The mRNA Vaccines and Their Application to Combat Infectious Diseases and Cancers: A Review Article

Document Type : Review Article

Authors

1 Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran

2 Professor, Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran

Abstract

Background: In the last several decades, numerous attempts have been made to develop medications based on mRNA. These efforts have been able to take a crude idea and evolve it into a clinical reality, which is a significant accomplishment. After the COVID-19 pandemic, the fastest-ever known development of a vaccine in history was recorded, with mRNA vaccines leading the way.
Methods: By searching the ISI Web of Science, Science Direct, Scopus, PubMed, and Google Scholar databases and using the keywords (mRNA vaccine, Cancer, Infectious disease) as well as their synonyms, appropriate articles were included in the present study.
Findings: This review article describes the technology that is used to develop mRNA vaccines, focusing on lipid nanoparticles and other non-viral delivery carriers. In addition, recent developments in the clinical application of mRNA vaccines for the treatment of infectious diseases and cancers are reviewed, and a future outlook for this revolutionary technology is provided.
Conclusion: Even though it has been shown that mRNA vaccines effectively protect patients from infectious diseases, further study is needed to improve mRNA design, intracellular delivery, and applications other than the prevention of SARS-CoV-2.

Keywords

Main Subjects


  1. Dolgin E. The tangled history of mRNA vaccines. Nature 2021; 597(7876): 318-24.
  2. Beckert B, Masquida B. Synthesis of RNA by in vitro transcription. Methods Mol Biol 2011; 703: 29-41.
  3. Bloom K, van den Berg F, Arbuthnot P. Self-amplifying RNA vaccines for infectious diseases. Gene Ther 2021; 28(3-4): 117-29.
  4. Wadhwa A, Aljabbari A, Lokras A, Foged C, Thakur A. Opportunities and challenges in the delivery of mRNA-based vaccines. Pharmaceutics 2020; 12(2): 102.
  5. Linares-Fernández S, Lacroix C, Exposito JY, Verrier B. Tailoring mRNA vaccine to balance innate/adaptive immune response. Trends Mol Med 2020; 26(3): 311-23.
  6. Mugridge JS, Coller J, Gross JD. Structural and molecular mechanisms for the control of eukaryotic 5′-3′ mRNA decay. Nat Struct Mol Biol 2018; 25(12): 1077-85.
  7. Berkovits BD, Mayr C. Alternative 3′ UTRs act as scaffolds to regulate membrane protein localization. Nature 2015; 522(7556): 363-7.
  8. Weng Y, Li C, Yang T, Hu B, Zhang M, Guo S, et al. The challenge and prospect of mRNA therapeutics landscape. Biotechnol Adv 2020; 40: 107534.
  9. Leppek K, Das R, Barna M. Functional 5′ UTR mRNA structures in eukaryotic translation regulation and how to find them. Nat Rev Mol Cell Biol 2018; 19(3): 158-74.
  10. Chaudhary N, Weissman D, Whitehead KA. mRNA vaccines for infectious diseases: principles, delivery and clinical translation. Nat Rev Drug Discov 2021; 20(11): 817-38.
  11. Spencer PS, Siller E, Anderson JF, Barral JM. Silent substitutions predictably alter translation elongation rates and protein folding efficiencies. J Mol Biol 2012; 422(3): 328-35.
  12. Hajj KA, Whitehead KA. Tools for translation: non-viral materials for therapeutic mRNA delivery. Nat Rev Mater 2017; 2(10): 1-17.
  13. Vaidyanathan S, Azizian KT, Haque AKM,
    Henderson JM, Hendel A, Shore S, et al. Uridine depletion and chemical modification increase Cas9 mRNA activity and reduce immunogenicity without HPLC purification. Mol Ther Nucleic Acids 2018; 12: 530-42.
  14. Buschmann MD, Carrasco MJ, Alishetty S, Paige M, Alameh MG, Weissman D. Nanomaterial delivery systems for mRNA vaccines. Vaccines (Basel) 2021; 9(1): 65.
  15. Thess A, Grund S, Mui BL, Hope MJ, Baumhof P, Fotin-Mleczek M, et al. Sequence-engineered mRNA without chemical nucleoside modifications enables an effective protein therapy in large animals. Mol Ther 2015; 23(9): 1456-64.
  16. Sahin U, Muik A, Vogler I, Derhovanessian E, Kranz LM, Vormehr M, et al. BNT162b2 vaccine induces neutralizing antibodies and poly-specific T cells in humans. Nature 2021; 595(7868): 572-7.
  17. Pardi N, Hogan MJ, Weissman D. Recent advances in mRNA vaccine technology. Curr Opin Immunol 2020; 65: 14-20.
  18. Eberle F, Sahin U, Kuhn A, Vallazza B, Diken M. Stabilization of poly (A) sequence encoding Dna sequences. Google Patents; 2020.
  19. Kim J, Eygeris Y, Gupta M, Sahay G. Self-assembled mRNA vaccines. Adv Drug Deliv Rev 2021; 170:
    83-112.
  20. Kauffman KJ, Webber MJ, Anderson DG. Materials for non-viral intracellular delivery of messenger RNA therapeutics. J Control Release 2016; 240: 227-34.
  21. Cui S, Wang Y, Gong Y, Lin X, Zhao Y, Zhi D, et al. Correlation of the cytotoxic effects of cationic lipids with their headgroups. Toxicol Res (Camb) 2018; 7(3): 473-9.
  22. Cullis PR, Hope MJ. Lipid nanoparticle systems for enabling gene therapies. Mol Ther 2017; 25(7): 1467-75.
  23. Sahay G, Alakhova DY, Kabanov AV. Endocytosis of nanomedicines. J Control Release 2010; 145(3): 182-95.
  24. Jayaraman M, Ansell SM, Mui BL, Tam YK, Chen J,
    Du X, et al. Maximizing the potency of siRNA lipid nanoparticles for hepatic gene silencing in vivo. Angew Chem Int Ed Engl 2012; 51(34): 8529-33.
  25. Hajj KA, Melamed JR, Chaudhary N, Lamson NG, Ball RL, Yerneni SS, et al. A potent branched-tail lipid nanoparticle enables multiplexed mRNA delivery and gene editing in vivo. Nano Lett 2020; 20(7): 5167-75.
  26. Sabnis S, Kumarasinghe ES, Salerno T, Mihai C, Ketova T, Senn JJ, et al. 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): 1509-19.
  27. Yang ST, Kreutzberger AJB, Lee J, Kiessling V, Tamm LK. The role of cholesterol in membrane fusion. Chem Phys Lipids 2016; 199: 136-43.
  28. Cheng X, Lee RJ. The role of helper lipids in lipid nanoparticles (LNPs) designed for oligonucleotide delivery. Adv Drug Deliv Rev 2016; 99(Pt A): 129-37.
  29. Liu S, Cheng Q, Wei T, Yu X, Johnson LT, Farbiak L, et al. Membrane-destabilizing ionizable phospholipids for organ-selective mRNA delivery and CRISPR-Cas gene editing. Nat Mater 2021; 20(5): 701-10.
  30. Cheng Q, Wei T, Farbiak L, Johnson LT, Dilliard SA, Siegwart DJ. Selective organ targeting (SORT) nanoparticles for tissue-specific mRNA delivery and CRISPR-Cas gene editing. Nat Nanotechnol 2020; 15(4): 313-20.
  31. Kulkarni JA, Darjuan MM, Mercer JE, Chen S, Van Der Meel R, Thewalt JL, et al. On the formation and morphology of lipid nanoparticles containing ionizable cationic lipids and siRNA. ACS Nano 2018; 12(5): 4787-95.
  32. Oberli MA, Reichmuth AM, Dorkin JR, Mitchell MJ, Fenton OS, Jaklenec A, et al. Lipid nanoparticle assisted mRNA delivery for potent cancer immunotherapy. Nano Lett 2017; 17(3): 1326-35.
  33. Zhu X, Tao W, Liu D, Wu J, Guo Z, Ji X, et al. Surface De-PEGylation controls nanoparticle-mediated siRNA delivery in vitro and in vivo. Theranostics 2017; 7(7): 1990-2002.
  34. Kowalski PS, Rudra A, Miao L, Anderson DG. Delivering the messenger: advances in technologies for therapeutic mRNA delivery. Mol Ther 2019; 27(4): 710-28.
  35. Bus T, Traeger A, Schubert US. The great escape: how cationic polyplexes overcome the endosomal barrier. J Mater Chem B 2018; 6(43): 6904-18.
  36. Tavazohi N, Mirian M, Varshosaz J, Shirani-Bidabadi S, Mir Mohammad Sadeghi H, Khanahmad H. Fabrication and evaluation of a dual-targeting nanoparticle mediated CRISPR/Cas9 delivery to combat drug resistance in breast cancer cells. J Drug Deliv Sci Technol 2023; 86: 104628.
  37. Ulkoski D, Bak A, Wilson JT, Krishnamurthy VR. Recent advances in polymeric materials for the delivery of RNA therapeutics. Expert Opin Drug Deliv 2019; 16(11): 1149-67.
  38. Kaczmarek JC, Kauffman KJ, Fenton OS, Sadtler K, Patel AK, Heartlein MW, et al. Optimization of a degradable polymer-lipid nanoparticle for potent systemic delivery of mRNA to the lung endothelium
    and immune cells. Nano Lett 2018; 18(10): 6449-54.
  39. Lynn DM, Langer R. Degradable poly (β-amino esters): synthesis, characterization, and self-assembly with plasmid DNA. J Am Chem Soc 2000; 122(44): 10761-8.
  40. Zhou K, Nguyen LH, Miller JB, Yan Y, Kos P, Xiong H, et al. Modular degradable dendrimers enable small RNAs to extend survival in an aggressive liver cancer model. Proc Natl Acad Sci U S A 2016; 113(3): 520-5.
  41. Mintzer MA, Simanek EE. Nonviral vectors for gene delivery. Chem Rev 2009; 109(2): 259-302.
  42. Kim HJ, Ogura S, Otabe T, Kamegawa R, Sato M, Kataoka K, et al. Fine-tuning of hydrophobicity in amphiphilic polyaspartamide derivatives for rapid and transient expression of messenger RNA directed toward genome engineering in brain. ACS Cent Sci 2019; 5(11): 1866-75.
  43. McCarthy HO, McCaffrey J, McCrudden CM, Zholobenko A, Ali AA, McBride JW, et al. Development and characterization of self-assembling nanoparticles using a bio-inspired amphipathic peptide for gene delivery. J Control Release 2014; 189: 141-9.
  44. Udhayakumar VK, De Beuckelaer A, McCaffrey J, McCrudden CM, Kirschman JL, Vanover D, et al. Arginine-rich peptide-based mRNA nanocomplexes efficiently instigate cytotoxic T cell immunity dependent on the amphipathic organization of the peptide. Adv Healthc Mater 2017; 6(13): 1601412.
  45. Gómez-Aguado I, Rodríguez-Castejón J, Vicente-Pascual M, Rodríguez-Gascón A, Solinís MÁ, Del Pozo-Rodríguez A. Nanomedicines to deliver mRNA: state of the art and future perspectives. Nanomaterials (Basel) 2020; 10(2): 364.
  46. Kouhpayeh S, Shariati L, Boshtam M, Rahimmanesh I, Mirian M, Esmaeili Y, et al. The molecular basis of COVID-19 pathogenesis, conventional and nanomedicine therapy. Int J Mol Sci 2021; 22(11): 5438.
  47. Knezevic I, Liu MA, Peden K, Zhou T, Kang HN. Development of mRNA vaccines: scientific and regulatory issues. Vaccines (Basel) 2021; 9(2): 81.
  48. Wrapp D, Wang N, Corbett KS, Goldsmith JA, Hsieh CL, Abiona O, et al. Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation. Science 2020; 367(6483): 1260-3.
  49. Walls AC, Park YJ, Tortorici MA, Wall A, McGuire AT, Veesler D. Structure, function, and antigenicity of the SARS-CoV-2 spike glycoprotein. Cell 2020; 181(2): 281-92. e6.
  50. Vogel AB, Kanevsky I, Che Y, Swanson KA, Muik A, Vormehr M, et al. BNT162b vaccines protect rhesus macaques from SARS-CoV-2. Nature 2021; 592(7853): 283-9.
  51. Walsh EE, Frenck Jr RW, Falsey AR, Kitchin N, Absalon J, Gurtman A, et al. Safety and immunogenicity of two RNA-based Covid-19 vaccine candidates. N Engl J Med 2020; 383(25): 2439-50.
  52. Mulligan MJ, Lyke KE, Kitchin N, Absalon J, Gurtman A, Lockhart S, et al. Phase I/II study of COVID-19 RNA vaccine BNT162b1 in adults. Nature 2020; 586(7830): 589-93.
  53. Polack FP, Thomas SJ, Kitchin N, Absalon J, Gurtman A, Lockhart S, et al. Safety and efficacy of the BNT162b2 mRNA Covid-19 vaccine. N Engl J Med 2020; 383(27): 2603-15.
  54. Dagan N, Barda N, Kepten E, Miron O, Perchik S, Katz MA, et al. BNT162b2 mRNA Covid-19 vaccine in a nationwide mass vaccination setting. N Engl J Med 2021; 384(15): 1412-23.
  55. Corbett KS, Edwards DK, Leist SR, Abiona OM, Boyoglu-Barnum S, Gillespie RA, et al. SARS-CoV-2 mRNA vaccine design enabled by prototype pathogen preparedness. Nature 2020; 586(7830): 567-71.
  56. Corbett KS, Flynn B, Foulds KE, Francica JR, Boyoglu-Barnum S, Werner AP, et al. Evaluation of the mRNA-1273 vaccine against SARS-CoV-2 in nonhuman primates. N Engl J Med 2020; 383(16): 1544-55.
  57. Corbett KS, Nason MC, Flach B, Gagne M, O’Connell S, Johnston TS, et al. Immune correlates of protection by mRNA-1273 vaccine against SARS-CoV-2 in nonhuman primates. Science 2021; 373(6561): eabj0299.
  58. Baden LR, El Sahly HM, Essink B, Kotloff K, Frey S, Novak R, et al. Efficacy and safety of the mRNA-1273 SARS-CoV-2 vaccine. N Engl J Med 2021; 384(5): 403-16.
  59. Moderna announces longer shelf life for its COVID-19 vaccine candidate at refrigerated temperatures. [Online]. [cited 16 Nov 2020]; Available from: URL:

https://investors.modernatx.com/news/news-details/2020/Moderna-Announces-Longer-Shelf-Life-for-its-COVID-19-Vaccine-Candidate-at-Refrigerated-Temperatures/default.aspx

  1. Pfizer and BioNTech submit COVID-19 vaccine stability data at standard freezer temperature to the U.S. FDA. [Online]. [cited 19 Feb 2021]; Available from: URL:

https://www.pfizer.com/news/press-release/press-release-detail/pfizer-and-biontech-submit-covid-19-vaccine-stability-data

  1. Shi T, McAllister DA, O'Brien KL, Simoes EA, Madhi SA, Gessner BD, et al. Global, regional, and national disease burden estimates of acute lower respiratory infections due to respiratory syncytial virus in young children in 2015: a systematic review and modelling study. Lancet 2017; 390(10098): 946-58.
  2. Mazur NI, Higgins D, Nunes MC, Melero JA, Langedijk AC, Horsley N, et al. The respiratory syncytial virus vaccine landscape: lessons from the graveyard and promising candidates. Lancet Infect Dis 2018; 18(10): e295-e311.
  3. Crank MC, Ruckwardt TJ, Chen M, Morabito KM, Phung E, Costner PJ, et al. A proof of concept for structure-based vaccine design targeting RSV in humans. Science 2019; 365(6452): 505-9.
  4. Mortezaee K. Immune escape: A critical hallmark in solid tumors. Life Sci 2020; 258: 118110.
  5. Haibe Y, El Husseini Z, El Sayed R, Shamseddine A. Resisting resistance to immune checkpoint therapy: a systematic review. Int J Mol Sci 2020; 21(17): 6176.
  6. Sarmadi M, Gheibi A, Khanahmad H,
    Khorramizadeh MR, Hejazi SH, Zahedi N, et al. Design and characterization of a recombinant brucella abortus RB51 vaccine that elicits enhanced T cell-mediated immune response. Vaccines (Basel) 2022; 10(3): 388.
  7. Blass E, Ott PA. Advances in the development of personalized neoantigen-based therapeutic cancer vaccines. Nat Rev Clin Oncol 2021; 18(4): 215-29.
  8. Rahimmanesh I, Esmaili Y, Ghafouri E, Hejazi SH, Khanahmad H. Enhanced in vivo anti-tumor efficacy of whole tumor lysate in combination with whole tumor cell-specific polyclonal antibody. Res Pharm Sci 2023; 18(2): 138-48.
  9. Zahm CD, Moseman JE, Delmastro LE, G. Mcneel D. PD-1 and LAG-3 blockade improve anti-tumor vaccine efficacy. Oncoimmunology 2021; 10(1): 1912892.
  10. Mohammadzadeh S, Andalib A, Khanahmad H, Esmaeil N. Human recombinant soluble PD1 can interference in T cells and Treg cells function in response to MDA-MB-231 cancer cell line. Am J Clin Exp Immunol 2023; 12(2): 11-23.
  11. Sahin U, Oehm P, Derhovanessian E, Jabulowsky RA, Vormehr M, Gold M, et al. An RNA vaccine drives immunity in checkpoint-inhibitor-treated melanoma. Nature 2020; 585(7823): 107-12.
  12. CureVac B.V. Securities and exchange commission filing. [Online] [cited 24 July 2020]; Available from: URL:

https://www.sec.gov/Archives/edgar/data/1809122/000110465920086354/tm2016252-11_f1.htm

  1. Gandhi L, Aufiero Ramirez K, Schwarzenberger P, Ricciardi T, Macri MJ, Ryan A, et al. Phase 1/2 study of mRNA vaccine therapy+ durvalumab (durva)±tremelimumab (treme) in patients with metastatic non-small cell lung cancer (NSCLC).
    J Clin Oncol 2018; 36(15): TPS9107.
  2. Esprit A, de Mey W, Bahadur Shahi R, Thielemans K, Franceschini L, Breckpot K. Neo-antigen mRNA vaccines. Vaccines 2020; 8(4): 776.
  3. Yarchoan R, Uldrick TS. HIV-associated cancers and related diseases. N Engl J Med 2018; 378(11): 1029-41.
  4. Diken M, Kranz LM, Kreiter S, Sahin U. mRNA: a versatile molecule for cancer vaccines. Curr Issues Mol Biol 2017; 22(1): 113-28.
  5. Securities and exchange commission filing. [Online]. [cited 03 Feb 2020]; Available from: URL: https://www.sec.gov/Archives/edgar/data/1776985/000119312520022991/d838504df1.htm
  6. Barbier AJ, Jiang AY, Zhang P, Wooster R, Anderson DG. The clinical progress of mRNA vaccines and immunotherapies. Nat Biotechnol 2022; 40(6): 840-54.
  7. Hosseini R, Askari N. A review of neurological side effects of COVID-19 vaccination. Eur J Med Res 2023; 28(1): 1-8.
  8. Yasmin F, Najeeb H, Naeem U, Moeed A, Atif AR, Asghar MS, et al. Adverse events following COVIDÔÇÉ19 mRNA vaccines: A systematic review of cardiovascular complication, thrombosis, and thrombocytopenia. Immun Inflamm Dis 2023; 11(3): e807.
  9. Kremsner PG, Guerrero RAA, Arana-Arri E,
    Martinez GJA, Bonten M, Chandler R, et al. Efficacy and safety of the CVnCoV SARS-CoV-2 mRNA vaccine candidate in ten countries in Europe and Latin America (HERALD): a randomised, observer-blinded, placebo-controlled, phase 2b/3 trial. Lancet
    Infect Dis 2022; 22(3): 329-40.
  10. Wu K, Choi A, Koch M, Ma L, Hill A, Nunna N,
    et al. Preliminary analysis of safety and immunogenicity of a SARS-CoV-2 variant vaccine booster. MedRxiv 2021.