microbeПроблемы особо опасных инфекцийProblems of Particularly Dangerous Infections0370-10692658-719XRussian Research Anti-Plague Institute “Microbe”10.21055/0370-1069-2019-1-50-63microbe-1125Research ArticleОБЗОРЫREVIEWSСовременное состояние проблемы разработки вакцин для специфической профилактики чумыCurrent State of the Problem of Vaccine Development for Specific Prophylaxis of PlagueМикшисН. И.MikshisN. I.

Российская Федерация, 410005, Саратов, ул. У ниверситетская, 46

46, Universitetskaya St., Saratov, 410005, Russian Federation

rusrapi@microbe.ruКутыревВ. В.KutyrevV. V.

Российская Федерация, 410005, Саратов, ул. У ниверситетская, 46

46, Universitetskaya St., Saratov, 410005, Russian Federation

ФКУЗ «Российский научно-исследовательский противочумный институт «Микроб»РоссияRussian Research Anti-Plague Institute “Microbe”Russian Federation201902042019015063Copyright © Микшис Н.И., Кутырев В.В., 20192019Микшис Н.И., Кутырев В.В.Mikshis N.I., Kutyrev V.V.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://journal.microbe.ru/jour/article/view/1125

Возникновение в современный период в странах Африки и Южной Америки крупных вспышек чумы, характеризующихся высокой частотой развития легочной формы болезни (в том числе со смертельным исходом) поддерживает интерес ученых к проблемам разработки и испытания средств специфической профилактики этой особо опасной инфекционной болезни. На состоявшемся в 2018 г. семинаре ВОЗ были определены общие принципы оптимизации проектирования и испытания вакцин нового поколения, эффективно защищающих население от заражения чумой. Использование достижений биологических и медицинских наук для определения рациональной стратегии конструирования иммунобиологических препаратов позволило в последние годы достигнуть определенного прогресса в создании не только субъединичных вакцин на основе рекомбинантных антигенов, но также живых и векторных препаратов на платформе безопасных штаммов бактерий и реплицирующихся и нереплицирующихся вирусов. В обзоре подробно рассмотрены актуальные направления конструирования вакцин для профилактики чумы, определены преимущества использования современных методологий для повышения безопасности и эффективности вакцинации.

Emergence of large-scale plague outbreaks in Africa and South America countries in the modern period, characterized by high frequency of pneumonic plague development (including with lethal outcome) keeps up the interest of scientists to the matters of development and testing of means for specific prophylaxis of this particularly dangerous infectious disease. WHO workshop that was held in 2018 identified the general principles of optimization of design and testing of new-generation vaccines effectively protecting the population from plague infection. Application of the achievements of biological and medical sciences for outlining rational strategy for construction of immunobiological preparations led to a certain progress in the creation of not only sub-unit vaccines based on recombinant antigens, but also live and vector preparations on the platform of safe bacterial strains and replicating and non-replicating viruses in recent years. The review comprehensively considers the relevant trends in vaccine construction for plague  prevention, describes advantages of the state-of-the art methodologies for their safety and efficiency enhancement.

чумаY. pestisспецифическая профилактика чумывакциныplagueY. pestisspecific prophylaxis of plaguevaccinesReferencesAbramov V., Kosarev I., Motin V., Khlebnikov V., Vasilenko R., Sakulin V., Machulin A., Uversky V., Karlyshev A. Binding of LcrV protein from Yersinia pestis to human T-cells induces apoptosis, which is completely blocked by specific antibodies. Int. J. Biol. Macromol. 2019; 122:1062–70. DOI: 10.1016/j.ijbiomac.2018.09.054.Abramov V., Kosarev I., Motin V., Khlebnikov V., Vasilenko R., Sakulin V., Machulin A., Uversky V., Karlyshev A. Binding of LcrV protein from Yersinia pestis to human T-cells induces apoptosis, which is completely blocked by specific antibodies. Int. J. Biol. Macromol. 2019; 122:1062–70. DOI: 10.1016/j.ijbiomac.2018.09.054.WHO Target Product Profile for Plague Vaccines. [Электронный ресурс]. URL: http://www.who.int/blueprint/what/norms-standards/Plague_vaccines_workshop-23-april-2018/en/. (дата обращения 07.08.2018 г.).WHO Target Product Profile for Plague Vaccines. [Internet]. (Cited 07 Aug 2018). Available from: http://www.who.int/blueprint/what/norms-standards/Plague_vaccines_workshop-23-april-2018/en/.Mead P. Plague in Madagascar. A Tragic Opportunity for Improving Public Health. N. Engl. J. Med. 2018; 378(2):106−8. DOI: 10.1056/NEJMp1713881.Mead P. Plague in Madagascar. A Tragic Opportunity for Improving Public Health. N. Engl. J. Med. 2018; 378(2):106−8. DOI: 10.1056/NEJMp1713881.Plague. [Электронный ресурс]. URL: http://www.who.int/ru/news-room/fact-sheets/detail/plague. (дата обращения 12.08.2018 г.).Plague. [Internet]. (Cited 12 Aug 2018). Available from: http://www.who.int/ru/news-room/fact-sheets/detail/plague.Попова А.Ю., Кутырев В.В., Балахонов С.В., Ежлова Е.Б., Демина Ю.В., Пакскина Н.Д., Щучинов Л.В., Попов Н.В., Косилко С.А., Дубровина В.И., Корзун В.М., Михайлов Е.П., Мищенко А.И., Денисов А.В., Рождественский Е.Н., Бугоркова С.А., Ерошенко Г.А., Краснов Я.М., Топорков В.П., Слудский А.А., Раздорский А.С., Матросов А.Н., Поршаков А.М., Лопатин А.А., Щербакова С.А. Координация мероприятий противочумных учреждений Роспотребнадзора по оздоровлению Горно-Алтайского высокогорного природного очага чумы в 2016 г. Проблемы особо опасных инфекций. 2016; 4:5–10. DOI: 10.21055/0370-1069-2016-4-5-10.Popova A.Y., Kutyrev V.V., Balakhonov S.V., Ezhlova E.B., Demina Y.V., Pakskina N.D., Shchuchinov L.V., Popov N.V., Kosilko S.A., Dubrovina V.I., Korzun V.M., Mikhailov E.P., Mishchenko A.I., Denisov A.V., Rozhdestvensky E.N., Bugorkova S.A., Eroshenko G.A., Krasnov Y.M., Toporkov V.P., Sludsky A.A., Razdorsky A.S., Matrosov A.N., Porshakov A.M., Lopatin A.A., Shcherbakova S.A. [Coordination of measures of Plague Control Institutions, aimed at rehabilitation and sanitation of Gorno-Altai high-mountain natural plague focus in 2016. Problemy Osobo Opasnykh Infektsii [Problems of Particularly Dangerous Infections]. 2016; (4):5–10. DOI: 10.21055/0370-1069-2016-4-5-10.Попов Н.В., Матросов А.Н., Князева Т.В., Кузнецов А.А., Федоров Ю.М., Попов В.П., Корзун В.М., Вержуцкий Д.Б., Чипанин Е.В., Косилко С.А., Малецкая О.В., Григорьев М.П., Дубянский В.М., Шкарлет Г.П., Топорков В.П., Лопатин А.А., Зенкевич Е.С., Безсмертный В.Е., Балахонов С.В., Кутырев В.В. Эпизоотическая активность природных очагов чумы Российской Федерации в 2016 г., прогноз на 2017 г. Проблемы особо опасных инфекций. 2017; 1:5–12. DOI: 10.21055/0370-1069-2017-1-5-12.Popov N.V., Matrosov A.N., Knyazeva T.V., Kuznetsov A.A., Fedorov Yu.M., Popov V.P., Korzun V.M., Verzhutsky D.B., Chipanin Е.V., Kosilko S.А., Maletskaya O.V., Grigor’ev M.P., Dubyansky V.M., Shkarlet G.P., Toporkov V.P., Lopatin A.A., Zenkevich E.S., Bezsmertny V.E., Balakhonov S.V., Kutyrev V.V. [Epizootic Activity of Natural Plague Foci in the Russian Federation in 2016, and Prognosis for 2017]. Problemy Osobo Opasnykh Infektsii [Problems of Particularly Dangerous Infections].2017; (1):5–12. DOI: 10.21055/0370-1069-2017-1-5-12.Одиноков Г.Н., Ерошенко Г.А., Краснов Я.М., Куклева Л.М., Черкасов А.В., Шавина Н.Ю., Кутырев В.В. Анализ полногеномной последовательности штаммов Yersinia pestis на основе ступенчатого 680-SNP алгоритма. Проблемы особо опасных инфекций. 2013; 3:49–54. DOI: 10.21055/0370-1069-2013-3-49-54.Odinokov G.N., Eroshenko G.A., Krasnov Ya.M., Kukleva L.M., Cherkasov A.V., Shavina N.Y., Kutyrev V.V. [Analysis of the genome wide sequence of Yersinia pestis strains based on the consecutive 680-SNP algorithm]. Problemy Osobo Opasnykh Infektsii [Problems of Particularly Dangerous Infections]. 2013; (3):49–54. DOI: 10.21055/0370-1069-2013-3-49-54.Бывалов А.А., Кутырев В.В. Современное состояние проблемы совершенствования средств вакцинопрофилактики чумы. Журнал микробиологии, эпидемиологии и иммунобиологии. 2011; 2:97–104.Byvalov A.A., Kutyrev V.V. [Current state of the problem of improving the tools for plague vaccine prophylaxis]. Zhurnal Mikrobiologii, Epidemiologii i Immunobiologii. 2011; 2:97–104.Quenee L., Hermanas T., Ciletti N., Louvel H., Miller N., Elli D., Blaylock B, Mitchell A, Schroeder J, Krausz T, Kanabrocki J, Schneewind O. Hereditary hemochromatosis restores the virulence of plague vaccine strains. J. Infect. Dis. 2012; 206(7):1050–8. DOI: 10.1093/infdis/jis433.Quenee L., Hermanas T., Ciletti N., Louvel H., Miller N., Elli D., Blaylock B, Mitchell A, Schroeder J, Krausz T, Kanabrocki J, Schneewind O. Hereditary hemochromatosis restores the virulence of plague vaccine strains. J. Infect. Dis. 2012; 206(7):1050–8. DOI: 10.1093/infdis/jis433.Cornelius C., Quenee L., Overheim K., Koster F., Brasel T., Elli D., Ciletti N., Schneewind O. Immunization with recombinant V10 protects cynomolgus macaques from lethal pneumonic plague. Infect. Immun. 2008; 76(12):5588–97. DOI: 10.1128/IAI.00699-08.Cornelius C., Quenee L., Overheim K., Koster F., Brasel T., Elli D., Ciletti N., Schneewind O. Immunization with recombinant V10 protects cynomolgus macaques from lethal pneumonic plague. Infect. Immun. 2008; 76(12):5588–97. DOI: 10.1128/IAI.00699-08.Williamson E., Packer P., Waters E., Simpson A., Dyer D., Hartings J., Twenhafel N., Pitt M. Recombinant (F1+V) vaccine protects cynomolgus macaques against pneumonic plague. Vaccine. 2011; 29(29–30):4771–7. DOI: 10.1016/j.vaccine.2011.04.084.Williamson E., Packer P., Waters E., Simpson A., Dyer D., Hartings J., Twenhafel N., Pitt M. Recombinant (F1+V) vaccine protects cynomolgus macaques against pneumonic plague. Vaccine. 2011; 29(29–30):4771–7. DOI: 10.1016/j.vaccine.2011.04.084.Fellows P., Price J., Martin S., Metcalfe K., Krile R., Barnewall R., Hart M., Lockman H. Characterization of a Cynomolgus Macaque Model of Pneumonic Plague for Evaluation of Vaccine Efficacy. Clin. Vaccine Immunol. 2015; 22(9):1070−8. DOI: 10.1128/CVI.00290-15.Fellows P., Price J., Martin S., Metcalfe K., Krile R., Barnewall R., Hart M., Lockman H. Characterization of a Cynomolgus Macaque Model of Pneumonic Plague for Evaluation of Vaccine Efficacy. Clin. Vaccine Immunol. 2015; 22(9):1070−8. DOI:Chichester J., Musiychuk K., Farrance C., Mett V., Lyons J., Mett V., Yusibov V. A single component two-valent LcrV-F1 vaccine protects non-human primates against pneumonic plague. Vaccine. 2009; 27(25–26):3471–4. DOI: 10.1016/j.vaccine.2009.01.050.1128/CVI.00290-15.Mizel S., Graff A., Sriranganathan N., Ervin S., Lees C., Lively M., Hantgan R., Thomas M., Wood J., Bell B. Flagellin-F1-V fusion protein is an effective plague vaccine in mice and two species of nonhuman primates. Clin. Vaccine Immunol. 2009; 16(1):21−8. DOI: 10.1128/CVI.00333-08.Chichester J., Musiychuk K., Farrance C., Mett V., Lyons J., Mett V., Yusibov V. A single component two-valent LcrV-F1 vaccine protects non-human primates against pneumonic plague. Vaccine. 2009; 27(25–26):3471–4. DOI: 10.1016/j.vaccine.2009.01.050.Verma S., Tuteja U. Plague Vaccine Development: Current Research and Future Trends. Front. Immunol. 2016; 7:602. DOI: 10.3389/fimmu.2016.00602.Mizel S., Graff A., Sriranganathan N., Ervin S., Lees C., Lively M., Hantgan R., Thomas M., Wood J., Bell B. Flagellin-F1-V fusion protein is an effective plague vaccine in mice and two species of nonhuman primates. Clin. Vaccine Immunol. 2009; 16(1):21−8. DOI: 10.1128/CVI.00333-08.Williamson E., Flick-Smith H., LeButt C., Rowland C., Jones S., Waters E., Gwyther R., Miller J., Packer P., Irving M. Human immune response to a plague vaccine comprising recombinant F1 and rV antigens. Infect. Immun. 2005; 73(6):3598–608. DOI: 10.1128/IAI.73.6.3598-3608.2005.Verma S., Tuteja U. Plague Vaccine Development: Current Research and Future Trends. Front. Immunol. 2016; 7:602. DOI: 10.3389/fimmu.2016.00602.Chu K., Hu J., Meng F., Li J., Luo L., Xu J., Yuan Z., Li Z., Chen W., Jiao L., Chang Y., Wang B., Hu Y. Immunogenicity and safety of subunit plague vaccine: A randomized phase 2a clinical trial. Hum. Vaccin. Immunother. 2016; 12(9):2334−40. DOI: 10.1080/21645515.2016.1175261.Williamson E., Flick-Smith H., LeButt C., Rowland C., Jones S., Waters E., Gwyther R., Miller J., Packer P., Irving M. Human immune response to a plague vaccine comprising recombinant F1 and rV antigens. Infect. Immun. 2005; 73(6):3598–608. DOI: 10.1128/IAI.73.6.3598-3608.2005.Frey S., Lottenbach K., Graham I., Anderson E., Bajwa K., May R., Mizel S., Graff A., Belshe R. A phase I safety and immunogenicity dose escalation trial of plague vaccine, Flagellin/F1/V, in healthy adult volunteers (DMID 08-0066).Vaccine. 2017; 35(48 Pt B):6759−65. DOI: 10.1016/j.vaccine.2017.09.070.Chu K., Hu J., Meng F., Li J., Luo L., Xu J., Yuan Z., Li Z., Chen W., Jiao L., Chang Y., Wang B., Hu Y. Immunogenicity and safety of subunit plague vaccine: A randomized phase 2a clinical trial. Hum. Vaccin. Immunother. 2016; 12(9):2334−40. DOI: 10.1080/21645515.2016.1175261.FDA Grants Orphan Drug Designation for Plague Vaccine. [Электронный ресурс]. URL: https://globalbiodefense.com/2017/03/10/fda-grants-orphan-drug-designation-plague-vaccine/.Frey S., Lottenbach K., Graham I., Anderson E., Bajwa K., May R., Mizel S., Graff A., Belshe R. A phase I safety and immunogenicity dose escalation trial of plague vaccine, Flagellin/F1/V, in healthy adult volunteers (DMID 08-0066).Vaccine. 2017; 35(48 Pt B):6759−65. DOI: 10.1016/j.vaccine.2017.09.070.(дата обращения 13.09.2018 г.).FDA Grants Orphan Drug Designation for Plague Vaccine. [Internet]. (Cited 13 Sep 2018). Available from: https://globalbiodefense.com/2017/03/10/fda-grants-orphan-drug-designation-plaguevaccine/.Price J.L., Manetz T.S., Shearer J.D., House R.V. Preclinical safety assessment of a recombinant plague vaccine (rF1V). Int. J. Toxicol. 2013; 32(5):327–5. DOI: 10.1177/1091581813497405.Price J.L., Manetz T.S., Shearer J.D., House R.V. Preclinical safety assessment of a recombinant plague vaccine (rF1V). Int. J. Toxicol. 2013; 32(5):327–5. DOI: 10.1177/1091581813497405.Копылов П.Х., Бахтеева И.В., Анисимов А.П., Дентовская С.В., Иванов С.А., Киселева Н.В., Левчук В.П., Панферцев Е.А., Платонов М.Е., Светоч Т.Э., Титарева Г.М. Нуклеотидная последовательность, кодирующая иммуногенный полипептид LcrV (G113), вызывающий защитный иммунный ответ против Yersinia pestis, рекомбинантная плазмидная ДНК pETV-I-3455, кодирующая иммуногенный полипептид LcrV(G113); рекомбинантный штамм Escherichia coli BL21/DE3 pETV-I-3455 – продуцент иммуногенного полипептида LcrV(G113); полипепид LcrV(G113) и способ его получения. Патент РФ № 2439155, опубл.10.01.2012 г. Бюл. № 1.Kopylov P.Kh., Bakhteeva I.V., Anisimov A.P., Dentovskaya S.V., Ivanov S.A., Kiseleva N.V., Levchuk V.P., Panfertsev E.A., Platonov M.E., Svetoch T.E., Titareva G.M. [Nucleotide sequence encoding immunogenic polypeptide LcrV (G113), inducing protective immune response to Yersinia pestis, recombinant plasmid DNA pETV-I-3455 encoding L immunogenic polypeptide crV (G113); recombinant strain Escherichia coli BL21/ DE3 pETV-I-3455 – producer of immunogenic polypeptide LcrV (G113); polypeptide LcrV (G113) and method for its production]. RF Patent No 2439155, publ. January 10, 2012. Bulletin No 1.Вакцина чумная молекулярная микроинкапсулированная (ВЧММ ). Бактериология. 2018; 3(1):74–5.[Molecular micro-encapsulated plague vaccine (MMPV)]. Bakteriologiya. 2018; 3(1):74–5.Hill J., Leary S., Smither S., Best A., Pettersson J., Forsberg A., Lingard B., Lipka A., Brown K., Williamson E., Titball R. N255 is a key residue for recognition by a monoclonal antibody which protects against Yersinia pestis infection. Vaccine. 2009; 27(50):7073–9. DOI: 10.1016/j.vaccine.2009.09.061.Hill J., Leary S., Smither S., Best A., Pettersson J., Forsberg A., Lingard B., Lipka A., Brown K., Williamson E., Titball R. N255 is a key residue for recognition by a monoclonal antibody which protects against Yersinia pestis infection. Vaccine. 2009; 27(50):7073–9. DOI: 10.1016/j.vaccine.2009.09.061.Liu L., Wei D., Qu Z., Sun L., Miao Y., Yang Y., Lu J., Du W., Wang B., Li B. A safety and immunogenicity study of a novel subunit plague vaccine in cynomolgus macaques. J. Appl. Toxicol. 2018; 38(3):408–17. DOI: 10.1002/jat.3550.Liu L., Wei D., Qu Z., Sun L., Miao Y., Yang Y., Lu J., Du W., Wang B., Li B. A safety and immunogenicity study of a novel subunit plague vaccine in cynomolgus macaques. J. Appl. Toxicol. 2018; 38(3):408–17. DOI: 10.1002/jat.3550.Musson J.A., Ingram R., Durand G., Ascough S., Waters E.L., Hartley M.G., Robson T., Maillere B., Williamson E.D., Sriskandan S., Altmann D., Robinson J.H.. Repertoire of HLA-DR1-restricted CD4 T-cell responses to capsular Caf1 antigen of Yersinia pestis in human leukocyte antigen transgenic mice. Infect Immun. 2010; 78(10):4356–62. DOI: 10.1128/IAI.00195-10.Musson J.A., Ingram R., Durand G., Ascough S., Waters E.L., Hartley M.G., Robson T., Maillere B., Williamson E.D., Sriskandan S., Altmann D., Robinson J.H.. Repertoire of HLA-DR1-restricted CD4 T-cell responses to capsular Caf1 antigen of Yersinia pestis in human leukocyte antigen transgenic mice. Infect Immun. 2010; 78(10):4356–62. DOI: 10.1128/IAI.00195-10.Zvi A., Rotem S., Zauberman A., Elia U., Aftalion M., Bar-Haim E., Mamroud E., Cohen O. Novel CTL epitopes identified through a Y. pestis proteome-wide analysis in the search for vaccine candidates against plague. Vaccine. 2017; 35(44):5995–6006. DOI: 10.1016/j.vaccine.2017.05.092.Zvi A., Rotem S., Zauberman A., Elia U., Aftalion M., Bar-Haim E., Mamroud E., Cohen O. Novel CTL epitopes identified through a Y. pestis proteome-wide analysis in the search for vaccine candidates against plague. Vaccine. 2017; 35(44):5995–6006. DOI: 10.1016/j.vaccine.2017.05.092.Li B., Zhou L., Guo J., Wang X., Ni B., Ke Y., Yang R. High-throughput identification of new protective antigens from a Yersinia pestis live vaccine by enzyme-linked immunospot assay. Infect. Immun. 2009; 77(10):4356–61. DOI: 10.1128/IAI.00242-09.Li B., Zhou L., Guo J., Wang X., Ni B., Ke Y., Yang R. High-throughput identification of new protective antigens from a Yersinia pestis live vaccine by enzyme-linked immunospot assay. Infect. Immun. 2009; 77(10):4356–61. DOI: 10.1128/IAI.00242-09.Matson J.S., Durick K.A., Bradley D.S., Nilles M.L. Immunization of mice with YscF provides protection from Yersinia pestis infections. BMC Microbiol. 2005; 24(5):38. DOI: 10.1186/1471-2180-5-38.Matson J.S., Durick K.A., Bradley D.S., Nilles M.L. Immunization of mice with YscF provides protection from Yersinia pestis infections. BMC Microbiol. 2005; 24(5):38. DOI: 10.1186/1471-2180-5-38.Erova T., Rosenzweig J., Sha J., Suarez G., Sierra J., Kirtley M., van Lier C., Telepnev M., Motin V., Chopra A. Evaluation of protective potential of Yersinia pestis outer membrane protein antigens as possible candidates for a new-generation recombinant plague vaccine. Clin. Vaccine Immunol. 2013; 20(2):227–38. DOI: 10.1128/CVI.00597-12.Erova T., Rosenzweig J., Sha J., Suarez G., Sierra J., Kirtley M., van Lier C., Telepnev M., Motin V., Chopra A. Evaluation of protective potential of Yersinia pestis outer membrane protein antigens as possible candidates for a new-generation recombinant plague vaccine. Clin. Vaccine Immunol. 2013; 20(2):227–38. DOI: 10.1128/CVI.00597-12.Andrews G.P., Strachan S.T., Benner G.E., Sample A.K., Anderson G.W.Jr, Adamovicz J.J., Welkos S.L., Pullen J.K., Friedlander A.M. Protective efficacy of recombinant Yersinia outer proteins against bubonic plague caused by encapsulated and nonencapsulated Yersinia pestis. Infect. Immun. 1999; 67(3):1533–7. PMCID: PMC96493. PMID: 10024607.Andrews G.P., Strachan S.T., Benner G.E., Sample A.K., Anderson G.W.Jr, Adamovicz J.J., Welkos S.L., Pullen J.K., Friedlander A.M. Protective efficacy of recombinant Yersinia outer proteins against bubonic plague caused by encapsulated and nonencapsulated Yersinia pestis. Infect. Immun. 1999; 67(3):1533–7. PMCID: PMC96493. PMID: 10024607.Tao P., Mahalingam M., Zhu J., Moayeri M., Kirtley M.L., Fitts E.C., Andersson J.A., Lawrence W.S., Leppla S.H., Chopra A.K., Rao V.B. A Bivalent Anthrax-Plague Vaccine That Can Protect against Two Tier-1 Bioterror Pathogens, Bacillus anthracis and Yersinia pestis. Front. Immunol. 2017; 8:687. DOI: 10.3389/fimmu.2017.00687.Tao P., Mahalingam M., Zhu J., Moayeri M., Kirtley M.L., Fitts E.C., Andersson J.A., Lawrence W.S., Leppla S.H., Chopra A.K., Rao V.B. A Bivalent Anthrax-Plague Vaccine That Can Protect against Two Tier-1 Bioterror Pathogens, Bacillus anthracis and Yersinia pestis. Front. Immunol. 2017; 8:687. DOI: 10.3389/fimmu.2017.00687.Verma S., Batra L., Tuteja U. A Recombinant Trivalent Fusion Protein F1-LcrV-HSP70(II) Augments Humoral and Cellular Immune Responses and Imparts Full Protection against Yersinia pestis. Front. Microbiol. 2016; 7:1053. DOI: 10.3389/fmicb.2016.01053.Verma S., Batra L., Tuteja U. A Recombinant Trivalent Fusion Protein F1-LcrV-HSP70(II) Augments Humoral and Cellular Immune Responses and Imparts Full Protection against Yersinia pestis. Front. Microbiol. 2016; 7:1053. DOI: 10.3389/fmicb.2016.01053.Takeda K., Akira S. Toll-like receptors. Curr. Protoc. Immunol. 2015; 77(1):14.12.1–14.12.10. DOI: 10.1002/0471142735.im1412s77.Takeda K., Akira S. Toll-like receptors. Curr. Protoc. Immunol. 2015; 77(1):14.12.1–14.12.10. DOI: 10.1002/0471142735.im1412s77.Amemiya K., Meyers J.L., Rogers T.E., Fast R.L., Bassett A.D., Worsham P.L., Powell B.S., Norris S.L., Krieg A.M., Adamovicz J.J. CpG oligodeoxynucleotides augment the murine immune response to the Yersinia pestis F1-V vaccine in bubonic and pneumonic models of plague. Vaccine. 2009; 27(16):2220–9. DOI: 10.1016/j.vaccine.2009.02.016.Amemiya K., Meyers J.L., Rogers T.E., Fast R.L., Bassett A.D., Worsham P.L., Powell B.S., Norris S.L., Krieg A.M., Adamovicz J.J. CpG oligodeoxynucleotides augment the murine immune response to the Yersinia pestis F1-V vaccine in bubonic andHickey A.J., Lin J.S., Kummer L.W., Szaba F.M., Duso D.K., Tighe M., Parent M.A., Smiley S.T. Intranasal prophylaxis with CpG oligodeoxynucleotide can protect against Yersinia pestis infection. Infect. Immun. 2013; 81(6):2123–32. DOI: 10.1128/IAI.00316-13.pneumonic models of plague. Vaccine. 2009; 27(16):2220–9. DOI: 10.1016/j.vaccine.2009.02.016.Honko A.N., Sriranganathan N., Lees C.J., Mizel S.B. Flagellin is an effective adjuvant for immunization against lethal respiratory challenge with Yersinia pestis. Infect. Immun. 2006; 74(2):1113–20. DOI: 10.1128/IAI.74.2.1113-1120.2006.Hickey A.J., Lin J.S., Kummer L.W., Szaba F.M., Duso D.K., Tighe M., Parent M.A., Smiley S.T. Intranasal prophylaxis with CpG oligodeoxynucleotide can protect against Yersinia pestis infection. Infect. Immun. 2013; 81(6):2123–32. DOI: 10.1128/IAI.00316-13.Uppada J.B., Khan A.A., Bhat A.A., Deshmukh R., Rao D.N. Humoral immune responses and protective efficacy of sequential B- and T-cell epitopes of V antigen of Yersinia pestis by intranasal immunization in microparticles. Med. Microbiol. Immunol. 2009; 198(4):247–56. DOI: 10.1007/s00430-009-0124-7.Honko A.N., Sriranganathan N., Lees C.J., Mizel S.B. Flagellin is an effective adjuvant for immunization against lethal respiratory challenge with Yersinia pestis. Infect. Immun. 2006; 74(2):1113–20. DOI: 10.1128/IAI.74.2.1113-1120.2006.Do Y., Koh H., Park C.G., Dudziak D., Seo P., Mehandru S., Choi J.H., Cheong C., Park S., Perlin D.S., Powell B.S., Steinma R.M. Targeting of LcrV virulence protein from Yersinia pestis to dendritic cells protects mice against pneumonic plague. Eur. J. Immunol. 2010. 40(10):2791–6. DOI: 10.1002/eji.201040511.Uppada J.B., Khan A.A., Bhat A.A., Deshmukh R., Rao D.N. Humoral immune responses and protective efficacy of sequential B- and T-cell epitopes of V antigen of Yersinia pestis by intranasal immunization in microparticles. Med. Microbiol. Immunol. 2009; 198(4):247–56. DOI: 10.1007/s00430-009-0124-7.Jones A., Bosioa C., Duffya A., Goodyeara A., Schrieferb M., Dowa S. Protection against pneumonic plague following oral immunization with a non-replicating vaccine. Vaccine. 2010; 28(36):5924–9. DOI: 10.1016/j.vaccine.2010.06.020.Do Y., Koh H., Park C.G., Dudziak D., Seo P., Mehandru S., Choi J.H., Cheong C., Park S., Perlin D.S., Powell B.S., Steinma R.M. Targeting of LcrV virulence protein from Yersinia pestis to dendritic cells protects mice against pneumonic plague. Eur. J. Immunol. 2010. 40(10):2791–6. DOI: 10.1002/eji.201040511.Dinc G., Pennington J.M., Yolcu E.S., Lawrenz M.B., Shirwan H. Improving the Th1 cellular efficacy of the lead Yersinia pestis rF1-V subunit vaccine using SA-4-1BBL as a novel adjuvant. Vaccine. 2014; 32(39):5035–40. DOI: 10.1016/j.vaccine.2014.07.015.Jones A., Bosioa C., Duffya A., Goodyeara A., Schrieferb M., Dowa S. Protection against pneumonic plague following oral immunization with a non-replicating vaccine. Vaccine. 2010; 28(36):5924–9. DOI: 10.1016/j.vaccine.2010.06.020.Derbise A., Hanada Y., Khalifé M., Carniel E., Demeure C.E. Complete Protection against Pneumonic and Bubonic Plague after a Single Oral Vaccination. PLoS Negl. Trop. Dis. 2015; 9(10):e0004162. DOI: 10.1371/journal.pntd.0004162.Dinc G., Pennington J.M., Yolcu E.S., Lawrenz M.B., Shirwan H. Improving the Th1 cellular efficacy of the lead Yersinia pestis rF1-V subunit vaccine using SA-4-1BBL as a novel adjuvant. Vaccine. 2014; 32(39):5035–40. DOI: 10.1016/j.vaccine.2014.07.015.Demeure C.E., Derbise A., Carniel E. Oral vaccination against plague using Yersinia pseudotuberculosis. Chem. Biol. Interact. 2017; 267:89–95. DOI: 10.1016/j.cbi.2016.03.030.Derbise A., Hanada Y., Khalifé M., Carniel E., Demeure C.E. Complete Protection against Pneumonic and Bubonic Plague after a Single Oral Vaccination. PLoS Negl. Trop. Dis. 2015; 9(10):e0004162. DOI: 10.1371/journal.pntd.0004162.Demeure C.E., Derbise A., Guillas C., Gerke C., Cauchemez S., Carniel E., Pizarro-Cerdá J. Humoral and cellular immune correlates of protection against bubonic plague by a live Yersinia pseudotuberculosis vaccine. Vaccine. 2019; 37(1):123–9. DOI: 10.1016/j.vaccine.2018.11.022.Demeure C.E., Derbise A., Carniel E. Oral vaccination against plague using Yersinia pseudotuberculosis. Chem. Biol. Interact. 2017; 267:89–95. DOI: 10.1016/j.cbi.2016.03.030.Yang X., Hinnebusch B.J., Trunkle T., Bosio C.M, Suo Z., Tighe M., Harmsen A., Becker T., Crist K., Walters N., Avci R., Pascual D.W. Oral vaccination with Salmonella simultaneously expressing Yersinia pestis F1 and V antigens protects against bubonic and pneumonic plague. J. Immunol. 2007; 178(20):1059–67. PMID: 17202369.Demeure C.E., Derbise A., Guillas C., Gerke C., Cauchemez S., Carniel E., Pizarro-Cerdá J. Humoral and cellular immune correlates of protection against bubonic plague by a live Yersinia pseudotuberculosis vaccine. Vaccine. 2019; 37(1):123–9. DOI: 10.1016/j.vaccine.2018.11.022.Sun W., Roland K., Curtiss R. Developing live vaccines against plague. J. Infect. Dev. Ctries. 2011; 5:614–27. DOI: 10.3855/jidc.2030.Yang X., Hinnebusch B.J., Trunkle T., Bosio C.M, Suo Z., Tighe M., Harmsen A., Becker T., Crist K., Walters N., Avci R., Pascual D.W. Oral vaccination with Salmonella simultaneously expressing Yersinia pestis F1 and V antigens protects against bubonic and pneumonic plague. J. Immunol. 2007; 178(20):1059–67. PMID:17202369.Branger C.G., Sun W., Torres-Escobar A., Perry R., Roland K.L., Fetherston J., Curtiss R. 3rd. Evaluation of Psn HmuR and a modified LcrV protein delivered to mice by live attenuated Salmonella as a vaccine against bubonic and pneumonic Yersinia pestis challenge. Vaccine. 2010; 29(2):274–82. DOI: 10.1016/j.vaccine.2010.10.033.Sun W., Roland K., Curtiss R. Developing live vaccines against plague. J. Infect. Dev. Ctries. 2011; 5:614–27. DOI: 10.3855/jidc.2030.Sanapala S., Rahav H., Patel H., Sun W., Curtiss R. Multiple antigens of Yersinia pestis delivered by live recombinant attenuated Salmonella vaccine strains elicit protective immunity against plague. Vaccine. 2016; 34(21):2410–16. DOI: 10.1016/j.vaccine.2016.03.094.Branger C.G., Sun W., Torres-Escobar A., Perry R., Roland K.L., Fetherston J., Curtiss R. 3rd. Evaluation of Psn HmuR and a modified LcrV protein delivered to mice by live attenuated Salmonella as a vaccine against bubonic and pneumonic Yersinia pestis challenge. Vaccine. 2010; 29(2):274–82. DOI: 10.1016/j.vaccine.2010.10.033.Jia Q., Bowen R., Dillon B.J., Masleša-Galić S., Chang B.T., Kaidi A.C., Horwitz M.A. Single vector platform vaccine protects against lethal respiratory challenge with Tier 1 select agents of anthrax, plague, and tularemia. Sci. Rep. 2018; 8(1):7009. DOI: 10.1038/s41598-018-24581-y.Sanapala S., Rahav H., Patel H., Sun W., Curtiss R. Multiple antigens of Yersinia pestis delivered by live recombinant attenuated Salmonella vaccine strains elicit protective immunity against plague. Vaccine. 2016; 34(21):2410–16. DOI: 10.1016/j.Chattopadhyaya A., Park S., Delmas G., Suresh R., Senina S., Perlin D.S., Rose J.K. Single-dose, virus-vectored vaccine protection against Yersinia pestis challenge: CD4+ cells are required at the time of challenge for optimal protection. Vaccine. 2008; 26(50):6329–37. DOI: 10.1016/j.vaccine.2008.09.031.vaccine.2016.03.094.Arnaboldi P.M., Sambir M., D’Arco C., Peters L.A., Seegers J.F., Mayer L., McCormick A.A., Dattwyler R.J. Intranasal delivery of a protein subunit vaccine using a Tobacco Mosaic Virus platform protects against pneumonic plague. Vaccine. 2016; 34(47):5768–76. DOI: 10.1016/j.vaccine.2016.09.063.Jia Q., Bowen R., Dillon B.J., Masleša-Galić S., Chang B.T., Kaidi A.C., Horwitz M.A. Single vector platform vaccine protects against lethal respiratory challenge with Tier 1 select agents of anthrax, plague, and tularemia. Sci. Rep. 2018; 8(1):7009. DOI: 10.1038/s41598-018-24581-y.Brewoo J.N., Powell T.D., Stinchcomb D.T., Osorio J.E. Efficacy and safety of a modified vaccinia Ankara (MVA) vectored plague vaccine in mice. Vaccine. 2010; 28(36):5891–9. DOI: 10.1016/j.vaccine.2010.06.054.Chattopadhyaya A., Park S., Delmas G., Suresh R., Senina S., Perlin D.S., Rose J.K. Single-dose, virus-vectored vaccine protection against Yersinia pestis challenge: CD4+ cells are required at the time of challenge for optimal protection. Vaccine. 2008; 26(50):6329–37. DOI: 10.1016/j.vaccine.2008.09.031.Boyer J.L., Sofer-Podesta C., Ang J., Hackett N.R., Chiuchiolo M.J., Senina S., Perlin D., Crystal R.G. Protective immunity against a lethal respiratory Yersinia pestis challenge induced by V antigen or the F1 capsular antigen incorporated into adenovirus capsid. Hum. Gene Ther. 2010; 21(7):891–901. DOI: 10.1089/hum.2009.148.Arnaboldi P.M., Sambir M., D’Arco C., Peters L.A., Seegers J.F., Mayer L., McCormick A.A., Dattwyler R.J. Intranasal delivery of a protein subunit vaccine using a Tobacco Mosaic Virus platform protects against pneumonic plague. Vaccine. 2016; 34(47):5768–76. DOI: 10.1016/j.vaccine.2016.09.063.Chiuchiolo M.J., Boyer J.L., Krause A., Senina S., Hackett N.R., Crystal R.G. Protective immunity against respiratory tract challenge with Yersinia pestis in mice immunized with an adenovirusbased vaccine vector expressing V antigen. J. Infect. Dis. 2006; 194:1249–57. DOI: 10.1086/507644.Brewoo J.N., Powell T.D., Stinchcomb D.T., Osorio J.E. Efficacy and safety of a modified vaccinia Ankara (MVA) vectored plague vaccine in mice. Vaccine. 2010; 28(36):5891–9. DOI: 10.1016/j.vaccine.2010.06.054.Sha J., Kirtley M.L., Klages C., Erova T.E., Telepnev M., Ponnusamy D., Fitts E.C., Baze W.B., Sivasubramani S.K., Lawrence W.S., Patrikeev I., Peel J.E., Andersson J.A., Kozlova E.V., Tiner B.L., Peterson J.W., McWilliams D., Patel S., Rothe E., Motin V.L., Chopra A.K. A Replication-Defective Human Type 5 Adenovirus-Based Trivalent Vaccine Confers Complete Protection against Plague in Mice and Nonhuman Primates. Clin. Vaccine Immunol. 2016; 23(7):586–600. DOI: 10.1128/CVI.00150-16.Boyer J.L., Sofer-Podesta C., Ang J., Hackett N.R., Chiuchiolo M.J., Senina S., Perlin D., Crystal R.G. Protective immunity against a lethal respiratory Yersinia pestis challenge induced by V antigen or the F1 capsular antigen incorporated into adenovirus capsid. Hum. Gene Ther. 2010; 21(7):891–901. DOI: 10.1089/hum.2009.148.Tao P., Mahalingam M., Kirtley M.L., van Lier C.J., Sha J., Yeager L.A., Chopra A.K., Rao V.B. Mutated and bacteriophage T4 nanoparticle arrayed F1-V immunogens from Yersinia pestis as next generation plague vaccines. PLOS Pathogens. 2013; 9(7):e1003495. DOI: 10.1371/journal.ppat.1003495.Chiuchiolo M.J., Boyer J.L., Krause A., Senina S., Hackett N.R., Crystal R.G. Protective immunity against respiratory tract challenge with Yersinia pestis in mice immunized with an adenovirusbased vaccine vector expressing V antigen. J. Infect. Dis. 2006; 194:1249–57. DOI: 10.1086/507644.Tao P., Mahalingam M., Zhu J., Moayeri M., Sha J., Lawrence W.S., Leppla S.H., Chopra A.K., Rao V.B. A Bacteriophage T4 Nanoparticle-Based Dual Vaccine against Anthrax and Plague. MBio. 2018; 9(5):e01926-18. DOI: 10.1128/mBio.01926-18.Sha J., Kirtley M.L., Klages C., Erova T.E., Telepnev M., Ponnusamy D., Fitts E.C., Baze W.B., Sivasubramani S.K., Lawrence W.S., Patrikeev I., Peel J.E., Andersson J.A., Kozlova E.V., Tiner B.L., Peterson J.W., McWilliams D., Patel S., Rothe E., Motin V.L., Chopra A.K. A Replication-Defective Human Type 5 Adenovirus-Based Trivalent Vaccine Confers Complete Protection against Plague in Mice and Nonhuman Primates. Clin. Vaccine Immunol. 2016; 23(7):586–600. DOI: 10.1128/CVI.00150-16.Агеев С.А., Шайхутдинова П.З., Бахтеева И.В., Титарева Г.М., Комбарова Т.И., Дентовская С.В., Анисимов А.П. Конструирование кандидата в вакцинные штаммы Yersinia pestis с пониженной реактогенностью. Проблемы особо опасных инфекций. 2011; 1:70–3. DOI: 10.21055/0370-1069-2011-1(107)-70-73.Tao P., Mahalingam M., Kirtley M.L., van Lier C.J., Sha J., Yeager L.A., Chopra A.K., Rao V.B. Mutated and bacteriophage T4 nanoparticle arrayed F1-V immunogens from Yersinia pestis as next generation plague vaccines. PLOS Pathogens. 2013; 9(7):e1003495. DOI: 10.1371/journal.ppat.1003495.Rebeil R., Ernst R.K., Jarrett C.O., Adams K.N., Miller S.I., Hinnebusch B.J. Characterization of late acyltransferase genes of Yersinia pestis and their role in temperature-dependent lipid A variation. J. Bacteriol. 2006; 188:1381–8. DOI: 10.1128/JB.188.4.1381-1388.2006.Tao P., Mahalingam M., Zhu J., Moayeri M., Sha J., Lawrence W.S., Leppla S.H., Chopra A.K., Rao V.B. A Bacteriophage T4 Nanoparticle-Based Dual Vaccine against Anthrax and Plague. MBio. 2018; 9(5):e01926-18. DOI: 10.1128/mBio.01926-18.Szaba F.M., Kummer L.W., Wilhelm L.B., Lin J.S., Parent M.A., Montminy-Paquette S.W., Lien E., Johnson L.L., Smiley S.T. D27-pLpxL, an avirulent strain of Yersinia pestis, primes T cells that protect against pneumonic plague. Infect. Immun. 2008; 77:4295–304. DOI: 10.1128/IAI.00273-09.Ageev S.A., Shaikhutdinova R.Z., Bakhteeva I.V., Titareva G.M., Kombarova T.I., Dentovskaya S.V., Anisimov A.P. [Construction of candidate Yersinia pestis vaccine strains with reduced reactogenicity]. Problemy Osobo Opasnykh Infektsii [Problems of Particularly Dangerous Infections]. 2011; (1):70–3. DOI: 10.21055/0370-1069-2011-1(107)-70-73.Sun W., Six D., Kuang X., Roland K.L., Raetz C.R., Curtiss R. 3rd. A live attenuated strain of Yersinia pestis KIM as a vaccine against plague. Vaccine. 2011; 29(16):2986–98. DOI: 10.1016/j.vaccine.2011.01.099.Rebeil R., Ernst R.K., Jarrett C.O., Adams K.N., Miller S.I., Hinnebusch B.J. Characterization of late acyltransferase genes of Yersinia pestis and their role in temperature-dependent lipid A variation. J. Bacteriol. 2006; 188:1381–8. DOI: 10.1128/JB.188.4.1381-1388.2006.Tiner B.L., Sha J., Cong Y., Kirtley M.L., Andersson J.A., Chopra A.K. Immunisation of two rodent species with new live-attenuated mutants of Yersinia pestis CO92 induces protective long-term humoral- and cell-mediated immunity against pneumonic plague. NPJ Vaccines. 2016; 1:16020. DOI: 10.1038/npjvaccines.2016.20.Szaba F.M., Kummer L.W., Wilhelm L.B., Lin J.S., Parent M.A., Montminy-Paquette S.W., Lien E., Johnson L.L., Smiley S.T. D27-pLpxL, an avirulent strain of Yersinia pestis, primes T cells that protect against pneumonic plague. Infect. Immun. 2008; 77:4295–304. DOI: 10.1128/IAI.00273-09.Sha J., Kirtley M.L., van Lier C.J., Wang S., Erova T.E., Kozlova E.V., Cao A., Cong Y., Fitts E.C., Rosenzweig J.A., Chopra A.K. Deletion of the Braun lipoprotein-encoding gene and altering the function of lipopolysaccharide attenuate the plague bacterium. Infect. Immun. 2013; 81(3):815–28. DOI: 10.1128/IAI.01067-12.Sun W., Six D., Kuang X., Roland K.L., Raetz C.R., Curtiss R. 3rd. A live attenuated strain of Yersinia pestis KIM as a vaccine against plague. Vaccine. 2011; 29(16):2986–98. DOI: 10.1016/j.vaccine.2011.01.099.van Lier C.J., Sha J., Kirtley M.L., Cao A., Tiner B.L., Erova T.E., Cong Y., Kozlova E.V., Popov V.L., Baze W.B., Chopra A.K. Deletion of Braun lipoprotein and plasminogen-activating protease-encoding genes attenuates Yersinia pestis in mouse models of bubonic and pneumonic plague. Infect. Immun. 2014; 82(6):2485–503. DOI: 10.1128/IAI.01595-13.Tiner B.L., Sha J., Cong Y., Kirtley M.L., Andersson J.A., Chopra A.K. Immunisation of two rodent species with new live-attenuated mutants of Yersinia pestis CO92 induces protective long-term humoral- and cell-mediated immunity against pneumonic plague. NPJ Vaccines. 2016; 1:16020. DOI: 10.1038/npjvaccines.2016.20.Tiner B.L., Sha J. Kirtley M.L., Erova T.E., Popov V.L., Baze W.B., van Lier C.J., Ponnusamy D., Andersson J.A., Motin V.L., Chauhan S., Chopra A.K. Combinational deletion of three membraneSha J., Kirtley M.L., van Lier C.J., Wang S., Erova T.E., Kozlova E.V., Cao A., Cong Y., Fitts E.C., Rosenzweig J.A., Chopra A.K. Deletion of the Braun lipoprotein-encoding gene and altering the function of lipopolysaccharide attenuate the plague bacterium. Infect. Immun. 2013; 81(3):815–28. DOI: 10.1128/IAI.01067-12.protein-encoding genes highly attenuates Yersinia pestis while retaining immunogenicity in a mouse model of pneumonic plague. Infect. Immun. 2015; 83(4):1318–38. DOI: 10.1128/IAI.02778-14.van Lier C.J., Sha J., Kirtley M.L., Cao A., Tiner B.L., Erova T.E., Cong Y., Kozlova E.V., Popov V.L., Baze W.B., Chopra A.K. Deletion of Braun lipoprotein and plasminogen-activating protease-encoding genes attenuates Yersinia pestis in mouse models of bubonic and pneumonic plague. Infect. Immun. 2014; 82(6):2485–503. DOI: 10.1128/IAI.01595-13.Andersson J.A., Sha J., Erova T.E., Fitts E.C., Ponnusamy D., Kozlova E.V., Kirtley M.L., Chopra A.K. Identification of New Virulence Factors and Vaccine Candidates for Yersinia pestis. Front. Cell Infect. Microbiol. 2017; 7:448. DOI: 10.3389/fcimb.2017.00448.Tiner B.L., Sha J. Kirtley M.L., Erova T.E., Popov V.L., Baze W.B., van Lier C.J., Ponnusamy D., Andersson J.A., Motin V.L., Chauhan S., Chopra A.K. Combinational deletion of three membrane protein-encoding genes highly attenuates Yersinia pestis while retaining immunogenicity in a mouse model of pneumonic plague. Infect. Immun. 2015; 83(4):1318–38. DOI: 10.1128/IAI.02778-14.Bubeck S.S., Dube P.H. Yersinia pestis CO92 delta yopH is a potent live, attenuated plague vaccine. Clin Vaccine Immunol. 2007; 14(9):1235–8. DOI: 10.1128/CVI.00137-07.Andersson J.A., Sha J., Erova T.E., Fitts E.C., Ponnusamy D., Kozlova E.V., Kirtley M.L., Chopra A.K. Identification of New Virulence Factors and Vaccine Candidates for Yersinia pestis. Front. Cell Infect. Microbiol. 2017; 7:448. DOI: 10.3389/fcimb.2017.00448.Tidhar A., Flashner Y., Cohen S., Levi Y., Zauberman A., Gur D., Gur D., Aftalion M., Elhanany E., Zvi A., Shafferman A., Mamroud E. The NlpD lipoprotein is a novel Yersinia pestis virulence factor essential for the development of plague. PLoS One. 2009; 4(9):e7023. DOI: 10.1371/journal.pone.0007023.Bubeck S.S., Dube P.H. Yersinia pestis CO92 delta yopH is a potent live, attenuated plague vaccine. Clin Vaccine Immunol. 2007; 14(9):1235–8. DOI: 10.1128/CVI.00137-07.Flashner Y., Mamroud E., Tidhar A., Ber R., Aftalion M., Gur D., Lazar S., Zvi A., Bino T., Ariel N., Velan B., Shafferman A., Cohen S. Generation of Yersinia pestis attenuated strains by signature-tagged mutagenesis in search of novel vaccine candidates. Infect. Immun. 2004; 72(2):908–15. PMID: 14742535. PMCID: PMC321629.Tidhar A., Flashner Y., Cohen S., Levi Y., Zauberman A., Gur D., Gur D., Aftalion M., Elhanany E., Zvi A., Shafferman A., Mamroud E. The NlpD lipoprotein is a novel Yersinia pestis virulence factor essential for the development of plague. PLoS One. 2009; 4(9):e7023. DOI: 10.1371/journal.pone.0007023.Robinson V.L., Oyston P.C., Titball R.W. A dam mutant of Yersinia pestis is attenuated and induces protection against plague. FEMS Microbiol. Lett. 2005; 252(2):251–6. DOI: 10.1016/j.femsle.2005.09.001.Flashner Y., Mamroud E., Tidhar A., Ber R., Aftalion M., Gur D., Lazar S., Zvi A., Bino T., Ariel N., Velan B., Shafferman A., Cohen S. Generation of Yersinia pestis attenuated strains by signature-tagged mutagenesis in search of novel vaccine candidates. Infect. Immun. 2004; 72(2):908–15. PMID: 14742535. PMCID: PMC321629.Oyston P.C., Mellado-Sanchez G., Pasetti M.F., Nataro J.P., Titball R.W., Atkins H.S. A Yersinia pestis guaBA mutant is attenuated in virulence and provides protection against plague in a mouse model of infection. Microb. Pathog. 2010; 48(5):191–5. DOI: 10.1016/j.micpath.2010.01.005.Robinson V.L., Oyston P.C., Titball R.W. A dam mutant of Yersinia pestis is attenuated and induces protection against plague. FEMS Microbiol. Lett. 2005; 252(2):251–6. DOI: 10.1016/j.femsle.2005.09.001.Oyston P.C., Mellado-Sanchez G., Pasetti M.F., Nataro J.P., Titball R.W., Atkins H.S. A Yersinia pestis guaBA mutant is attenuated in virulence and provides protection against plague in a mouse model of infection. Microb. Pathog. 2010; 48(5):191–5. DOI: 10.1016/j.micpath.2010.01.005.Oyston P.C., Mellado-Sanchez G., Pasetti M.F., Nataro J.P., Titball R.W., Atkins H.S. A Yersinia pestis guaBA mutant is attenuated in virulence and provides protection against plague in a mouse model of infection. Microb. Pathog. 2010; 48(5):191–5. DOI: 10.1016/j.micpath.2010.01.005.

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