The present article adduces the evidence in support of the need in the development of personalized vaccines and provides with case studies, substantiating the possibility of the mentioned approach. In order to personalize vaccines one should perform preliminary determination of antibody titers (or delayed-type hypersensitivity skin testing) and the subsequent correction of the immunity in patients with low titers of protective antibodies or hyperimmunization symptoms. Vaccine personalization does not require serious financial expenses. The article provides with the advantages of vaccine personalization and the measures that should be taken to achieve this goal. The difficulties of the personalization and the ways to overcome them are described in the article. Vaccine personalization does not require serious financial expenses. It will contribute to the development of preventive vaccination. Personalization of vaccines is necessary for achieving herd immunity, which leads to the reduction in the incidence of the mentioned infection and usually to the reduction of agent circulation. «Immune domain», which includes mostly recovered and vaccinated patients as well as naturally immuned individuals (by circulating infectious agents), plays a decisive role in the development of herd immunity. The effectiveness of herd immunity is reduced due to genetic variability of an agent, frequent vaccination refusals and rejections. Long-term herd immunity is stipulated by immunological memory.

The review deals with the issues related to the special aspects of the development of the first available similar biopharmaceuticals/biological analogues («biosimilars») based on monoclonal antibodies. In June 2013 the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) approved for licensing Remsima and Inflectra which are biosimilars of the brand-name product Remicade^® (infliximab). The review describes the general principles of the development of the mentioned biosimilars. It highlights the features of the quality assessment studies, including characterization of the physical and chemical properties, specific biological activity, as well as comparative preclinical and clinical trials confirming the similarity of the candidate and the brand-name (reference) product. The review provides with the analysis of the results of comparative studies to assess the clinical relevance of the differences detected at the stage of quality assessment. The data substantiating the possibility of extrapolating the results obtained in clinical trials, against the approved standards for the brand-name product is provided.

The review covers problems of construction and production of new recombinant rabies vaccine. New approaches are being investigated to develop rabies vaccine and include methods of reverse genetic, production of virus antigens in plant cells cultures, obtaining of virus like particles and DNA and virus vector-based vaccines. Reverse genetics techniques let to manipulate the rabies genome and construct new attenuated strains of rabies virus. The production of the rabies virus main antigen (the glycoprotein G) in the plant cells cultures is promising for getting «edible» vaccines that do not require cleaning of antigen and repeated parenteral administration. Virus-like particles are capable to carry several rabies virus antigens, as well as different molecular adjuvants. DNA vaccines are characterized by ease preparation and low cost, but require different ways to enhance immunogenicity. Such approaches as DNA and virus vector-based vaccines delivering foreign genes, for example the gene of the glicoprotein G. Nowadays veterinary vaccines based on recombinant replication-competent vaccinia virus and human adenovirus type 5 are being actively used. Non-replicative human adenovirus type 5, expressing rabies glycoprotein G gene, is a good candidate for development of vaccines for mass immunization of the population.

Pharmacopoeial analytical methods involving reference standards (RS) are used for manufacture and quality control of medicinal products, including biologicals, these RS should now to be called pharmacopoeal. The introduction of the mentioned term reflects special drug characteristics, which are regulated not by the State Union Standards but by the Russian State Pharmacopoeia in terms of quality control. Drug and RS special characteristics require the establishment of legal and methodological framework. The recommendations stated in ISO REMCO are general do not fully cover the special aspects of the certification of reference standards for each specific area. The documents of the Federal Agency for Technical Regulating and Metrology (Rosstandart) on reference standards can not be used for biological medicinal products due to their specificity as the test methods do not allow to separate systematic and random components of uncertainty of test results, as required by Rosstandart. The regulatory framework for biological RS should be developed on the basis of WHO and ICH Guidelines. The classification of drug reference standards and the list of priority documents required for the elaboration of normative and procedural framework regulating their development, certification, approval and use is considered in the article. The development of the documents for the mentioned system is exemplified by a new pattern for an RS certificate.

Tissue cross-reactivity (TCR) studies are screening immunohistochemical (IHC) assays, usually conducted on frozen human and animal tissues. This study is obligatory for getting the permission for clinical trials in Russia for all innovative therapeutic products based on monoclonal antibodies or antibody-like molecules that contain complementarity-determining region (CDR). In this article are represented approaches and methodical features for successful conduction of tissue cross-reactivity studies with examples from own authors’ experience.

Production of recombinant proteins is a steadily growing industry in Russia and all over the world. Both producer and substance should be properly characterized and tested against all safety criteria. One of the mandatory requirements to the mentioned drugs is the assessment of the content of residual DNA-producing cells, which should be less than 10 ng per dose. There are not many commercial kits for detection of residual DNA and they are based on four different methods. The article provides a brief overview of these methods and highlights their advantages and disadvantages. Common disadvantage of all the commercial kits is their price. The main goal of the research was to choose an optimal method of DNA extraction from protein substances and samples of various protein purification steps, as well as to work over measuring the amount of residual E. coli DNA and CHO by qPCR method not using commercial kits. The article also provides with a number of practical recommendations on specific aspects of DNA extraction and reference standard storage. The aim of the study was to find a reliable and inexpensive method for determining residual DNA-producing cells in recombinant protein samples. The article provides with an overview of DNA extraction methods, stipulates the necessity of DNA extraction prior to the analysis. The advantage was given to the method of spin-column extraction. Optimal DNA extraction method for its assay in a substance is the method, which provides with a stable DNA yield, including different chemical structure of the samples, and upon the condition that no protein and other impurities are detected in the isolated DNA solution. The proposed method for DNA spin-column extraction is the least labor-intensive, is optimized for DNA isolation from protein substances and samples of various protein purification steps. Self preparation of solutions for DNA extraction is a simple procedure and can reduce analysis costs. The report on successful adaptation of the methods of residual E. coli and CHO DNA detection by qPCR using fluorescent probes was provided. The sensitivity of the method was demonstrated at least 1 pg/ml for the analysis of the amount of residual DNA both for E. coli and CHO.

The results of the tests for the quality assessment of live tularemia vaccine under the Federal State Budgetary Institution «Scientific Centre for Expert Evaluation of Medicinal Products» of the Ministry of Health of the Russian Federation in 2011-2015 were analyzed in the present article. There were 14 batches (of 34) which did not comply with the requirements of regulatory documents (RD) in terms of «Specific activity (percentage of live microbial cells)», «Number of cutaneous doses» and «Thermal stability». The experimental results had confirmed the irregularity of tularemia vaccine batch samples in terms of «Specific activity (percentage of live microbial cells)» which, respectively, led to differences in vaccine samples in terms of the number of cutaneous and intradermal doses. It was confirmed that FT-agar is a nutrient providing all the necessary conditions for cultivating Francisella tularensis strain. Possible causes of irregular quality of the batches released in 2011 was considered in the present article. Test results for 93 batches of tularemia vaccine manufactured in 2012-2015 shown their full compliance with the requirements of RD. Consistent quality assurance of tularemia vaccine became the basis for the possibility of choice, certification and approval of new drug batches as industrial reference standards.

The article highlights the materials on the development and certification of the industrial reference standard (IRS) for identification of meningococcal polysaccharide vaccine group A. The scheme and methodology for IRS certification have been developed. Samples of the vaccine IRS candidate have been tested in terms of: «Description», «Dissolution time», «Transparency of reconstituted solution «, «Colourity of reconstituted solution», «Particulate matter «, «Loss on drying», «Accuracy of filling» «Phosphorus», «Sterility», «Pyrogenicity», «Abnormal toxicity», confirming their compliance with the current Pharmacopoeia monograph MP-00392-180512. The certified characteristic has been determined: IRS should slow down passive hemagglutination (PHIA) in «A» homologous system with polysaccharide concentration in the range from 0.19 to 0.39 μg per 1 ml in the absence of the inhibitory effect in «C» heterologous system with polysaccharide concentration of 50 μg per 1 ml. The shelf life of the IRS meningococcal group A polysaccharide vaccine for identification has been set against the vaccine shelf life and has been equal to 2 years. The set of regulatory documents on the scientific and technical product IRS 42-28-428-2014 IRS meningococcal group A polysaccharide vaccine for identification (certificate, draft label of primary package and patient information leaflet) has been approved.