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To counterbalance the unsubstantial declarations of some vaccinologists that vaccines and vaccination are not only useless, but also injurious to the health, this work represents the evidence that vaccines and vaccination not only reduce the morbidity of viral infection, but also allow some viral diseases to be eradicated and eliminated. The work also adduces the data about reducing economic impact of viral infections with the help of vaccination, as well as the data, which clearly show that serious reactions to vaccination are thousands of times less frequent than reactions and complications caused by infectious diseases.

Cold-adapted (CA) strains A/Krasnodar/35 and B/Victoria/63 were isolated using passages of A/Krasnodar/101/59 and B/Victoria/2/87 wild type strains at low temperatures. The resulting CA strains possessed TS and CA phenotypes and had a reduced ability to reproduce in mouse lungs and nasal turbinates. They displayed a high protective efficacy in experiments on mice. The two CA strains reproduced well in chick embryos and MDCK cell line without change of TS and CA markers. The CA A/Krasnodar/35 strain during passages at low temperature acquired 13 mutations in the 6 internal genes, 8 of those mutations led to amino acid changes. The CA B/Victoria/63 strain acquired 8 mutations in the internal genes, 6 of which led to amino acid changes. The intranasal vaccination of mice with the CA A/Krasnodar/35 strain led to a transitory suppression of various lymphocyte subpopulations, as well as to an increase in the number of some other cell types. The CA strains in question may be used in the future as attenuation donors for live influenza vaccines.

Epidemiologic and economic effectiveness of school closure during influenza epidemics and pandemics is discussed. Optimal effect of school closure is observed when this measure is taken at the start of the epidemic or pandemic and for a sufficiently long time. School closure during high morbidity among schoolchildren, in the middle (at the peak) and by the end of epidemic or pandemic does not influence significantly the spread of influenza or morbidity. Significant economic losses and other negative consequences of school closure are noted. School closure may be the most appropriate during the emergence of influenza pandemic when the pandemic vaccine is not yet available, however timely mass immunization of schoolchildren against influenza may be a more appropriate measure than school closure for the reduction of influenza morbidity and spread during seasonal influenza epidemics.

Study of immunogenicity and protective efficacy of a novel inactivated vaccine with chitosan against influenza A/H1N1/2009.Influenza virus A/California/7/2009 (H1N1) strain was used in the study. Mice were immunized twice (21 day interval) with experimental samples of inactivated influenza vaccine: No. 1--without the addition of chitosan, No. 2--with addition of chitosan. The blood was obtained 21 days after the first and 10 days after the second immunization with the vaccines and was treated with RDE. Antibody levels were evaluated in HI reaction.HI reaction method showed that antibody titers induced after immunization of vaccine No. 2 were higher than those induced after immunization with vaccine No. 1. Evaluation of protective efficacy of the vaccines against an experimental form of influenza infection in mice showed that after immunization with vaccine that does not contain chitosan the level of virus accumulation does not differ from the control statistically significantly (por = 0.05), at the same time the level of virus accumulation in the lungs of infected animals immunized with chitosan containing vaccine significantly (significantly with 95% probability) decreased by an average 3.01g when compared with control.Comparative analysis of immunogenicity and protective efficacy of experimental samples of inactivated influenza vaccine against influenza A/H 1N1/2009 showed that the vaccine with the addition of chitosan stimulates the formation of a higher immune response and promotes a more significant suppression of influenza A infectious agent reproduction in the lung target-organ.

Scientific data is presented and problems of influenza prophylaxis in various age groups are discussed. Influenza prophylaxis in neonates is possible by inducing maternal antibodies, this dictates the necessity of influenza vaccination in pregnancy. Problems of influenza prophylaxis are most pressing in the group of children from 6 months to 2 years of age. More effective vaccines that do not cause adverse reactions are necessary for the children of this age group. Influenza prophylaxis in healthy working adults is most important for reducing economical impact during influenza epidemics. Influenza prophylaxis in the elderly is reasonable by using novel and more effective vaccines with adjuvants. The optimal method for influenza prophylaxis in the population in general is mass vaccination of children (80%), when, besides the induction of protection in children, influenza morbidity may decrease up to 80% in the other age groups of unvaccinated population.

The review characterizes the currently used cold-adapted donor strains of influenza virus attenuation to prepare cold-adapted reassortants with actual epidemic influenza virus strains. It considers new procedures for preparing attenuated influenza virus strains for live influenza vaccines, as well as analytical methods and the genome composition of reassortants. Recent data on the safety of live cold-adapted influenza vaccines (LCAIVs), including those on the genetic stability of vaccine reassortants and the immunogenicity and efficacy of these vaccines for different age groups, are discussed. There is evidence for the design of live human vaccines against avian influenza. It is concluded that LCAIVs are highly effective for immunization of children.

To assess increase of protective efficacy of live cold-adapted (ca) influenza vaccine after addition of adjuvant chitozan.Used viruses: ca donor of attenuation A/Krasnodar/101/35/59 (H2N2) and epidemic strain A/Krasnodar/101/59 (H2N2); as an adjuvant--derivative of chitozan and microparticles of chitozan. Experiments were performed in outbred mice. Protective effect of immunization was measured by intranasal challenge by virulent strain of virus. Immune response was assessed by ELISA and indirect hemagglutination inhibition assay.During intranasal immunization of mice with intact CA donor of attenuation A/Krasnodar/101/35/59 (H2N2) addition of 1% solution of chitozan glutamate to vaccine material resulted in increased serum IgG in immunized mice and protective effect of immunization. Addition of adjuvant to ca donor strain did not influence on its ts-characteristic. It was shown that inactivated with ultraviolet radiation ca donor strain in combination with chitozan did not protect against infection caused by virulent strain A/Krasnodar/101/59, whereas the same doses of intact ca donor strain with chitozan were protective. Chitozan did not enhance replication of donor strain in upper respiratory tract of mice.Obtained data demonstrate that chitozan as a mucous-adhesive adjuvant could increase efficacy of live ca influenza vaccine.

Analysis of pandemic caused by swine influenza virus H1N1/California showed moderate virulence of this virus compared to pandemic viruses, which caused pandemics in 1918, 1957, and 1968. During seasonal influenza epidemic in countries of southern hemisphere (June-August 2009) despite on circulation of H1N1/California strain, epidemics was caused by human influenza viruses H3N2 and H1N1. It was concluded that strain H1N1/California could not be attributed to pandemic strains of influenza viruses.

The review presents the data available in the literature on the incidence of influenza, postinfluenza complications, hospitalizations, and deaths in pregnant women, on the negative fetal and neonatal impact of this disease in pregnant women, on vaccination of pregnant women with inactivated influenza vaccines. It also gives data on the high rates of influenza complications, admissions, and death in the newborns and on possible prevention of neonatal influenza at the expense of maternal antibodies. It is concluded that it is expedient to vaccinate pregnant women against influenza to reduce the rates of morbidity, hospitalization, and mortality due to influenza infection among both women themselves and neonatal infants.

In the overwhelming majority of countries inactivated vaccines, which form mainly humoral immunity, are used for prevention of influenza. The objective of the study was to assess the combined effect of inactivated influenza vaccine and chitozan on cellular immunity in CBA line mice. Intramuscular administration of 2 doses (with 4 week interval) of inactivated influenza vaccine and chitozan resulted in increased cytotoxic activity of splenic NK cells against NK-sensitive cell line K562 as well as in increased proliferative activity of mononuclear leukocytes, and numbers of CD3 T-lymphocytes, NKT cells, B-lymphocytes in animals' spleens. Combination of inactivated influenza vaccine with chitozan modulated the number MHC II-expressing cells by eliminating the increased reactivity of immune system cells as well as increased the number of MHC I-expressing cells. This point on the activation of cellular properties, which recognize intracellular pathogens, and thus on activation of both humoral and cellular factors of immune response. It can be proposed that inclusion of chitozan in the vaccine allows to modulate switching of the immune response from Th-2 to Th-1 type.

Addition of 0.5% chitosan derivative to parenteral inactivated influenza vaccines increased antibody titers in the single immunization of mice by 4-5 times while double immunization showed 6-to-10-fold increases as compared with immunization without chitosan. Moreover, chitosan-containing vaccines induced the generation of antibodies to the drift variants of influenza virus. When the mice were given inactivated influenza virus A/H5N2 vaccine containing chitosan, immunogenicity and protective efficacy were much higher than when they received a vaccine containing no chitosan.

Data on influenza pandemics as well as on the characteristics of influenza viruses, which caused pandemicsin 1918, 1957, 1968, and 1977 are presented. Mechanisms of pandemic influenza virus strains evolving, including mutations resulting in increase of virulence, as well as possibility of human and avian influenza viruses reassortment process as the source of pandemic strains are discussed. Mechanisms of transformation of mildly virulent influenza virus strains to highly virulent, which can cause epizootics, are reviewed. Genes and proteins determining species specificity of avian influenza viruses as well as possible emergence of influenza pandemic caused by H5N1 strain are discussed. Suggestion of low probability of such event is expressed.

The data about high morbidity of children influenza and their hospitalization, and principle role of children in speacling of influenza are presented. Total influenza vaccination of children decrease the influenza morbidity and hospitalization of children, and also may be to decrease the influenza morbidity of nonvaccinated population whole during influenza epidemics. Problems of effective vaccination of infants are discussed and data about economic effect of their total vaccination are presented.

The review gives data on the reactogenicity, immunogenicity, and protective efficacy of the existing influenza vaccines, such as inactivated (conjugate, subunit, virosomal, cultural vaccines with adjuvants) and live vaccines, as well as on the new directions in the design of influenza vaccines. It also provides data on specific medications against influenza and discusses the problem associated with the occurrence of influenza viruses resistantto these drugs. The economic efficiency of the prevention of influenza with vaccines and drugs is under debate.

A ts+ revertant of cold-adapted (ca) strain A/Leningrad/134/47/57--the attenuation donor for live influenza reassortant vaccines--was obtained by passages of the ca strain in chick embryos at nonpermissive temperatures. The ts+ revertant acquired the ability to grow in chick embryos at 40 degrees C and lost the capacity to reproduce there at 25 degrees C. A complementation-recombination test using the fowl plague virus (FPV0 ts-mutants showed the loss of the ts-phenotype in the RNA-segments of ts+ revertants' genome coding for PB2, NP, and NS (NS2) proteins. However, PCR-restriction analysis revealed a true reversion in RNA-segment coding for PB2 protein only. All the investigated mutations in the ts+ revertant genome were preserved. This phenomenon could be explained by the appearance of intragenic and extragenic suppression mutations in the ts+ revertant genome. The data of the complementation-recombination test suggest that reversion of ts-phenotype occurs more frequently due to extra- or intragenic suppression rather than as a result of a true mutation loss. Estimation of the genetic stability of vaccine ca strains of influenza virus should be based on the combined use of PCR-restriction and complementation tests.

In the review cited the data about avian flu epizootia for last years, about economic damage by epizootia, the information on an infection of people by viruses of animals. Problems the development of vaccines against a avian flu, including ways of designing of vaccine strains are discussed. Data on methods of struggle with avian influenza epizootia of poultry, about methods of prevention the epizootia and uses for this purpose of vaccines and drugs are resulted.

The review summarizes recent data on the incidence of influenza and hospital admissions for this disease among infants aged 0 to 2 years. It considers the optimal influenza prevention regimens in the age groups of 0 to 6 months and 6 months to 2 years, by using influenza vaccines for immunization of infants and all those contacting them inside and outside, as well as pregnant women. Whether prophylaxis of influenza A can be made in Russia is also discussed.

Optimal conditions were developed for cultivating the cold-adapted reassortant live influenza vaccine (CARLIV) in MDCK cells, which were in their turn cultivated in fermenters with serum-free medium and microcarrier. The use of MDCK cells meets all national and WHO requirements to continuous cells used in the production of biological preparations. CARLIV cultivated under such conditions well preserve their ts-mutations and mutation, which entail substitutions of amino acids, in all CARLIV genome segments. Provided the cultivation conditions are optimal, the output of multivalent CARLIV in a 101 fermenter can reach 100000 doses.

Seeding and working banks of the continuous MDCK cell culture suitable for the production of cultured influenza vaccine were created and deposited at liquid nitrogen temperature at the "Vector" State Research Center of Virology and Biotechnology. The MDCK cell culture was shown to have morphology typical of the discussed cell line; it does not have any alien agents and is oncogenically safe; its enzimogram and karyotype are typical of the donor line; finally, its biological properties are stable during a long period of cultivation and its sensitivity to influenza virus is high, therefore, it can be recommended for the production of influenza vaccine. The continuous MDCK cell line was certified at Tarasevich Committee and was recommended by the MIBP Committee, Russia's Health Ministry, for its use as a substrate in the production of diagnostic and preventive immunoglobulins.

Immunization of children aged 3-6 years in kindergartens and school children aged 7-17 years against influenza with inactivated influenza vaccine was carried out in two districts of the Moscow region. The comparison of morbidity in influenza-like diseases among the immunized children with that among nonimmunized children in control districts revealed that the effectiveness of immunization was 60.9% in kindergartens and 68.8% in schools. The analysis of morbidity in a number of diseases among 158,451 elderly persons not immunized against influenza demonstrated that, in comparison with the control districts, in those districts where mass immunization of children was carried out morbidity in influenza-like diseases among elderly persons was 3.4 times lower and, out of other 10 diseases under study, morbidity in 8 diseases was 1.5-2.6 times lower. As indicated by the data obtained in this study, total anti-influenza immunization of children in organized groups not only essentially decreased influenza morbidity among children, but also greatly decreased morbidity in influenza and a number of diseases, appearing as complications of influenza infection, among nonimmunized elderly persons during influenza epidemic.

Influenza remains a serious health problem, annually causing epidemics embracing up to 10% of the population of the world, and at the periods of pandemics this number may rise 4- to 6-fold. In the overwhelming majority of the countries the prophylaxis of influenza is carried out at present out with the use of inactivated vaccines. One of such vaccines is the highly purified split vaccine Vaxigrip (Aventis-Pasteur, France), permitted for use in Russia since 1992. The article contains the review of the data of literature, as well as the materials provided by the authors, which indicate that the preparation has low reactogenicity (also for children starting from the age of 6 months) and high reactogenic properties, leading to antibody formation at protective levels with respect to all three components of the vaccine. The vaccine has been found to ensure pronounced prophylactic efficacy for 70-90% of vaccinees and a decrease in influenza morbidity even in case of using the preparation a week before the onset of the epidemic. This shows the advantage of Vaxigrip in comparison with other inactivated vaccines.

Published data related with comparison studies of safety, efficiency and some other properties of cold-adapted live influenza vaccine (LIV) and of inactivated influenza vaccine (IIV) are analyzed. LIV and IIV do not differ by systemic reactions after administration; however, it is not ruled out that there can be unfavorable reactions in vaccination of persons with allergy to the chicken-embryo proteins as well as in cases of persistence/reversion of cold-adapted strain observed in vaccination of persons with primary impairments of the immune system. There are no convincing data, up to now, on that LIV is superior to IIV in coping with influenza pandemics. The efficiency of LIV and IIV for children aged 3 years and more and for healthy adults is virtually identical. Additional controllable field comparative studies of LIV and IIV efficiency in immunization of elderly persons are needed. Limited data on LIV efficiency for children aged 2 months and more were obtained. The need in a 2-stage vaccination of all age group with the aim of ensuring responses to all 3 LIV components is, certainly, a LIV disadvantage. In case of IIV, the 2-stage vaccination is needed only for persons who were not ill with influenza. The intranasal LIV administration has, from the practical and psychological standpoints, an advantage before the IIV administration by syringe. The ability of LIV to protect from the drift influenza-virus variations could be its advantage before IIV; still, more research is needed to verify it. Transplantable cell lines meeting the WHO requirements could be an optimal substrate for the production of LIV and IIV. Children are the optimal age group for influenza prevention by cold-adapted LIV, whereas, IIV fits better for vaccination of adults and elderly persons.

In this review recent data on the development of mucosal influenza inactivated vaccines with the use of mucosoadhesive adjuvants are presented. After the intranasal administration of such vaccines the formation of not only systemic, but also local immunity (IgA antibodies), as well as cross protection against the variants of influenza virus within its serotype, can be observed. Some mucosal influenza vaccines have passed clinical tests. Certain drawbacks of Escherichia thermolabile enterotoxin, used as mucosoadhesive adjuvant, and difficulties which may arise in mass immunization with mucosal vaccines due to the necessity of introducing them in two or three intranasal administrations are indicated.

Recent achievements in development of influenza vaccines using long-term cell cultures MDSK or Vero are reviewed. Cell cultures were grown in bioreactors (fermenters) filled with microcarriers using serum-free culture media. Inactivated cultural influenza vaccines were clinically tested in many countries. The results of these trials showed that cultural influenza vaccines are as safe and immunogenic as conventional vaccines prepared using chicken embryos. It is emphasized that cultural influenza vaccines prepared using serum-free culture media have a number of advantages over embryonic influenza vaccines: standard preparation technology, intactness of all hemagglutinin antigen domains, absence of protein allergens and possible viral contamination inherent in chicken embryos and blood serum, and possibility of easy intensification of vaccine production in case of influenza pandemic. Taking into consideration these advantages, it may be suggested that cultural influenza vaccines will soon be widely used in medical practice.

The author reviews studies of live cold-adapted reassortant influenza vaccines developed in Russia and USA. These vaccines are safe and weakly reactogenic for all age groups. The vaccines (two immunizations) are highly effective in children of preschool and school age and far less effective in adults. For elderly subjects simultaneous vaccination with live and inactivated vaccines is recommended. The probability of influenza prevention by a single injection of cold-adapted vaccines is to be further investigated. Modern data indicate that cold-adapted reassortant influenza vaccines can be used for influenza prevention only in children of preschool and school age.

Reviews published reports on the progress in development of DNA vaccines protecting from viral diseases. Emphasizes the advantages of the preparation injection into the epidermis and the possibility of stimulating the immunogenicity of DNA vaccines with adjuvants and cytokines. Discusses the results of studies on the immunogenicity of DNA vaccines from human, simian, and feline immunodeficiency viruses, hepatitis B and C viruses, herpes simplex virus, cytomegalovirus, influenza and measles viruses, rotavirus, rabies virus, foot-and-mouth disease virus, etc., and the safety of DNA vaccines.

Reviews published reports on the development of mucosal antiviral vaccines administered through the mucous membranes and inducing systemic and local immunity. Describes methods ensuring the optimal conditions for penetration of mucosal vaccines in mucosal cells and discusses the possibility of local immunity induction in the vagina and rectum after intranasal administration of vaccine. Presents data on the development and trials of mucosal vaccines against some virus infections.

In developing countries, every year about 70 million measles cases occur with 1.5 million deaths, over 200,000 children contract paralytic poliomyelitis, 50 million people get infected with viral B hepatitis causing over 1 million deaths, and several thousand people perish because of yellow fever according to WHO data. At the present time, there are 12 vaccines against viruses: vaccines against German measles and mumps in addition to the above. The universal immunization program (UIP) of WHO targets measles and polio. In 1989, a WHO resolution envisioned a 90% immunization coverage by the year 2000. Measles vaccination is recommended for children aged 9-23 months, since most children have maternal antibodies during the first 3-13 months of age. The Edmonston-Zagreb vaccine provided seroconversion of 92, 96, and 98% for 18 months vs. the 66, 76, and 91% rate of the Schwarz vaccine. In the US, measles incidence increased from 1497 cases in 1983 to 6382 cases in 1988 to over 14,000 cases in 1989, prompting second vaccination in children of school age. The highest incidence of polio was registered in Southeast Asia, although it declined from 1 case/100,000 population in 1975 to .5/100,000 in 1988. Oral poliomyelitis vaccine (OPV) provides protection: there is only 1 case/2.5 million vaccinations. Hepatitis B has infected over 2 billion people. About 300 million are carriers, with a prevalence of 20% in African, Asian, and Pacific region populations. Plasmatic and bioengineered recombinant vaccine type have been used in 30 million people. The first dose is given postnatally, the second at 1-2 months of age, and the 3rd at 1 year of age. Yellow fever vaccine was 50 years old in 1988, yet during 1986-1988 there were 5395 cases with 3172 deaths in Africa and South America. Vaccination provides 90-95% seroconversion, and periodic follow-up vaccinations under UIP could eradicate these infections and their etiologic agents.

Using mutants of fowl plague virus (FRV) which have single temperature-sensitive (ts) mutations in some genes, an analysis was carried out on reisolates from children of 3-6 years, vaccinated with a monovaccine from recombinant strains of influenza type A virus. The recombinants were obtained by crossing of current epidemic strains of subtypes A (HINI) and a (H3N2) with the cold-adapted (XA) ts-donor of attenuation A/Leningrad/134/47/57 (H2N2) from which they, as a rule, inherited 5 ts-mutations in genes 1 (PB2), 2 (PB1), 5 (NP), 7 (M), and 8 (NS). All the reisolates were shown to retain the ts-phenotype. However, in the recombination test some reisolates (most frequently those isolated at late periods of vaccination infection) no ts-mutations could be found in 1-3 genes coding for proteins of the polymerase complex, less frequently for NP and NS proteins but not for M proteins.

The extent of inhibition of transcription realized in vitro by fowl plague virus (FPV) ribonucleoprotein (RNP) upon the addition of M protein isolated from FPV virions does not depend on nonionic detergent concentration in the reaction medium but does depend greatly on NaCl concentration. The highest inhibition of transcription is observed at a low ionic strength (0.02 M NaCl); inhibition is completely eliminated by increasing NaCl concentration to 0.3 M. When M protein isolated from FPV virions with ts mutation of M protein is added to RNP, addition to the system of 0.3 M NaCl decreases transcription inhibition but does not eliminate it completely.

The recombination test demonstrated that in the genome of a highly attenuated cold-adapted variant of influenza A/Leningrad/134/47/57 virus five genes coding for nonglycosylated proteins (1, 2, 5, 7, 8) carried ts mutations. Hybridization of this variant with epidemically important strains of influenza H1N1 and H3N2 viruses produced recombinants which inherited hemagglutinin and neuraminidase from the epidemic strains and 5 (H1N1) and 6 (H3N2) genes coding for nonglycosylated proteins from the cold-adapted variant. The genomes of both recombinants were found to contain five genes coding for nonglycosylated proteins which carried ts mutations. High genetic stability of cold-adapted recombinant vaccine strains was established in immunized children.

Treatment with neuraminidase (100 units/ml) of chick embryo fibroblasts in vitro only partially inhibits adsorption of fowl plague virus on these cells. Cultivation of chick embryo fibroblasts in the presence of 50 units/ml neuraminidase had no effect on the sensitivity of these cells to fowl plague virus and on the extent of virus reproductions. It is suggested that neuraminic acid which is a component of the external cell membrane is not only substance responsible for adsorption of orthomyxoviruses.