biopreparatБИОпрепараты. Профилактика, диагностика, лечениеBiological Products. Prevention, Diagnosis, Treatment2221-996X2619-1156Scientific Centre for Expert Evaluation of Medicinal Products10.30895/2221-996X-2019-19-2-72-80biopreparat-218Research ArticleОБЗОРЫREVIEWSДНК- и РНК-вакцины: современное состояние, требования к качеству и особенности проведения доклинических исследованийDNA and RNA Vaccines: Current Status, Quality Requirements and Specific Aspects of Preclinical Studieshttps://orcid.org/0000-0003-1620-6233ГоряевА. А.GoryaevA. A.

Горяев Артем Анатольевич, кандидат биолологических наук

SPIN-код: 6401-2199, AuthorID: 604848

Петровский б-р, д. 8, стр. 2, Москва, 127051, Российская Федерация

Artem A. Goryaev, Cand. Sci. (Biol.)

8/2 Petrovsky Blvd, Moscow 127051, Russian Federation

goryaev@expmed.ruhttps://orcid.org/0000-0002-8527-2157СавкинаМ. В.SavkinaM. V.

Савкина Мария Владимировна, кандидат биологических наук

SPIN-код: 2280-2897 AuthorID: 921167

Петровский б-р, д. 8, стр. 2, Москва, 127051, Российская Федерация

Maria V. Savkina, Cand. Sci. (Biol.)

8/2 Petrovsky Blvd, Moscow 127051, Russian Federation

savkina@expmed.ruhttps://orcid.org/0000-0002-7729-9800ОбуховЮ. И.ObukhovYu. I.

Обухов Юрий Иванович

SPIN-код: 6321-7453, AuthorID: 688280

Петровский б-р, д. 8, стр. 2, Москва, 127051, Российская Федерация

Yuri I. Obukhov

8/2 Petrovsky Blvd, Moscow 127051, Russian Federation

Obukhov@expmed.ruhttps://orcid.org/0000-0003-4891-973XМеркуловВ. А.MerkulovV. A.

Меркулов Вадим Анатольевич, доктор медицинских наук, профессор

SPIN-код: 8294-5605, AuthorID: 548698

Петровский б-р, д. 8, стр. 2, Москва, 127051, Российская Федерация

Трубецкая ул., д. 8, стр. 2, Москва, 119991, Российская Федерация

Vadim A. Merkulov, Dr. Sci. (Med.), Professor

8/2 Petrovsky Blvd, Moscow 127051, Russian Federation

8/2 Trubetskaya St, Moscow 119991, Russian Federation

merkulov@expmed.ruhttps://orcid.org/0000-0001-7652-4642ОлефирЮ. В.OlefirYu. V.

Олефир Юрий Витальевич, доктор медицинских наук, старший научный сотрудник

SPIN-код: 2414-4437, AuthorID: 811931

Петровский б-р, д. 8, стр. 2, Москва, 127051, Российская Федерация

Yuri V. Olefir, Dr. Sci. (Med.), Senior Research Associate

8/2 Petrovsky Blvd, Moscow 127051, Russian Federation

 

olefir@expmed.ruФедеральное государственное бюджетное учреждение «Научный центр экспертизы средств медицинского применения» Министерства здравоохранения Российской ФедерацииРоссияScientific Centre for Expert Evaluation of Medicinal ProductsRussian FederationФедеральное государственное бюджетное учреждение «Научный центр экспертизы средств медицинского применения» Министерства здравоохранения; Федеральное государственное автономное образовательное учреждение высшего образования «Первый Московский государственный медицинский университет им. И. М. Сеченова» Министерства здравоохранения Российской ФедерацииРоссияScientific Centre for Expert Evaluation of Medicinal Products I.M.Sechenov First Moscow State Medical UniversityRussian Federation201929052019192БИОпрепараты. Профилактика, диагностика, лечение7280Copyright © Горяев А.А., Савкина М.В., Обухов Ю.И., Меркулов В.А., Олефир Ю.В., 20192019Горяев А.А., Савкина М.В., Обухов Ю.И., Меркулов В.А., Олефир Ю.В.Goryaev A.A., Savkina M.V., Obukhov Y.I., Merkulov V.A., Olefir Y.V.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.biopreparations.ru/jour/article/view/218

Обзор посвящен ДНК- и РНК-вакцинам, возможность использования которых была показана еще в конце XX века. При этом до сих пор ни одна вакцина, основанная на использовании бактериальных плазмид и мРНК, не нашла применения в практике здравоохранения для профилактики инфекционных заболеваний. Но, несмотря на это, интерес к вакцинам, действующим веществом которых являются рекомбинантные нуклеиновые кислоты, сохраняется из-за возможности их быстрой разработки, малозатратного производства, безопасности технологии и возможности активации клеточного и гуморального иммунитета. Последние технологические достижения в значительной степени преодолели проблемы низкой иммуногенности, нестабильности и трудности доставки при применении ДНК- и РНК-вакцин у человека. Цель работы — изложение основных стратегий создания ДНК- и РНК-вакцин, предназначенных для профилактики инфекционных заболеваний, обобщение требований к оценке их качества и проведению доклинических исследований. Представлены общие принципы создания плазмидных векторов, кодирующих протективные антигены. Описаны новые технологии создания ДНК-вакцин, плазмиды которых кодируют геном аттенуированного вируса (iDNA и PPLAV). Приведены стратегии создания РНК-вакцин на основе мРНК и самоамплифицирующихся РНК. Представлены современные регуляторные требования к выбору необходимых показателей качества и общим принципам проведения доклинических исследований ДНК- и РНК-вакцин.

This review focuses on DNA and RNA vaccines whose potential use was first considered at the end of the 20th century. However, not a single bacterial plasmid-based or mRNA vaccine has been used since that time in public healthcare for the prevention of infectious diseases. Nevertheless, vaccines containing recombinant nucleic acids as the active ingredient still attract interest due to the possibility of rapid development, low-cost production, safety of the technology and the potential to activate cellular and humoral immunity. Recent technological advances have largely overcome the problems of low immunogenicity, instability, and difficulties with the delivery of DNA and RNA vaccines in humans. The aim of this review was to present the main strategies of development of DNA and RNA vaccines designed to prevent infectious diseases, and to summarise requirements for the quality control and preclinical studies. The article examines the general principles of creation of plasmid vectors encoding protective antigens. It describes new technologies used in the creation of DNA vaccines with plasmids encoding an attenuated virus genome (iDNA and PPLAV), and RNA vaccines based on mRNA and self-amplifying RNAs. The article presents current regulatory requirements for the choice of quality parameters to be tested and the general principles of preclinical studies of DNA and RNA vaccines.

вакцинаДНК-вакцинаплазмидамини-кольцевые ДНКРНК-вакцинамРНКРНК-репликонсамоамплифицирующиеся РНКиммунизационная ДНКPPLAVvaccineDNA vaccineplasmidmini-circle DNARNA vaccinemRNARNA repliconself-amplifying RNAiDNAPPLAVРабота выполнена в рамках государственного задания ФГБУ «НЦЭСМП» Минздрава России № 056-00154-19-00 на проведение прикладных научных исследований (номер государственного учета НИР AAAA-A18-118021590046-9)The study reported in this publication was carried out as part of a publicly funded research project No. 056-00154-19-00 and was supported by the Scientific Centre for Expert Evaluation of Medicinal Products (R&D public accounting No. AAAA-A18-118021590046-9).ReferencesTang DC, DeVit M, Johnston SA. Genetic immunization is a simple method for eliciting an immune response. Nature. 1992;356(6365):152–4. https://doi.org/10.1038/356152a0Tang DC, DeVit M, Johnston SA. Genetic immunization is a simple method for eliciting an immune response. Nature. 1992;356(6365):152–4. https://doi.org/10.1038/356152a0Ulmer JB, Donnelly JJ, Parker SE, Rhodes GH, Felgner PL, Dwarki VJ, et al. Heterologous protection against influenza by injection of DNA encoding a viral protein. Science. 1993;259(5102):1745–9. https://doi.org/10.1126/science.8456302Ulmer JB, Donnelly JJ, Parker SE, Rhodes GH, Felgner PL, Dwarki VJ, et al. Heterologous protection against influenza by injection of DNA encoding a viral protein. Science. 1993;259(5102):1745–9. https://doi.org/10.1126/science.8456302Donnelly JJ, Ulmer JB, Shiver JW, Liu MA. DNA vaccines. Annu Rev Immunol. 1997;15:617–48. https://doi.org/10.1146/annurev.immunol.15.1.617Donnelly JJ, Ulmer JB, Shiver JW, Liu MA. DNA vaccines. Annu Rev Immunol. 1997;15:617–48. https://doi.org/10.1146/annurev.immunol.15.1.617Gurunathan S, Klinman DM, Seder RA. DNA vaccines: immunology, application, and optimization. Annu Rev Immunol. 2000;18:927–74. https://doi.org/10.1146/annurev.immunol.18.1.927Gurunathan S, Klinman DM, Seder RA. DNA vaccines: immunology, application, and optimization. Annu Rev Immunol. 2000;18:927–74. https://doi.org/10.1146/annurev.immunol.18.1.927Hobernik D, Bros M. DNA vaccines — how far from clinical use? Int J Mol Sci. 2018;19(11):3605. https://doi.org/10.3390/ijms19113605Hobernik D, Bros M. DNA vaccines — how far from clinical use? Int J Mol Sci. 2018;19(11):3605. https://doi.org/10.3390/ijms19113605Liu MA, Ulmer JB. Human clinical trials of plasmid DNA vaccines. Adv Genet. 2005;55:25–40. https://doi.org/10.1016/S0065-2660(05)55002-8Liu MA, Ulmer JB. Human clinical trials of plasmid DNA vaccines. Adv Genet. 2005;55:25–40. https://doi.org/10.1016/S0065-2660(05)55002-8Weniger BG, Anglin IE, Tong T, Pensiero M, Pullen JK, Nucleic Acid Delivery Devices for HIV Vaccines Workshop Group. Workshop report: nucleic acid delivery devices for HIV vaccines: workshop proceedings, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland, USA, May 21, 2015. Vaccine. 2018;36(4):427–37. https://doi.org/10.1016/j.vaccine.2017.10.071Weniger BG, Anglin IE, Tong T, Pensiero M, Pullen JK, Nucleic Acid Delivery Devices for HIV Vaccines Workshop Group. Workshop report: nucleic acid delivery devices for HIV vaccines: workshop proceedings, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland, USA, May 21, 2015. Vaccine. 2018;36(4):427–37. https://doi.org/10.1016/j.vaccine.2017.10.071Pardi N, Hogan MJ, Porter FW, Weissman D. mRNA vaccines — a new era in vaccinology. Nat Rev Drug Discov. 2018;17(4):261–79. https://doi.org/10.1038/nrd.2017.243Pardi N, Hogan MJ, Porter FW, Weissman D. mRNA vaccines — a new era in vaccinology. Nat Rev Drug Discov. 2018;17(4):261–79. https://doi.org/10.1038/nrd.2017.243Kumaragurubaran K, Kaliaperumal K. DNA vaccine: the miniature miracle. Vet. World. 2013;6(4):228–32. https://doi.org/10.5455/vetworld.2013.228-232Kumaragurubaran K, Kaliaperumal K. DNA vaccine: the miniature miracle. Vet. World. 2013;6(4):228–32. https://doi.org/10.5455/vetworld.2013.228-232Cranenburgh R. Development of the ideal DNA vaccine requires the optimization of delivery strategies and plasmid vectors. BioPharm International. 2011;2011 Suppl.(7). http://www.biopharminternational.com/dna-vaccine-deliveryCranenburgh R. Development of the ideal DNA vaccine requires the optimization of delivery strategies and plasmid vectors. BioPharm International. 2011;2011 Suppl.(7). http://www.biopharminternational.com/dna-vaccine-deliveryGarmory HS, Brown KA, Titball RW. DNA vaccines: improving expression of antigens. Genet Vaccines Ther. 2003;1:2. https://doi.org/10.1186/1479-0556-1-2Garmory HS, Brown KA, Titball RW. DNA vaccines: improving expression of antigens. Genet Vaccines Ther. 2003;1:2. https://doi.org/10.1186/1479-0556-1-2Li L, Petrovsky N. Molecular mechanisms for enhanced DNA vaccine immunogenicity. Expert Rev Vaccines. 2016;15(3):313–29. https://doi.org/10.1586/14760584.2016.1124762Li L, Petrovsky N. Molecular mechanisms for enhanced DNA vaccine immunogenicity. Expert Rev Vaccines. 2016;15(3):313–29. https://doi.org/10.1586/14760584.2016.1124762Liu Z, Chen O, Wall JBJ, Zheng M, Zhou Y, Wang L, et al. Systematic comparison of 2A peptides for cloning multigenes in a polycistronic vector. Sci Rep. 2017;7(1):2193. https://doi.org/10.1038/s41598-017-02460-2Liu Z, Chen O, Wall JBJ, Zheng M, Zhou Y, Wang L, et al. Systematic comparison of 2A peptides for cloning multigenes in a polycistronic vector. Sci Rep. 2017;7(1):2193. https://doi.org/10.1038/s41598-017-02460-2Li L, Petrovsky N. Molecular adjuvants for DNA vaccines. Curr Issues Mol Biol. 2017;22:17–40. https://doi.org/10.21775/cimb.022.017Li L, Petrovsky N. Molecular adjuvants for DNA vaccines. Curr Issues Mol Biol. 2017;22:17–40. https://doi.org/10.21775/cimb.022.017Darquet AM, Cameron B, Wils P, Scherman D, Crouzet J. A new DNA vehicle for nonviral gene delivery: supercoiled minicircle. Gene Ther. 1997;4:1341–9. https://doi.org/10.1038/sj.gt.3300540Darquet AM, Cameron B, Wils P, Scherman D, Crouzet J. A new DNA vehicle for nonviral gene delivery: supercoiled minicircle. Gene Ther. 1997;4:1341–9. https://doi.org/10.1038/sj.gt.3300540Hardee CL, Arévalo-Soliz LM, Hornstein BD, Zechiedrich L. Advances in non-viral DNA vectors for gene therapy. Genes (Basel). 2017;8(2):65. https://doi.org/10.3390/genes8020065Hardee CL, Arévalo-Soliz LM, Hornstein BD, Zechiedrich L. Advances in non-viral DNA vectors for gene therapy. Genes (Basel). 2017;8(2):65. https://doi.org/10.3390/genes8020065Stenler S, Blomberg P, Smith CE. Safety and efficacy of DNA vaccines: plasmids vs. minicircles. Hum Vaccin Immunother. 2014;10(5):1306–8. https://doi.org/10.4161/hv.28077Stenler S, Blomberg P, Smith CE. Safety and efficacy of DNA vaccines: plasmids vs. minicircles. Hum Vaccin Immunother. 2014;10(5):1306–8. https://doi.org/10.4161/hv.28077Riede O, Seifert K, Oswald D, Endmann A, Hock C, Winkler A, et al. Preclinical safety and tolerability of a repeatedly administered human leishmaniasis DNA vaccine. Gene Therapy. 2015;22(8):628–35. https://doi.org/10.1038/gt.2015.35Riede O, Seifert K, Oswald D, Endmann A, Hock C, Winkler A, et al. Preclinical safety and tolerability of a repeatedly administered human leishmaniasis DNA vaccine. Gene Therapy. 2015;22(8):628–35.https://doi.org/10.1038/gt.2015.35Pushko P, Ишмухаметов АА, Вredenbeek PP, Lukashevich IS. Экспериментальные живые аттенуированные вакцины против желтой лихорадки на основе инфекционных ДНК. Эпидемиология и вакцинопрофилактика. 2019;18(1):18–25. https://doi.org/10.31631/2073-3046-2019-18-1-18-25Pushko P, Ishmukhametov АА, Bredenbeek PP, Lukashevich IS. Experimental DNAlaunched live-attenuated vaccines against yellow fever. Èpidemiologiâ i vakcinoprofilaktika = Epidemiology and Vaccinal Prevention. 2019;18(1):18–25 (In Russ.) https://doi.org/10.31631/2073-3046-2019-18-1-18-25Pushko P, Lukashevich IS, Weaver SC, Tretyakova I. DNA-launched live-attenuated vaccines for biodefense applications. Expert Rev Vaccines. 2016;15(9):1223–34. https://doi.org/10.1080/14760584.2016.1175943Pushko P, Lukashevich IS, Weaver SC, Tretyakova I. DNA-launched live-attenuated vaccines for biodefense applications. Expert Rev Vaccines. 2016;15(9):1223–34. https://doi.org/10.1080/14760584.2016.1175943Dallmeier K, Neyts J. Bacterial artificial chromosomes. Patent WIPO N WO2014174078; 2014.Dallmeier K, Neyts J. Bacterial artificial chromosomes. Patent WIPO N WO2014174078; 2014.Ulmer JB, Mason PW, Geall A, Mandl CW. RNA-based vaccines. Vaccine. 2012;30(30):4414–8. https://doi.org/10.1016/j.vaccine.2012.04.060Ulmer JB, Mason PW, Geall A, Mandl CW. RNA-based vaccines. Vaccine. 2012;30(30):4414–8. https://doi.org/10.1016/j.vaccine.2012.04.060Lundstrom K. RNA-based drugs and vaccines. Expert Rev Vaccines. 2015;14(2):253–63. https://doi.org/10.1586/14760584.2015.959932Lundstrom K. RNA-based drugs and vaccines. Expert Rev Vaccines. 2015;14(2):253–63. https://doi.org/10.1586/14760584.2015.959932Sahin U, Karikó K, Türeci Ö. mRNA-based therapeutics — developing a new class of drugs. Nat Rev Drug Discov. 2014;13(10):759–80. https://doi.org/10.1038/nrd4278Sahin U, Karikó K, Türeci Ö. mRNA-based therapeutics — developing a new class of drugs. Nat Rev Drug Discov. 2014;13(10):759–80. https://doi.org/10.1038/nrd4278Geall AJ, Mandl CW, Ulmer JB. RNA: the new revolution in nucleic acid vaccines. Semin Immunol. 2013;25(2):152–9. https://doi.org/10.1016/j.smim.2013.05.001Geall AJ, Mandl CW, Ulmer JB. RNA: the new revolution in nucleic acid vaccines. Semin Immunol. 2013;25(2):152–9. https://doi.org/10.1016/j.smim.2013.05.001Weissman D. mRNA transcript therapy. Expert Rev Vaccines. 2015;14(2):265–81. https://doi.org/10.1586/14760584.2015.973859Weissman D. mRNA transcript therapy. Expert Rev Vaccines. 2015;14(2):265–81. https://doi.org/10.1586/14760584.2015.973859Youn H, Chung JK. Modified mRNA as an alternative to plasmid DNA (pDNA) for transcript replacement and vaccination therapy. Expert Opin Biol Ther. 2015;15(9):1337–48. https://doi.org/10.1517/14712598.2015.1057563Youn H, Chung JK. Modified mRNA as an alternative to plasmid DNA (pDNA) for transcript replacement and vaccination therapy. Expert Opin Biol Ther. 2015;15(9):1337–48. https://doi.org/10.1517/14712598.2015.1057563Lundstrom K. Latest development on RNA-based drugs and vaccines. Future Sci OA. 2018;4(5):FSO300. https://doi.org/10.4155/fsoa-2017-0151Lundstrom K. Latest development on RNA-based drugs and vaccines. Future Sci OA. 2018;4(5):FSO300. https://doi.org/10.4155/fsoa-2017-0151Eberhardt W, Doller A, Akool el-S, Pfeilschifter J. Modulation of mRNA stability as a novel therapeutic approach. Pharmacol Ther. 2007;114(1):56–73. https://doi.org/10.1016/j.pharmthera.2007.01.002Eberhardt W, Doller A, Akool el-S, Pfeilschifter J. Modulation of mRNA stability as a novel therapeutic approach. Pharmacol Ther. 2007;114(1):56–73. https://doi.org/10.1016/j.pharmthera.2007.01.002Atkins GJ, Fleeton MN, Sheahan BJ. Therapeutic and prophylactic applications of alphavirus vectors. Expert Rev Mol Med. 2008;10:e33. https://doi.org/10.1017/S1462399408000859Atkins GJ, Fleeton MN, Sheahan BJ. Therapeutic and prophylactic applications of alphavirus vectors. Expert Rev Mol Med. 2008;10:e33. https://doi.org/10.1017/S1462399408000859Brito LA, Kommareddy S, Maione D, Uematsu Y, Giovani C, Berlanda Scorza F, et al. Self-amplifying mRNA vaccines. Adv Genet. 2015;89:179–233. https://doi.org/10.1016/bs.adgen.2014.10.005Brito LA, Kommareddy S, Maione D, Uematsu Y, Giovani C, Berlanda Scorza F, et al. Self-amplifying mRNA vaccines. Adv Genet. 2015;89:179–233. https://doi.org/10.1016/bs.adgen.2014.10.005Klinman DM, Klaschik S, Tross D, Shirota H, Steinhagen F. FDA guidance on prophylactic DNA vaccines: analysis and recommendations. Vaccine. 2010;28(16):2801–5. https://doi.org/10.1016/j.vaccine.2009.11.025Klinman DM, Klaschik S, Tross D, Shirota H, Steinhagen F. FDA guidance on prophylactic DNA vaccines: analysis and recommendations. Vaccine. 2010;28(16):2801–5. https://doi.org/10.1016/j.vaccine.2009.11.025Klug B, Reinhardt J, Robertson J. Current status of regulations for DNA vaccines. In: Thalhamer J, Weiss R, Scheiblhofer S, eds. Gene Vaccines. New York: Springer; 2012. P. 285–95. https://doi.org/10.1007/978-3-7091-0439-2_14Klug B, Reinhardt J, Robertson J. Current status of regulations for DNA vaccines. In: Thalhamer J, Weiss R, Scheiblhofer S, eds. Gene Vaccines. New York: Springer; 2012. P. 285–95. https://doi.org/10.1007/978-3-7091-0439-2_14Bahl K, Senn JJ, Yuzhakov O, Bulychev A, Brito LA, Hassett KJ, et al. Preclinical and clinical demonstration of immunogenicity by mRNA vaccines against H10N8 and H7N9 influenza viruses. Mol Ther. 2017;25(6):1316–27. https://doi.org/10.1016/j.ymthe.2017.03.035Bahl K, Senn JJ, Yuzhakov O, Bulychev A, Brito LA, Hassett KJ, et al. Preclinical and clinical demonstration of immunogenicity by mRNA vaccines against H10N8 and H7N9 influenza viruses. Mol Ther. 2017;25(6):1316–27. https://doi.org/10.1016/j.ymthe.2017.03.035Ledwith BJ, Manam S, Troilo PJ, Barnum AB, Pauley CJ, Griffiths TG 2nd. Plasmid DNA vaccines: assay for integration into host genomic DNA. Dev Biol. 2000;104:33–43.Ledwith BJ, Manam S, Troilo PJ, Barnum AB, Pauley CJ, Griffiths TG 2nd. Plasmid DNA vaccines: assay for integration into host genomic DNA. Dev Biol. 2000;104:33–43.

The authors declare that there are no conflicts of interest present.