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.     

Basic results of a committee trial of the new vaccine Grippovac SE-AZh

In the trial of the trivalent subunit influenza vaccine Grippovac CE-AK observations on children aged 3-6 years were made. The preparation showed insignificant reactogenicity and moderate antigenic potency. The trial established that at the period of the epidemic rise of influenza B morbidity the vaccine showed, according to the data of the clinical diagnosis of influenza, insignificant effectiveness, its index of effectiveness (IE) being 1.08; according to the data of the serological diagnosis of influenza, only the A (H1N1) component of the vaccine was found to have IE equal to 1.58.     

Modern features of the epidemiology and prophylaxis of influenza

Modern concepts concerning influenza pandemics and epidemics in different countries of the world are presented. The influenza epidemics of the last decade in different countries of the world and their specific features linked with the "drifting" variability of influenza virus have been analyzed. Information on influenza morbidity during the last 30 years is given; on the basis of this information the role of vaccinal prophylaxis and mainly the mass vaccination of school children and students, is shown. The results of the efficacy of such vaccines as live influenza vaccine, American split vaccine, Russian live recombinant vaccine and Grippovac (1995-1996), as well as new-generation vaccine Grippol (1998), are presented. The prospects of the combined use of specific and unspecific prophylaxis have been determined.     

Evaluation of the reactogenicity and immunogenic potency of combined vaccine "Bubo-Kok" in the immunization of children against diphtheria, tetanus, pertussis and viral hepatitis B

Combined vaccine "Bubo-Kok" is characterized by safety and high immunological activity. The number of postvaccinal reactions in children aged 1 and 2 years, immunized with vaccine "Bubo-Kok", was not statistically different from those in groups of children immunized with adsorbed DPT vaccine, as well with such vaccine in combination with vaccine against hepatitis B. After the completion of the primary course of immunization 100% of children had protective antibody titers against diphtheria, tetanus and hepatitis B. Antibody titers against pertussis, equal to or exceeding protective titers, were found in more than 70% of immunized children. The immunogenic potency of vaccine "Bubo-Kok" with respect to all its components was not inferior to that of adsorbed DPT vaccine and vaccine against hepatitis B, when introduced simultaneously in different areas of the body. Vaccine "Bubo-Kok" successfully passed state trials and was recommended for registration.     

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.     

Protective effect of nasal immunization of influenza virus hemagglutinin with recombinant cholera toxin B subunit as a mucosal adjuvant in mice

To develop an efficient nasal influenza vaccine, influenza A and B virus HA with rCTB as a mucosal adjuvant were administered to mice intranasally. Serum anti-HA IgG and IgA antibody responses for both HA vaccines were significantly increased in the presence of rCTB. Higher HI and neutralizing antibody titers and higher mucosal IgA antibody responses in the respiratory tract were detected when rCTB was added than without rCTB. When mice were immunized with HA vaccine with or without rCTB and challenged by intranasal administration of mouse-adapted pathogenic influenza A virus, all mice immunized with HA plus rCTB survived for seven days without any inflammatory changes in the lungs, while not all the mice immunized with HA without rCTB survived, and all of them had lung consolidations. These results demonstrate that intranasal co-administration of rCTB as a mucosal adjuvant with influenza virus HA is necessary not only for the induction of systemic and mucosal HA antibodies, but also for the protection of mice from morbidity and mortality resulting from virus infection.     

Matrix-M™ adjuvation broadens protection induced by seasonal trivalent virosomal influenza vaccine

Background

Influenza virus infections are responsible for significant morbidity worldwide and therefore it remains a high priority to develop more broadly protective vaccines. Adjuvation of current seasonal influenza vaccines has the potential to achieve this goal.

Methods

To assess the immune potentiating properties of Matrix-M?, mice were immunized with virosomal trivalent seasonal vaccine adjuvated with Matrix-M?. Serum samples were isolated to determine the hemagglutination inhibiting (HAI) antibody titers against vaccine homologous and heterologous strains. Furthermore, we assess whether adjuvation with Matrix-M? broadens the protective efficacy of the virosomal trivalent seasonal vaccine against vaccine homologous and heterologous influenza viruses.

Results

Matrix-M? adjuvation enhanced HAI antibody titers and protection against vaccine homologous strains. Interestingly, Matrix-M? adjuvation also resulted in HAI antibody titers against heterologous influenza B strains, but not against the tested influenza A strains. Even though the protection against heterologous influenza A was induced by the adjuvated vaccine, in the absence of HAI titers the protection was accompanied by severe clinical scores and body weight loss. In contrast, in the presence of heterologous HAI titers full protection against the heterologous influenza B strain without any disease symptoms was obtained.

Conclusion

The results of this study emphasize the promising potential of a Matrix-M?-adjuvated seasonal trivalent virosomal influenza vaccine. Adjuvation of trivalent virosomal vaccine does not only enhance homologous protection, but in addition induces protection against heterologous strains and thus provides overall more potent and broad protective immunity.

     

Oral immunization with a replication-deficient recombinant vaccinia virus protects mice against influenza.

Mice immunized with two intragastrically administered doses of a replication-deficient recombinant vaccinia virus containing the hemagglutinin and nucleoprotein genes from H1N1 influenza virus developed serum anti-H1 immunoglobulin G (IgG) antibody that completely protected the lungs from challenge with H1N1. Almost all of the mice given two intragastric doses also developed mucosal anti-H1 IgA antibody, and those with high anti-H1 IgA titers had completely protected noses. Intramuscular injection of the vaccine protected the lungs but not the noses from challenge. We also found that the vaccine enhanced recovery from infection caused by a shifted (H3N2) influenza virus, probably through the induction of nucleoprotein-specific cytotoxic T-lymphocyte activity. A replication-deficient, orally administered, enteric-coated, vaccinia virus-vectored vaccine might safely protect humans against influenza.     

甲型H1N1流感病毒佐剂疫苗小鼠免疫效果

为了探讨甲型H1N1流感病毒氢氧化铝佐剂疫苗对小鼠的免疫作用及对小鼠繁殖性能的影响,以不同剂量、不同免疫程序免疫小鼠后定期采血;用血凝抑制(HI)方法检测血清H1N1流感病毒HI抗体滴度,观察H1N1流感病毒佐剂疫苗对小鼠受孕、产仔、哺乳的影响;比较孕鼠及非孕鼠的抗体滴度,免疫后孕鼠所产仔鼠的体重及H1N1胎传抗体水平。结果显示,以0.5μg组开始的不同剂量、不同免疫程序均可使小鼠产生90倍以上水平的H1N1流感病毒抗体;免疫后的小鼠不影响受孕、产仔及哺乳;仔鼠保护性抗体可持续1个月以上。H1N1流感病毒佐剂疫苗是一种高免疫原性的制剂,用低剂量免疫,即可产生90倍以上持续时间较长的保护性抗体。这种佐剂疫苗对小鼠的繁殖性能无明显影响,免疫产生的抗体经胎盘可垂直传递给仔鼠。     

Immune responses of mice to influenza subunit vaccine in combination with CIA07 as an adjuvant

CIA07 is an immunostimulatory agent composed of E. coli DNA fragments and modified LPS lacking the lipid A moiety. In this study, we investigated whether CIA07 promotes immune responses as an adjuvant to the influenza subunit vaccine. Balb/c mice were immunized intramuscularly once or twice at a 4-week interval with the trivalent influenza subunit vaccine antigen alone or in combination with CIA07 as adjuvant. Antigen-specific serum antibody titers and hemagglutination-inhibition (HI) antibody titers were assessed. At 4 weeks after each immunization, the antigen-specific total serum IgG antibody titer in mice receiving CIA07 was 2 to 3 times higher than that in animals administered antigen alone (P<0.05). The CIA07-treated group additionally displayed higher HI antibody titers against each of the 3 vaccine strains, compared to the antigen group. Animals receiving antigen alone displayed barely detectable antigen-specific serum IgG2a antibody titers. In contrast, coadministration of CIA07 with antigen led to significantly enhanced IgG2a antibody responses, suggesting that CIA07 stimulates a Th1-type immune response. Moreover, the CIA07-treated group displayed a marked increase in the number of interferon gamma-producing CD8(+) T cells in splenocytes. These data collectively demonstrate that CIA07 has the ability to induce both Th1-type cellular and Th2-type humoral immune responses to the influenza subunit vaccine, and support its potential as an effective adjuvant to the influenza vaccine.     

Effect of apoptosis‐associated speck‐like protein containing a caspase recruitment domain on vaccine efficacy: Overcoming the effects of its deficiency with aluminum hydroxide adjuvant

Host factors such as nutritional status and immune cell state are important for vaccine efficacy. Inflammasome activation may be important for triggering vaccine‐induced humoral and cell‐mediated immune responses. Formulations with alum as a typical adjuvant to overcome the effects of host factors have recently been shown to induce inflammasome activation, which augments vaccine efficacy. Apoptosis‐associated speck‐like protein containing a caspase recruitment domain (ASC) is one of the main components of inflammasomes, but it is not clear whether ASC affects the vaccine‐induced immune response. Herein, we used two types of vaccines: inactivated influenza vaccine not formulated with alum, and HPV vaccine formulated with alum. We gave the vaccines to ASC knockout (ASC^?/?) mice to investigate the role of ASC in vaccine efficacy. Influenza vaccine‐immunized ASC^?/? mice did not show antibody titers in week 2 after the first vaccination. After boosting, the antibody titer in ASC^?/? mice was about half that in wild type (WT) mice. Furthermore, a cytotoxic T‐lymphocyte response against influenza vaccine was not induced in ASC^?/? mice. Therefore, vaccinated ASC^?/? mice did not show effective protection against viral challenge. ASC^?/? mice immunized with alum‐formulated HPV vaccine showed similar antibody titers and T‐cell proliferation compared with immunized WT mice. However, the HPV vaccine without alum induced up to threefold lower titers of HPV‐specific antibody titers in ASC^?/? mice compared with those in WT mice. These findings suggest that alum in vaccine can overcome the ASC‐deficient condition.

     

Use of highly purified subvirion trivalent flue vaccine ("Grippovak") in groups with a high risk of complications]

During the epidemic season of 1989-1990 the subunit vaccine Grippovac was used in 20 asylums for old people and psychoneurological invalids in Moscow for the protection of the inhabitants and the personnel from influenza. Follow-up of the vaccinees during the period from November 1989 to March 1990 revealed that the use of this vaccine decreased the incidence of influenza-like diseases (ILD) 3.4-4.1 times among the vaccinees in comparison with that in the nonvaccinated control groups and significantly decreased the severity of the course of ILD, as well as the mortality because of ILD, among those vaccinees who had contacted ILD. This is indicative of good prospects of regular vaccinal prophylaxis of influenza at asylums for old people and other persons at a high risk of influenza complications.     

Enhanced Neutralizing Antibody Titers and Th1 Polarization from a Novel Escherichia coli Derived Pandemic Influenza Vaccine

Influenza pandemics can spread quickly and cost millions of lives; the 2009 H1N1 pandemic highlighted the shortfall in the current vaccine strategy and the need for an improved global response in terms of shortening the time required to manufacture the vaccine and increasing production capacity. Here we describe the pre-clinical assessment of a novel 2009 H1N1 pandemic influenza vaccine based on the E. coli-produced HA globular head domain covalently linked to virus-like particles derived from the bacteriophage Qβ. When formulated with alum adjuvant and used to immunize mice, dose finding studies found that a 10 µg dose of this vaccine (3.7 µg globular HA content) induced antibody titers comparable to a 1.5 µg dose (0.7 µg globular HA content) of the licensed 2009 H1N1 pandemic vaccine Panvax, and significantly reduced viral titers in the lung following challenge with 2009 H1N1 pandemic influenza A/California/07/2009 virus. While Panvax failed to induce marked T cell responses, the novel vaccine stimulated substantial antigen-specific interferon-γ production in splenocytes from immunized mice, alongside enhanced IgG2a antibody production. In ferrets the vaccine elicited neutralizing antibodies, and following challenge with influenza A/California/07/2009 virus reduced morbidity and lowered viral titers in nasal lavages.     

Epidemiological and immunological criteria of the effectiveness of immunization with adsorbed DPT vaccine by the old and new schedules

The study revealed that the immunization of children with adsorbed DPT vaccine from the age of 3-4 months, as compared with the immunization of children from the age of 5-6 months, did not lead to an essential increase in the coverage of children with immunization at the period under study (1970-1983) and did not affect the total level of pertussis morbidity, as well as the proportion of children aged up to 1 year in the total number of pertussis cases. Children immunized at an early age produced antibodies in titers, equivalent to the titers in older children, but their immunity against pertussis, in contrast to their immunity against diphtheria and tetanus, was retained for a shorter period. The injection of adsorbed DPT vaccine at the age of 3-4 months was accompanied by a poorly pronounced increase in the content of IgG, the predominant synthesis of IgM and the suppression of the synthesis of IgA. The shift of the start of vaccination to the age of 3-4 months has probably some immunological grounds for diphtheria and tetanus, but it is premature with respect to pertussis.     

The Effect of Age and Recent Influenza Vaccination History on the Immunogenicity and Efficacy of 2009–10 Seasonal Trivalent Inactivated Influenza Vaccination in Children

Background

There is some evidence that annual vaccination of trivalent inactivated influenza vaccine (TIV) may lead to reduced vaccine immunogenicity but evidence is lacking on whether vaccine efficacy is affected by prior vaccination history. The efficacy of one dose of TIV in children 6–8 y of age against influenza B is uncertain. We examined whether immunogenicity and efficacy of influenza vaccination in school-age children varied by age and past vaccination history.

Methods and Findings

We conducted a randomized controlled trial of 2009–10 TIV. Influenza vaccination history in the two preceding years was recorded. Immunogenicity was assessed by comparison of HI titers before and one month after receipt of TIV/placebo. Subjects were followed up for 11 months with symptom diaries, and respiratory specimens were collected during acute respiratory illnesses to permit confirmation of influenza virus infections. We found that previous vaccination was associated with reduced antibody responses to TIV against seasonal A(H1N1) and A(H3N2) particularly in children 9–17 y of age, but increased antibody responses to the same lineage of influenza B virus in children 6–8 y of age. Serological responses to the influenza A vaccine viruses were high regardless of vaccination history. One dose of TIV appeared to be efficacious against confirmed influenza B in children 6–8 y of age regardless of vaccination history.

Conclusions

Prior vaccination was associated with lower antibody titer rises following vaccination against seasonal influenza A vaccine viruses, but higher responses to influenza B among individuals primed with viruses from the same lineage in preceding years. In a year in which influenza B virus predominated, no impact of prior vaccination history was observed on vaccine efficacy against influenza B. The strains that circulated in the year of study did not allow us to study the effect of prior vaccination on vaccine efficacy against influenza A.     

Comparative evaluation of the reactogenicity and immunogenicity of inactivated influenza vaccines in the elderly

A comparative study was carried out to assess reactogenicity and immunogenicity of inactivated influenza vaccines (Begrivac, Vaxigrip, Grippol, Influvac, and Fluarix), licensed in Russia. Immunization of the elderly demonstrated low reactogenicity and high immunogenicity for all vaccines. Concomitant chronic diseases had no influence on the vaccine immunogenicity levels, which testifies to the benefit of vaccination in this age group. In the group of vaccinated the highest seroconversion to all vaccine strains was found for Vaxigrip (82-89% for group A viruses and 86% for group B virus); the vaccine demonstrated the highest level of diagnostic increase of antibody titers to all 3 viruses, i.e. 69.0% (p < .05), with 22.0% of vaccinees gained antibodies to 2 vaccine viruses (91.0% in total). The number of positive responses to 3 and 2 strains in subjects immunized with Fluarix, Begrivac and Influvac reached 85.0%, 85.0% and 83.0% respectively. It is noteworthy that the combination of surface antigens of A and B flu viruses in low concentration with polyoxidonium immune modulator in Grippol induced intensive immune response.     

Results of a study of a live intranasal influenza vaccine in the immunization of children 3 to 15 years old

A total of 10,971 children aged 3-15 years were immunized with live influenza vaccine (the variant intended for children), type A (H1N1). The vaccine proved to be nonreactogenic and produced no harmful effect on the child organism. The genetic stability of the vaccine strain and its high immunogenic activity were shown.     

The evaluation of the reactogenicity, harmlessness and prophylactic efficacy of Grippol trivalent polymer-subunit influenza vaccine administered to schoolchildren

Vaccine "Grippol"--has been developed at the State Research Center--Institute of Immunology. The preparation belongs to new generation vaccines and is a trivalent polymer-subunit vaccine containing the sterile conjugate of influenza virus surface proteins, types A and B, bound with copolymer polyoxidonium. The administration of "Grippol" to children of school age (6-18 years) demonstrated low reactogenicity of the vaccine, its safety and sufficient prophylactic effectiveness. During observations on total morbidity (with the exception of influenza and acute respiratory diseases) no side effects produced by "Grippol" were registered. At the same time the fact that the morbidity rate of upper respiratory tract disease in the group of children immunized with the vaccine decreased in comparison with the control group (by 2.4 times) cannot be disregarded.     

Abnormal humoral immune response to influenza vaccination in pediatric type-1 human immunodeficiency virus infected patients receiving highly active antiretroviral therapy

Given that highly active antiretroviral therapy (HAART) has been demonstrated useful to restore immune competence in type-1 human immunodeficiency virus (HIV-1)-infected subjects, we evaluated the specific antibody response to influenza vaccine in a cohort of HIV-1-infected children on HAART so as to analyze the quality of this immune response in patients under antiretroviral therapy. Sixteen HIV-1-infected children and 10 HIV-1 seronegative controls were immunized with a commercially available trivalent inactivated influenza vaccine containing the strains A/H1N1, A/H3N2, and B. Serum hemagglutinin inhibition (HI) antibody titers were determined for the three viral strains at the time of vaccination and 1 month later. Immunization induced a significantly increased humoral response against the three influenza virus strains in controls, and only against A/H3N2 in HIV-1-infected children. The comparison of post-vaccination HI titers between HIV-1+ patients and HIV-1 negative controls showed significantly higher HI titers against the three strains in controls. In addition, post vaccination protective HI titers (defined as equal to or higher than 1:40) against the strains A/H3N2 and B were observed in a lower proportion of HIV-1+ children than in controls, while a similar proportion of individuals from each group achieved protective HI titers against the A/H1N1 strain. The CD4+ T cell count, CD4/CD8 T cells ratio, and serum viral load were not affected by influenza virus vaccination when pre- vs post-vaccination values were compared. These findings suggest that despite the fact that HAART is efficient in controlling HIV-1 replication and in increasing CD4+ T cell count in HIV-1-infected children, restoration of immune competence and response to cognate antigens remain incomplete, indicating that additional therapeutic strategies are required to achieve a full reconstitution of immune functions.     

Immunization of primates with a Newcastle disease virus-vectored vaccine via the respiratory tract induces a high titer of serum neutralizing antibodies against highly pathogenic avian influenza virus

The ongoing outbreak of highly pathogenic avian influenza virus (HPAIV) in birds, the incidence of transmission to humans with a resulting high mortality rate, and the possibility of a human pandemic warrant the development of effective human vaccines against HPAIV. We developed an experimental live-attenuated vaccine for direct inoculation of the respiratory tract based on recombinant avian Newcastle disease virus (NDV) expressing the hemagglutinin (HA) glycoprotein of H5N1 HPAIV (NDV-HA). Expression of the HPAIV HA gene slightly reduced NDV virulence, as evidenced by the increased mean embryo death time and reduced replication in chickens. NDV-HA was administered to African green monkeys in two doses of 2 x 10(7) infectious units each with a 28-day interval to evaluate the systemic and local antibody responses specific to H5N1 HPAIV. The virus was shed only at low titers from the monkeys, indicative of safety. Two doses of NDV-HA induced a high titer of H5N1 HPAIV-neutralizing serum antibodies in all of the immunized monkeys. Moreover, a substantial mucosal immunoglobulin A response was induced in the respiratory tract after one and two doses. The titers of neutralizing antibodies achieved in this study suggest that the vaccine would be likely to prevent mortality and reduce morbidity caused by the H5N1 HPAIV. In addition, induction of a local immune response in the respiratory tract is an important advantage that is likely to reduce or prevent transmission of the virus during an outbreak or a pandemic. This vaccine is a candidate for clinical evaluation in humans.