The review article presents a summary of adverse drug reactions (ADR)  in children, information about which was received in 1968–2018 in the International database VigiBase (Uppsala monitoring center, UMC).  Of the  18.4 million Individual Safety Case Reports (ICSR)  received over  50 years by VigiBase, 1.47 million ICSR contain information on the  safety of pharmacotherapy in patients under the  age of 18,  including: 34 510  reports contain information on ADR  in children under the  age  of 27 days, 415  678  — in children aged  28 days  to 23 months, 613 676 — aged 2 to 11 years and 405 202 ICSR — in patients aged 12 to 17 years inclusive. During 2018  141 655 ICSR ADR of children in VigiBase was received. The most common reason for submitting reports on adverse effects in children was vaccines, antibiotics, non-steroidal antiinflammatory drugs, analgesics-antipyretics, anti-acne and valproic acid. The most common side effects of drugs in children were the following ADR: hyperthermia, rash, vomiting, nausea, urticaria, diarrhea, itching, headache, erythema at injection site, convulsion. Separate data on 6 age groups about 10 most frequent ADR in children and  about 10 medicines which ICSR most often arrived in VigiBase for 50 years and for 2018  are given.

/pdf/bezopasnost-primeneniia-lekarstvennykh-sredstv-u-detei-2lk3yyx2tp.pdf

Безопасность применения лекарственных средств у детей — данные международного мониторинга за 50 лет

Investigated is the effect of azoximer bromide (polioxidonium - PO) and dalargin (DA) on the immune system cell reactivity in the anti-tularemia vaccine prosess modeling in Balb/c mice. The animals were immunized subcutaneously with a dose of 10 4 live microbial cells of vaccine strain Francisella tularensis 15 NIIEG. PO or DA subcutaneously administered 60 min before vaccination, respectively, in doses of 4 mg and 2 mg. On 3rd and 21st days of immunogenesis the peripheral organs of the immune system and the contents of the abdominal cavity were investigated. Cell response to vaccination and investigated immunomodulators evaluated by flow cytometry (CyAn ADP) for two light scatter parameters and for changing the proliferating and apoptotic cell number. Additionally, for the characterization of changes in the functional status of lymphocytes nuclei the light microscopy was used and titers of specific antibodies were determined. Installed is the different response of intact mice lymphocytes and phagocytes to PO and DA introduction. As distinct from PO, DA stimulated the lymphocete proliferation and macrophage apoptosis by acting on their cytoplasmic granules. PO activated the migration of phagocytes with high cytoplasmic granules from mice abdominal cavity in the spleen. Only when using the PO as an immunomodulator in anti-tularemia vaccine process modeling recorded a significant increase in specific antibody titers against the background of a long-term functional splenocyte activation and macrophages reduced macrophage damage intensity in the spleen and abdomen.

/pdf/vliianie-immunomoduliatorov-na-reaktivnost-kletok-immunnoi-13sjeimks6.pdf

Влияние иммуномодуляторов на реактивность клеток иммунной системы при моделировании противотуляремийного вакцинного процесса

The paper presents a review of the data on the methods of isolation and control of Vibrio cholerae antigens – cholerogen-anatoxin and O-antigens of Inaba and Ogawa – components of the oral bivalent chemical cholera vaccine produced by the RusRAPI “Microbe”, the only prophylactic drug against cholera registered in the territory of the Russian Federation. Currently, the vaccine is produced using the method of segregated manufacturing of cholerogenanatoxin and O-antigens Inaba and Ogawa with step-by-step control of their main properties, which ensures the production of a high-quality finished product. Ultrafiltration is an effective method for concentrating a semi-finished product, which helps to reduce losses and increases the yield of the final product. It remains promising to develop a method for gentle steril ization of O-antigens to maximize the preservation of specific activity. To control the specific activity of the antigenic components and the finished vaccine preparation, a complex of in vivo and in vitro methods is applied. However, the multi-stage process and duration, the use of several types of laboratory animals, as well as modern WHO requirements determine the need for the introduction of alternative in vitro control methods. The use of cell cultures as a replacement for the biological method appears prospective, and demonstrates a positive correlation with animal tests. To assess the activity of antigens, the use of an immunochemical method – dot-immunoassay with gold nanoparticles – is put forward, which will make it possible to harmonize the control method at all stages of the production process, as well as to determine the serovar specificity of Vibrio cholerae O-antigens. The development of molecular-genetic, microbiological, immunochemical methods is relevant for a more complete and comprehensive control of the main immunogens of industrial strains of cholera vibrio. The introduction of promising methods for obtaining antigens and monitoring their properties will allow for a more complete characterization of the component composition of the finished dosage form of the chemical cholera vaccine.

https://journal.microbe.ru/jour/article/download/1688/1294

Antigenic Components of Chemical Bivalent Cholera Vaccine, Methods of their Isolation and Control

Objective of the study was to select the standardized substrate containing dry hydrolysate of casein for preparation of nutrient medium utilized for manufacturing bivalent chemical cholera vaccine under submerged cultivation of cholera vibrio strains in fermenters. Materials and methods . We used Vibrio cholerae O1 strains of classical biovar: strain 569B Inaba and strain M-41 Ogawa. Examined were two dry substrates of the medium: enzymatic hydrolysate of casein, Type I Himedia (India) and pancreatic hydrolysate of casein, produced by the State Scientific Center of Applied Microbiology and Biotechnology (Russian Federation). Produced under laboratory conditions at the premises of the RusRAPI “Microbe” medium was used as a control. Submerged cultivation was conducted in bioreactors during (9±1) h with aeration and automatic feeding of glucose and ammonia. Production of protective antigens was measured applying immunochemical and biological methods. Results and discussion . It is demonstrated that submerged cultivation of cholera vibrio production strains on nutrient media under study provides for synthesis of protective antigens the parameters of which comply with the requirements of normative documentation. More standardized and higher indicator values of the target product are ensured by cultivation of producer strains on nutrient medium with a substrate from dry enzymatic hydrolysate of casein, containing (1.5±0.1) g/l of amino nitrogen for the strain V. cholerae M-41 and (2±0.1) g/l – for V. cholerae 569 B. Transition to the use of standardized dry protein components of cultivation media does not lower the quality of the chemical cholera vaccine, but allows for the reduction of cost price and duration of technological process.

/pdf/ispolzovanie-pitatelnoi-sredy-na-osnove-sukhogo-gidrolizata-21lqal0v2v.pdf

Использование питательной среды на основе сухого гидролизата казеина в производстве холерной бивалентной химической вакцины

The aim of the study was to improve the methods for verifying the vaccine strain Francisella tularensis 15 NIIEG during long-term storage under current conditions.Materials and methods. The paper summarizes the results of studying the phenotypic and genetic properties of lyophilized cultures of the vaccine strain F. tularensis 15 NIIEG (1953, 1966, 1969, 1987, 1990, 2003, 2012 and 2013) stored at SCEMAP for a period of one to 60 years.Results and discussion. Previous studies have revealed that freeze-dried cultures of F. tularensis 15 NIIEG generally had the characteristics of the vaccine strain, with the exception of deviations from the regulatory requirements for residual virulence and specific safety. The stability of preservation of deletions in the pilA and pilE genes (the region of differentiation RD19) and the genes encoding lpp lipoprotein (RD18) in the vaccine strain, which was stored for various periods of time in a lyophilized state, has been confirmed. The vaccine-strain-specific mutation C178404T (by the genome of F. tularensis LVS strain, GenBank NCBI no. CP009694) has been identified, and an approach to determine it has been developed. The data obtained are promising as regards using the above deletions in the RD18/RD19 regions in combination with the C178404T mutation to assess the authenticity of the vaccine strain using molecular genetic methods. Thus, the conducted retrospective analysis of the data on the cultures of tularemia microbe vaccine strain from the 1940s to 2013 and the gathered experimental data, made it possible to supplement the uniform requirements for the manufacture, study, maintenance, storage and movement of F. tularensis 15 NIIEG vaccine strain with new evidence. Based on the results obtained, the authors have drawn a draft methodological recommendations of the federal level “Vaccinal strain Francisella tularensis 15 NIIEG: order of handling”.

/pdf/improvement-of-approaches-to-the-verification-of-the-vaccine-17uwe7tg.pdf

Improvement of Approaches to the Verification of the Vaccine Strain Francisella tularensis 15 NIIEG during Long-Term Storage

Cholera is an acute diarrheal disease caused by toxigenic strains of Vibrio cholerae O1 and O139 serogroups. It still remains a major  global healthcare problem. According to WHO, about 100,000 people die from cholera every year, despite the modern methods of  treatment, improvement in the quality of drinking water, sanitation and hygiene. In recent years, oral cholera vaccines have proved an  effective tool for preventing and curbing cholera epidemics.  According to the WHO Ending Cholera — A Global Roadmap, mass  vaccination should help reduce the mortality resulting from cholera  by 90 % worldwide by 2030 and eliminate the disease in 20  countries. The review outlines the main historical stages in the  development of cholera vaccines: parenteral, chemical, inactivated and live oral vaccines. The paper compares active  ingredients and excipients used in Dukoral®, mORC-VAX®, Shanchol®, Euvichol®, Vaxchora®, Oravacs® and the cholera bivalent chemical vaccine. The results of international multicenter clinical trials of oral inactivated, live and  chemical cholera vaccines are analysed. Issues related to efficacy and safety studies of cholera vaccines are considered.

/pdf/effektivnost-i-bezopasnost-vaktsin-dlia-profilaktiki-kholery-49escra86s.pdf

Эффективность и безопасность вакцин для профилактики холеры

Investigated have been 8 cultures of Francisella tularensis strain 15 NIIEG (lyophilized in 1953, 1966, 1969, 1987, 1990, 2003, 2012, and 2013, respectively) stored at the State Collection of Microorganisms of the Scientific Center on Expertise of Medical Application Products. It is established that the majority of cultures has maintained their immunobiological properties. However, it is of note that liophilization does not prevent F. tularensis strain 15 NIIEG from changes in its residual virulence under extended storage. Revealed is the fact that LD 50 for 7 cultures of tularemia microbe strain is within the limits of 100-250 microbial cells (m.c.). At the same time, residual virulence for the strain which dates back 1966 is 7.3·10 5 m.c. Immunogenic activity rates in F. tularensis 15 NIIEG strain cultures range within specified limits. Apart from this, F. tularensis 1987 strain does not comply with the established requirements to the “specific safety”, as subcutaneous inoculation with 5·10 9 m.c./ml caused death of Guinea pigs within the scheduled observation time. Demonstrated is the necessity in maintaining constant stability of the original immunobiological properties in Francisella tularensis strain 15 NIIEG under extended storage conditions.

/pdf/izuchenie-immunobiologicheskikh-svoistv-vaktsinnogo-shtamma-l360ffm4l2.pdf

Изучение иммунобиологических свойств вакцинного штамма Francisella tularensis 15 НИИЭГ в условиях длительного хранения

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Эффективность и безопасность вакцин для профилактики холеры

Изучение иммунобиологических свойств вакцинного штамма Francisella tularensis 15 НИИЭГ в условиях длительного хранения