The paper presents the data on safety and efficacy assessment of adjuvants and vaccines with adjuvants at the stages of development and preclinical studies based on international recommendations. The presence of an adjuvant in vaccine content ensures higher expressing and prolonged specific immunity. The origin and nature of adjuvants currently used for various vaccines are different. Adjuvants can be classified by origin, mechanism of action, physical and chemical properties. The finished vaccine may contain one or more adjuvants which can be intended for one antigen or a number of antigens in vaccine content. Antigen-adjuvant combination is a key part in the production of a vaccine with an adjuvant. Due to the diversity of adjuvant nature and their physical and chemical properties and mechanisms of action, as well as to antigens in adjuvant vaccines content, it is rather complicated to plan and to conduct preclinical studies. The present article describes various aspects of preclinical studies of adjuvants and vaccines with adjuvants based on the analysis of current guidelines and requirements.

The authors prepared proposals for preventing undesired reactions at application immunobiological medicinal products in the Russian Federation. Given the significant number of osteitis when carrying out vaccination against tuberculosis in a nursing home as BCG and BCG-vaccine, it is proposed to consider with experts of the respective profiles of the question of the possible adjustments in the existing system of prevention of tuberculosis. To ensure timely diagnosis BCG-ASTIC and destination specific treatment of the disease to carry out consultation with the coordinators of all children under the age of 5 years with a diagnosis of octet regardless of the localization of the inflammatory process. When exercising pharmacovigilance for side effects of vaccination against tuberculosis note that unlike bone tuberculosis caused by virulent bacteria, and striking in most cases, the spine, BCG osteitis virtually no this localization, and strike thigh 21, 2% of cases, tibia and fibula - 20%, sternum - 15, 6%, humerus and 11.6%, the bones of the foot is 9, 3%, fin - 8, 5%. It is considered necessary to conduct a complete replacement drugs heterologous sera, especially tetanus toxoid and rabies immunoglobulin from the serum of a horse, on preparations of human serum, as it is implemented in all developed countries. This event will lead to the exclusion of the possibility of allergic reactions of immediate type, including anaphylactic shock, when an emergency prophylaxis of these infections. Registration sterile abscesses after application of drugs DTP vaccine and the absence of such complications after the use of other adsorbed preparations (for example hepatitis In vaccines and vaccine encephalitis) do not exclude the possibility of communication first with the quality of the used sorbent and this allows us to recommend further study and evaluation of physicochemical parameters of the series of sorbent, used in the production of adsorbed vaccine containing the pertussis component.

The article presents an analysis of 522 cases of complications after BCG vaccination, i.e. post-vaccinal osteomyelitis, based on pharmacovigilance data obtained between 2001 and 2012. A detailed study of ill children revealed no clinical manifestations (severe bacterial, viral or fungal infections, repeat bacterial infections of respiratory tract, paraproctitis, chronic eczema etc) suggesting primary or secondary immunodeficiency. All of the 135 children who were vaccinated with measles, mumps and rubella vaccine and all of the 315 children who were vaccinated with live polio vaccine had no complications in the post-vaccinal period.

The article presents results of analysis of adverse reactions in patients after administration of human blood products (normal and specific immunoglobulins, albumin), animal blood products (antitoxin sera, specific immunoglobulins), and recombinant blood products, that are registered in the international and two national databases. Whereas in the international database blood products have never been among top 20 drugs accounting for the largest number of reports on adverse reactions over 46 years of monitoring, in the Russian Federation severe allergic reactions caused by administration of heterologous serum products (antitetanica horse serum, antirabies immunoglobulin from horse blood serum) accounted for 5,6-11 % of all annual reports of adverse reactions caused by administration of immunobiological products, including vaccines of the National immunizations schedule. Main clinical signs of serious adverse reactions to blood products are immediate-type (type 1) allergic reactions that are registered after administration of both homoand heterologous products and type 3 reactions (serum disease) that arise after administration of heterologous sera. Prevention of serum disease development is only possible by replacement of animal serum-derived drugs by a corresponding human blood serum-derived products.

The analysis of medical documentation of 460 post-vaccination complications of bone system in children vaccinated with BCG-M was made. In 2001-2010, the significant increase of numbers of this form of post-vaccination complications developed exclusively after initial vaccination was established. The characteristics of localization of bone lesions as compared with lesions in case of tuberculosis were established. Despite the present health disorders in mothers during pregnancy most of ill children had no clinical symptoms of diseases testifying the presence of development defects of immune system.

Modern data substantiating the expediency of the use of acellular pertussis vaccine were analyzed. Serious postvaccinal complications caused by the action of the corpuscular pertussis component of adsorbed DPT vaccine served as the basis for the development of acellular pertussis vaccine (APV). During the period of 1990-1996 as many as 8 international field trials of the effectiveness of APV were carried out. The results of these trials and studies were evaluated in accordance with the unified programs and criteria. The vaccines under test differed by the composition of Bordetella pertussis purified antigens they contained, the methods of their purification and the detoxification of pertussis toxin. All tested APV, with the exception SKB-2, possessed pronounced prophylactic activity.

Bubo-M, the first Russian associated vaccine, was found to have low reactogenicity and high immunogenic potency. The frequency of postvaccinal reactions in the group of persons immunized with Bubo-M (20%) appeared to be considerably lower than among persons who received the combined injection of adsorbed DT toxoid with reduced antigen content and vaccine against hepatitis B (47.7%). Following the course of vaccination the level of anti-HBs considerably exceeded the protective level. Immune response to the diphtheria and tetanus components of Bubo-M exceeded that observed after immunization with absorbed DT toxoid with reduced antigen content (p < 0.05).

Bubo-M, the first Russian combined vaccine, was found to have low reactogenicity. The difference between the number of postvaccinal reactions in the group of children immunized with Bubo-M (25.9%) and those in the group of children who had been simultaneously injected into different sites of the body with ADS-M toxoid (adsorbed DT toxoid with reduced antigen content) and hepatitis B vaccine (26.7%) was not statistically significant. Following immunization a considerable increase in the level of diphtheria and tetanus antibodies (p < 0.005) was observed in all children (100%), the level of HBs antibodies in the group of children immunized with Bubo-M (the geometric mean titer: 13,721 IU/l) essentially exceeding that observed in the control group injected with ADS-M toxoid and hepatitis B vaccine (the geometric mean of the titer: 2,441 IU/l). Bubo-M was duly registered and allowed for industrial production and medical use.

A safe, moderately reactogenic and immunologically effective scheme of complex (combined) immunization against meningitis A, diphtheria, typhoid fever, viral hepatitis A and influenza has been developed as the result of experimental and clinico-immunological studies. Depending on the epidemiological situation, the newly developed scheme can be used in two variants. According to the first variant of this scheme, the following preparations are injected subcutaneously into three different sites: a mixture of group A meningococcal vaccine and diphtheria toxoid, typhoid vaccine and influenza vaccine. The second variant of the scheme differs from its first variant in using intramuscular injection of normal human immunoglobulin instead of injection of influenza vaccine. Moreover, in practical realization these variants may be altered by excluding vaccines, unnecessary under present conditions. The newly developed scheme of vaccinal prophylaxis is recommended for practical use.

The influence of pertussis preparations, introduced by oral and parenteral routes, on the detoxifying function of the liver and the state of the nervous system of the animals was studied by methods used in pharmacology and toxicology. The use of these methods made it possible to find out side effects produced by corpuscular pertussis vaccine, introduced parenterally, on the detoxifying function of the liver and the state of the nervous system of the animals. The negative influence on the nervous system was more pronounced after the injection of the commercial adsorbed diphtheria-pertussis-tetanus vaccine used in this investigation than after the injection of pertussis monovaccine. The oral administration of corpuscular pertussis vaccine exerted no negative influence on the above-mentioned body functions of the animals.