Russian Journal of Infection and ImmunityRussian Journal of Infection and ImmunityИнфекция и иммунитет2220-76192313-7398SPb RAACI39710.15789/2220-7619-2016-2-117-132REVIEWSОБЗОРЫCURRENT APPROACHES TO UNIVERSAL VACCINE AGAINST INFLUENZA VIRUSСОВРЕМЕННЫЕ ПОДХОДЫ К СОЗДАНИЮ УНИВЕРСАЛЬНОЙ ВАКЦИНЫ ПРОТИВ ВИРУСА ГРИППАEsmagambetovI. B.ЕсмагамбетовИ. Б.
Russian Federation

PhD, MD (Biology), Researcher, Laboratory of Molecular Biotechnology,

123098, Moscow, Gamaleya str., 18

к.б.н., научный сотрудник лаборатории молекулярной биотехнологии,

123098, Москва, ул. Гамалеи, 18

dmitrovboy@mail.ruAlekseevaS. V.АлексееваС. В.
Russian Federation

PhD, MD (Biology), Researcher, Laboratory of Molecular Biotechnology,

123098, Moscow, Gamaleya str., 18

к.б.н., научный сотрудник лаборатории молекулярной биотехнологии,

123098, Москва, ул. Гамалеи, 18

SayadyanK. S.СаядянХ. С.
Russian Federation

PhD, MD (Medicine), Professor, Professor of the Department of Pharmaceutical Technology and Pharmacology,

Moscow

д.м.н., профессор, профессор кафедры фармацевтической технологии и фармакологии

ShmarovM. M.ШмаровМ. М.
Russian Federation

PhD, MD (Biology), Head of the Laboratory of Molecular Biotechnology,

123098, Moscow, Gamaleya str., 18

д.б.н., зав. лабораторией молекулярной биотехнологии,

123098, Москва, ул. Гамалеи, 18

Gamaleya Research Center of Microbiology and EpidemiologyФГБУ ФНИЦ эпидемиологии и микробиологии им. Н.Ф. Гамалеи Минздрава России, МоскваI.M. Sechenov First Moscow State Medical UniversityПервый Московский Государственный Медицинский Университет им. Сеченова, Москва25062016621171322306201623062016Copyright ©; 2016, Esmagambetov I.B., Alekseeva S.V., Sayadyan K.S., Shmarov M.M.Copyright ©; 2016, Есмагамбетов И.Б., Алексеева С.В., Саядян Х.С., Шмаров М.М.2016Esmagambetov I.B., Alekseeva S.V., Sayadyan K.S., Shmarov M.M.Есмагамбетов И.Б., Алексеева С.В., Саядян Х.С., Шмаров М.М.https://creativecommons.org/licenses/by/4.0https://iimmun.ru/iimm/article/view/397

Influenza is a seasonal infectious disease widespread across the globe. In Russia the share of influenza and other acute respiratory viral infections account for up to 90% of all infectious diseases. Scientific and reasonable method of influenza prevention is vaccination. However, traditional current influenza vaccines can’t induce protection against various virus strains that differ substantially in terms of their antigenic structure, and thus require periodic updates to its immunogenic components. In addition, there is the risk of a pandemic caused by an entirely new antigen in relation to variants of influenza virus A. Attempts to improve on traditional approaches to vaccination have focused primarily on improving production technologies and to increase immunogenicity of vaccines. Therefore, the urgent task is the creation of vaccines able to induce immune response a broad spectrum against different influenza virus strains and human strains of avian influenza, also can cause disease in humans. Protective effect of universal vaccine should be the induction of integrated immune response, based on the formulation of cross-reactive antibodies and T cells. The development of such universal vaccine could remove the need for periodical strain composition update of existing vaccines and, accor dingly, will be able to give the vaccine manufacturer itself, production planning regardless of epidemic seasons. Currently, the most widely studied antigens as key components of flu vaccines are proteins M2 and NP as well as the hemagglutinin of influenza virus. This review summarizes and lists some data of domestic and foreign research on a universal influenza virus vaccine.

Грипп является сезонным инфекционным заболеванием, широко распространенным по всему земному шару. В России на долю гриппа и других ОРВИ приходится до 90% всей инфекционной патологии. Научно обоснованным методом профилактики гриппа является вакцинация. Однако современные классические вакцины против гриппа не способны индуцировать защиту от всего многообразия штаммов вируса, существенно различающихся по своей антигенной структуре, и таким образом требуют периодического обновления своих ключевых компонентов. Кроме того, существует угроза возникновения пандемии, связанной с появле- нием совершенно нового в антигеном отношении варианта вируса гриппа А. Попытки улучшить традиционные подходы к вакцинации были сосредоточены в основном на совершенствовании технологий производства вакцин и повышении их иммуногенности. Следовательно, актуальной задачей является создание вакцин, способных индуцировать иммунный ответ широкого спектра против различных штаммов вируса гриппа человека и штаммов вируса гриппа птиц, также способных вызывать заболевания у людей. Протективный эффект универсальных вакцин должен обеспечиваться индукцией комплексного иммунного ответа, базирующегося на выработке кросс-реактивных антител и Т-клеток. Разработка такой универсальной вакцины сможет снять необходимость в периодическом обновлении штаммового состава существующих вакцин и, соответственно, сможет дать возможность производителю вакцин самому вести производственное планирование вне зависимости от эпидемических сезонов. В настоящее время наиболее широко исследуемыми антигенами в качестве ключевых компонентов противогриппозных вакцин являются белки М2, NP а также гемагглютинин вируса гриппа. В данном обзоре суммированы и приведены некоторые данные отечественных и зарубежных исследований по созданию универсальных противогриппозных вакцин.

influenza virusuniversal vaccinehaemagglutininM2 (ion channel)nucleoproteinwide range immune responseвирус гриппауниверсальная вакцинагемагглютининМ2 (ионный канал)нуклеопротеиниммунный ответ широкого спектра1. Есмагамбетов И.Б., Седова Е.С., Щербинин Д.Н., Лысенко А.А., Гарас М.Н., Шмаров М.М, Логунов Д.Ю. Конструирование рекомбинантного аденовируса человека, экспрессирующего гены консервативных антигенов вируса гриппа А ионного канала М2 и нуклеопротеина // Молекулярная генетика, микробиология и вирусология. 2014. № 2. С. 22–28. [Esmagambetov I.B., Sedova E.S., Shcherbinin D.N., Lysenko A.A., Garas M.N., Shmarov M.M., Logunov D.Yu. Construction of recombinant adenoviral vector expressing genes of the conservative influenza proteins M2 and nucleoprotein. Molekulyarnaya genetika, mikrobiologiya i virusologiya = Molecular Genetics, Microbiology and Virology, 2014, no. 2, pp. 22–28. doi: 10.3103/S0891416814020050 (In Russ.)]2. Патент 2358981 Российская Федерация, МПК8 C07K14/00, C12N7/01, A61K39/145, C12N15/70. Универсальная вакцина против вируса гриппа птиц / Равин Н.В., Киселев О.И., Скрябин К.Г.; заявитель и патентообладатель Центр «Биоинженерия» РАН (RU), ГУ НИИ гриппа РАМН (RU). № 2358981 С 2; заявл. 07.08.2007; опубл. 20.06.2009, Бюл. № 17 [Patent 2358981 Russian Federation, IPC 8 C07K14/00, C12N7/01, A61K39/145, C12N15/70. Universal’naya vaktsina protiv virusa grippa ptits [A universal vaccine against avian influenza] / Ravin N.V., Kiselev O.I., Skryabin K.G.; appl. and patent holder Center «Bioengineering» RAS (RU), State Research Institute of Influenza RAMS (RU). № 2358981 С 2; stat. 07.08.2007; publ. 20.06.2009, Bul. No. 17]3. Седова Е.С., Шмаров М.М., Тутыхина И.Л., Барыков Ю.А., Верховская Л.В., Логунов Д.Ю., Народицкий Б.С., Гинцбург А.Л. Протективные свойства кандидатных генно-инженерных вакцин против вируса гриппа птиц, созданных на основе рекомбинантных аденовирусных векторов // Журнал микробиологии, эпидемиологии и иммунобиологии. 2010. № 3. C. 44–48. [Sedova E.S., Shmarov M.M., Tutykhina I.L., Barykov Yu.A., Verkhovskaia L.V., Logunov D.Yu., Naroditskiy B.S., Ginzburg A.L. Protective properties of candidate genetically engineered vaccines against avian influenza viruses constructed on the basis of recombinant adenoviral vectors. Zhurnal mikrobiologii, epidemiologii i immunobiologii = Journal of Microbiology, Epidemiology and Immunobiology, 2010, vol. 3, pp. 44–48. (In Russ.)]4. Шмаров М.М., Седова Е.С., Верховская Л.В., Руднева И.А., Богачева Е.А., Барыкова Ю.А., Щербинин Д.Н., Лысенко А.А., Тутыхина И.Л., Логунов Д.Ю., Смирнов Ю.А., Народицкий Б.С., Гинцбург А.Л. Индукция протективного гетеросубтипического иммунного ответа против вируса гриппа при иммунизации рекомбинантными адено-вирусными векторами, экспрессирующими гемагглютинин вируса гриппа H5 // Acta Naturae. 2010. Т. 2, № 1. С. 119–126. [Shmarov M.M., Sedova E.S., Verkhovskaya L.V., Rudneva I.A., Bogacheva E.A., Barykova Y.A., Shcherbinin D.N., Lysenko A.A., Tutykhina I.L., Logunov D.Y., Smirnov Y.A., Naroditsky B.S., Gintsburg A.L. Induction of a protective heterosubtypic immune response against the influenza virus by using recombinant adenoviral vectors expressing hemagglutinin of the influenza H5 virus. Acta Naturae, 2010, vol. 2, no. 1, pp. 119–126. (In Russ.)]5. Altstein A.D., Gitelman A.K., Smirnov Y.A., Piskareva L.M., Zakharova L.G., Pashvykina G.V., Shmarov M.M., Zhirnov O.P., Varich N.P., Ilyinskii P.O., Shneider A.M. Immunization with influenza A NP-expressing vaccinia virus recombinant protects mice against experimental infection with human and avian influenza viruses. Arch. Virol., 2006, vol. 151, no. 5, pp. 921–931.6. Acosta-Rodriguez E.V., Napolitani G., Lanzavecchia A., Sallusto F. Interleukins 1beta and 6 but not transforming growth factorbeta are essential for the differentiation of interleukin 17-producing human T helper cells. Nat. Immunol., 2007, vol. 8, pp. 942–949. doi: 10.1038/ni14967. Assarsson E., Bui H.H., Sidney J., Zhang Q., Glenn J., Oseroff C., Mbawuike I.N., Alexander J., Newman M.J., Grey H., Sette A. Immunomic analysis of the repertoire of T-cell specificities for influenza A virus in humans. J. Virol., 2008, vol. 82, no. 24, pp. 12241–12251. doi: 10.1128/JVI.01563-088. Bennink J.R., Yewdell J.W., Smith G.L., Moller C., Moss B. Recombinant vaccinia virus primes and stimulates influenza haemagglutinin specific cytotoxic T cells. Nature, 1984, vol. 311, no. 5986, pp. 578–579.9. Berkhoff E.G., Geelhoed-Mieras M.M., Fouchier R.A., Osterhaus A.D., Rimmelzwaan G.F. Assessment of the extent of variation in influenza A virus cytotoxic T-lymphocyte epitopes by using virus-specific CD8+ T-cell clones. J. Gen. Virol., 2007, vol. 88, pp. 530–535. doi: 10.1099/vir.0.82120-010. Braciale T.J. Immunologic recognition of influenza virus-infected cells. I. Generation of a virus-strain specific and a cross-reactive subpopulation of cytotoxic T cells in the response to type A influenza viruses of different subtypes. Cell. Immunol., 1977, vol. 33, no. 2, pp. 423–436.11. Braciale T.J. Immunologic recognition of influenza virus-infected cells. II. Expression of influenza A matrix protein on the infected cell surface and its role in recognition by cross-reactive cytotoxic T cells. J. Exp. Med., 1977, vol. 146, pp. 673–689.12. Carragher D.M., Kaminski D.A., Moquin A., Hartson L., Randall T.D. A novel role for non-neutralizing antibodies against nucleoprotein in facilitating resistance to influenza virus. J. Immunol., 2008, vol. 181, no. 6, pp. 4168–4176.13. Conenello G.M., Tisoncik J.R., Rosenzweig E., Varga Z.T., Palese P., Katze M.G. A single N66S mutation in the PB1-F2 protein of influenza A virus increases virulence by inhibiting the early interferon response in vivo. J. Virol., 2011, vol. 85, no. 2, pp. 652–662. doi: 10.1128/JVI.01987-1014. Corti D., Suguitan A.L.Jr., Pinna D., Silacci C., Fernandez-Rodriguez B.M., Vanzetta F., Santos C., Luke C.J., Torres-Velez F.J., Temperton N.J., Weiss R.A., Sallusto F., Subbarao K., Lanzavecchia A. Heterosubtypic neutralizing antibodies are produced by individuals immunized with a seasonal influenza vaccine. J. Clin. Invest., 2010, vol. 120, no. 5, pp. 1663–1673. doi: 10.1172/JCI4190215. Corti D., Voss J., Gamblin S.J., Codoni G., Macagno A., Jarrossay D., Vachieri S.G., Pinna D., Minola A., Vanzetta F., Silacci C., Fernandez-Rodriguez B.M., Agatic G., Bianchi S., Giacchetto-Sasselli I., Calder L., Sallusto F., Collins P., Haire L.F., Temperton N., Langedijk J.P., Skehel J.J., Lanzavecchia A. A neutralizing antibody selected from plasma cells that binds to group 1 and group 2 influenza A hemagglutinins. Science, 2011, vol. 333, no. 6044, pp. 850–856. doi: 10.1126/science.120566916. Ekiert D.C., Friesen R.H., Bhabha G., Kwaks T., Jongeneelen M., Yu W., Ophorst C., Cox F., Korse H.J., Brandenburg B., Vogels R., Brakenhoff J.P., Kompier R., Koldijk M.H., Cornelissen L.A., Poon L.L., Peiris M., Koudstaal W., Wilson I.A., Goudsmit J. A highly conserved neutralizing epitope on group 2 influenza A viruses. Science, 2011, vol. 333, no. 6044, pp. 843–850. doi: 10.1126/science.120483917. Ekiert D.C., Bhabha G., Elsliger M.A., Friesen R.H., Jongeneelen M., Throsby M., Goudsmit J., Wilson I.A. Antibody recognition of a highly conserved influenza virus epitope. Science, 2009, vol. 324, no. 5924, pp. 246–251. doi: 10.1126/science.117149118. Ekiert D.C., Kashyap A.K., Steel J., Rubrum A., Bhabha G., Khayat R., Lee J.H., Dillon M.A., O’Neil R.E., Faynboym A.M., Horowitz M., Horowitz L., Ward A.B., Palese P., Webby R., Lerner R.A., Bhatt R.R., Wilson I.A. Cross-neutralization of influenza A viruses mediated by a single antibody loop. Nature, 2012, vol. 489, no. 7417, pp. 526–532. doi: 10.1038/nature1141419. El Bakkouri K., Descamps F., De Filette M., Smet A., Festjens E., Birkett A., Van Rooijen N., Verbeek S., Fiers W., Saelens X. Universal vaccine based on ectodomain of matrix protein 2 of influenza A: Fc receptors and alveolar macrophages mediate protection. J. Immunol., 2011, vol. 186, no. 2, pp. 1022–1031. doi: 10.4049/jimmunol.090214720. Elaish M., Kang K.I., Xia M., Ali A., Shany S.A., Wang L., Jiang X., Lee C.W. Immunogenicity and protective efficacy of the norovirus P particle-M2e chimeric vaccine in chickens. Vaccine, 2015, vol. 33, no. 38, pp. 4901–4909. doi: 10.1016/j.vaccine.2015.07.04921. Epstein S.L., Kong W.P., Misplon J.A., Lo C.Y., Tumpey T.M., Xu L., Nabel G.J. Protection against multiple influenza A subtypes by vaccination with highly conserved nucleoprotein. Vaccine, 2005, vol. 23, no. 46–47, pp. 5404–5410. doi: 10.1016/j.vaccine.2005.04.04722. Fan J., Liang X., Horton M.S., Perry H.C., Citron M.P., Heidecker G.J., Fu T.M., Joyce J., Przysiecki C.T., Keller P.M., Garsky V.M., Ionescu R., Rippeon Y., Shi L., Chastain M.A., Condra J.H., Davies M.E., Liao J., Emini E.A., Shiver J.W. Preclinical study of influenza virus A M2 peptide conjugate vaccines in mice, ferrets, and rhesus monkeys. Vaccine, 2004, vol. 22, no. 23–24, pp. 2993–3003. doi: 10.1016/j.vaccine.2004.02.02123. Fernandez Gonzalez S., Jayasekera J.P., Carroll M.C. Complement and natural antibody are required in the long-term memory response to influenza virus. Vaccine, 2008, vol. 26, no. 8, pp. 186–193.24. Friesen R.H., Koudstaal W., Koldijk M.H., Weverling G.J., Brakenhoff J.P., Lenting P.J., Stittelaar K.J., Osterhaus A.D., Kompier R., Goudsmit J. New class of monoclonal antibodies against severe influenza: prophylactic and therapeutic efficacy in ferrets. PLoS ONE, 2010, vol. 5, no. 2, e9106. doi: 10.1371/journal.pone.000910625. Garcia-Sastre A. Identification and characterization of viral antagonists of type I interferon in negative-strand RNA viruses. Curr. Top. Microbiol. Immunol., 2004, vol. 283, pp. 249–280.26. GeurtsvanKessel C.H., Lambrecht B.N. Division of labor between dendritic cell subsets of the lung. Mucosal Immunol., 2008, vol. 1, pp. 442–450. doi: 10.1038/mi.2008.3927. Gorman O.T., Bean W.J., Webster R.G. Evolutionary processes in influenza viruses: divergence, rapid evolution, and stasis. Curr. Top. Microbiol. Immunol., 1992, vol. 176, pp. 75–97.28. Graef K.M., Vreede F.T., Lau Y.F., McCall A.W., Carr S.M., Subbarao K., Fodor E. The PB2 subunit of the influenza virus RNA polymerase affects virulence by interacting with the mitochondrial antiviral signaling protein and inhibiting expression of beta interferon. J. Virol., 2010, vol. 84, no. 17, pp. 8433–8445. doi: 10.1128/JVI.00879-1029. Grant E., Wu C., Chan K.F., Eckle S., Bharadwaj M., Zou Q.M. Nucleoprotein of influenza A virus is a major target of immune dominant CD8+ T-cell responses. Immunol. Cell Biol., 2013, vol. 91, pp. 184–194. doi: 10.1038/icb.2012.7830. Guan Z., Liu D., Mi S., Zhang J., Ye Q., Wang M., Gao G.F., Yan J. Interaction of Hsp40 with influenza virus M2 protein: implications for PKR signaling pathway. Protein Cell, 2010, vol. 1, no. 10, pp. 944–955. doi: 10.1007/s13238-010-0115-x.31. Guo Z., Chen L.M., Zeng H., Gomez J.A., Plowden J., Fujita T., Katz J.M., Donis R.O., Sambhara S. NS1 protein of influenza A virus inhibits the function of intracytoplasmic pathogen sensor, RIG-I. Am. J. Respir. Cell Mol. Biol., 2007, vol. 36, no. 3, pp. 263–269. doi: 10.1165/rcmb.2006-0283RC32. Haanen J.B., Wolkers M.C., Kruisbeek A.M., Schumacher T.N. Selective expansion of cross-reactive CD8+ memory T cells by viral variants. J. Exp. Med., 1999, vol. 190, no. 9, pp. 1319–1328.33. Haller O., Kochs G. Interferon-induced mx proteins: dynamin-like GTPases with antiviral activity. Traffic, 2002, vol. 3, no. 10, pp. 710–717. doi: 10.1034/j.1600-0854.2002.31003.x34. Hashem A.M., Gravel C., Chen Z., Yi Y., Tocchi M., Jaentschke B., Fan X., Li C., Rosu-Myles M., Pereboev A., He R., Wang J., Li X. CD40 ligand preferentially modulates immune response and enhances protection against influenza virus. J. Immunol., 2014, vol. 193, no. 2, pp. 722–734. doi: 10.4049/jimmunol.130009335. Heil F., Hemmi H., Hochrein H., Ampenberger F., Kirschning C., Akira S., Lipford G., Wagner H., Bauer S. Species-specific recognition of single-stranded RNA via toll-like receptor 7 and 8. Science, 2004, vol. 303, no. 5663, pp. 1526–1529. doi: 10.1126/science.109362036. Hoelscher M.A., Garg S., Bangari D.S., Belser J.A., Lu X., Stephenson I., Bright R.A., Katz J.M., Mittal S.K., Sambhara S. Development of adenoviral-vector-based pandemic influenza vaccine against antigenically distinct human H5N1 strains in mice. Lancet, 2006, vol. 367, no. 9509, pp. 475–481. doi: 10.1016/S0140-6736(06)68076-837. Holsinger L., Nichani D., Pinto L., Lamb R. Influenza A virus M2 ion channel protein: a structure-function analysis. J. Virol., 1994, vol. 68, no. 3, pp. 1551–1563.38. Holsinger L., Lamb R. Influenza virus M2 integral membrane protein is a homotetramer stabilized by formation of disulfide bonds. Virology, 1991, vol. 183, no. 1, pp. 32–43.39. Holzinger D., Jorns C., Stertz S., Boisson-Dupuis S., Thimme R., Weidmann M., Casanova J.L., Haller O., Kochs G. Induction of MxA gene expression by influenza A virus requires type I or type III interferon signaling. J. Virol., 2007, vol. 81, no. 14, pp. 7776–7785. doi: 10.1128/JVI.00546-0640. Hwang S.D., Shin J.S., Ku K.B., Kim H.S., Cho S.W., Seo S.H. Protection of pregnant mice, fetuses and neonates from lethality of H5N1 influenza viruses by maternal vaccination. Vaccine, 2010, vol. 28, no. 17, pp. 2957–2964. doi: 10.1016/j.vaccine.2010.02.01641. Ichinohe T., Pang I.K., Iwasaki A. Influenza virus activates inflammasomes via its intracellular M2 ion channel. Nat. Immunol., 2010, vol. 11, no. 5, pp. 404–410. doi: 10.1038/ni.186142. Imai M., Watanabe T., Hatta M., Das S.C., Ozawa M., Shinya K., Zhong G., Hanson A., Katsura H., Watanabe S., Li C., Kawakami E., Yamada S., Kiso M., Suzuki Y., Maher E.A., Neumann G., Kawaoka Y. Experimental adaptation of an influenza H5 HA confers respiratory droplet transmission to a reassortant H5 HA/H1N1 virus in ferrets. Nature, 2012, vol. 486, no. 7403, pp. 420–428. doi: 10.1038/nature1083143. Impagliazzo A., Milder F., Kuipers H., Wagner M.V., Zhu X., Hoffman R.M., Van Meersbergen R., Huizingh J., Wanningen P., Verspuij J., De Man M., Ding Z., Apetri A., Kükrer B., Sneekes-Vriese E., Tomkiewicz D., Laursen N.S., Lee P.S., Zakrzewska A., Dekking L., Tolboom J., Tettero L., Van Meerten S., Yu W., Koudstaal W., Goudsmit J., Ward A.B., Meijberg W., Wilson I.A., Radošević K. A stable trimeric influenza hemagglutinin stem as a broadly protective immunogen. Science, 2015, vol. 349, no. 6254, pp. 1301–1306. doi: 10.1126/science.aac726344. Ito T., Gorman O., Kawaoka Y., Bean W., Webster R. Evolutionary analysis of the influenza A virus M gene with comparison of the M1 and M2 proteins. J. Virol., 1991, vol. 65, no. 10, pp. 5491–5498.45. Jameson J., Cruz J., Terajima M., Ennis F.A. Human CD8+ and CD4+ T lymphocyte memory to influenza A viruses of swine and avian species. J. Immunol., 1999, vol. 162, no. 12, pp. 7578–7583.46. Jayasekera J.P., Moseman E.A., Carroll M.C. Natural antibody and complement mediate neutralization of influenza virus in the absence of prior immunity. J. Virol., 2007, vol. 81, no. 7, pp. 3487–3494. doi: 10.1128/JVI.02128-0647. Jegaskanda S., Job E.R., Kramski M., Laurie K., Isitman G., De Rose R. Cross-reactive influenza-specific antibody-dependent cellular cytotoxicity antibodies in the absence of neutralizing antibodies. J. Immunol., 2013, vol. 190, no. 4, pp. 1837–1848. doi: 10.4049/jimmunol.120157448. Jegerlehner A., Schmitz N., Storni T., Bachmann M.F. Influenza A vaccine based on the extracellular domain of M2: weak protection mediated via antibody-dependent NK cell activity. J. Immunol., 2004, vol. 172, no. 9, pp. 5598–5605.49. Kammer A.R., Amacker M., Rasi S., Westerfeld N., Gremion C., Neuhaus D., Zurbriggen R. A new and versatile virosomal antigen delivery system to induce cellular and humoral immune responses. Vaccine, 2007, vol. 25, no. 41, pp. 7065–7074. doi: 10.1016/j.vaccine.2007.07.05250. Kim H.M., Lee Y.W., Lee K.J., Kim H.S., Cho S.W., Van Rooijen N., Guan Y., Seo S.H. Alveolar macrophages are indispensable for controlling influenza viruses in lungs of pigs. J. Virol., 2008, vol. 82, no. 9, pp. 4265–4274. doi: 10.1128/JVI.02602-0751. Kuiken T., Riteau B., Fouchier R.A., Rimmelzwaan G.F. Pathogenesis of influenza virus infections: the good, the bad and the ugly. Curr. Opin. Virol., 2012, vol. 2, no. 3, pp. 276–286. doi: 10.1016/j.coviro.2012.02.01352. Lamere M.W., Moquin A., Lee F.E., Misra R.S., Blair P.J., Haynes L., Randall T.D., Lund F.E., Kaminski D.A. Regulation of antinucleoprotein IgG by systemic vaccination and its effect on influenza virus clearance. J. Virol., 2011, vol. 85, no. 10, pp. 5027–5035. doi: 10.1128/JVI.00150-1153. Lee L.Y., Ha D.L., Simmons C., De Jong M.D., Chau N.V., Schumacher R., Peng Y.C., McMichael A.J., Farrar J.J., Smith G.L., Townsend A.R., Askonas B.A., Rowland-Jones S., Dong T. Memory T cells established by seasonal human influenza A infection cross-react with avian influenza A (H5N1) in healthy individuals. J. Clin. Invest., 2008, vol. 118, no. 10, pp. 3478–3490. doi: 10.1172/JCI3246054. Lei H., Peng X., Jiao H., Zhao D., Ouyang J. Broadly protective immunity against divergent influenza viruses by oral co-administration of Lactococcus lactis expressing nucleoprotein adjuvanted with cholera toxin B subunit in mice. Microb Cell Fact., 2015, vol. 14, e111. doi: 10.1186/s12934-015-0287-455. Leung H.C., Chan C.C., Poon V.K., Zhao H.J., Cheung C.Y., Ng F., Huang J.D., Zheng B.J. An H5N1-based matrix protein 2 ectodomain tetrameric peptide vaccine provides cross-protection against lethal infection with H7N9 influenza virus. Emerg. Microbes Infect., 2015, vol. 4, no. 4, e22. doi: 10.1038/emi.2015.2256. Li R., Chowdhury M.Y., Kim J.H., Kim T.H., Pathinayake P., Koo W.S., Park M.E., Yoon J.E., Roh J.B., Hong S.P., Sung M.H., Lee J.S., Kim C.J. Mucosally administered Lactobacillus surface-displayed influenza antigens (sM2 and HA2) with cholera toxin subunit A1 (CTA1) Induce broadly protective immune responses against divergent influenza subtypes. Vet. Microbiol., 2015, vol. 179, no. 3–4, pp. 250–263. doi: 10.1016/j.vetmic.2015.07.02057. Lin K.L., Suzuki Y., Nakano H., Ramsburg E., Gunn M.D. CCR2+ monocyte-derived dendritic cells and exudate macrophages produce influenzainduced pulmonary immune pathology and mortality. J. Immunol., 2008, vol. 180, no. 4, pp. 2562–2572.58. Liu W., Zou P., Ding J., Lu Y., Chen Y.H. Sequence comparison between the extracellular domain of M2 protein human and avian influenza A virus provides new information for bivalent influenza vaccine design. Microbes Infect., 2005, vol. 7, no. 2, pp. 171–177. doi: 10.1016/j.micinf.2004.10.00659. Lund J.M., Alexopoulou L., Sato A., Karow M., Adams N.C., Gale N.W., Iwasaki A., Flavell R.A. Recognition of single-stranded RNA viruses by Toll-like receptor 7. Proc. Natl. Acad. Sci. USA, 2004, vol. 101, no. 15, pp. 5598–5603. doi: 10.1073/pnas.040093710160. Mardanova E.S., Kotlyarov R.Y., Kuprianov V.V., Stepanova L.A., Tsybalova L.M., Lomonosoff G.P., Ravin N.V. Rapid highyield expression of a candidate influenza vaccine based on the ectodomain of M2 protein linked to flagellin in plants using viral vectors. BMC Biotechnol., 2015, vol. 15, e42. doi: 10.1186/s12896-015-0164-661. Mazanec M.B., Coudret C.L., Fletcher D.R. Intracellular neutralization of influenza virus by immunoglobulin A anti-hemagglutinin monoclonal antibodies. J. Virol., 1995, vol. 69, no. 2, pp. 1339–1343.62. Mbawuike I.N., Six H.R., Cate T.R., Couch R.B. Vaccination with inactivated influenza A virus during pregnancy protects neonatal mice against lethal challenge by influenza A viruses representing three subtypes. J. Virol., 1990, vol. 64, pp. 1370–1374.63. McMichael A.J., Gotch F.M., Noble G.R., Beare P.A. Cytotoxic T-cell immunity to influenza. N. Engl. J. Med., 1983, vol. 309, no. 1, pp. 13–17. doi: 10.1056/NEJM19830707309010364. Meurs E., Chong K., Galabru J., Thomas N.S., Kerr I.M., Williams B.R., Hovanessian A.G. Molecular cloning and characterization of the human double-stranded RNA-activated protein kinase induced by interferon. Cell, 1990, vol. 62, no. 2, pp. 379–390. doi: 10.1016/0092-8674(90)90374-N65. Murphy B.R., Nelson D.L., Wright P.F., Tierney E.L., Phelan M.A., Chanock R.M. Secretory and systemic immunological response in children infected with live attenuated influenza A virus vaccines. Infect. Immun., 1982, vol. 36, no. 3, pp. 1102–1108.66. Neirynck S., Deroo T., Saelens X., Vanlandschoot P., Jou W.M., Fiers W. A universal influenza A vaccine based on the extracellular domain of the M2 protein. Nat. Med., 1999, vol. 5, no. 10, pp. 1157–1163. doi: 10.1038/1348467. Ohba K., Yoshida S., Zahidunnabi Dewan M., Shimura H., Sakamaki N., Takeshita F., Yamamoto N., Okuda K. Mutant influenza A virus nucleoprotein is preferentially localized in the cytoplasm and its immunization in mice shows higher immunogenicity and cross-reactivity. Vaccine, 2007, vol. 25, no. 21, pp. 4291–4300. doi: 10.1016/j.vaccine.2007.02.07468. Okuda K., Ihata A., Watabe S., Okada E., Yamakawa T., Hamajima K., Yang J., Ishii N., Nakazawa M., Okuda K., Ohnari K., Nakajima K., Xin K.Q. Protective immunity against influenza A virus induced by immunization with DNA plasmid containing influenza M gene. Vaccine, 2001, vol. 19, no. 27, pp. 3681–3691. doi: 10.1016/S0264-410X(01)00078-069. Onodera T., Takahashi Y., Yokoi Y., Ato M., Kodama Y., Hachimura S., Kurosaki T., Kobayashi K. Memory B cells in the lung participate in protective humoral immune responses to pulmonary influenza virus reinfection. Proc. Natl. Acad. Sci. USA, 2012, vol. 109, no. 7, pp. 2485–2490. doi: 10.1073/pnas.111536910970. Ozawa T., Jin A., Tajiri K., Takemoto M., Okuda T., Shiraki K., Kishi H., Muraguchi A. Characterization of a fully human monoclonal antibody against extracellular domain of matrix protein 2 of influenza A virus. Antiviral Res., 2011, vol. 91, no. 3. pp. 283–287. doi: 10.1016/j.antiviral.2011.06.01271. Paget C., Ivanov S., Fontaine J., Blanc F., Pichavant M., Renneson J., Bialecki E., Pothlichet J., Vendeville C., Barba-Speath G., Huerre M.R., Faveeuw C., Si-Tahar M., Trottein F. Potential role of invariant NKT cells in the control of pulmonary inflammation and CD8+ T cell response during acute influenza A virus H3N2 pneumonia. J. Immunol., 2011, vol. 186, no. 10, pp. 5590–5602. doi: 10.4049/jimmunol.100234872. Rothbarth P.H., Groen J., Bohnen A.M., De Groot R., Osterhaus A.D. Influenza virus serology – a comparative study. J. Virol. Methods, 1999, vol. 78, no. 1–2, pp. 163–169.73. Sambhara S., Kurichh A., Miranda R., Tumpey T., Rowe T., Renshaw M., Arpino R., Tamane A., Kandil A., James O., Underdown B., Klein M., Katz J., Burt D. Heterosubtypic immunity against human influenza A viruses, including recently emerged avian H5 and H9 viruses, induced by FLU-ISCOM vaccine in mice requires both cytotoxic T-lymphocyte and macrophage function. Cell. Immunol., 2001, vol. 211, no. 2, pp. 143–153. doi: 10.1006/cimm.2001.183574. Sandbulte M.R., Jimenez G.S., Boon A.C., Smith L.R., Treanor J.J., Webby R.J. Cross-reactive neuraminidase antibodies afford partial protection against H5N1 in mice and are present in unexposed humans. PLoS Med., 2007, vol. 4, no. 2, e59. doi: 10.1371/journal.pmed.004005975. Scheible K., Zhang G., Baer J., Azadniv M., Lambert K., Pryhuber G., Treanor J.J., Topham D.J. CD8+ T cell immunity to 2009 pandemic and seasonal H1N1 influenza viruses. Vaccine, 2011, vol. 29, no. 11, pp. 2159–2168. doi: 10.1016/j.vaccine.2010.12.07376. Scholtissek C., Ludwig S., Fitch W.M. Analysis of influenza A virus nucleoproteins for the assessment of molecular genetic mechanisms leading to new phylogenetic virus lineages. Arch. Virol., 1993, vol. 13, no. 3–4, pp. 237–250.77. Schotsaert M., De Filette M., Fiers W., Saelens X. Universal M2 ectodomainbased influenza A vaccines: preclinical and clinical developments. Expert Rev. Vaccines, 2009, vol. 8, no. 4, pp. 499–508. doi: 10.1586/erv.09.678. Schwartzman L.M., Cathcart A.L., Pujanauski L.M., Li Q., Kash J.C., Taubenberger J.K. An intranasal virus-like particle vaccine broadly protects mice from multiple subtypes of influenza A virus. mBio, 2015, vol. 6, no. 4, e01044-15. doi: 10.1128/mBio.01044-1579. Sharma K., Tripathi S., Ranjan P., Kumar P., Garten R., Deyde V., Katz J.M., Cox N.J., Lal R.B., Sambhara S., Lal S.K. Influenza A virus nucleoprotein exploits Hsp40 to inhibit PKR activation. PLoS ONE, 2011, vol. 6, no. 6, e20215. doi: 10.1371/journal.pone.002021580. Shedlock D.J., Shen H. Requirement for CD4 T cell help in generating functional CD8 T cell memory. Science, 2003, vol. 300, no. 5617, pp. 337–339. doi: 10.1126/science.108230581. Shu L.L., Bean W.J., Webster R.G. Analysis of the evolution and variation of the human influenza A virus nucleoprotein gene from 1933 to 1990. J. Virol., 1993, vol. 67, no. 5. pp. 2723–2729.82. Slepushkin V.A., Katz J.M., Black R.A., Gamble W.C., Rota P.A, Cox N.J. Protection of mice against influenza A virus challenge by vaccination with baculovirus-expressed M2 protein. Vaccine, 1995, vol. 13, no. 15, pp. 1399–1402. doi: 10.1016/0264-410X(95)92777-Y83. Smith D.J., Lapedes A.S., De Jong J.C., Bestebroer T.M., Rimmelzwaan G.F., Osterhaus A.D., Fouchier R.A. Mapping the antigenic and genetic evolution of influenza virus. Science, 2004, vol. 305, no. 5682, pp. 371–376. doi: 10.1126/science.109721184. Soghoian D.Z., Streeck H. Cytolytic CD4(+) T cells in viral immunity. Expert Rev. Vaccines, 2010, vol. 9, no. 12, pp. 1453–1463. doi: 10.1586/erv.10.13285. Sui Z., Chen Q., Wu R., Zhang H., Zheng M., Wang H., Chen Z. Cross-protection against influenza virus infection by intranasal administration of M2-based vaccine with chitosan as an adjuvant. Arch. Virol., 2010, vol. 155, no. 4, pp. 535–544.86. Takeda M., Pekosz A., Shuck K., Pinto L., Lamb R. Influenza A virus M2 ion channel activity is essential for efficient replication in tissue culture. J. Virol., 2002, vol. 76, no. 3, pp. 1391–1399. doi: 10.1128/JVI.76.3.1391-1399.200287. Tan S.L., Katze M.G. Biochemical and genetic evidence for complex formation between the influenza A virus NS1 protein and the interferon-induced PKR protein kinase. J. Interferon Cytokine Res., 1998, vol. 18, no. 9, pp. 757–766.88. Thompson W.W., Shay D.K., Weintraub E., Brammer L., Bridges C.B., Cox N.J., Fukuda K. Influenza-associated hospitalizations in the United States. JAMA, 2004, vol. 292, no. 11, pp. 1333–1340. doi: 10.1001/jama.292.11.1333.89. Throsby M., Van den Brink E., Jongeneelen M., Poon L.L., Alard P., Cornelissen L., Bakker A., Cox F., Van Deventer E., Guan Y., Cinatl J., Ter Meulen J., Lasters I., Carsetti R., Peiris M., De Kruif J., Goudsmit J. Heterosubtypic neutralizing monoclonal antibodies cross-protective against H5N1 and H1N1 recovered from human IgM+ memory B cells. PLoS One, 2008, vol. 3, no. 12, e3942. doi: 10.1371/journal.pone.000394290. Tompkins S.M., Zhao Z.S., Lo C.Y., Misplon J.A., Liu T., Ye Z., Hogan R.J., Wu Z., Benton K.A., Tumpey T.M., Epstein S.L. Matrix protein 2 vaccination and protection against influenza viruses, including subtype H5N1. Emerg. Infect. Dis., 2007, vol. 13, no. 3, pp. 426–435. doi: 10.3201/eid1303.06112591. Tong S., Li Y., Rivailler P., Conrardy C., Castillo D.A., Chen L.M., Recuenco S., Ellison J.A., Davis C.T., York I.A., Turmelle A.S., Moran D., Rogers S., Shi M., Tao Y., Weil M.R., Tang K., Rowe L.A., Sammons S., Xu X., Frace M., Lindblade K.A., Cox N.J., Anderson L.J., Rupprecht C.E., Donis R.O. A distinct lineage of influenza A virus from bats. Proc. Natl. Acad. Sci. USA, 2012, vol. 109, no. 11, pp. 4269–4274. doi: 10.1073/pnas.111620010992. Topham D.J., Tripp R.A., Doherty P.C. CD8 T cells clear influenza virus by perforin or Fas- dependent processes. J. Immunol., 1997, vol. 159, no. 11, pp. 5197–5200.93. Treanor J.J., Tierney E.L., Zebedee S.L., Lamb R.A., Murphy B.R. Passively transferred monoclonal antibody to the M2 protein inhibits influenza A virus replication in mice. J. Virol., 1990, vol. 64, no. 3, pp. 1375–1377.94. Ungchusak K., Auewarakul P., Dowell S.F., Kitphati R., Auwanit W., Puthavathana P., Uiprasertkul M., Boonnak K., Pittayawonganon C., Cox N.J., Zaki S.R., Thawatsupha P., Chittaganpitch M., Khontong R., Simmerman J.M., Chunsutthiwat S. Probable personto-person transmission of avian influenza A (H5N1). N. Engl. J. Med., 2005, vol. 352, pp. 333–340. doi: 10.1056/NEJMoa04402195. Van Reeth K., Braeckmans D., Cox E., Van Borm S., Van den Berg T., Goddeeris B., De Vleeschauwer A. Prior infection with an H1N1 swine influenza virus partially protects pigs against a low pathogenic H5N1 avian influenza virus. Vaccine, 2009, vol. 27, no. 45, pp. 6330–6339.96. Van Reeth K., Gregory V., Hay A., Pensaert M. Protection against a European H1N2 swine influenza virus in pigs previously infected with H1N1 and/or H3N2 subtypes. Vaccine, 2003, vol. 21, no. 13–14, pp. 1375–1381. doi: 10.1016/S0264-410X(02)00688-697. Whittle J.R., Zhang R., Khurana S., King L.R., Manischewitz J., Golding H., Dormitzer P.R., Haynes B.F., Walter E.B., Moody M.A., Kepler T.B., Liao H.X., Harrison S.C. Broadly neutralizing human antibody that recognizes the receptor-binding pocket of influenza virus hemagglutinin. Proc. Natl. Acad. Sci. USA, 2011, vol. 108, no. 34, pp. 14216–14221. doi: 10.1073/pnas.111149710898. Wu C., Zanker D., Valkenburg S., Tan B., Kedzierska K., Zou Q.M. Systematic identification of immune dominant CD8+ T-cell responses to influenza A virus in HLA-A2 individuals. Proc. Natl. Acad. Sci. USA, 2011, vol. 108, no. 22, pp. 9178–9183. doi: 10.1073/pnas.110562410899. Wu Y., Wu Y., Tefsen B., Shi Y., Gao G.F. Bat-derived influenza-like viruses H17N10 and H18N11. Trends Microbiol., 2014, vol. 22, no. 4, pp. 183–91. doi: 10.1016/j.tim.2014.01.010100. Yassine H.M., Boyington J.C., McTamney P.M., Wei C.J., Kanekiyo M., Kong W.P., Gallagher J.R., Wang L., Zhang Y., Joyce M.G., Lingwood D., Moin S.M., Andersen H., Okuno Y., Rao S.S., Harris A.K., Kwong P.D., Mascola J.R., Nabel G.J., Graham B.S. Hemagglutinin-stem nanoparticles generate heterosubtypic influenza protection. Nat. Med., 2015, vol. 21, no. 9, pp. 1065–1070. doi: 10.1038/nm.3927101. Yewdell J.W., Bennink J.R. Immunodominance in major histocompatibility complex class I-restricted T lymphocyte responses. Annu. Rev. Immunol., 1999, vol. 17, pp. 51–88.102. Yoshida R., Igarashi M., Ozaki H., Kishida N., Tomabechi D., Kida H., Ito K., Takada A. Cross-protective potential of a novel monoclonal antibody directed against antigenic site B of the hemagglutinin of influenza A viruses. PLoS Pathog., 2009, vol. 5, no. 3, e1000350. doi: 10.1371/journal.ppat.1000350103. Zaman M., Ashraf S., Dreyer N.A., Toovey S. Human infection with avian influenza virus, Pakistan, 2007. Emerg. Infect. Dis., 2011, vol. 17, no. 6, pp. 1056–1059. doi: 10.3201/eid1706.091652104. Zhou D., Wu T.L., Lasaro M.O., Latimer B.P., Parzych E.M., Bian A., Li Y., Li H., Erikson J., Xiang Z., Ertl H.C. A universal influenza A vaccine based on adenovirus expressing matrix-2 ectodomain and nucleoprotein protects mice from lethal challenge. Mol. Ther., 2010, vol. 18, no. 12, pp. 2182–2189. doi: 10.1038/mt.2010.202105. Zuccotti G., Pogliani L., Pariani E., Amendola A., Zanetti A. Transplacental antibody transfer following maternal immunization with a pandemic 2009 influenza A(H1N1) MF59-adjuvanted vaccine. JAMA, 2010, vol. 304, no. 21, pp. 2360–2361. doi: 10.1001/jama.2010.1729