vavilovВавиловский журнал генетики и селекцииVavilov Journal of Genetics and Breeding2500-3259Institute of Cytology and Genetics of Siberian Branch of the RAS10.18699/VJ21.017vavilov-2971Research ArticleГЕНЕТИКА РАЗВИТИЯGENETIC ENGINEERINGМутации в гене A34R, приводящие к увеличению иммуногенности вируса осповакциныMutations in the A34R gene increase the immunogenicity of vaccinia virushttps://orcid.org/0000-0002-6255-9745ЩелкуновС. Н.ShchelkunovS. N.

р. п. Кольцово, Новосибирская область;

Новосибирск

Koltsovo, Novosibirsk region;

Novosibirsk

snshchel@vector.nsc.ruhttps://orcid.org/0000-0002-4954-9905БауэрТ. В.BauerT. V.

р. п. Кольцово, Новосибирская область

Koltsovo, Novosibirsk region

https://orcid.org/0000-0002-0496-390XЯкубицкийС. Н.YakubitskiyS. N.

р. п. Кольцово, Новосибирская область

Koltsovo, Novosibirsk region

СергеевА. А.SergeevA. A.

р. п. Кольцово, Новосибирская область

Koltsovo, Novosibirsk region

КабановА. С.KabanovA. S.

р. п. Кольцово, Новосибирская область

Koltsovo, Novosibirsk region

ПьянковС. А.PyankovS. A.

р. п. Кольцово, Новосибирская область

Koltsovo, Novosibirsk region

Государственный научный центр вирусологии и биотехнологии «Вектор» Роспотребнадзора; Федеральный исследовательский центр Институт цитологии и генетики Сибирского отделения Российской академии наукРоссияState Research Center of Virology and Biotechnology “Vector”, Rospotrebnadzor; Institute of Cytology and Genetics of the Siberian Branch of the Russian Academy of SciencesRussian FederationГосударственный научный центр вирусологии и биотехнологии «Вектор» РоспотребнадзораРоссияState Research Center of Virology and Biotechnology “Vector”, RospotrebnadzorRussian FederationState Research Center of Virology and Biotechnology “Vector”, RospotrebnadzorRussian Federation202128042021252139146Copyright © Щелкунов С.Н., Бауэр Т.В., Якубицкий С.Н., Сергеев А.А., Кабанов А.С., Пьянков С.А., 20212021Щелкунов С.Н., Бауэр Т.В., Якубицкий С.Н., Сергеев А.А., Кабанов А.С., Пьянков С.А.Shchelkunov S.N., Bauer T.V., Yakubitskiy S.N., Sergeev A.A., Kabanov A.S., Pyankov S.A.This work is licensed under a Creative Commons Attribution 4.0 License.https://vavilov.elpub.ru/jour/article/view/2971

Самым простым и надежным способом защиты от вирусных инфекций является вакцинопрофилактика. При этом наибольшей протективной эффективностью обладают живые вакцины, в основе которых используют слабовирулентные для человека вирусы, близкородственные патогенным, или аттенуированные (ослабленные за счет мутаций/делеций в вирусном геноме) варианты патогенного для человека вируса. Вакцинация против оспы с использованием живого вируса осповакцины (vaccinia virus, VACV), близкородственного вирусу натуральной оспы, сыграла важнейшую роль в успехе программы глобальной ликвидации оспы, которая осуществлялась под эгидой Всемирной организации здравоохранения. Прекращение после 1980 г. противооспенной вакцинации привело к тому, что огромная часть населения Земли в настоящее время не имеет иммунитета не только к оспе, но и любым другим зоонозным ортопоксвирусным инфекциям. Это создает возможность циркуляции зоонозных ортопоксвирусов в человеческой популяции и, как следствие, приводит к изменению экологии и круга чувствительных хозяев для разных видов ортопоксвирусов. При этом использование классической живой вакцины на основе VACV для защиты от этих инфекций в настоящее время не приемлемо, так как она может обусловливать тяжелые побочные реакции. В связи с этим все более актуальной становится разработка новых безопасных вакцин против ортопоксвирусных инфекций человека и животных. Аттенуация (ослабление вирулентности) VACV достигается в результате направленной инактивации определенных генов вируса и обычно приводит к уменьшению эффективности размножения VACV in vivo. Следствием этого может быть снижение иммунного ответа при введении аттенуированного вируса пациентам в стандартных дозах. Часто используемым для встройки/инактивации в геноме VACV является ген тимидинкиназы, нарушение которого приводит к аттенуации вируса. В данной работе изучено, как введение двух точечных мутаций в ген A34R аттенуированного штамма LIVP-GFP (ТК-), увеличивающих выход внеклеточныхоболочечных вирионов (EEV), влияет на свойства пато- и иммуногенности варианта VACV LIVP-GFP-A34R при интраназальном заражении лабораторных мышей. Показано, что увеличение продукции EEV рекомбинантным штаммом VACV LIVP-GFP-A34R не меняет аттенуированный фенотип, характерный для родительского штамма LIVP-GFP, но приводит к существенно большей продукции VACV-специфичных антител.

Vaccination is the most simple and reliable approach of protection to virus infections. The most effective agents are live vaccines, usually low-virulence organisms for humans and closely related to pathogenic viruses or attenuated as a result of mutations/deletions in the genome of pathogenic virus. Smallpox vaccination with live vaccinia virus (VACV) closely related to smallpox virus played a key role in the success of the global smallpox eradication program carried out under the World Health Organization auspices. As a result of the WHO decision as of 1980 to stop smallpox vaccination, humankind has lost immunity not only to smallpox, but also to other zoonotic, orthopoxviruscaused human infections. This new situation allows orthopoxviruses to circulate in the human population and, as a consequence, to alter several established concepts of the ecology and range of sensitive hosts for various orthopoxvirus species. Classic VACV-based live vaccine for vaccination against orthopoxvirus infections is out of the question, because it can cause severe side effects. Therefore, the development of new safe vaccines against orthopoxviral infections of humans and animals is an important problem. VACV attenuation by modern approaches carried out by targeted inactivation of certain virus genes and usually leads to a decrease in the effectiveness of VACV in vivo propagation. As a result, it can cause a diminishing of the immune response after administration of attenuated virus to patients at standard doses. The gene for thymidine kinase is frequently used for insertion/inactivation of foreign genes and it causes virus attenuation. In this research, the effect of the introduction of two point mutations into the A34R gene of attenuated strain LIVP-GFP (ТК–), which increase the yield of extracellular enveloped virions (EEV), on the pathogenicity and immunogenicity of VACV LIVP-GFP-A34R administered intranasally to laboratory mice were studied. It was shown that increase in EEV production by recombinant strain VACV LIVP-GFP-A34R does not change the attenuated phenotype characteristic of the parental strain LIVP-GFP, but causes a significantly larger production of VACV-specific antibodies.

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