In vitro Safety and Immunotoxicity Assessment of a Novel mRNA-LNP Vaccine against Cytomegalovirus: Insights into Safety and Immunomodulatory Profiles
-
Somayeh Mami
,
Sajjad Shekarchian
,
Alireza Naderi Sohi
,
Jafar Kiani
,
Masoud Soleimani
,
Mohammad Hossein Nicknam
Abstract
Predominantly a widespread beta herpesvirus, human cytomegalovirus (HCMV) triggers lifelong latent infection in most of the people, and HCMV vaccine development has been designated a high public health priority.
In the current study, the in vitro safety profile and potential immunotoxic effects of a novel messenger RNA (mRNA)-lipid nanoparticle (LNP) vaccine designed against human cytomegalovirus (HCMV) were assessed. The aim was to measure inflammation, allergic reactions, complement activation, cytotoxicity, and hemolytic effects of the mRNA-LNP vaccine. Proinflammatory cytokine secretion, evident in human peripheral blood mononuclear cells (hPBMCs) treated with unmodified mRNA-LNP, was markedly attenuated by incorporating modified nucleotides.
The vaccine appeared incapable of sparking allergic cytokine production or complement activation. Cell viability assays indicated no pronounced cytotoxicity, and hemolysis assays showed no notable hemolytic activity.
The findings suggest that the modified mRNA-LNP vaccine exhibits a promising in vitro safety profile, supporting further development of this vaccine candidate.
1. Collins-McMillen D, Buehler J, Peppenelli M, Goodrum F. Molecular determinants and the regulation of human cytomegalovirus latency and reactivation. Viruses. 2018;10(8)\:E444.
2. Slobedman B, Cao JZ, Avdic S, Webster B, McAllery S, Cheung AK, et al. Human cytomegalovirus latent infection and associated viral gene expression. Future Microbiol. 2010;5(6):883-900.
3. Gilbert C, Boivin G. Human cytomegalovirus resistance to antiviral drugs. Antimicrob Agents Chemother. 2005;49(3):873-83.
4. Nogalski MT, Collins-McMillen D, Yurochko AD. Overview of human cytomegalovirus pathogenesis. Methods Mol Biol. 2014;1119:15-28.
5. Vancíková Z, Dvořák P. Cytomegalovirus infection in immunocompetent and immunocompromised individuals--a review. Curr Drug Targets Immune Endocr Metabol Disord. 2001;1(2):179-87.
6. Dollard SC, Grosse SD, Ross DS. New estimates of the prevalence of neurological and sensory sequelae and mortality associated with congenital cytomegalovirus infection. Rev Med Virol. 2007;17(5):355-63.
7. Marsico C, Kimberlin DW. Congenital cytomegalovirus infection: advances and challenges in diagnosis, prevention and treatment. Ital J Pediatr. 2017;43(1):38.
8. Ahmed A. Antiviral treatment of cytomegalovirus infection. Infect Disord Drug Targets. 2011;11(5):475-503.
9. Härter G, Michel D. Antiviral treatment of cytomegalovirus infection: an update. Expert Opin Pharmacother. 2012;13(5):623-7.
10. Steininger C. Novel therapies for cytomegalovirus disease. Recent Pat Antiinfect Drug Discov. 2007;2(1):53-72.
11. Byrne C, Coombs D, Gantt S. Modestly protective cytomegalovirus vaccination of young children effectively prevents congenital infection at the population level. Vaccine. 2022;40(35):5179-88.
12. Nelson CS, Herold BC, Permar SR. A new era in cytomegalovirus vaccinology: considerations for rational design of next-generation vaccines to prevent congenital cytomegalovirus infection. NPJ Vaccines. 2018;3:38.
13. Permar SR, Kaur A, Früh K. De-risking human cytomegalovirus vaccine clinical development in relevant preclinical models. J Infect Dis. 2022;225(Suppl\_2)\:S181–S188.
14. John SA, Yuzhakov O, Woods A, Deterling J, Hassett KJ, Shaw CA, et al. Multi-antigenic human cytomegalovirus mRNA vaccines that elicit potent humoral and cell-mediated immunity. Vaccine. 2018;36(12):1689-99.
15. Aldosari BN, Alfagih IM, Almurshedi AS. Lipid nanoparticles as delivery systems for RNA-based vaccines. Pharmaceutics. 2021;13(2):206.
16. Vlatkovic I. Non-immunotherapy application of LNP-mRNA: maximizing efficacy and safety. Biomedicines. 2021;9(5):530.
17. 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.
18. Sharma P, Hoorn D, Aitha A, Breier D, Peer D. The immunostimulatory nature of mRNA lipid nanoparticles. Adv Drug Deliv Rev. 2024;115175.
19. Wang J, Ding Y, Chong K, Cui M, Cao Z, Tang C, et al. Recent advances in lipid nanoparticles and their safety concerns for mRNA delivery. Vaccines (Basel). 2024;12(10):1148.
20. Catenacci L, Rossi R, Sechi F, Buonocore D, Sorrenti M, Perteghella S, et al. Effect of lipid nanoparticle physico-chemical properties and composition on their interaction with the immune system. Pharmaceutics. 2024;16(12):1521.
21. Jo H, Jeoung J, Kim W, Jeoung D. Regulating immune responses induced by PEGylated messenger RNA-lipid nanoparticle vaccine. Vaccines (Basel). 2024;13(1):41.
22. Nguyen H-M, Alexander KE, Collinge M, Hickey JC, Lanz TA, Li J, et al. mRNA-LNPs induce immune activation and cytokine release in human whole blood assays across diverse health conditions. Mol Ther. 2024;32(5):1045-60.
23. Henry SP, Beattie G, Yeh G, Chappel A, Giclas P, Mortari A, et al. Complement activation is responsible for acute toxicities in rhesus monkeys treated with a phosphorothioate oligodeoxynucleotide. Int Immunopharmacol. 2002;2(12):1657-66.
24. Shen L, Engelhardt JA, Hung G, Yee J, Kikkawa R, Matson J, et al. Effects of repeated complement activation associated with chronic treatment of cynomolgus monkeys with 2'-O-methoxyethyl modified antisense oligonucleotide. Nucleic Acid Ther. 2016;26(4):236-49.
25. Shen L, Frazer-Abel A, Reynolds PR, Giclas PC, Chappell A, Pangburn MK, et al. Mechanistic understanding for the greater sensitivity of monkeys to antisense oligonucleotide–mediated complement activation compared with humans. J Pharmacol Exp Ther. 2014;351(3):709-17.
26. Rampton D, Folkersen J, Fishbane S, Hedenus M, Howaldt S, Locatelli F, et al. Hypersensitivity reactions to intravenous iron: guidance for risk minimization and management. Haematologica. 2014;99(11):1671-6.
27. Chanan-Khan A, Szebeni J, Savay S, Liebes L, Rafique NM, Alving CR, et al. Complement activation following first exposure to pegylated liposomal doxorubicin (Doxil®): possible role in hypersensitivity reactions. Ann Oncol. 2003;14(9):1430-7.
28. Szebeni J. Complement activation-related pseudoallergy: a stress reaction in blood triggered by nanomedicines and biologicals. Mol Immunol. 2014;61(2):163-73.
29. Reddy ST, van der Vlies AJ, Simeoni E, Angeli V, Randolph GJ, O'Neil CP, et al. Exploiting lymphatic transport and complement activation in nanoparticle vaccines. Nat Biotechnol. 2007;25(10):1159-64.
30. Barbey C, Wolf HN, Wagner R, Pauly D, Breunig M. A shift of paradigm: from avoiding nanoparticular complement activation in the field of nanomedicines to its exploitation in the context of vaccine development. Eur J Pharm Biopharm. 2023;189:1-10.
31. Moghimi SM, Simberg D. Complement activation turnover on surfaces of nanoparticles. Nano Today. 2017;15:8-10.
32. Moghimi SM, Simberg D. The importance of having a reliable and reproducible complement assay for understanding complement activation-related pseudoallergy. J Control Release. 2018;286:46-9.
33. Moghimi SM, Andersen AJ, Ahmadvand D, Wibroe PP, Andresen TL, Hunter AC. Material properties in complement activation. Adv Drug Deliv Rev. 2011;63(12):1000-7.
34. Lee SE, Park SH, Lee IH, Lee YS, Lee HY, Cho YJ, et al. Systemic inflammatory responses to SARS-CoV-2 mRNA vaccination in a cohort of immunocompromised patients. Front Immunol. 2022;13:907230.
35. Liang F, Lindgren G, Lin A, Thompson EA, Ols S, Röhss J, et al. Efficient targeting and activation of antigen-presenting cells in vivo after modified mRNA vaccine administration in rhesus macaques. Mol Ther. 2017;25(12):2635-47.
36. Pardi N, Hogan MJ, Porter FW, Weissman D. mRNA vaccines—a new era in vaccinology. Nat Rev Drug Discov. 2018;17(4):261-79.
37. Pardi N, Secreto AJ, Shan X, Debonera F, Glover J, Yi Y, et al. Administration of nucleoside-modified mRNA encoding broadly neutralizing antibody protects humanized mice from HIV-1 challenge. Nat Commun. 2017;8(1):14630.
38. Pardi N, Tuyishime S, Muramatsu H, Karikó K, Mui BL, Tam YK, et al. Expression kinetics of nucleoside-modified mRNA delivered in lipid nanoparticles to mice by various routes. J Control Release. 2015;217:345-51.
39. Richner JM, Himansu S, Dowd KA, Butler SL, Salazar V, Fox JM, et al. Modified mRNA vaccines protect against Zika virus infection. Cell. 2017;168(6):1114-25.e10.
40. Moderna. mRNA-1647 vaccine for cytomegalovirus (CMV). ClinicalTrials.gov Identifier: NCT04232280.
41. Moderna. A Study to Evaluate the Safety and Immunogenicity of CMVictory™, a Cytomegalovirus (CMV) Vaccine, in Adults. ClinicalTrials.gov Identifier: NCT05477186.
42. Moderna. A Study to Evaluate mRNA-1647 Vaccine in Healthy Adolescents. ClinicalTrials.gov Identifier: NCT05884167.
43. 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.
44. Schlake T, Thess A, Fotin-Mleczek M, Kallen KJ. Developing mRNA-vaccine technologies. RNA Biol. 2012;9(11):1319-30.
45. Zhang C, Maruggi G, Shan H, Li J. Advances in mRNA vaccines for infectious diseases. Front Immunol. 2019;10:594.
46. 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.
47. Zhang C, Wang W, Zhang Y, Yang Z, Liu Y, Wang J, et al. Tailoring mRNA structure to improve protein expression. Nat Commun. 2021;12(1):5460.
48. Moyo N, Vogel AB, Buus S, Ermler ME, Munks MW, Lee SH, et al. Mechanism of action of mRNA vaccines: an innate immune sensing perspective. Front Immunol. 2021;12:695703.
49. Karikó K, Muramatsu H, Welsh FA, Ludwig J, Kato H, Akira S, et al. Incorporation of pseudouridine into mRNA yields superior nonimmunogenic vector with increased translational capacity and biological stability. Mol Ther. 2008;16(11):1833-40.
50. Krienke C, Kolb L, Diken E, Streuber M, Kirchhoff S, Bukur T, et al. A noninflammatory mRNA vaccine for treatment of experimental autoimmune encephalomyelitis. Science. 2021;371(6525):145-53.
51. Nance KD, Meier JL. Modifications in an emergency: the role of N1-methylpseudouridine in COVID-19 vaccines. ACS Cent Sci. 2021;7(5):748-56.
52. Zangi L, Lui KO, von Gise A, Ma Q, Ebina W, Ptaszek LM, et al. Modified mRNA directs the fate of heart progenitor cells and induces vascular regeneration after myocardial infarction. Nat Biotechnol. 2013;31(10):898-907.
53. Rauch S, Jasny E, Schmidt KE, Petsch B. New vaccine technologies to combat outbreak situations. Front Immunol. 2018;9:1963.
54. Kormann MS, Hasenpusch G, Aneja MK, Nica G, Flemmer AW, Herber-Jonat S, et al. Expression of therapeutic proteins after delivery of chemically modified mRNA in mice. Nat Biotechnol. 2011;29(2):154-7.
55. 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.
56. Holtkamp S, Kreiter S, Selmi A, Simon P, Koslowski M, Huber C, et al. Modification of antigen-encoding RNA increases stability, translational efficacy, and T-cell stimulatory capacity of dendritic cells. Blood. 2006;108(13):4009-17.
57. Geall AJ, Mandl CW, Ulmer JB. RNA: the new revolution in nucleic acid vaccines. Semin Immunol. 2013;25(2):152-9.
58. Sahin U, Karikó K, Türeci Ö. mRNA-based therapeutics—developing a new class of drugs. Nat Rev Drug Discov. 2014;13(10):759-80.
59. Pardi N, Hogan MJ, Naradikian MS, Parkhouse K, Cain DW, Jones L, et al. Nucleoside-modified mRNA vaccines induce potent T follicular helper and germinal center B cell responses. J Exp Med. 2018;215(6):1571-88.
60. Pardi N, Hogan MJ, Pelc RS, Muramatsu H, Andersen H, DeMaso CR, et al. Zika virus protection by a single low-dose nucleoside-modified mRNA vaccination. Nature. 2017;543(7644):248-51.
61. Freyn AW, da Silva JR, Rosado VC, Bliss CM, Pine M, Mui BL, et al. A multi-targeting, nucleoside-modified mRNA influenza virus vaccine provides broad protection in mice. Mol Ther. 2021;29(4):1492-504.
62. 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.
63. Zhang Y, Jiang T, Zhang M, Yin J, Liu J, Li S, et al. Engineering advanced liposome delivery systems for nucleic acid therapy. Pharmaceutics. 2023;15(3):936.
64. Hajj KA, Whitehead KA. Tools for translation: non-viral materials for therapeutic mRNA delivery.
2. Slobedman B, Cao JZ, Avdic S, Webster B, McAllery S, Cheung AK, et al. Human cytomegalovirus latent infection and associated viral gene expression. Future Microbiol. 2010;5(6):883-900.
3. Gilbert C, Boivin G. Human cytomegalovirus resistance to antiviral drugs. Antimicrob Agents Chemother. 2005;49(3):873-83.
4. Nogalski MT, Collins-McMillen D, Yurochko AD. Overview of human cytomegalovirus pathogenesis. Methods Mol Biol. 2014;1119:15-28.
5. Vancíková Z, Dvořák P. Cytomegalovirus infection in immunocompetent and immunocompromised individuals--a review. Curr Drug Targets Immune Endocr Metabol Disord. 2001;1(2):179-87.
6. Dollard SC, Grosse SD, Ross DS. New estimates of the prevalence of neurological and sensory sequelae and mortality associated with congenital cytomegalovirus infection. Rev Med Virol. 2007;17(5):355-63.
7. Marsico C, Kimberlin DW. Congenital cytomegalovirus infection: advances and challenges in diagnosis, prevention and treatment. Ital J Pediatr. 2017;43(1):38.
8. Ahmed A. Antiviral treatment of cytomegalovirus infection. Infect Disord Drug Targets. 2011;11(5):475-503.
9. Härter G, Michel D. Antiviral treatment of cytomegalovirus infection: an update. Expert Opin Pharmacother. 2012;13(5):623-7.
10. Steininger C. Novel therapies for cytomegalovirus disease. Recent Pat Antiinfect Drug Discov. 2007;2(1):53-72.
11. Byrne C, Coombs D, Gantt S. Modestly protective cytomegalovirus vaccination of young children effectively prevents congenital infection at the population level. Vaccine. 2022;40(35):5179-88.
12. Nelson CS, Herold BC, Permar SR. A new era in cytomegalovirus vaccinology: considerations for rational design of next-generation vaccines to prevent congenital cytomegalovirus infection. NPJ Vaccines. 2018;3:38.
13. Permar SR, Kaur A, Früh K. De-risking human cytomegalovirus vaccine clinical development in relevant preclinical models. J Infect Dis. 2022;225(Suppl\_2)\:S181–S188.
14. John SA, Yuzhakov O, Woods A, Deterling J, Hassett KJ, Shaw CA, et al. Multi-antigenic human cytomegalovirus mRNA vaccines that elicit potent humoral and cell-mediated immunity. Vaccine. 2018;36(12):1689-99.
15. Aldosari BN, Alfagih IM, Almurshedi AS. Lipid nanoparticles as delivery systems for RNA-based vaccines. Pharmaceutics. 2021;13(2):206.
16. Vlatkovic I. Non-immunotherapy application of LNP-mRNA: maximizing efficacy and safety. Biomedicines. 2021;9(5):530.
17. 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.
18. Sharma P, Hoorn D, Aitha A, Breier D, Peer D. The immunostimulatory nature of mRNA lipid nanoparticles. Adv Drug Deliv Rev. 2024;115175.
19. Wang J, Ding Y, Chong K, Cui M, Cao Z, Tang C, et al. Recent advances in lipid nanoparticles and their safety concerns for mRNA delivery. Vaccines (Basel). 2024;12(10):1148.
20. Catenacci L, Rossi R, Sechi F, Buonocore D, Sorrenti M, Perteghella S, et al. Effect of lipid nanoparticle physico-chemical properties and composition on their interaction with the immune system. Pharmaceutics. 2024;16(12):1521.
21. Jo H, Jeoung J, Kim W, Jeoung D. Regulating immune responses induced by PEGylated messenger RNA-lipid nanoparticle vaccine. Vaccines (Basel). 2024;13(1):41.
22. Nguyen H-M, Alexander KE, Collinge M, Hickey JC, Lanz TA, Li J, et al. mRNA-LNPs induce immune activation and cytokine release in human whole blood assays across diverse health conditions. Mol Ther. 2024;32(5):1045-60.
23. Henry SP, Beattie G, Yeh G, Chappel A, Giclas P, Mortari A, et al. Complement activation is responsible for acute toxicities in rhesus monkeys treated with a phosphorothioate oligodeoxynucleotide. Int Immunopharmacol. 2002;2(12):1657-66.
24. Shen L, Engelhardt JA, Hung G, Yee J, Kikkawa R, Matson J, et al. Effects of repeated complement activation associated with chronic treatment of cynomolgus monkeys with 2'-O-methoxyethyl modified antisense oligonucleotide. Nucleic Acid Ther. 2016;26(4):236-49.
25. Shen L, Frazer-Abel A, Reynolds PR, Giclas PC, Chappell A, Pangburn MK, et al. Mechanistic understanding for the greater sensitivity of monkeys to antisense oligonucleotide–mediated complement activation compared with humans. J Pharmacol Exp Ther. 2014;351(3):709-17.
26. Rampton D, Folkersen J, Fishbane S, Hedenus M, Howaldt S, Locatelli F, et al. Hypersensitivity reactions to intravenous iron: guidance for risk minimization and management. Haematologica. 2014;99(11):1671-6.
27. Chanan-Khan A, Szebeni J, Savay S, Liebes L, Rafique NM, Alving CR, et al. Complement activation following first exposure to pegylated liposomal doxorubicin (Doxil®): possible role in hypersensitivity reactions. Ann Oncol. 2003;14(9):1430-7.
28. Szebeni J. Complement activation-related pseudoallergy: a stress reaction in blood triggered by nanomedicines and biologicals. Mol Immunol. 2014;61(2):163-73.
29. Reddy ST, van der Vlies AJ, Simeoni E, Angeli V, Randolph GJ, O'Neil CP, et al. Exploiting lymphatic transport and complement activation in nanoparticle vaccines. Nat Biotechnol. 2007;25(10):1159-64.
30. Barbey C, Wolf HN, Wagner R, Pauly D, Breunig M. A shift of paradigm: from avoiding nanoparticular complement activation in the field of nanomedicines to its exploitation in the context of vaccine development. Eur J Pharm Biopharm. 2023;189:1-10.
31. Moghimi SM, Simberg D. Complement activation turnover on surfaces of nanoparticles. Nano Today. 2017;15:8-10.
32. Moghimi SM, Simberg D. The importance of having a reliable and reproducible complement assay for understanding complement activation-related pseudoallergy. J Control Release. 2018;286:46-9.
33. Moghimi SM, Andersen AJ, Ahmadvand D, Wibroe PP, Andresen TL, Hunter AC. Material properties in complement activation. Adv Drug Deliv Rev. 2011;63(12):1000-7.
34. Lee SE, Park SH, Lee IH, Lee YS, Lee HY, Cho YJ, et al. Systemic inflammatory responses to SARS-CoV-2 mRNA vaccination in a cohort of immunocompromised patients. Front Immunol. 2022;13:907230.
35. Liang F, Lindgren G, Lin A, Thompson EA, Ols S, Röhss J, et al. Efficient targeting and activation of antigen-presenting cells in vivo after modified mRNA vaccine administration in rhesus macaques. Mol Ther. 2017;25(12):2635-47.
36. Pardi N, Hogan MJ, Porter FW, Weissman D. mRNA vaccines—a new era in vaccinology. Nat Rev Drug Discov. 2018;17(4):261-79.
37. Pardi N, Secreto AJ, Shan X, Debonera F, Glover J, Yi Y, et al. Administration of nucleoside-modified mRNA encoding broadly neutralizing antibody protects humanized mice from HIV-1 challenge. Nat Commun. 2017;8(1):14630.
38. Pardi N, Tuyishime S, Muramatsu H, Karikó K, Mui BL, Tam YK, et al. Expression kinetics of nucleoside-modified mRNA delivered in lipid nanoparticles to mice by various routes. J Control Release. 2015;217:345-51.
39. Richner JM, Himansu S, Dowd KA, Butler SL, Salazar V, Fox JM, et al. Modified mRNA vaccines protect against Zika virus infection. Cell. 2017;168(6):1114-25.e10.
40. Moderna. mRNA-1647 vaccine for cytomegalovirus (CMV). ClinicalTrials.gov Identifier: NCT04232280.
41. Moderna. A Study to Evaluate the Safety and Immunogenicity of CMVictory™, a Cytomegalovirus (CMV) Vaccine, in Adults. ClinicalTrials.gov Identifier: NCT05477186.
42. Moderna. A Study to Evaluate mRNA-1647 Vaccine in Healthy Adolescents. ClinicalTrials.gov Identifier: NCT05884167.
43. 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.
44. Schlake T, Thess A, Fotin-Mleczek M, Kallen KJ. Developing mRNA-vaccine technologies. RNA Biol. 2012;9(11):1319-30.
45. Zhang C, Maruggi G, Shan H, Li J. Advances in mRNA vaccines for infectious diseases. Front Immunol. 2019;10:594.
46. 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.
47. Zhang C, Wang W, Zhang Y, Yang Z, Liu Y, Wang J, et al. Tailoring mRNA structure to improve protein expression. Nat Commun. 2021;12(1):5460.
48. Moyo N, Vogel AB, Buus S, Ermler ME, Munks MW, Lee SH, et al. Mechanism of action of mRNA vaccines: an innate immune sensing perspective. Front Immunol. 2021;12:695703.
49. Karikó K, Muramatsu H, Welsh FA, Ludwig J, Kato H, Akira S, et al. Incorporation of pseudouridine into mRNA yields superior nonimmunogenic vector with increased translational capacity and biological stability. Mol Ther. 2008;16(11):1833-40.
50. Krienke C, Kolb L, Diken E, Streuber M, Kirchhoff S, Bukur T, et al. A noninflammatory mRNA vaccine for treatment of experimental autoimmune encephalomyelitis. Science. 2021;371(6525):145-53.
51. Nance KD, Meier JL. Modifications in an emergency: the role of N1-methylpseudouridine in COVID-19 vaccines. ACS Cent Sci. 2021;7(5):748-56.
52. Zangi L, Lui KO, von Gise A, Ma Q, Ebina W, Ptaszek LM, et al. Modified mRNA directs the fate of heart progenitor cells and induces vascular regeneration after myocardial infarction. Nat Biotechnol. 2013;31(10):898-907.
53. Rauch S, Jasny E, Schmidt KE, Petsch B. New vaccine technologies to combat outbreak situations. Front Immunol. 2018;9:1963.
54. Kormann MS, Hasenpusch G, Aneja MK, Nica G, Flemmer AW, Herber-Jonat S, et al. Expression of therapeutic proteins after delivery of chemically modified mRNA in mice. Nat Biotechnol. 2011;29(2):154-7.
55. 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.
56. Holtkamp S, Kreiter S, Selmi A, Simon P, Koslowski M, Huber C, et al. Modification of antigen-encoding RNA increases stability, translational efficacy, and T-cell stimulatory capacity of dendritic cells. Blood. 2006;108(13):4009-17.
57. Geall AJ, Mandl CW, Ulmer JB. RNA: the new revolution in nucleic acid vaccines. Semin Immunol. 2013;25(2):152-9.
58. Sahin U, Karikó K, Türeci Ö. mRNA-based therapeutics—developing a new class of drugs. Nat Rev Drug Discov. 2014;13(10):759-80.
59. Pardi N, Hogan MJ, Naradikian MS, Parkhouse K, Cain DW, Jones L, et al. Nucleoside-modified mRNA vaccines induce potent T follicular helper and germinal center B cell responses. J Exp Med. 2018;215(6):1571-88.
60. Pardi N, Hogan MJ, Pelc RS, Muramatsu H, Andersen H, DeMaso CR, et al. Zika virus protection by a single low-dose nucleoside-modified mRNA vaccination. Nature. 2017;543(7644):248-51.
61. Freyn AW, da Silva JR, Rosado VC, Bliss CM, Pine M, Mui BL, et al. A multi-targeting, nucleoside-modified mRNA influenza virus vaccine provides broad protection in mice. Mol Ther. 2021;29(4):1492-504.
62. 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.
63. Zhang Y, Jiang T, Zhang M, Yin J, Liu J, Li S, et al. Engineering advanced liposome delivery systems for nucleic acid therapy. Pharmaceutics. 2023;15(3):936.
64. Hajj KA, Whitehead KA. Tools for translation: non-viral materials for therapeutic mRNA delivery.
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| Issue | Articles in Press | |
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| Keywords | ||
| Cytomegalovirus CMV Immunotoxicity Lipid Nanoparticles mRNA-LNP Safety Vaccine | ||
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How to Cite
1.
Mami S, Shekarchian S, Naderi Sohi A, Kiani J, Soleimani M, Nicknam MH. In vitro Safety and Immunotoxicity Assessment of a Novel mRNA-LNP Vaccine against Cytomegalovirus: Insights into Safety and Immunomodulatory Profiles. Iran J Allergy Asthma Immunol. 2025;:1-13.
