzicons. Front Mol Biosci. 2018;5:71. doi: 10.3389/fmolb.2018.00071
- Komori M, Nogimori T, Morey AL, et al. saRNA vaccine expressing membrane-anchored RBD elicits broad and durable immunity against SARS-CoV-2 variants of concern. Nat Commun. 2023;14(1):2810. doi: 10.1038/s41467-023-38457-x
- Low JG, De Alwis R, Chen S, et al. A phase I/II randomized, double-blinded, placebo-controlled trial of a self-amplifying Covid-19 mRNA vaccine. NPJ Vaccines. 2022;7(1):161. doi: 10.1038/s41541-022-00590-x
- Oda Y, Kumagai Y, Kanai M, et al. Immunogenicity and safety of a booster dose of a self-amplifying RNA COVID-19 vaccine (ARCT-154) versus BNT162b2 mRNA COVID-19 vaccine: A double-blind, multicentre, randomised, controlled, phase 3, non-inferiority trial. Lancet Infect Dis. 2024;24(4):351-360. doi: 10.1016/S1473-3099(23)00650-3
- Arevalo CP, Bolton MJ, Le Sage V, et al. A multivalent nucleoside-modified mRNA vaccine against all known influ enza virus subtypes. Science. 2022;378(6622):899-904. doi: 10.1126/science.abm0271
- Alberer M, Gnad-Vogt U, Hong HS, 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):1511-1520. doi: 10.1016/S0140-6736(17)31665-3
- Lutz J, Lazzaro S, Habbeddine M, et al. Unmodified mRNA in LNPs constitutes a competitive technology for prophylactic vaccines. NPJ Vaccines. 2017;2(1):29. doi: 10.1038/s41541-017-0032-6
- Aldrich C, Leroux-Roels I, Huang KB, et al. Proof-of-concept of a low-dose unmodified mRNA-based rabies vaccine formulated with lipid nanoparticles in human volunteers: A phase 1 trial. Vaccine. 2021;39(8):1310-1318. doi: 10.1016/j.vaccine.2020.12.070
- Jackson LA, Anderson EJ, Rouphael NG, et al. An mRNA vaccine against SARS-CoV-2 - preliminary report. N Engl J Med. 2020;383(20):1920-1931. doi: 10.1056/NEJMoa2022483
- Ali K, Berman G, Zhou H, et al. Evaluation of mRNA- 1273 SARS-CoV-2 vaccine in adolescents. N Engl J Med. 2021;385(24):2241-2251. doi: 10.1056/NEJMoa2109522
- Han X, Zhang H, Butowska K, et al. An ionizable lipid toolbox for RNA delivery. Nat Commun. 2021;12(1):7233. doi: 10.1038/s41467-021-27493-0
- Conde E, Bertrand R, Balbino B, et al. Dual vaccination against IL-4 and IL-13 protects against chronic allergic asthma in mice. Nat Commun. 2021;12(1):2574. doi: 10.1038/s41467-021-22834-5
- Lin M, Yin Y, Zhao X, et al. A truncated pre-F protein mRNA vaccine elicits an enhanced immune response and protection against respiratory syncytial virus. Nat Commun. 2025;16(1):1386. doi: 10.1038/s41467-025-56302-1
- Castilow EM, Olson MR, Varga SM. Understanding respiratory syncytial virus (RSV) vaccine-enhanced disease. Immunol Res. 2007;39(1):225-239. doi: 10.1007/s12026-007-0071-6
- Welliver RC, Wong DT, Sun M, Middleton E Jr., Vaughan RS, Ogra PL. The development of respiratory syncytial virus-specific IgE and the release of histamine in nasopharyngeal secretions after infection. N Engl J Med. 1981;305(15):841-846. doi: 10.1056/nejm198110083051501
- Shi L, Yu Y, Liu J, et al. Analysis of full-length gene sequence of a rabies vaccine strain CTN-1 for human use in China. Bing Du Xue Bao. 2010;26(3):195-201.
- Yang R, Deng Y, Huang B, et al. A core-shell structured COVID-19 mRNA vaccine with favorable biodistribution pattern and promising immunity. Signal Transduct Target Ther. 2021;6(1):213. doi: 10.1038/s41392-021-00634-z
- Gui YZ, Li XN, Li JX, et al. Safety and immunogenicity of a modified COVID-19 mRNA vaccine, SW-BIC-213, as a heterologous booster in healthy adults: An open-labeled, two-centered and multi-arm randomised, phase 1 trial. EBioMedicine. 2023;91:104586. doi: 10.1016/j.ebiom.2023.104586
- Persano S, Guevara ML, Li Z, et al. Lipopolyplex potentiates anti-tumor immunity of mRNA-based vaccination. Biomaterials. 2017;125:81-89. doi: 10.1016/j.biomaterials.2017.02.019
- Alameh MG, Tombácz I, Bettini E, et al. Lipid nanoparticles enhance the efficacy of mRNA and protein subunit vaccines by inducing robust T follicular helper cell and humoral responses. Immunity. 2021;54(12):2877-2892.e7. doi: 10.1016/j.immuni.2021.11.001
- Papillion A, Powell MD, Chisolm DA, et al. Inhibition of IL-2 responsiveness by IL-6 is required for the generation of GC-TFH cells. Sci Immunol. 2019;4(39):eaaw7636. doi: 10.1126/sciimmunol.aaw7636
- Ndeupen S, Qin Z, Jacobsen S, Bouteau A, Estanbouli H, Igyártó BZ. The mRNA-LNP platform’s lipid nanoparticle component used in preclinical vaccine studies is highly inflammatory. Iscience. 2021;24(12):103479. doi: 10.1016/j.isci.2021.103479
- Krieg AΜ. Therapeutic potential of toll-like receptor 9 activation. Nat Rev Cancer. 2006;5(6):471-484. doi: 10.1038/nrd2059
- Volpi C, Fallarino F, Pallotta MT, et al. High doses of CpG oligodeoxynucleotides stimulate a tolerogenic TLR9-TRIF pathway. Nat Commun. 2013;4(1):1852. doi: 10.1038/ncomms2874
- Lamb YN. BNT162b2 mRNA COVID-19 vaccine: First approval. Drugs. 2021;81(4):495-501. doi: 10.1007/s40265-021-01480-7
- Goto H, Minamoto N, Ito H, et al. Mapping of epitopes and structural analysis of antigenic sites in the nucleoprotein of rabies virus. J Gen Virol. 2000;81(Pt 1):119-127. doi: 10.1099/0022-1317-81-1-119
