Results of introducing a comprehensive system of influenza control in the population of Severodvinsk

A complex differentiated system of influenza control, based on scientific principles, was introduced into practice during 1976-1980 in Severodvinsk. The main component of this system was the mass prophylactic immunization of the population of the city, including children and elderly persons, with live and inactivated vaccines manufactured in the USSR. At the period of influenza epidemics remantadin was used for the urgent prophylaxis and treatment of influenza. As a result, influenza morbidity in Severodvinsk was reduced 1.5-2 times in comparison with that in the neighboring control cities. The cases of pneumonia and bronchitis, the most severe postinfluenza complications, decreased in number 1.8 and 1.4 times, respectively. The proportion of influenza A in the structure of acute respiratory diseases decreased by one-half. These results demonstrate the effectiveness of the prophylactic and therapeutic measures carried out in the city.     

Efficacy of a complex program for controlling influenza in a large industrial city

The epidemiological and economic effectiveness of the realization of the complex three-year (1980-1982) program for the control of influenza in Perm is shown. The coverage of 46-51% of the city population, including working people, pensioners and children, with immunization carried out with the use of live and inactivated vaccines made it possible to decrease morbidity rate 2.12 times in comparison with the average data for many years. The greatest effect was achieved at large industrial enterprises where, simultaneously with vaccination covering 90% of the employees, urgent prophylaxis with remantadin and the early treatment of influenza patients were carried out. Due to these measures the morbidity rate and the number of disability days per 100 employees decreased 3-6 times.     

Live enteroviral vaccines for the emergency nonspecific prevention of mass respiratory diseases during fall-winter epidemics of influenza and acute respiratory diseases]

The results of the 3-year controlled trials of a new method of nonspecific urgent prophylaxis of influenza and acute respiratory diseases (ADR) by immunization of healthy adults with standard live enterovirus oral vaccines, introduced in 2-3 administrations at intervals of 7-10 days, at the initial stages of autumn and winter epidemics are presented. Observations, carried out in three republics, covered more than 150,000 persons immunized with enterovirus interferonogenic vaccines. A considerable decrease in morbidity rate among the vaccinees was achieved (on the average, by 3.2 times) in comparison to that among nonimmunized subjects. The method of nonspecific prophylaxis with live enterovirus interferonogenic vaccines is recommended during outbreaks of diseases induced simultaneously by several causative agents of influenza and ARD, as well as by pathogenic enterovirus strains.     

Assessment of the effectiveness of inactivated influenza vaccines for adults

In 9 controlled epidemiological observations (1977-1984) the effectiveness of modern Soviet whole-virion vaccines was studied in organized groups of adults and at industrial enterprises. During the epidemic outbreaks of influenza of different etiology and intensity morbidity rate in influenza and acute respiratory diseases was shown to decrease 1.1-2.2 times among the vaccinees, depending on the correspondence of epidemic and vaccine influenza strains. The absence of influenza virus B in inactivated influenza vaccines was the reason for their low effectiveness during influenza outbreaks of mixed etiology B + A (H1N1).     

Epidemiological effectiveness of an inactivated three-component flu vaccine with an increased concentration of hemagglutinin in the inoculation dose]

The work presents the results of the evaluation of mass immunization of working adults with inactivated trivalent influenza vaccine under the conditions of an epidemic caused by influenza viruses A (H1N1), A (H3N2) and B. This immunization produced no effect on influenza morbidity in the groups of vaccinees in comparison with those of nonvaccinated persons. The index of effectiveness was 1.0 and less. The ineffectiveness of mass immunization was due to a high level of natural immunity to influenza and the extensive use of influenza vaccine in past years.     

Assessment of the prophylactic effectiveness of an inactivated influenza vaccine by immunizing schoolchildren in the springtime

To evaluate the prophylactic effectiveness of influenza inactivated chromatographic vaccine, limited epidemiological observations were made on school children aged 11-14 years in Leningrad, in the autumn of 1981 and the spring of 1982. For immunization, made in a single administration, the vaccine composed of A (H3N2) + +A (H1N1) and containing 3.0-3.4 micrograms of hemagglutinin of each component per 0.2 ml of the preparation was used. Altogether 6928 schoolchildren were under observation; of these, 3686 children were immunized and 3242 children received placebo. The results of questioning and the analysis of morbidity rate among the schoolchildren, both immunized and receiving placebo, showed the safety and low reactogenicity of the vaccine irrespective of the time of the immunization campaign. The immunogenic potency of the preparation, as indicated by all observation results, proved to be higher in spring, than in autumn. The data thus obtained indicate that children immunized in spring were better protected and retained a higher level of protection within 12 months after immunization. The shift of the time of the immunization campaign from autumn to spring increased the immune layer in the groups of children by 16.5%. In 10 months after spring immunization the morbidity rate in influenza and acute respiratory diseases among the vaccinees was found to decrease 1.7 times.     

Total immunization of children against influenza decreases morbidity in a number of diseases among elderly persons during influenza epidemic

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.     

Induction of heterosubtypic immunity to influenza virus by intranasal immunization

Recovery from live influenza virus infection is known to induce heterosubtypic immunity. In contrast, immunity induced by inactivated vaccines is predominantly subtype specific. In this study, we investigated the heterosubtypic protective immunity induced by inactivated influenza virus. Intranasal immunization of mice with inactivated influenza virus A/PR8 (H1N1) provided complete protection against the homologous virus and a drift virus within the same subtype, A/WSN (H1N1), but not against the heterosubtypic virus A/Philippines (H3N2). However, coadministration of inactivated virus with cholera toxin as an adjuvant conferred complete heterosubtypic protection, without observed illness, even under conditions of CD4⁺ or CD8⁺ T-cell depletion. Analysis of immune correlates prior to challenge and postchallenge indicated that humoral immune responses with cross-neutralizing activity in lungs and in sera play a major role in conferring protective immunity against heterosubtypic challenge. This study has significant implications for developing broadly cross-reactive vaccines against newly emerging pathogenic influenza viruses.     

Evaluation of the potential use of inactivated influenza centrifuged vaccines with various hemagglutinin levels for immunizing schoolchildren

The safety, reactogenic properties and immunogenic potency of inactivated influenza centrifuged vaccines with different hemagglutinin content were studied in observations on children aged 11-15 and 7-10 years. According to the results of clinico-laboratory investigations, commercial influenza vaccine and its variant with hemagglutinin content reduced by half were found to be safe and showed faintly pronounced reactogenic properties in children. After vaccination hyperemia developed at the site of injection, moderate in 5% of the vaccinees aged 7-10 years and mild in other vaccinees of both age groups. The immunogenic potency of the preparations was determined by the specific features of influenza virus strains: strain A (H1N1) induced seroconversion in 62-94% and strain A (H3N2), in 67-96% of children.     

Influence of multiplicity of immunizations of children with inactivated influenza vaccine on immune response and the effectiveness of protection

The formation of immunity and epidemiological effectiveness of inactivated influenza vaccines in children, regularly immunized against influenza for three years, were evaluated. The study revealed that a year after each immunization the number of children having antibodies in liters regarded as protective decreased 2-2.5 times. At the periods of epidemics morbidity rate among the vaccines dynamically decreased in these years 1.3, 2.0 and 2.8 times. Considering that a year after the second immunization a high immune stratum (60-78%) was retained in the group under study, we propose that annual immunization of the same children be limited by a period of three years, followed by an interval of one year.     

Results of a study of new preparations of inactivated whole-virion influenza vaccines for the protection of children in the USSR

The safety, reactogenic properties and antigenic potency of inactivated whole-virion influenza vaccines produced in the USSR were studied on 1,117 schoolchildren in limited coded clinico-immunological observations. Inactivated chromatographic influenza vaccine obtained from strain A/Texas/1/77 (H3N2) and a variant of this vaccine, developed specially for children and obtained from strains A/Texas/1/77 and B/Leningrad/76, were used for immunization. Both preparations were introduced intradermally in a single injection in a volume of 0.1-0.2 ml by means of bi-3 jet injector. The content of hemagglutinin in this volume varied from 3.0 to 8.0 micrograms. Clinico-laboratory investigations demonstrated the safety of mono- and bivalent inactivated whole-virion influenza vaccine administered intradermally in a single injection to children of school age. The vaccines showed low reactogenicity and high antigenic potency in children aged 7-10 and 11-14 years, and the optimal doses of the preparations were selected for children of different age groups. The distinct prophylactic effectiveness of inactivated chemical chromatographic influenza vaccines in children aged 11-14 years was revealed 11 months after immunization, the index of immunological effectiveness being 1.7.     

Evaluation of influenza vaccine Vaxigrip in the combined immunization of conscripts during influenza seasons of 2002-2003

The immunization properties of the influenza vaccine Vaxigrip, used in combination with vaccines against pneunococcal infection and hepatitis A (respectively, Pneumo 23 and Avaxim), were evaluated. In Central Russia in one of the units of the internal forces of the RF Ministry of Internal Affairs 3 groups totaling 755 servicemen were formed, depending on the complex of the introduced vaccines. Active medical observation and the registration of the complaints of the vaccinees at the postvaccinal period did not reveal unusual reactions and complications in none of the groups under observation. In the evaluation of the level of specific antibodies to the circulating influenza viruses prior to vaccination the low level of collective protection to influenza B virus was determined: protective antibody levels were registered only in 14-18% of the servicemen, while the corresponding data with respect of influenza viruses A(H1N1) and A(H3N2) were 45-50% and 56-63% respectively. At the same time, in seronegative persons the vaccine Vaxigrip exhibited high immunogenic activity with respect of all 3 influenza strains; seroconversion to them was determined in 84-92% of the vaccines, and the level of protective antibody titers before the beginning of the epidemic season was 86-99% in the whole of the group. The characteristics of the prophylactic effectiveness of the vaccine Vaxigrip in relation to the influenza virus infection level 1 were 4.7 (index) and 79% (coefficient). In addition, the frequency of influenza cases, clinically pronounced and confirmed by laboratory methods, in patients who had been immunized with 3 vaccines was 6.7%, which was 10.3 times less frequent than number of cases in the groups of comparison (68.2% on the average). The coefficient of epidemiological effectiveness of the prophylaxis of influenza was 90.2%. The complex use of 3 preparations did not affect the immunization properties of the vaccine Vaxigrip.     

Immunologic response to the influenza virus neuraminidase is influenced by prior experience with the associated viral hemagglutinin. I. Studies in human vaccinees

Analysis of an earlier study of H3N2 and H7N2 inactivated influenza vaccines in schoolchildren demonstrated a greater viral neuraminidase (NA) immunogenicity of the vaccine containing the H7 hemagglutinin (HA) antigen to which they had not been primed, despite the lesser NA antigen content of that vaccine. Thus, prior experience with the influenza viral HA appeared to have a negative influence on immune response to NA, the associated external glycoprotein, presumably on the basis of intermolecular antigenic competition. In a second study, sequential immunologic response to influenza viral NA was compared in college students who were immunized with either conventional commercial vaccine or an antigenic reassortant H7N1 vaccine, and who subsequently experienced natural infection with an H1N1 influenza virus. Although both vaccines were only marginally immunogenic in inducing NA antibody response in seronegative subjects, in vaccinees initially seropositive for HA antibody significant NA antibody titer increases occurred with H7N1 vaccine. Subsequent natural infection boosted NA antibody less effectively in the population previously primed by natural infection than in initially seronegative subjects primed by H7N1 vaccination. It is suggested that primary immunization monospecific for influenza viral NA may alter the subsequent pattern of immune response to one more favorable to the induction of NA antibody when virus is encountered.     

Effectiveness of non-adjuvanted pandemic influenza A vaccines for preventing pandemic influenza acute respiratory illness visits in 4 U.S. communities

We estimated the effectiveness of four monovalent pandemic influenza A (H1N1) vaccines (three unadjuvanted inactivated, one live attenuated) available in the U.S. during the pandemic. Patients with acute respiratory illness presenting to inpatient and outpatient facilities affiliated with four collaborating institutions were prospectively recruited, consented, and tested for influenza. Analyses were restricted to October 2009 through April 2010, when pandemic vaccine was available. Patients testing positive for pandemic influenza by real-time RT-PCR were cases; those testing negative were controls. Vaccine effectiveness was estimated in logistic regression models adjusted for study community, patient age, timing of illness, insurance status, enrollment site, and presence of high-risk medical conditions. Pandemic virus was detected in 1,011 (15%) of 6,757 enrolled patients. Fifteen (1%) of 1,011 influenza positive cases and 1,042 (18%) of 5,746 test-negative controls had record-verified pandemic vaccination >14 days prior to illness onset. Adjusted effectiveness (95% confidence interval) for pandemic vaccines combined was 56% (23%, 75%). Adjusted effectiveness for inactivated vaccines alone (79% of total) was 62% (25%, 81%) overall and 32% (-92%, 76%), 89% (15%, 99%), and -6% (-231%, 66%) in those aged 0.5 to 9, 10 to 49, and 50+ years, respectively. Effectiveness for the live attenuated vaccine in those aged 2 to 49 years was only demonstrated if vaccination >7 rather than >14 days prior to illness onset was considered (61%∶ 12%, 82%). Inactivated non-adjuvanted pandemic vaccines offered significant protection against confirmed pandemic influenza-associated medical care visits in young adults.     

Current status for influenza control

Influenza viruses are responsible for respiratory illness with significant morbidity and mortality. To curb the disease, two-pronged attack on the virus, therapeutic and prophylactic, is being actively pursued. The therapeutic use of existing anti-influenza drugs, such as amantadine and rimantadine, is limited by their significant adverse side effect, emergence of resistant viral strains, and lack of activity against influenza B virus. A new class of antiviral agents designed to inhibit influenza neuraminidase are currently under active development for use in the prophylaxis and treatment of influenza A and B virus infections. Two of these compounds, zanamivir (GG167) and GS4104 have reached clinical trials. Limitations in the effectiveness and application of inactivated vaccines have stimulated development of alternative approaches to influenza immunization. One such approach is a live, intranasally administered vaccine, attenuated by cold-adaptation of a master strain with subsequent genetic reassortment with circulating wild-type strains. Recently developed reverse-genetics techniques have made it possible to use RNA viruses as vector. Besides DNA viral vectors, live influenza virus vectors may emerge as a useful alternative for the vaccination against different pathogens.     

Effectiveness of the 2012/13 Trivalent Live and Inactivated Influenza Vaccines in Children and Adolescents in Saxony-Anhalt,Germany: A Test-Negative Case-Control Study

A live attenuated influenza vaccine has been available in Germany since the influenza season 2012/13, which is approved for children aged 2-17 years. Using data from our laboratory-based surveillance system, we described the circulation of influenza and non-influenza respiratory viruses during the influenza season 2012/13 in Saxony-Anhalt. We estimated the effectiveness of live and inactivated trivalent influenza vaccines in preventing laboratory-confirmed cases among children and adolescents. From week 40/2012 to 19/2013, sentinel paediatricians systematically swabbed acute respiratory illness patients for testing of influenza and 5 non-influenza viruses by PCR. We compared influenza cases and influenza-negative controls. Among children aged 2-17 years, we calculated overall and vaccine type-specific effectiveness against laboratory-confirmed influenza, stratified by age group (2-6; 7-17 years). We used multivariable logistic regression to adjust estimates for age group, sex and month of illness. Out of 1,307 specimens, 647 (35%) were positive for influenza viruses and 189 (15%) for at least one of the tested non-influenza viruses. For vaccine effectiveness estimation, we included 834 patients (mean age 7.3 years, 53% males) in our analysis. Of 347 (42%) influenza-positive specimens, 61 (18%) were positive for A(H1N1)pdm09, 112 (32%) for A(H3N2) and 174 (50%) for influenza B virus. The adjusted overall vaccine effectiveness including both age groups was 38% (95% CI: 0.8-61%). The adjusted effectiveness for inactivated vaccines was 37% (95% CI: -35-70%) and for live vaccines 84% (95% CI: 45-95%). Effectiveness for the live vaccine was higher in 2-6 year-old children (90%, 95% CI: 20-99%) than in children aged 7-17 years (74%, 95% CI: -32-95%). Our study of the strong influenza season in 2012/13 suggests a high preventive effect of live attenuated influenza vaccine especially among young children, which could not be reached by inactivated vaccines. We recommend the use of live attenuated influenza vaccines in children unless there are contraindications.     

The results of state trials of inactivated influenza vaccines for children

Controlled epidemiological surveillance covering the total number of 13,355 schoolchildren aged 11-14 years and adolescents was carried out with a view to compare the efficacies of inactivated influenza vaccines. The children were immunized intradermally in a single injection with inactivated influenza vaccines containing A (H3N2) and A (H1N1) hemagglutinins, 3.5 micrograms per 0.2 ml of the preparation each. The studies demonstrated the safety and low reactogenicity of these vaccines, as well as their high antigenic potency. In 1984 during mixed influenza B + A (H1N1) epidemic the preparations produced a pronounced prophylactic effect: the efficacy indices were 1.6-1.9 (p less than 0.001). The results obtained in these studies made it possible to recommend two inactivated influenza vaccines (chromatographic and centrifugal) for practical medicine with the aim of protecting children aged 11 years and over from influenza.     

Vaccination activity of live influenza vaccine in different seasons of the year

Reactogenicity, immunogenicity and viability of the vaccine virus were studied during vaccination of adults with live allantoic influenza vaccines of the types A (H1N1), A (H3N2) and B in different seasons of the year. Seasonal oscillations of reactogenicity of the vaccines (minimum in summer, maximum in winter) were demonstrated. A decrease in the re-isolation rate of vaccine viruses and in their content in the secretions of the upper respiratory passages was observed in summer. Seasonal oscillations of immunogenicity of the commercial live allantoic influenza vaccine with a marked reduction in its activity in summer were established. The administration of moderately attenuated influenza vaccine viruses in summer results in the production of antibodies up to the level observed in other seasons of the year. Theoretical problems and practical aspects of seasonal oscillations of vaccination activity of live influenza vaccines were studied in connection with the necessity of investigation new vaccine strains in varying seasons of the year.     

Organization and evaluation of the effectiveness of emergency prophylaxis and early treatment of influenza with remantadine in Serevodvinsk

The complex system of influenza control was introduced into practice at the public health institutions of Severodvinsk in 1976-1980. The effectiveness of the urgent prophylaxis and early treatment of influenza with remantadin, one of the most important elements of this system, was evaluated. The use of remantadin for the early and preventive treatment (urgent prophylaxis) of influenza among the population of the city decreased influenza morbidity 1.7-1.85 times, reduced the duration of the main clinical symptoms of the disease and sick leaves, the frequency of post-influenza complications, as well as the number of visitations of the sick by physicians.     

Immunogenicity and the protective effectiveness of the subunit trivalent influenza vaccine Grippovac

In the process of the immunological approbation of several experimental batches of the triyalent subunit influenza vaccine Grippovac, the pronounced immunogenicity of the antigens of all strains contained in the vaccine was established; most of the vaccinees were found to retain sufficiently high antibody titers for a year, and the essential total increase of antibody titers was found to occur after a single booster immunization. The serological checking of the diagnosed cases of influenza among immunized and nonimmunized children, carried out in two boarding schools during the influenza epidemic in the winter of 1984-1985 provided the proofs of the high effectiveness of Grippovac in preventing viral influenza, types A and B: the decrease of influenza morbidity among the immunized children reached 79,5-67,2-66,5% and the total morbidity rate in influenza in these two boarding scholls dropped, on the average, 3,0-3,5 times.