Статья посвящена эпилепсии Кожевникова, одному из наиболее распространенных и по сути патогномоничных проявлений хронического течения клещевого энцефалита. Описаны стадийность в ее развитии, типы течения сформировавшейся кожевниковской эпилепсии, подходы к терапии. В статье представлен уникальный по продолжительности наблюдения случай хронического клещевого энцефалита (ХКЭ) (47 лет от начала заболевания и свыше 30 лет после вакцинотерапии). Показано, что замедленное развитие тяжелой неврологической симптоматики, прогрессирование болезни происходят на фоне дисиммуноглобулинемии. Штамм, выделенный от пациентки, обладал высокой нейровирулентностью для белых мышей, был высоконейроинвазивным, показал принадлежность к сибирскому подтипу вируса клещевого энцефалита. По мере прогрессирования ХКЭ развивался полиштаммовый иммунный ответ и напряженный иммунитет с высокой авидностью антител (через 30-32 года после вакцинотерапии). В неврологическом статусе – характерные постэнцефалитические изменения с элементами кортикальной моторной эпилепсии. Существенного когнитивного дефекта не было выявлено. The article is devoted to Kozhevnikov's epilepsy, one of the most common and, in fact, pathognomonic manifestations of the chronic course of tick-borne encephalitis. The stages in its development, the types of the course of the formed Kozhevnikovskaya epilepsy, and approaches to therapy are described. This material presents a unique case of chronic tick-borne encephalitis (TBE) (47 years from the beginning of the disease and more than 30 years after vaccination). It is shown that the delayed development of severe neurological symptoms and disease progression occur against the background of dysimmunoglobulinemia. The strain isolated from the patient had high neurovirulence for white mice, was highly neuroinvasive, and belong to the Siberian subtype of tick-borne encephalitis virus (TBEV). As TBE progressed, a polystrain immune response and a stressed immune response with high antibody avidity developed (30-32 years after vaccination). In the neurological status – pecular postencephalitic changes with elements of cortical motor epilepsy. No significant cognitive defect was detected.

Relevance. Vaccination against the tick-borne encephalitis (TBE), during the mass immunization, by using modern vaccines provides high epidemiological effect (98–99%); however, there are known cases of incidents among vaccinated population. The problem of incidents among vaccinated population is insufficiently studied, likewise a reliability of the diagnostic, vaccination conditions and causes of vaccinated people’s morbidity. Purpose of the article generalization of the information about morbidity among the vaccinated population. Conclusions. The review for the first time provides information about the main issues of this problem: the frequency of illness of vaccinated people in Russia (by federal districts and individual regions), disease development conditions, tied up with vaccination regimens and types of vaccines, clinical features and diagnosis of the disease of vaccinated people. Particular attention is paid to the state of post-vaccination immunity. The significance of two phenomena is being studied: incomplete neutralization of the virus, which leads to the formation of a fraction of a free infectious virus; and the phenomenon of the hyperimmunization with the development of immunological tolerance.

Relevance. Vaccination against the tick-borne encephalitis (TBE), during the mass immunization, by using modern vaccines provides high epidemiological effect (98–99%); however, there are known cases of incidents among vaccinated population. The problem of incidents among vaccinated population is insufficiently studied, likewise a reliability of the diagnostic, vaccination conditions and causes of vaccinated people’s morbidity.Purpose of the article generalization of the information about morbidity among the vaccinated population.Conclusions. The review for the first time provides information about the main issues of this problem: the frequency of illness of vaccinated people in Russia (by federal districts and individual regions), disease development conditions, tied up with vaccination regimens and types of vaccines, clinical features and diagnosis of the disease of vaccinated people. Particular attention is paid to the state of post-vaccination immunity. The significance of two phenomena is being studied: incomplete neutralization of the virus, which leads to the formation of a fraction of a free infectious virus; and the phenomenon of the hyperimmunization with the development of immunological tolerance.

In this review, the manifestations of the tick-borne encephalitis (TBE) evolution in different aspects, which are traced over the 80 years since the discovery of TBE virus, are highlighted and systematized. The evolution of infection is expressed in a change in the properties of the etiological agent (changing of the genetic structure of the pathogen populations in certain territories, phenomenon of changing in the dominant subtype, changing in virulence), the epidemiology and ecology of TBE (period of marked increase in incidence, changing in the endemicity of territories, level of population immunity, the appearance of foci TBE in suburban areas and cities, changing in the range of certain types of ticks and the appearance of «tick-mutants»), as well as the clinical picture of TBE (phenomenon of pathomorphosis, growing relevance of mixed infections transmitted by ticks). The analysis of the possible causes of evolutionary transformations is carried out, among which the main ones are natural factors (climate change), anthropogenic factors, namely disturbance of natural landscapes due to human activities and environmental pollution by some pesticides, and additional ones -impact of vaccination. Purpose of the article: characteristics of the main manifestations and probable causes of the evolution of TBE over 80 years. Conclusions: The review for the first time provides information about the main issues of this problem, identifies changes and transformations that affect pathogens and vectors, and, as a result, entails changes in the epidemiology and clinical picture of this disease, which are traced in different territories.

Currently available vaccines against tick-borne encephalitis (TBE) are highly effective; however, they do not ensure 100% protection. Laboratory diagnostics of TBE in vaccinated patients remains poorly developed. Objective. To compare the dynamics of humoral immunity in unvaccinated and vaccinated patients and to develop an algorithm of specific laboratory diagnostics of TBE. Patients and methods. We have tested 276 unvaccinated and 59 vaccinated patients using enzyme-linked immunosorbent assay for the detection of IgG and IgM against antigens of tick-borne encephalitis virus (TBEV). In hemagglutination inhibition assay, we used dry TBEV reagent. TBEV RNA was detected using reverse transcription polymerase chain reaction (RT-PCR). Results. We have identified three types of humoral immunity dynamics in vaccinated and unvaccinated patients: seroconversion, stable antibody titers, and negative (reverse) antibody dynamics with an at least 4-fold decrease in antibody levels. Among 39 vaccinated individuals, 18 patients demonstrated seroconversion, while 16 patients had stable antibody titers and 4 patients had negative dynamics. Patients with chronic TBE demonstrated different variants of humoral immunity dynamics. Discussion. We discuss the variants of antibody dynamics described above and diagnostic methods on the example of vaccinated patients. In individuals with stable antibody titers, we used an original method for detecting the dynamics of antibodies against Siberian strain of TBEV. Conclusion. In case of seroconversion, the level of specific immunity in vaccinated patients was higher than that in unvaccinated patients and healthy individuals vaccinated against TBE. Negative antibody dynamics is the rarest variant of humoral immunity development. The diagnosis of TBE in patients with stable antibody titers is confirmed by the detection of TBEV antigen, increasing serum levels of IgM, detection of TBEV RNA in the cerebrospinal fluid, and isolation of the virus. Keywords: vaccinated patients, humoral immunity, diagnosis, tick-borne encephalitis

A number of antibacterial drugs used for the treatment of combined viral and bacterial infections can cause immunosuppression, weighting of the acute course and activation of the persistent infection. Previously, it was found that among the antibacterial drugs, strong activators of persistent infection are streptomycin (group of aminoglycosides), cefamezin (group of cephalosporins), ristomycin (polypeptide antibiotic), the group of drugs that do not cause depression of humoral immunity includes gentamicin (aminoglycoside), kanamycin (aminoglycoside), levomycetin (synthetic antibacterial drug), florimycin (aminoglycoside). In this paper an experiment on Syrian hamsters shows the effect of using a new generation antibiotic — Ceftriaxone (beta-lactam antibiotic) on the course of acute tick-borne encephalitis.

Relevance.Modern inactivated culture vaccines against tick-borne encephalitis (TBE) with at least 70% of the population living in the natural foci of the FE give a high epidemiological effect. Unresolved issues are the simplification of the cumbersome vaccination scheme, the optimal number of revaccinations, the protective titer of antibodies against the Siberian subtype of the TBE virus dominant in Russia.Goalof this work is to study the state of postvaccinal immunity in the population of the highly endemic area of the Trans-Urals.Materials and methods. 1381 blood serum of the population vaccinated from 3 to 13 times with vaccines was studied: unconcentrated culture inactivated from strain No. 205 of the TBE virus produced by «Virion», Tomsk, «EnceVir» produced by «Microgen», Tomsk, produced by Chumakov Federal Scientific Center for Research and Development of Immuneand-Biological Products of Russian.To identify specific antibodies – IgG, IgM, antigen of TBE virus, sets of reagents of ELISA from «Vector-Best» were used. Neutralizing activity of sera was determined by the index of neutralization index with 4 strains of the Siberian subtype of TBE virus.Results.The immune layer among the vaccinated population in 10 districts of the Kurgan region, which differ in epidemiological tension, ranges from 69.9% to 94.6%. The intensity of humoral immunity varied according to IgG titers in ELISA from 1: 100 – 1: 200 to 1: 3200 (rarely 1: 6400). The duration and intensity of immunity depends on the number of vaccinations and the number of missed remote revaccinations. Preservation and intensity of immunity with reliability P = 95%, higher in persons vaccinated 6–10 times compared with the group of vaccinated 3 times. In persons who had 4–8 booster dose of vaccine, the immunity persisted for 15–19–36 years with an IgG titer of not more than 1: 100. The neutralizing activity of the sera of vaccinated individuals with antibody titers from 1:100 to 1: 6400 was studied for the Siberian subtype of BCE. The degree of protection of the vaccinated population against the doses of the virus found in individual mites is determined. From the doses of the virus, 57% of the vaccinated population are most often found in mites, and from the dose of 105– 8%. Recommendations are proposed on the tactics of revaccination of the population, depending on the level of immunity.

Relevance.Тhe Ural Federal district (Ural Federal district) is a highly endemic tick-borne viral encephalitis (TBEV) territories in the Russian Federation. The epidemiological situation on the TBEV is studied in Sverdlovsk and Chelyabinsk regions and slightly shown in the Kurgan region. There is no information about the evolution TBEV, the structure of immunity population, vaccine prevention in the Kurgan region. The article presents the dynamics epidemiological situation on TBEV in the Kurgan region over a 30-year period.Materials and methods: Used expedition reports, viral encephalitis named after the Academy of medical Sciences of the USSR for 1983–2007, as well as materials of medical institutions of the Kurgan region 2007–2017. For population immunity used: hemagglutination test (HAI-test), neutralization test (NT). To identify specific antibodies – IgG, IgM, antigen of TBEV, sets of reagents of ELISA from «Vector-Best» were used. To immunotypicalli and genotypically Strains and isolates RNA of TBEV isolated in 1983–2007, used precipitation in agar (RDPA) and by RT-PCR technique in real time with genotypespecific probes.Results and discussions: Kurgan region is a highly TBEV endemic area. the morbidity rate – 18,3 per 100 thousand people 1983. Maximum elevation – 44.1 in 1996 to and decrease to 13.5 in 2000–2012. The immune part of the population according hemagglutination tests, on epidemiologically significant territories is 15–20%, (66% NT), in the regions with sporadic incidence is 8%, (21–50% NT), in non-endemic territories – 3%. At the present stage, the region marked the expansion of nosoareal TBEV due to the previously less significant Eastern regions. In Kurgan region vaccination coverage against TBE 39.3%. The clinical efficacy of vaccination was manifested in an increase in fever forms of TBE disease and a decrease in meningeal and focal forms of the disease. In the period 2004–2012 the number of vaccinated patients was 20.3% of the total number of patients.Сonclusions. Evolution of tick-borne encephalitis manifested the expansion of nosoareal TBEV, increase seasonal activity of ticks, the TBEV Siberian subtype is absolutely dominating.

Relevance. Modern inactivated culture vaccines against tick-borne encephalitis (TBE) with at least 70% of the population living in the  natural foci of the FE give a high epidemiological effect. Unresolved  issues are the simplification of the cumbersome vaccination scheme,  the optimal number of revaccinations, the protective titer of  antibodies against the Siberian subtype of the TBE virus dominant in Russia. Goal of this work is to study the state of postvaccinal immunity in the population of the highly endemic area of the Trans-Urals. Materials and methods . 1381 blood serum of the population vaccinated from 3 to 13 times with vaccines was studied: unconcentrated culture inactivated from strain No. 205 of the TBE  virus produced by «Virion», Tomsk, «EnceVir» produced by  «Microgen», Tomsk, produced by Chumakov Federal Scientific Center for Research and Development of Immuneand-Biological Products of  Russian.To identify specific antibodies – IgG, IgM, antigen of TBE  virus, sets of reagents of ELISA from «Vector-Best» were used.  Neutralizing activity of sera was determined by the index of  neutralization index with 4 strains of the Siberian subtype of TBE  virus. Results. The immune layer among the vaccinated population in 10 districts of the Kurgan region, which differ in epidemiological tension, ranges from 69.9% to 94.6%. The intensity of humoral immunity  varied according to IgG titers in ELISA from 1: 100 – 1: 200 to 1:  3200 (rarely 1: 6400). The duration and intensity of immunity  depends on the number of vaccinations and the number of missed  remote revaccinations. Preservation and intensity of immunity with  reliability P = 95%, higher in persons vaccinated 6–10 times  compared with the group of vaccinated 3 times. In persons who had 4–8 booster dose of vaccine, the immunity persisted for 15–19–36 years with an IgG titer of not more than 1: 100. The neutralizing  activity of the sera of vaccinated individuals with antibody titers from 1:100 to 1: 6400 was studied for the Siberian subtype of BCE. The  degree of protection of the vaccinated population against the doses  of the virus found in individual mites is determined. From the doses  of the virus, 57% of the vaccinated population are most often found  in mites, and from the dose of 105– 8%. Recommendations are  proposed on the tactics of revaccination of the population, depending on the level of immunity.

Tick-borne encephalitis virus is the etiological agent of a severe human disease transmitted by hard ticks. It occurs in large parts of eastern, central, and western Asia and in Europe with thousands of human cases each year. Here, the discovery of the virus by Soviet scientists in the late 1930s in the Far East is described. The pioneering work involved with this discovery, which resulted in great scientific and epidemiological achievement, was undertaken under the most difficult conditions, and some of the scientists and their technical assistants paid for it with their health and even their lives. This paper briefly outlines the steps on the way that elucidated the basic etiology and eco-epidemiology of the disease, and does not omit that, as one result of the expeditions and the political situation in the former Soviet Union at that time, some scientists were sent to prison.

The Chelyabinsk Region (Southern Urals) is high endemic territory. The TBE incidence is 3.57 ± 1.7 per 100 000 of population. A level of vaccination against TBE increased from 0.3 to 34.8% in 1999 - 2013. Specific immunity of population in 35.9% is connected with vaccination, in 64.1% with natural immunity consequently latent contact with TBE virus. Dynamics of vaccinal prevention, increasing of population immunity in different landscapes, and in different age groups were studied. 77.7% of TBE patients did not vaccinated, 18.2% received of specific immunoglobulin at postexposition and 3.7% persons were vaccinated. Unusual lethal case in patient, who received 8 doses of vaccine is analysed in this article.

Siberian subtype of TBE virus dominates in the most part of Russia outside of the Far East. Peculiarity of immunity induced by Siberian subtype during disease or inapparent infection and change of immunity after vaccination are described in this article. Protective titre of antibodies and persistence of TBE virus (TBEV) in vaccinated organism are discussed.

Lethal cases of tick-borne encephalitis in previously vaccinated patients have not been described. Modern inactivated vaccines against Tick-borne encephalitis (TBE) are high effective. The TBE cases, preference unfocal forms, are developed in persons with incomplete irregular vaccination. First case of lethal TBE after plural vaccination was described in the Kurgan region, the second case - in the Chelyabinsk region. These very rare unusual cases were studied. Being dominant the Siberian subtype of TBE virus is related with lethal TBE cases in the Chelyabinsk region. Unusual TBE case was developed in patient who had been vaccinated 8 limes with vaccines produced from strains of Far-Eastern TBE subtype («Virion», Tomsk, Chumakov institute, Moscow) and European TBE subtype (Encepur; FSME-Immun). Two years after the last vaccination a focal form of TBE was developed with lethal outcome at 9 th day. Specific antibodies IgM and IgG seroconversion were detected. The TBE virus antigen was detected in brain neurons by immunofluorescent test. Destructed neurons and gliocyles were shown by hystological study in cerebral hemispheres and cerebellum. The Purkinje cells were destructed. Possible reasons of surmounting vaccinal immunity including a genetic difference of vaccine and infection virus strains are discussed.

Tick-borne encephalitis (TBE) is a disease mainly affecting the central nervous system, serious medical and social problem in Russia and many European countries. TBE virus (TBEV) genetically divided into three major subtypes: the Far Eastern, European and Siberian. Siberian subtype of TBEV dominates in most part of Russia outside of the Far East. Modern cultural inactivated vaccine of domestic and foreign production prepared from the strains of the Far Eastern and European subtypes. In a review of the literature and our own researches are shown: the dominance of Siberian subtype (TBE) and data of vaccine-prevention. The importance of genetic differences between the Siberian subtype strains and vaccines strains are analyzed as well new approaches of the test strain selection.

Tick-borne encephalitis (TBE) is a disease mainly affecting the central nervous system, serious medical and social problem in Russia and many European countries. TBE virus (TBEV) genetically divided into three major subtypes: the Far Eastern, European and Siberian. Siberian subtype of TBEV dominates in most part of Russia outside of the Far East. Modern cultural inactivated vaccine of domestic and foreign production prepared from the strains of the Far Eastern and European subtypes. In a review of the literature and our own researches are shown: the dominance of Siberian subtype (TBE) and data of vaccine-prevention. The importance of genetic differences between the Siberian subtype strains and vaccines strains are analyzed as well new approaches of the test strain selection.

Chronic tick-borne encephalitis (CTBE) is a severe form of the disease, leading to permanent disability and death. Most cases of CTBE caused Siberian subtype of a virus of tick-borne encephalitis virus (TBEV), dominant in the Russian Federation. The pathogenesis of CTBE associated with persistence of TBEV in the central nervous system and the organs of the immune system. Specific vaccine therapy with using of inactivated full-virion vaccines prevents immunosuppression, leading to activation of persisting tick-borne encephalitis. The article describes various schemes of CTBE vaccinotherapy. Dynamics of humoral immunity in CTBE caused by Siberian subtype of TBEV. In the early stages and during remission antibodies against this subtype are detected. Vaccine therapy increases the level of immunity to all subtypes of TBEV, slowing the progression of the disease. In seronegative status of the patient vaccine therapy is not effective: from the central nervous system of a deceased patient severe strain «Zausaev» was isolated. Mechanisms of high immunity after 30-32 years after vaccine therapy and advantages of vaccine therapy compared with treatment of CTBE using specific immunoglobulin are discussed.

In the Yaroslavl region (Central Federal District of Russia), endemic of tick-borne encephalitis (TBE), the features of epidemiology of this infection were studied during 1992-2012. Cyclical fluctuations in the incidence of TBE, the lack of the trend to decrease of the incidence were observed, the average annual incidence was 1,6 ± 0,32 per 100 thousand ofpopulation. The prevalence offebrile forms of disease was 62,2%, meningeal forms - 16,3%, the total percentage offocal forms was 13,9%. Manifestations of evolution of TBE were: the increase of the epidemiological significance of anthropogenically transformed natural foci, anthropurgical foci of TBE, until 81% of TBE cases were unvaccinated citizens, the high lethality of 4% and the high frequency of cases of alimentary infection of TBE of 7,8% with lethality of 10,8%. The aethiological agent of 10 lethal cases was Siberian subtype of TBE virus.

1 . VAccINE thERApy OF chRONIc tIcK-BORNE ENcEphALItIS 1 Chumakov Institute of polyomielitis and viral encephalitides of Russian academy of medical sciences, 142782, Moscow, Russia; 2 Aldan central hospital, 678900 Republic Saha (Yakutia), Aldan, Russia. Chronic tick-borne encephalitis (CTBE) is a severe form of the disease, leading to permanent disability and death. Most cases of CTBE caused Siberian subtype of a virus of tick-borne encephalitis virus (TBEV), dominant in the Russian Federation. The pathogenesis of CTBE associated with persistence of TBEV in the central nervous system and the organs of the immune system. Specific vaccine therapy with using of inactivated full-virion vaccines prevents immunosuppression, leading to activation of persisting tick-borne encephalitis. The article describes various schemes of CTBE vaccinotherapy. Dynamics of humoral im- munity in CTBE caused by Siberian subtype of TBEV. In the early stages and during remission antibodies against this subtype are detected. Vaccine therapy increases the level of immunity to all subtypes of TBEV, slowing the progression of the disease. In seronegative status of the patient vaccine therapy is not effective: from the central nervous system of a deceased patient severe strain «Zausaev» was isolated. Mechanisms of high immunity after 30-32 years after vaccinу therapy and advantages of vac- cine therapy compared with treatment of CTBE using specific immunoglobulin are discussed. Key w ords: tick-borne encephalitis; chronic tick-borne encephalitis; Siberian subtype of tick-borne encephalitis virus; persistence; vaccine therapy; immune system; antibodies.