microbeПроблемы особо опасных инфекцийProblems of Particularly Dangerous Infections0370-10692658-719XRussian Research Anti-Plague Institute “Microbe”10.21055/0370-1069-2025-1-105-111microbe-2121Research ArticleОБЗОРЫREVIEWSАнтивекторный иммунный ответ, формируемый при применении рекомбинантных вакцин на основе вируса вакцины, штамм MVAAnti-Vector Immune Response Formed after Immunization with Recombinant Vaccines Based on the Vaccinia Virus, MVA Strainhttps://orcid.org/0000-0002-7985-5516СтовбаЛ. Ф.StovbaL. F.

141306, Московская обл., Сергиев Посад.

Sergiev Possad, Moscow Region, 141306

https://orcid.org/0000-0002-1491-6293ЧерниковаН. К.ChernikovaN. K.

141306, Московская обл., Сергиев Посад.

Sergiev Possad, Moscow Region, 141306

ХмелевА. Л.KhmelevA. L.

141306, Московская обл., Сергиев Посад.

Sergiev Possad, Moscow Region, 141306

https://orcid.org/0000-0002-6742-3919БорисевичС. В.BorisevichS. V.

141306, Московская обл., Сергиев Посад.

Sergiev Possad, Moscow Region, 141306

48cnii@mil.ruФГБУ «48 Центральный научно-исследовательский институт» Министерства обороны Российской ФедерацииРоссия48th Central Research Institute of the Ministry of Defense of the Russian FederationRussian Federation20250704202501105111Copyright © Стовба Л.Ф., Черникова Н.К., Хмелев А.Л., Борисевич С.В., 20252025Стовба Л.Ф., Черникова Н.К., Хмелев А.Л., Борисевич С.В.Stovba L.F., Chernikova N.K., Khmelev A.L., Borisevich S.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/2121

Поиск безопасных путей первичной иммунизации взрослого населения в условиях отсутствия популяционного иммунитета к ортопоксвирусам в случае необходимости возобновления оспопрививания в настоящее время очень актуален. Вместе с тем клинические испытания рекомбинантных вакцин на основе вируса вакцины (штамм MVA) против различных заболеваний подтверждают их безопасность для людей и, помимо целевой эффективности (способности индуцировать иммунитет на белки, экспрессируемые встроенными чужеродными генами), иммуногенность в отношении вектора – вируса вакцины. Цель обзора – анализ уровня антивекторного иммунитета при иммунизации людей рекомбинантными вакцинами на основе вируса вакцины, штамм MVA. Представлены конкретные экспериментальные данные об уровне антивекторного иммунитета в ответ на иммунизацию рекомбинантными вакцинами в различных странах. В основном эти исследования выполнены при испытании рекомбинантов, содержащих встроенные иммунодоминантные гены вируса иммунодефицита человека (ВИЧ), поскольку их количество значительно превышает количество остальных рекомбинантных препаратов на основе вируса вакцины, они успешно применяются в медицинской практике и безопасны даже для лиц с иммунодефицитными состояниями. Полученные результаты свидетельствуют о повышении уровня антивекторного иммунитета с увеличением дозы вакцины и о достижении максимальных значений его показателей после двукратного введения вакцин. Дальнейшее увеличение кратности иммунизации не приводило к повышению титров специфических антител, а затем их количество снижалось в течение года и более. Помимо гуморального иммунного ответа, выявлена стимуляция факторов клеточного антивекторного иммунитета, представленного в основном полифункциональными CD8+  Т-клетками. Встраивание чужеродных генов не влияло на формирование антивекторного иммунитета, так же как и его уровень не оказывал влияния на развитие гуморального и клеточного иммунного ответа к белкам, экспрессируемым встроенными генами. Сравнительная характеристика показателей антивекторного иммунитета после иммунизации рекомбинантными вакцинами и специфического иммунитета в ответ на вакцину IMVAMUNE® свидетельствовала, что их уровни либо соответствовали друг другу, либо в первом случае их значения даже были выше.

The search for safe approaches to primary immunization of the adult population under the absence of herd immunity to orthopoxviruses, when re-initiation of smallpox vaccination campaign is required, is currently very relevant. Thereat, the clinical trials of recombinant vaccines based on the vaccinia virus, MVA strain, against different illnesses confirm that they are safe for humans and in addition to target efficiency (capacity to induce immunity to proteins expressed by embedded foreign genes), show immunogenicity to vector – vaccinia virus. The aim of the review was to evaluate anti-vector immunity level in people immunized by recombinant viral vaccines, based on vaccinia virus, MVA strain. Explicit experimental data on the level of anti-vector immunity in response to immunization with recombinant vaccines in different countries of the world are presented. Those studies were mainly carried out with recombinants containing embedded immunodominant genes of human immunodeficiency virus (HIV), as the number of works on the creation of recombinant vaccines expressing the antigen determinants of HIV significantly exceeds the number of those on recombinant preparations based on vaccinia virus; the vaccines are successfully used in medical practice and are safe even for people with immunodeficiency conditions. The results obtained indicated an increase in anti-vector immunity with escalation of vaccine dose and peak indicators after two immunizations. Further injections of the vaccine did not lead to increase in the virus neutralizing antibodies, their production gradually decreased over a period of one year or more. In addition to the humoral immune response, cellular anti-vector immunity, represented mainly by CD8+ T-cells, was induced. The insertion of foreign genes did not affect the formation of anti-vector immunity, just as its level did not affect the development of humoral and cellular immune responses to proteins expressed by the embedded genes. Comparative characterization of the anti-vector immunity indices after immunization with recombinant vaccines and specific immunity in response to the IMVAMUNE® vaccine showed that their levels either corresponded to each other, or in the first case the values were even higher.

вирус вакциныортопоксвирусыантивекторный иммунитетклинические испытанияиммунодоминантные антигеныантителаклеточный иммунитетvaccinia virusorthopoxvirusesanti-vector immunityclinical trialsimmunodominant antigensantibodiescellular immunityReferencesSilva N.I.O., de Oliveira J.S., Kroon E.G., Trindade G.S., Drumond B.P. Here, there, and everywhere: The wide host range and geographic distribution of zoonotic orthopoxviruses. Viruses. 2020; 13(1):43. DOI: 10.3390/v13010043.Silva N.I.O., de Oliveira J.S., Kroon E.G., Trindade G.S., Drumond B.P. Here, there, and everywhere: The wide host range and geographic distribution of zoonotic orthopoxviruses. Viruses. 2020; 13(1):43. DOI: 10.3390/v13010043.Gao J., Gigante C., Khmaladze E., Liu P., Tang S., Wilkins K., Zhao K., Davidson W., Nakazawa Y., Maghlakelidze G., Geleishvili M., Kokhreidze M., Carroll D.S., Emerson G., Li Y. Genome sequences of Akhmeta virus, an early divergent old world orthopoxvirus. Viruses. 2018; 10(5):252. DOI: 10.3390/v10050252.Gao J., Gigante C., Khmaladze E., Liu P., Tang S., Wilkins K., Zhao K., Davidson W., Nakazawa Y., Maghlakelidze G., Geleishvili M., Kokhreidze M., Carroll D.S., Emerson G., Li Y. Genome sequences of Akhmeta virus, an early divergent old world orthopoxvirus. Viruses. 2018; 10(5):252. DOI: 10.3390/v10050252.Cardetti G., Gruber C.E.M., Eleni C., Carletti F., Castilletti C., Manna G., Rosone F., Giombini E., Selleri M., Lapa D., Puro V., Di Caro A., Lorenzetti R., Scicluna M.T., Grifoni G., Rizzoli A., Tagliapietra V., De Marco L., Capobianchi M.R., Autorino G.L. Fatal outbreak in Tonkean macaques cause by possible novel orthopoxvirus, Italy, January 2015. Emerg. Infect. Dis. 2017; 23(12):1941–9. DOI: 10.3201/eid2312.162098.Cardetti G., Gruber C.E.M., Eleni C., Carletti F., Castilletti C., Manna G., Rosone F., Giombini E., Selleri M., Lapa D., Puro V., Di Caro A., Lorenzetti R., Scicluna M.T., Grifoni G., Rizzoli A., Tagliapietra V., De Marco L., Capobianchi M.R., Autorino G.L. Fatal outbreak in Tonkean macaques cause by possible novel orthopoxvirus, Italy, January 2015. Emerg. Infect. Dis. 2017; 23(12):1941–9. DOI: 10.3201/eid2312.162098.Gruber C.E.M., Giombini E., Selleri M., Tausch S.H., Andrusch A., Tyshaieva A., Cardeti G., Lorenzetti R., De Marco L., Carletti F., Nitsche A., Capobianchi M.R., Ippolito G., Autorino G.L., Castilletti C. Whole genome characterization of orthopoxvirus (OPV) Abatino, a zoonotic virus representing a putative novel clade of old world orthopoxvirus. Viruses. 2018; 10(10):546. DOI: 10.3390/v10100546.Gruber C.E.M., Giombini E., Selleri M., Tausch S.H., Andrusch A., Tyshaieva A., Cardeti G., Lorenzetti R., De Marco L., Carletti F., Nitsche A., Capobianchi M.R., Ippolito G., Autorino G.L., Castilletti C. Whole genome characterization of orthopoxvirus (OPV) Abatino, a zoonotic virus representing a putative novel clade of old world orthopoxvirus. Viruses. 2018; 10(10):546. DOI: 10.3390/v10100546.Gigante C.M., Gao J., Tang S., McCollum A.M., Wilkins K., Reynolds M.G., Davidson W., McLaughlin J., Olson V.A., Li Y. Genome of Alaskapox virus, a novel orthopoxvirus isolated from Alaska. Viruses. 2019; 11(8):708. DOI: 10.3390/v11080708.Gigante C.M., Gao J., Tang S., McCollum A.M., Wilkins K., Reynolds M.G., Davidson W., McLaughlin J., Olson V.A., Li Y. Genome of Alaskapox virus, a novel orthopoxvirus isolated from Alaska. Viruses. 2019; 11(8):708. DOI: 10.3390/v11080708.Gorse G.J., Newman M.J., deCamp A., Hay C.M., De Rosa S.C., Noonan E., Livingston B.D., Fuchs J.D., Kalams S.A., CassisGhavami F.L.; NIAID HIV Vaccine Trials Network. DNA and modified vaccinia virus Ankara vaccines encoding multiple cytotoxic and helper T-lymphocyte epitopes of human immunodeficiency virus type 1 (HIV-1) are safe but weakly immunogenic in HIV-1-uninfected, vaccinia virus-naive adults. Clin. Vaccine Immunol. 2012; 19(5):649–58. DOI: 10.1128/CVI.00038-12.Gorse G.J., Newman M.J., deCamp A., Hay C.M., De Rosa S.C., Noonan E., Livingston B.D., Fuchs J.D., Kalams S.A., CassisGhavami F.L.; NIAID HIV Vaccine Trials Network. DNA and modified vaccinia virus Ankara vaccines encoding multiple cytotoxic and helper T-lymphocyte epitopes of human immunodeficiency virus type 1 (HIV-1) are safe but weakly immunogenic in HIV-1-uninfected, vaccinia virus-naive adults. Clin. Vaccine Immunol. 2012; 19(5):649–58. DOI: 10.1128/CVI.00038-12.Vasan S., Schlesinger S.J., Chen Z., Hurley A., Lombardo A., Than S., Adesanya P., Bunce C., Boaz M., Boyle R., Sayeed E., Clark L., Dugin D., Boente-Carrera M., Schmidt C., Fang Q., LeiBa, Huang Y., Zaharatos G.J., Gardiner D.F., Caskey M., Seamons L., Ho M., Dally L., Smith C., Cox J., Gill D., Gilmour J., Keefer M.C., Fast P., Ho D.D. Phase 1 safety and immunogenicity evaluation of ADMVA, a multigenic, modified vaccinia Ankara-HIV-1B'/C candidate vaccine. PLoS One. 2010; 5(1):e8816. DOI: 10.1371/journal. pone.0008816.Vasan S., Schlesinger S.J., Chen Z., Hurley A., Lombardo A., Than S., Adesanya P., Bunce C., Boaz M., Boyle R., Sayeed E., Clark L., Dugin D., Boente-Carrera M., Schmidt C., Fang Q., LeiBa, Huang Y., Zaharatos G.J., Gardiner D.F., Caskey M., Seamons L., Ho M., Dally L., Smith C., Cox J., Gill D., Gilmour J., Keefer M.C., Fast P., Ho D.D. Phase 1 safety and immunogenicity evaluation of ADMVA, a multigenic, modified vaccinia Ankara-HIV-1B'/C candidate vaccine. PLoS One. 2010; 5(1):e8816. DOI: 10.1371/journal. pone.0008816.Walsh S.R., Seaman M.S., Grandpre L.E. Charbonneau C., Yanosick K.E., Metch B., Keefer M.C., Dolin R., Baden L.R. Impact of anti-orthopoxvirus neutralizing antibodies induced by heterologous prime-boost HIV-1 vaccine on insert-specific immune responses. Vaccine. 2012; 31(1):114–9. DOI: 10.1016/jvaccine.2012.10.093.Walsh S.R., Seaman M.S., Grandpre L.E. Charbonneau C., Yanosick K.E., Metch B., Keefer M.C., Dolin R., Baden L.R. Impact of anti-orthopoxvirus neutralizing antibodies induced by heterologous prime-boost HIV-1 vaccine on insert-specific immune responses. Vaccine. 2012; 31(1):114–9. DOI: 10.1016/jvaccine.2012.10.093.Sandström E., Nilsson C., Hejdeman B., Bråve A., Bratt G., Robb M., Cox J., Vancott T., Marovich M., Stout R., Aboud S., Bakari M., Pallangyo K., Ljungberg K., Moss B., Earl P., Michael N., Birx D., Mhalu F., Wahren B., Biberfeld G.; HIV Immunogenicity Study 01/02 Team. Broad immunogenicity of a multigene, multiclade HIV-1 DNA vaccine boosted with heterologous HIV-1 recombinant modified vaccinia virus Ankara. J. Infect. Dis. 2008; 198(10):1482– 90. DOI: 10.1086/592507.Sandström E., Nilsson C., Hejdeman B., Bråve A., Bratt G., Robb M., Cox J., Vancott T., Marovich M., Stout R., Aboud S., Bakari M., Pallangyo K., Ljungberg K., Moss B., Earl P., Michael N., Birx D., Mhalu F., Wahren B., Biberfeld G.; HIV Immunogenicity Study 01/02 Team. Broad immunogenicity of a multigene, multiclade HIV-1 DNA vaccine boosted with heterologous HIV-1 recombinant modified vaccinia virus Ankara. J. Infect. Dis. 2008; 198(10):1482– 90. DOI: 10.1086/592507.Nilsson C., Godoy-Ramirez K., Hejdeman B., Bråve A., Gudmundsdotter L., Hallengärd D., Currier J.R., Wieczorek L., Hasselrot K., Earl P.L., Polonis V.R., Marovich M.A., Robb M.L., Sandström E., Wahren B., Biberfeld G. Broad and potent cellular and humoral immune responses after a second late HIV-modified vaccinia virus Ankara vaccination in HIV-DNA-primed and HIV-modified vaccinia virus Ankara-boosted Swedish vaccinees. AIDS Res. Hum. Retroviruses. 2014; 30(3):299–311. DOI: 10.1089/AID.2013.0149.Nilsson C., Godoy-Ramirez K., Hejdeman B., Bråve A., Gudmundsdotter L., Hallengärd D., Currier J.R., Wieczorek L., Hasselrot K., Earl P.L., Polonis V.R., Marovich M.A., Robb M.L., Sandström E., Wahren B., Biberfeld G. Broad and potent cellular and humoral immune responses after a second late HIV-modified vaccinia virus Ankara vaccination in HIV-DNA-primed and HIV-modified vaccinia virus Ankara-boosted Swedish vaccinees. AIDS Res. Hum. Retroviruses. 2014; 30(3):299–311. DOI: 10.1089/AID.2013.0149.García F., Bernaldo de Quirós J.C.L., Gómez C.E., Perdiguero B., Nájera J.L., Jiménez V., García-Arriaza J., Guardo A.C., Pérez I., Díaz-Brito V., Conde M.S., González N., Alvarez A., Alcamí J., Jiménez J.L., Pich J., Arnaiz J.A., Maleno M.J., León A., Muñoz-Fernández M.A., Liljeström P., Weber J., Pantaleo G., Gatell J.M., Plana M., Esteban M. Safety and immunogenicity of a modified pox vector-based HIV/AIDS vaccine candidate expressing Env, Gag, Pol and Nef proteins of HIV-1 subtype B (MVA-B) in healthy HIV-1-uninfected volunteers: A phase I clinical trial (RISVAC02). Vaccine. 2011; 29(46):8309–16. DOI: 10.1016/j.vaccine.2011.08.098.García F., Bernaldo de Quirós J.C.L., Gómez C.E., Perdiguero B., Nájera J.L., Jiménez V., García-Arriaza J., Guardo A.C., Pérez I., Díaz-Brito V., Conde M.S., González N., Alvarez A., Alcamí J., Jiménez J.L., Pich J., Arnaiz J.A., Maleno M.J., León A., Muñoz-Fernández M.A., Liljeström P., Weber J., Pantaleo G., Gatell J.M., Plana M., Esteban M. Safety and immunogenicity of a modified pox vector-based HIV/AIDS vaccine candidate expressing Env, Gag, Pol and Nef proteins of HIV-1 subtype B (MVA-B) in healthy HIV-1-uninfected volunteers: A phase I clinical trial (RISVAC02). Vaccine. 2011; 29(46):8309–16. DOI: 10.1016/j.vaccine.2011.08.098.Guardo A.C., Gómez C.E., Díaz-Brito V., Pich J., Arnaiz J.A., Perdiguero B., García-Arriaza J., González N., Sorzano C.O.S., Jiménez L., Jiménez J.L., Muñoz-Fernández M.Á., Gatell J.M., Alcamí J., Esteban M., de Quirós J.C.L.B., García F., Plana M.; RISVAC02boost study. Safety and vaccine-induced HIV-1 immune responses in healthy volunteers following a late MVA-B boost 4 years after the last immunization. PLoS One. 2017; 12(10):e0186602. DOI: 10.1371/journal.pone.0186602.Guardo A.C., Gómez C.E., Díaz-Brito V., Pich J., Arnaiz J.A., Perdiguero B., García-Arriaza J., González N., Sorzano C.O.S., Jiménez L., Jiménez J.L., Muñoz-Fernández M.Á., Gatell J.M., Alcamí J., Esteban M., de Quirós J.C.L.B., García F., Plana M.; RISVAC02boost study. Safety and vaccine-induced HIV-1 immune responses in healthy volunteers following a late MVA-B boost 4 years after the last immunization. PLoS One. 2017; 12(10):e0186602. DOI: 10.1371/journal.pone.0186602.Mehendаle S., Thakar M., Sahay S., Kumar M., Shete A., Sathyamurthi P., Verma A., Kurle S., Shrotri A., Gilmour J., Goyal R., Dally L., Sayeed E., Zachariah D., Ackland J., Kochhar S., Cox J.H., Excler J.-L., Kumaraswami V., Paranjape R., Ramanathan V.D. Safety and immunogenicity of DNA and MVA HIV-1 subtype C vaccine prime-boost regimens: a phase I randomised trial in HIVuninfected Indian volunteers. PLoS One. 2013; 8(2):e55831. DOI: 10.1371/journal.pone.0055831.Mehendаle S., Thakar M., Sahay S., Kumar M., Shete A., Sathyamurthi P., Verma A., Kurle S., Shrotri A., Gilmour J., Goyal R., Dally L., Sayeed E., Zachariah D., Ackland J., Kochhar S., Cox J.H., Excler J.-L., Kumaraswami V., Paranjape R., Ramanathan V.D. Safety and immunogenicity of DNA and MVA HIV-1 subtype C vaccine prime-boost regimens: a phase I randomised trial in HIVuninfected Indian volunteers. PLoS One. 2013; 8(2):e55831. DOI: 10.1371/journal.pone.0055831.Hayes P., Gilmour J., von Lieven A., Gill D., Clark L., Kopycinski J., Cheeseman H., Chung A., Alter G., Dally L., Zachariah D., Lombardo A., Ackland J., Sayeed E., Jackson A., Boffito M., Gazzard B., Fast P.E., Cox J.H., Laufer D. Safety and immunogenicity of DNA prime and modified vaccinia Ankara virus-HIV sub-type C vaccine boost in healthy adults. Clin. Vaccine Immunol. 2013; 20(3):397–408. DOI: 10.1128/CVI.00637-12.Hayes P., Gilmour J., von Lieven A., Gill D., Clark L., Kopycinski J., Cheeseman H., Chung A., Alter G., Dally L., Zachariah D., Lombardo A., Ackland J., Sayeed E., Jackson A., Boffito M., Gazzard B., Fast P.E., Cox J.H., Laufer D. Safety and immunogenicity of DNA prime and modified vaccinia Ankara virus-HIV sub-type C vaccine boost in healthy adults. Clin. Vaccine Immunol. 2013; 20(3):397–408. DOI: 10.1128/CVI.00637-12.Gómez C.E., Perdiguero B., García-Arriaza J., Cepeda V., Sánchez-Sorzano C.Ó., Mothe B., Jiménez J. L., Muñoz-Fernández M.Á., Gatell J.M., López Bernaldo de Quirós J.C., Brander C., García F., Esteban M. A phase I randomized therapeutic MVA-B vaccination improves the magnitude and quality of the T cell immune responses in HIV-1-infected subjects on HAART. PLoS One. 2015; 10(11):e0141456. DOI: 10.1371/journal.pone.0141456.Gómez C.E., Perdiguero B., García-Arriaza J., Cepeda V., Sánchez-Sorzano C.Ó., Mothe B., Jiménez J. L., Muñoz-Fernández M.Á., Gatell J.M., López Bernaldo de Quirós J.C., Brander C., García F., Esteban M. A phase I randomized therapeutic MVA-B vaccination improves the magnitude and quality of the T cell immune responses in HIV-1-infected subjects on HAART. PLoS One. 2015; 10(11):e0141456. DOI: 10.1371/journal.pone.0141456.Goepfert P.A., Elizaga M.L., Sato A., Qin L., Cardinali M., Hay C.M., Hural J., DeRosa S.C., DeFawe O.D., Tomaras G.D., Montefiori D.C., Xu Y., Lai L., Kalams S.A., Baden L.R., Frey S.E., Blattner W.A., Wyatt L.S., Moss B., Robinson H.L.; National Institute of Allergy and Infectious Diseases HIV Vaccine Trials Network. Phase 1 safety and immunogenicity testing of DNA and recombinant modified vaccinia Ankara vaccines expressing HIV-1 virus-like particles. J. Infect. Dis. 2011; 203(5):610–9. DOI: 10.1093/infdis/jiq105.Goepfert P.A., Elizaga M.L., Sato A., Qin L., Cardinali M., Hay C.M., Hural J., DeRosa S.C., DeFawe O.D., Tomaras G.D., Montefiori D.C., Xu Y., Lai L., Kalams S.A., Baden L.R., Frey S.E., Blattner W.A., Wyatt L.S., Moss B., Robinson H.L.; National Institute of Allergy and Infectious Diseases HIV Vaccine Trials Network. Phase 1 safety and immunogenicity testing of DNA and recombinant modified vaccinia Ankara vaccines expressing HIV-1 virus-like particles. J. Infect. Dis. 2011; 203(5):610–9. DOI: 10.1093/infdis/jiq105.Satti I., Meyer J., Harris S.A., Manjaly Thomas Z.-R., Griffiths K., Antrobus R.D., Rowland R., Ramon R.L., Smith M., Sheehan S., Bettinson H., McShane H. Safety and immunogenicity of a candidate tuberculosis vaccine MVA85A delivered by aerosol in BCG-vaccinated healthy adults: a phase 1, double-blind, randomized controlled trial. Lancet. Infect. Dis. 2014; 14(10):939–46. DOI: 10.1016/S1473-3099(14)70845-X.Satti I., Meyer J., Harris S.A., Manjaly Thomas Z.-R., Griffiths K., Antrobus R.D., Rowland R., Ramon R.L., Smith M., Sheehan S., Bettinson H., McShane H. Safety and immunogenicity of a candidate tuberculosis vaccine MVA85A delivered by aerosol in BCG-vaccinated healthy adults: a phase 1, double-blind, randomized controlled trial. Lancet. Infect. Dis. 2014; 14(10):939–46. DOI: 10.1016/S1473-3099(14)70845-X.von Krempelhuber A., Vollmar J., Pokorny R., Rapp P., Wulff N., Petzold B., Handley A., Mateo L., Siersbol H., Kollaritsch H., Chaplin P. A randomized, double-blind, dose-finding Phase II study to evaluate immunogenicity and safety of the third generation smallpox vaccine candidate IMVAMUNE®. Vaccine. 2010; 28(5):1209–16. DOI: 10.1016/j.vaccine.2009.11.030.von Krempelhuber A., Vollmar J., Pokorny R., Rapp P., Wulff N., Petzold B., Handley A., Mateo L., Siersbol H., Kollaritsch H., Chaplin P. A randomized, double-blind, dose-finding Phase II study to evaluate immunogenicity and safety of the third generation smallpox vaccine candidate IMVAMUNE®. Vaccine. 2010; 28(5):1209–16. DOI: 10.1016/j.vaccine.2009.11.030.Frey S.E., Winokur P.L., Hill H., Goll J.B., Chaplin P., Belshe R.B. Phase II randomized, double-blinded comparison of a single high dose (5·108 TCID50) of modified vaccinia Ankara compared to a standard dose (1·108 TCID50) in healthy vaccinianaïve individuals. Vaccine. 2014; 32(23):2732–9. DOI: 10/1016/j. vaccine.2014.02.043.Frey S.E., Winokur P.L., Hill H., Goll J.B., Chaplin P., Belshe R.B. Phase II randomized, double-blinded comparison of a single high dose (5·108 TCID50) of modified vaccinia Ankara compared to a standard dose (1·108 TCID50) in healthy vaccinianaïve individuals. Vaccine. 2014; 32(23):2732–9. DOI: 10/1016/j. vaccine.2014.02.043.Greenberg R.N., Hay C.M., Stapleton J.T., Marbury T.C., Wagner E., Kreitmeir E., Röesch S., von Krempelhuber A., Young P., Nichols R., Meyer T.P., Schmidt D., Weigl J., Virgin G., ArndtzWiedemann N., Chaplin P. A randomized, double-blind, placebo controlled Phase II trial investigating the safety and immunogeni city of modified vaccinia Ankara smallpox vaccine (MVA-BN®) in 56-80-year-old subjects. PLoS One. 2016; 11(6):e0157335. DOI: 10.1371/journal.pone.0157335.Greenberg R.N., Hay C.M., Stapleton J.T., Marbury T.C., Wagner E., Kreitmeir E., Röesch S., von Krempelhuber A., Young P., Nichols R., Meyer T.P., Schmidt D., Weigl J., Virgin G., ArndtzWiedemann N., Chaplin P. A randomized, double-blind, placebo controlled Phase II trial investigating the safety and immunogeni city of modified vaccinia Ankara smallpox vaccine (MVA-BN®) in 56-80-year-old subjects. PLoS One. 2016; 11(6):e0157335. DOI: 10.1371/journal.pone.0157335.

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