SCIENTIFIC RELEVANCE. The use of appropriately certified reference standards (RSs) is a necessary element of analytical procedure standardisation that ensures comparability of results across different laboratories assessing the quality of medicines, which is important for the quality control of biologicals. Marketing authorisation involves providing information on RSs, but no specific requirements are given for the relevant section of the dossier. Therefore, it is necessary to develop the requirements for the appropriate guidelines.AIM. This study aimed to develop specific requirements for the materials that should be included in the Reference Standards section of the dossier for a biological product.DISCUSSION. The authors analysed national and international regulatory frameworks governing RSs for biologicals, including documents by the World Health Organisation (WHO), the Eurasian Economic Union, the International Organisation for Standardisation (ISO), and the Russian Federal Agency for Technical Regulation and Metrology. Additionally, the authors analysed the experience of RS certification and use at the Scientific Centre for Expert Evaluation of Medicinal Products. This article covers specific aspects of biological RS certification, considering the differences between measurement techniques and analytical procedures. The authors formulated the key requirements for the documents submitted in the dossier section on RSs for biologicals (biological reference materials). The methods (analytical procedures) used for RS certification should be described in accordance with the requirements for standard operating procedures. Adequate validation studies should establish the necessary validation characteristics of these analytical procedures. Additionally, this article presents the requirements developed to certify primary RSs for structure confirmation of proteins in novel biologicals. The values of certified characteristics and critical quality indicators should be established, and the RS production technology should be described and in compliance with WHO recommendations and/or Good Manufacturing Practice (GMP) standards. The basic certification stages are common to all types of RSs. The RS shelf life should be established in real-time stability studies, whereas accelerated stability testing may be useful for studying degradation mechanisms and the effects of short-term deviations from the specified storage conditions. In accordance with WHO recommendations, the Reference Standards section of the registration dossier should specify changes to the RS that require regulatory approval.CONCLUSIONS. The authors believe that the requirements for the materials in the Reference Standards section of the dossier for a biological product, as systematised in this study for inclusion in the relevant guidelines, will provide a unified approach to RS development, certification, and documentation for applicants, developers, and competent authority experts and will streamline RS consideration during marketing authorisation.

Scientific relevance. The absence of blood-borne viruses in human plasma-derived medicinal products must be ensured by the control of raw materials and the manufacturing process.Aim. This study aimed to analyse system suitability criteria for analytical procedures to assess the viral safety of individual units of the substance "Human plasma for fractionation" in terms of the content of nucleic acids of blood-borne viruses, considering the requirements of the European Pharmacopoeia.Materials and methods. The authors analysed individual units of the substance "Human plasma for fractionation" (hereinafter, plasma). The study used the International Standards (ISs) for human immunodeficiency virus RNA, hepatitis A virus (HAV) RNA, hepatitis C virus (HCV) RNA, hepatitis B virus (HBV) DNA, and parvovirus B19 DNA, as well as nucleic acid detection kits for these viruses based on polymerase chain reaction (PCR).Results. HCV RNA was not detected in any of the eight plasma samples studied, and parvovirus B19 DNA was detected in one of the samples at a concentration not exceeding 104 IU/mL. Three tests with the corresponding ISs showed that the studied reagent kits detected HCV RNA at a concentration of 102 IU/mL and parvovirus B19 DNA (M1 genotype) at a concentration of 104 IU/mL. In additional tests that were conducted in two samples considering the requirements of the European Pharmacopoeia for the detection of HCV RNA and parvovirus B19 DNA, a new batch of reagent kit I detected the HCV RNA IS at a concentration of 102 IU/mL only in one of three replicates, which did not correspond to the claimed sensitivity of the reagent kit. HCV RNA was not detected in either replicate in one of two plasma samples spiked with the HCV RNA IS at concentrations of 102 and 103 IU/mL, possibly because of plasma inhibitory properties. The sensitivity of the reagent kits to parvovirus B19 DNA corresponded to the label claims; the study did not show any inhibitory properties of the plasma samples.Conclusions. Polymerase chain reaction testing of the viral safety of plasma intended for manufacturing medicinal products should include control samples calibrated in IU/mL. Further research and appropriate pharmacopoeial reference materials are needed to set system suitability criteria for analytical procedures using such control samples.

Scientific relevance. Anti-hepatitis B virus surface-antigen (HBsAg) immunoglobulins are used to prevent hepatitis B in adults and children after exposure and to treat mild to moderate acute viral hepatitis B. The clinical effectiveness of human immunoglobulin preparations is determined by their potency, which is assessed by the content of antibodies to hepatitis B virus surface antigen (anti-HBs antibodies). Currently, this assessment involves using immunoassay techniques, such as enzyme-linked immunosorbent assay (ELISA). Aim. This study examined several mathematical methods for analysing the experimental data obtained in ELISA-based anti-HBs antibody potency assays of human immunoglobulin preparations. Materials and methods. This study used the international standard for human anti-HBs immunoglobulin, two immunoglobulin preparations, and an ELISA test kit for the detection and quantification of anti-HBs antibodies in serum or plasma samples. Results. Using sandwich ELISA, the authors ascertained that the measured anti-HBs antibody concentration depended on the choice of calibration curve calculation method (i.e. manual analysis, parallel-line analysis using PARALINE software, linear regression, and 4-parameter logistic regression). The measured anti-HBs antibody concentrations varied by ± 19 IU/mL. According to the study results, an incorrectly selected method of data analysis can lead to an erroneous calculation of the analyte potency (concentration) in the test sample. Conclusions. The study demonstrated the need for improved mathematical methods for the evaluation of experimental data used to determine the anti-HBs antibody concentration in human immunoglobulin preparations. It is essential to switch from manual to automated calculation (for example, using a 4-parameter logistic model), taking into account the requirements for bioanalytical methods and the capabilities of the available equipment.

Scientific relevance. The immunoglobulin A (IgA) impurity content in parenteral human immunoglobulins should be determined in accordance with the State Pharmacopoeia of the Russian Federation by kinetic nephelometry, radial immunodiffusion, or enzyme immunoassay (ELISA) with a reference standard. The International Standard (IS) for the content of IgA is certified using gravimetry and radial immunodiffusion. However, neither of the existing standards for the content of IgA in human immunoglobulins is currently certified using all three compendial methods. This prevents analysts from comparing test results obtained by different methods and may lead to an underestimation of the IgA content in human immunoglobulins.Aim. This study aimed to determine the procedure for the development, certification, and use of a pharmacopoeial reference standard (RS) for the content of IgA in human immunoglobulins.Materials and methods. The authors studied candidate RSs for the IgA content derived from human plasma for fractionation. The IgA content determination involved kinetic nephelometry, radial immunodiffusion, and ELISA, as well as commercial test kits and the IS. The authors quantified the IgA impurity in samples of commercial human immunoglobulins from various manufacturers. The data analysis involved descriptive statistics and variance analysis using Microsoft Excel and Statistica 10.Results. The authors established a pharmacopoeial standard with a certified IgA content of 1.98 mg/mL (expanded uncertainty, 0.44 mg/mL; coverage coefficient, k=2; confidence level, 95%) for IgA impurity quantification in human immunoglobulins by radial immunodiffusion and ELISA and that of 1.31–2.64 mg/mL (expanded uncertainty, 0.67 mg/mL; coverage ratio, k=3; confidence level, 99%) for intralaboratory quality control of IgA impurity quantification by kinetic nephelometry, radial immunodiffusion, and ELISA.Conclusions. The pharmacopoeial standard developed in the study has been included in the register of standards of the State Pharmacopoeia of the Russian Federation as the Reference Standard for the Content of Immunoglobulin Class A (IgA) (Registry No. 3.1.00454). The pharmacopoeial standard is intended for the standardisation of analytical methods for the-determination of the IgA impurity content in parenteral human immunoglobulins.

The development and introduction of new bacteriophage-based medicinal products for human use is an important mission aimed at curbing the spread of infectious diseases caused by multi-resistant pathogens. The current global practice offers two approaches to the production of bacteriophage preparations: a systemic one, with regulatory participation of state control bodies, and a personalised one. The aim of the study was to analyse the legal and regulatory framework and differences of the mentioned methodological approaches to commercial and personalised production of bacteriophage medicinal products for human use in the Russian Federation and to identify the main stages for a comprehensive approach to the development of such medicinal products with the view of improving the state regulation and control intended to ensure the quality, efficacy, and safety. The article considers the experience of therapeutic bacteriophage use in Europe, the USA, and Russia, highlighting the main reasons for the termination of commercial bacteriophage production abroad and the success of phage therapy and prophylaxis development in the Soviet Union. Currently, the Russian Federation is the only state in the world that officially implements compendial quality standards for bacteriophage preparations. The article presents the advantages and disadvantages of the systemic and the personalised approaches to the production of bacteriophage preparations and analyses legal and regulatory documents governing it in the Russian Federation. The authors note that despite the relevance of personalised approaches to treatment and prevention of human infectious diseases, the legal grounds for the personalised use of bacteriophages are practically absent both in the Russian Federation and in other countries. To support the state control and supervision over the therapeutic and prophylactic bacteriophage preparations produced for the use in the framework of the personalised approach, the authors determined the main production and quality control stages for bacteriophage medicinal products.

To ensure the quality of immunobiologicals, it is required to quantify the thiomersal preservative present in a number of them. The authors have previously developed an analytical procedure for thiomersal quantification in non-adsorbed immunobiological medicinal products, which is based on cold vapor atomic absorption spectrometry (CV AAS). The aim of the study was to analyse the possibility of using the CV AAS procedure for thiomersal content determination in adsorbed immunobiologicals and evaluate the comparability of thiomersal quantification results obtained by colourimetry and CV AAS. Materials and methods: the study used the national reference standard of mercury ions content and the pharmacopoeial reference standard of thiomersal content in adsorbed medicinal products (PhRS 3.1.00427), as well as samples of immunobiologicals by different manufacturers: a DTP vaccine, anatoxins, hepatitis B and influenza vaccines, and combined vaccines. The study involved CV AAS and the colourimetric reaction between mercury and dithizone. Results: the specificity of the CV AAS procedure is demonstrated by the coefficient of variation (3.95%) and the coefficient of correlation between the test sample volume and thiomersal content (0.9956). The regression analysis and the Fisher’s test value of 0.16 indicate the absence of bias. The trueness of the method is satisfactory, as the percent recovery differs from the total spiked amount by less than 10%. For the sensitivity of the CV AAS procedure, its quantification and detection limits are 6.9×10-3 μg/ mL and 2.3×10-3 μg/ mL, respectively. The Fisher’s test value obtained in the comparability assessment of the results of thiomersal quantification by colourimetry and CV AAS (1.29) is lower than the conventional tabulated one (3.96). Conclusions: according to the study, it is possible to use the CV AAS procedure for thiomersal quantification in adsorbed immunobiologicals. The established detection limit allows evaluating residual amounts of thiomersal in in-process intermediates during the production of preservative-free immunobilogical dosage forms. The comparability assessment of the results of thiomersal quantification by colourimetry and CV AAS, carried out using oneway ANOVA and Fisher’s test, showed the possibility of using PhRS 3.1.00427 to control the consistency of operation when reproducing the CV AAS procedure.

Reference standards for structure identification of recombinant therapeutic proteins are essential for quality assessment of recombinant protein-based biotechnological medicinal products. The development and certification of such reference standards hold special relevance because of, firstly, the absence of international, national or compendial reference standards for a number of new or recently approved proteins and, secondly, the disruption of supply chains providing the biopharmaceutical industry of the Russian Federation with international reference standards. Moreover, international and national regulatory documents contain only general requirements for the procedure of reference standards certification but not the considerations specific to the standards for biotechnologicals’ structure identification, which vary with the production technologies for each individual active moiety. The aim of this work was to provide recommendations on the procedure for the development and certification of reference standards used to identify the structure of recombinant therapeutic proteins. These recommendations define 4 main stages of the procedure: stage 1 covers the development of requirements for the reference standard, including the justification of material and formulation choices, the elaboration of quality specifications, and the assessment of quality; stage 2 comprises the selection of analytical procedures and the establishment of the values for the certified parameters; stage 3 includes stability studies and shelf-life setting; and stage 4 involves the development of documentation for the reference standard. The paper dwells upon the scope of the stages, taking into account the specific considerations for recombinant therapeutic proteins and the use of reference standards. The recommendations are based upon the extensive experience in biotechnologicals testing and standardisation of the employees of the Scientific Centre for Expert Evaluation of Medicinal Products. These recommendations can provide a base for the establishment of protein-specific certification programmes for reference standards used in structure identification. This approach will allow for systematisation of the process for standards development and ensure the traceability of information and the validity of results. The reference standards certified in accordance with these recommendations can be considered primary standards, if necessary.

Quantitative characterisation of excipients in biologicals is an important part of the quality assurance process both at the level of finished products and intermediates, as well as active pharmaceutical ingredients. Ion chromatography with amperometric and conductometric detection of separation products has a number of advantages. The main of the advantages is the possibility of direct determination of semivolatile compounds that have neither chromophoric groups, nor intrinsic fluorescence. The aim of this study was to compare ion chromatography with alternative methods in order to identify promising areas for its use in assessing the quality of biologicals. The authors analysed regulatory documents and literature and summarised the methods applied for quantitative determination of ionic excipients in biological medicinal products. The authors investigated the possibility of using ion chromatography for determination of the main active pharmaceutical ingredient in polysaccharide vaccines and excipients in biologicals. The study demonstrated the feasibility of ion chromatography for simultaneous quantitation of cations (ammonium, calcium, magnesium) and anions (chlorides, sulfates, nitrates) in reconstitution solvents for lyophilised biologicals; quality assessment of active pharmaceutical ingredients in biologicals (quantitative analysis of polysaccharides in polysaccharide vaccines, profiling of glycosylated proteins, etc.); and determination of several carbohydrate stabilisers in biologicals with the same analytical procedure. According to the conclusions, ion-exchange chromatography with conductometric and amperometric detection, aimed at quality assessment of biological products, can shortly take a leading position in quantitation of ionic excipients, carbohydrate stabilisers, and main active ingredients (polysaccharides) in polysaccharide vaccines, including the vaccines in the immunisation schedule.

Phenol is used as a preservative in a number of biological products. Methods that are used for quantitative determination of phenol differ a lot. Current requirements for accredited laboratories include continuous internal quality control. Reference standards with a certified content of the analyte are an effective metrological tool for ensuring such control. The aim of the study was to develop and certify reference standards for phenolic content in biological products, based on comparison of results obtained by GLC, HPLC, spectrophotometric, and colorimetric methods. Materials and methods: diluent for allergens by (candidate reference standard), 2.5 and 5 mg/mL phenol solutions, and 2.5 mg/mL 2-phenoxyethanol solution were used in the study. The experiments were performed using spectrophotometric, colorimetric, HPLC, and GLC procedures. The statistical analysis of results included calculation of the arithmetic mean, standard deviation, coefficient of variation, and analysis of variance with Student’s t-test and Fisher’s F-test. Results: the results of phenolic content determination by the spectrophotometric, colorimetric, and HPLC methods were statistically comparable. The F value obtained for equal sample sizes (n = 40) was F = 0.9343, given the critical value Fcrit = 3.96. A reference standard certified by one of these methods can be used to control the consistency of phenol determination by a relevant method. The results of phenolic content determination by the GLC method showed statistically significantly differences: F = 17.47, given Fcrit = 3.96, which demonstrated the need for certification of another reference standard. Conclusions: two reference standards were certified in the study: reference standard 42-28-449 with the certified phenolic content of 2.56‒3.32 mg/mL, to be used with the spectrophotometric, colorimetric, and HPLC methods; and reference standard 42-28-451 with the certified phenolic content of 2.92‒3.28 mg/mL, to be used with the GLC method.

Relevance. The presence of pyrogenic impurities in finished dosage forms of concentrated cultural anti-rabies vaccines produced in the Russian Federation is determined using pyrogenicity tests on rabbits (in vivo). In accordance with the decision of the Board of the Eurasian Economic Commission dated September 7, 2018 N 151 «On the approval of guidelines for drawing up a regulatory document on the quality of a medicinal product», one of the requirements for parenteral drugs is the determination of bacterial endotoxins. This document indicates that the regulatory documentation should include a test and an admissibility criterion for bacterial endotoxins (BE) using the horseshoe crab amoebocyte lysate technique.Aims. Experimental evaluation of the possibility of using the LAL-test to determine bacterial endotoxins in national vaccines for the prevention of rabies.Materials and methods. The research of the drug «Cultural antirabies vaccine concentrated inactivated purified» of national production was carried out in accordance with the National Pharmacopoeia of the Russian Federation, General Pharmacopoeia Monograph OFS.1.2.4.0006.15 in three modifications: gel-clot test: methods A, B; turbidimetric kinetic test: method C; chromogenic kinetic test: method D.Results. Was investigated 6 series of the national vaccines for the prevention of rabies from two national manufacturers (using three pharmacopoeial methods). LAL reagent produced by two companies (Charles River Endosafe® and Lonza). In order to confirm the reproducibility of the method, the gel-clot test was carried out at different time intervals by one or two operators. During the research was determined the possibility of using photometric methods (method C and D).Conclusions. The research proved the possibility of determining bacterial endotoxins by methods: gel-clot test (method A), turbidimetric kinetic test (method C) and chromogenic kinetic test (method D). Method B is recommended for quantitative analysis of vaccine without instrumental methods. During the research all national vaccines for the prevention of rabies was free from bacterial endotoxins (no more 25 EU/ml).

The State Pharmacopoeia of the Russian Federation, 14th edition provides for determination of sub-visible particles (less than 100 µm in size) in parenteral dosage forms using the Coulter method, in addition to the light obscuration particle count test and microscopy. However, the proposed 100 µm aperture tube does not enable assessment of the whole range of sub-visible particle sizes. Therefore, research is needed to find optimal test conditions for determination of sub-visible particulate matter by the Coulter method. The aim of the study: modification of the Coulter-based procedure using a 200 µm aperture tube, and performance of validation studies. Materials and methods: Multisizer 4e Coulter counter, suspensions of reference latex particles (10 µm, 20 µm, and 43 µm), and a particulate count reference standard containing 0.998 × 106 particles/mL were used in the study. The following parameters were assessed during validation: accuracy, repeatability, linearity. Results: the study confirmed the feasibility of using the modified Coulter-based procedure with a 200 µm aperture tube. The following values were obtained during validation of the modified test procedure: accuracy was 5.3% (deviation from the mean value) as compared to the particulate count reference standard, and 4.2% as compared to the light obscuration method. Repeatability was 1% (relative standard deviation) for the particle concentration of approximately 10000 per 1 mL, and 7.6% for the particle concentration of approximately 300 per 1 mL. The study demonstrated the linearity of the procedure, the linear correlation coefficient was more than 0.99. Conclusions: the studied validation parameters of the modified test procedure were shown to comply with the acceptance criteria. The modified test procedure will enable assessment of the whole range of sub-visible particle sizes when testing parenteral solutions for particulate contamination: sub-visible particles.

Relevance. The need to increase vaccination coverage in order to eliminate measles in Russia and increase public confidence in vaccination requires constant monitoring of the quality of vaccines used for measles prevention. Aim. Analysis of laboratory quality parameters of commercial series of vaccines for measles prevention produced by JSC NPO Microgen, issued from 2015 to 2020, in comparison with the series issued in the period from 2002 to 2009. Materials and methods. The object of the study was a live measles culture vaccine and a live mumps-measles culture vaccine produced by JSC «NPO «Microgen». The quality analysis of vaccines was carried out according to the consolidated production and control protocols of 422 series of measles vaccine and 855 series of mumps-measles vaccine issued in 2015-2020, and 1043 series of measles vaccine and 902 series of mumpsmeasles vaccine issued in 2002-2009. Results and discussion. It is shown that the quality of the studied vaccines is stable during 16 years of monitoring. The sensitizing properties of both vaccines significantly decreased during the last 6 years of follow-up due to a decrease in the residual content of the antibiotic in the vaccination dose to less than the detection limit, as well as due to the low content of heterogeneous protein (bovine serum albumin). Conclusion. The quality of domestic vaccines for the prevention of measles and mumps meets who requirements; it is characterized by stability over 16 years of follow-up and minimal sensitizing properties. Information about the quality of domestic vaccines for the prevention of measles is an important argument for countering the antivaccination movement, which is a global problem and is recognized by who as one of the most important threats to the health of the world's population.

Relevance. Polysaccharide vaccine quality assessment must, on the one hand, comply with modern domestic and international regulatory documents, and on the other hand, reflect the characteristics of newly developed drugs. The list of drugs registered on the Russian market is constantly expanding due to the development of new effective vaccines and the introduction of new production sites. Thus, the expert requirements for assessing the quality of these drugs and the information content of the documents submitted as part of the registration dossier need to be updated.Aims. The aim is to update the expert assessment of quality in preclinical and clinical studies of polysaccharide vaccines, as well as to revise the evaluation of quality parameters depending on the composition and structure of the finished product.Conclusions. We highlight the key problematic aspects of assessing the protective properties of purified polysaccharides: in particular, the problems related to the natural immunity of animals to diseases caused by bacterial species that are relevant to humans and, as a result, the lack of an adequate experimental model. Modern trends in the characterization and subsequent confirmation of the structure authenticity of purified and conjugated polysaccharides are taken into account. An analysis of the latest international and domestic pharmacopoeial requirements for the quality of polysaccharide vaccines is carried out. The disadvantages of selected methodological approaches to the evaluation of quality parameters such as «Identification» and «Molecular mass distribution» are noted. It is shown that it is necessary to generate recommendations for the examination of polysaccharide vaccines which would unify the recommendations for completing registration dossiers and forming specification files by taking into account each individual peculiarity of this type of drugs.

Vaccination remains the only way to prevent tick-borne encephalitis (TBE). All TBE vaccines are based on strains of the Far Eastern and European subtypes of TBE virus. Currently, the Siberian subtype of the virus, which differs from the vaccine strains, accounts for 80–100% of the genetic population of TBE virus in most of Russia. The proportion of TBE vaccinated patients among those infected was different from year to year in Russia, e.g. 3.9% in 2012 and 1.5% in 2018, there were also some fatal cases registered among vaccinated patients. In this regard, evaluation of the effectiveness of vaccination against various genetic subtypes of TBE is a promising area of research. The purpose of this study was to summarise the results of studies investigating effectiveness of specific prevention of TBE as regards various genetic subtypes of the virus. The paper analyses data on the effectiveness of TBE vaccination in experimental settings and in real life. It was demonstrated that the use of vaccines for prevention of TBE is effective, provided the vaccination coverage is not less than 80%. The paper cites the data from a long-term study of the stability and protective activity of vaccine immunity against TBE virus strains isolated in highly endemic territories. It was established that TBE vaccines have high immunogenic activity and contribute to the production of stable protective antibodies against the strains of the three genetic subtypes of the virus. Protective efficacy of vaccination depends on the number of vaccinations received, the vaccination scheme, gender and age of those vaccinated. The paper concludes by saying that further studies are needed to assess TBE vaccine efficacy in order to improve vaccination tactics, to better understand causes of morbidity and mortality among vaccinated individuals.

Specific antiviral activity is one of the key indicators characterising pharmaceutical quality and pharmacological efficacy of interferon alpha products (IFN-α). Specific activity is determined using a bioassay measuring antiviral activity in cell culture. The aim of the study was to select the most appropriate conditions for in vitro determination of IFN-α product specific activity. Materials and methods: Vero, MDBK, Hep-2, and A-549 homologous and heterologous cell cultures, as well as vesicular stomatitis Indiana virus (VSV) and murine encephalomyocarditis (EMC) virus at a dose of 100 TCD50 /0.1 mL were used for determination of specific antiviral activity. The international reference standard of recombinant interferon alpha-2b activity (Interferon alpha 2b, human, rDNA, E. coli-derived, 2nd WHO International Standard, 1999, NIBSC Code No. 95/566) and human recombinant interferon alpha 2b in the form of solution (batch No. 040214, Pharmapark LLC, Russia) were used as IFN-α samples. Results: the analysis of the obtained data helped to determine: the combinations of cell lines and the indicator virus most sensitive to IFN-α; the optimal concentration of fetal serum in the medium, and the optimal time parameters; the preferred method of reporting test results. Conclusions: the following test conditions were found to be optimal: the MDBK/VSV and Hep-2/EMC combinations proved to be the most sensitive to IFN-α; the optimal period of interferon and cell culture incubation—24 hours; the optimal concentration of fetal bovine serum in the culture medium used for diluting interferon products—2–5%. The instrumental procedure is preferred for reporting the results of interferon antiviral activity determination, because it is up-to-date, reliable, accurate and time-efficient.

The urgency of the rabies problem for all mankind and the search for new ways of eradicating the disease entailed the creation of a new global initiative for rabies elimination ‒ «United Against Rabies» which sets a highly ambitious goal of achieving zero rabies human deaths by 2030. The many years of international experience in elimination of street dogs, which account for 99 % of rabies cases, did not produce the desired results, therefore the focus was shifted to mass vaccination of dogs (minimum 70 % of dog population). The rabies problem is complex and global, it requires efforts from all the parties involved as well as hefty investment. The paper presents the results of a continuous long-term analysis of the rabies situation in Russia and across the world, as well as analysis of the current state of vaccination against rabies which plays an important, if not crucial, role in prevention of rabies in humans who got bitten by infected animals. The paper formulates the main currently existing ways of solving the rabies problem, namely: mass vaccination of dogs; improvement of dosing schedules and administration routes of medicines against rabies; analysis of immunity development mechanisms in immunocompromised patients; progressive implementation of vaccination of people who got bitten by infected animals, and alternative administration routes; development of an express method of the neutralising antibody titer determination; raising public awareness about disease hazards.

The review provides information on topical issues of rabies spread in the world and the Russian Federation, the stages of development and directions of improvement of available preventive anti-rabies immunobiological preparation used in medical practice for active and passive immunization against rabies. The current level of biotechnology development with the use of molecular biology and genetic engineering methods opens up prospects for the design of new safe effective anti-rabies drugs using recombinant technologies. Expanding the range of immunobiological drugs against rabies and their introduction into health practice will contribute to the elimination of human mortality from rabies.

The review analyses measles incidence in Russia at the elimination stage. Epidemiological studies have revealed changes in the measles epidemic process in Russia. It was shown that whereas the specificity of the epidemic process in the pre-vaccination period was mainly determined by the influence of the infectious agent, lately the impact of the social factor has increased. There was an increase in the impact of decreed groups on maintaining the circulation of the virus in the Russian Federation. The aim of the study was to analyse the specificity of the measles epidemic process in Russia, to identify the major current problems of measles vaccination, to reveal reasons that prevent measles elimination in the country given the present environment, and to formulate possible ways of solving them. The article demonstrates the role of migration processes within the country and infection importation from neighboring territories in the rise of disease outbreaks. The article discusses Russian regulatory documents that are devoted to combating the spread of measles, their consistent replacement and refinement bearing in mind the changing epidemiological situation and the current WHO criteria and guidelines for the infection elimination. High-level epidemiological surveillance of the infection is a key factor in choosing the optimal strategy of measles vaccination. The article lists indicators of epidemiological surveillance effectiveness. It also highlights the importance of molecular genetic monitoring of the measles pathogen. The authors outline measures that are necessary to achieve measles elimination in the Russian Federation given the current epidemiological situation.