Inactivated H5N1 Vaccine Research Articles

Vaccination against highly pathogenic avian influenza H5N1 virus in zoos using an adjuvanted inactivated H5N2 vaccine

Highly pathogenic avian influenza (HPAI) H5N1 virus infections have recently caused unprecedented morbidity and mortality in a wide range of avian species. European Commission directive 2005/744/EC allowed vaccination in zoos under strict conditions, while reducing confinement measures. Vaccination with a commercial H5N2 vaccine with vaccine doses adapted to mean body weight per species was safe, and proved immunogenic throughout the range of species tested, with some variations between and within taxonomic orders. After booster vaccination the overall homologous geometric mean titre (GMT) to the vaccine strain, measured in 334 birds, was 190 (95% CI: 152–236), and 80.5% of vaccinated birds developed a titre of ≥40. Titres to the HPAI H5N1 virus followed a similar trend, but were lower (GMT: 61 (95% CI: 49–76); 61% ≥ 40). The breadth of the immune response was further demonstrated by measuring antibody titres against prototype strains of four antigenic clades of currently circulating H5N1 viruses. These data indicate that vaccination should be regarded as a beneficial component of the preventive measures (including increased bio-security and monitoring) that can be undertaken in zoos to prevent an outbreak of and decrease environmental contamination by HPAI H5N1 virus, while alleviating confinement measures.

Safety and immunogenicity of an inactivated adjuvanted whole-virion influenza A (H5N1) vaccine: a phase I randomised controlled trial

Avian influenza A virus H5N1 has caused widespread infections that have resulted in severe disease or death in poultry and wild birds as well as human beings. This virus has the potential to emerge as a pandemic threat and H5N1 vaccines are being developed in many countries. Our aim was to assess the safety and immunogenicity of an inactivated adjuvanted whole-virion H5N1 vaccine. A stratified randomised, placebo-controlled, double-blind phase I clinical trial was done in 120 volunteers aged 18-60 years. Volunteers were assigned to receive two doses of placebo (n=24) or an inactivated whole-virion influenza A (H5N1) vaccine with 1.25 microg (24), 2.5 microg (24), 5 microg (24), or 10 microg (24) haemagglutinin per dose with aluminium hydroxide adjuvant on day 0 and 28. Serum samples were obtained on day 0, 14, 28, 42, and 56 for haemagglutination inhibition and virus neutralisation assays. This trial is registered with the ClinicalTrials.gov registry with the number NCT00356798. All four formulations of vaccines were well tolerated. No serious adverse event was reported and most local and systemic reactions were mild and transient. All formulations induced antibody responses after the first dose; the highest immune response of 78% seropositivity was seen in the 10 mug group after two vaccine doses. Two individuals dropped out: one in the 1.25 microg group (withdrew consent) and one in the 10 microg group (discontinued); one individual was also excluded from the final analysis. A two-dose regimen of an adjuvanted 10 microg inactivated whole-virion H5N1 vaccine met all European regulatory requirements for annual licensing of seasonal influenza vaccine. Lower doses of this vaccine could achieve immune responses equivalent to those elicited by adjuvanted or non-adjuvanted split-virion vaccines. The use of a whole virion vaccine could be more adaptable to the antigen-sparing strategy recommended by WHO for protection against an influenza pandemic.

Safety and immunogenicity of an inactivated split-virion influenza A/Vietnam/1194/2004 (H5N1) vaccine: phase I randomised trial

Pathogenic avian influenza A virus H5N1 has caused outbreaks in poultry and migratory birds in Asia, Africa, and Europe, and caused disease and death in people. Although person-to-person spread of current H5N1 strains is unlikely, the virus is a potential source of a future influenza pandemic. Our aim was to assess the safety and immunogenicity of a vaccine against the H5N1 strain. We did a randomised, open-label, non-controlled phase I trial in 300 volunteers aged 18-40 years and assigned one of six inactivated split influenza A/Vietnam/1194/2004 (H5N1) influenza vaccine formulations, comprising 7.5 microg (with adjuvant n=50, without adjuvant n=49), 15 microg (n=50, n=50), or 30 microg (n=51, n=50) of haemagglutinin with or without aluminium hydroxide adjuvant. Individuals received two vaccinations (on days 0 and 21) and provided blood samples (on days 0, 21, and 42) for analysis by haemagglutination inhibition and microneutralisation. We recorded all adverse events. Analyses were descriptive. All formulations were well tolerated, with no serious adverse events, few severe reactions, and no oral temperatures of more than 38 degrees C. All formulations induced an immune response, and responses were detectable in some individuals after only one dose. The adjuvanted 30 microg formulation induced the greatest response (67% haemagglutinin-inhibition seroconversion rate after two vaccinations). Adjuvant did not improve the response to the lower doses. Two vaccinations of non-adjuvanted 7.5 microg, adjuvanted 15 microg, or non-adjuvanted 15 microg seroconverted more than 40% of participants (haemagglutinin-inhibition test only). Haemagglutinin inhibition and neutralising results were comparable. A two-dose regimen with an adjuvanted 30 microg inactivated H5N1 vaccine was safe and showed an immune response consistent with European regulatory requirements for licensure of seasonal influenza vaccine. We noted encouraging responses with lower doses of antigen that need further study to ascertain their relevance for the choice of the final pandemic vaccine.

Passive immunotherapy for influenza A H5N1 virus infection with equine hyperimmune globulin F(ab')2 in mice

BackgroundAvian influenza virus H5N1 has demonstrated considerable pandemic potential. Currently, no effective vaccines for H5N1 infection are available, so passive immunotherapy may be an alternative strategy. To investigate the possible therapeutic effect of antibody against highly pathogenic H5N1 virus on a mammal host, we prepared specific equine anti-H5N1 IgGs from horses vaccinated with inactivated H5N1 virus, and then obtained the F(ab')2 fragments by pepsin digestion of IgGs.MethodsThe horses were vaccinated with inactivated H5N1 vaccine to prepare anti-H5N1 IgGs. The F(ab')2 fragments were purified from anti-H5N1 hyperimmune sera by a protocol for 'enhanced pepsin digestion'. The protective effect of the F(ab')2 fragments against H5N1 virus infection was determined in cultured MDCK cells by cytopathic effect (CPE) assay and in a BALB/c mouse model by survival rate assay.ResultsBy the protocol for 'enhanced pepsin digestion', total 16 g F(ab')2 fragments were finally obtained from one liter equine antisera with the purity of over 90%. The H5N1-specific F(ab')2 fragments had a HI titer of 1:1024, and the neutralization titre of F(ab')2 reached 1: 2048. The in vivo assay showed that 100 μg of the F(ab')2 fragments could protect BALB/c mice infected with a lethal dose of influenza H5N1 virus.ConclusionThe availability of highly purified H5N1-specific F(ab')2 fragments may be promising for treatment of influenza H5N1 infection. Our work has provided experimental support for the application of the therapeutic equine immunoglobulin in future large primate or human trials.

PII: S0956-7135(00)00037-2

In this study, the adjuvant activity of sulfated glucan from saccharomyces cerevisiae (SGSC) was investigated. sGSC had molecular weight of 12.9 kDa and degrees of sulfation of 0.16. The effects of SGSC on the splenic lymphocyte cells of mice were measured in vitro. The results showed that SGSC could significantly promote lymphocyte proliferation singly or synergistically with Con A and LPS, and stimulate the cells to secrete IL-2 and INF-γ. The adjuvant activity of SGSC was researched in BALB/c mice inoculated with inactivated H5N1vaccine in vivo. The results showed that SGSC could significantly enhance lymphocyte proliferation, effectively increase the percentage of CD4+ T cells, decrease the percentage of CD8+ T cells, and elevate the CD4+/CD8+ ratio; enhance the HI antibody titre, and promote the production of IL-2, INF-γ, IL-4 and IL-6 at medium level. These results indicated that sulfated glucan showed an excellent adjuvant effect on H5N1vaccine in a mouse model. Therefore, SGSC could be used as an effective immune adjuvant for an inactivated H5N1vaccine.

Vaccination as a strategy to reduce the emergence of amantadine- and rimantadine-resistant strains of A/Chick/Pennsylvania/83 (H5N2) influenza virus

The influenza A virus (A/Chick/Pennsylvania/83 (H5N2) that caused up to 80% mortality in chickens provided a model system for testing the efficacy of chemotherapeutic agents against highly virulent influenza virus. Amantadine and rimantadine administered to chickens in drinking water were efficacious both prophylactically and therapeutically. However, under conditions simulating natural transmission of virus amantadine and rimantadine-resistant viruses arose and were transmitted to contact birds, causing mortality. Simultaneous administration of inactivated H5N2 vaccine and amantadine provided protection. Thus, chemotherapy may be useful in the treatment of a highly pathogenic influenza virus outbreak in humans or other animals when used in combination with vaccine.

Resistance of adults to challenge with influenza A wild-type virus after receiving live or inactivated virus vaccine

The efficacy of live attenuated cold-adapted (ca) reassortant influenza A H3N2 and H1N1 virus vaccines against experimental challenge with homologous wild-type virus 7 months after vaccination was compared with that of licensed inactivated virus vaccine in 106 seronegative (hemagglutination-inhibiting antibody titer less than or equal to 1:8) college students. The live attenuated virus vaccines induced as much resistance against illness as did the inactivated vaccine. Vaccine efficacy, measured by reduction in febrile or systemic illness in vaccines, compared with that in controls was 100% for ca H3N2 vaccine, 84% for inactivated H3N2 vaccine, 79% for ca H1N1 vaccine, and 67% for inactivated H1N1 vaccine. Less protection was conferred against upper respiratory tract illness; there was 50 and 77% protection in ca and inactivated H3N2 vaccines, respectively, but there was no protection in ca or inactivated H1N1 vaccinees. The duration, but not the magnitude, of H1N1 wild-type virus shedding in both ca and inactivated vaccinees was significantly reduced compared with controls. In contrast, a significant reduction in the duration and magnitude of H3N2 virus shedding was observed in ca vaccinees but not in inactivated vaccines. After wild-type virus challenge, live ca virus vaccinees demonstrated resistance at least as great 7 months postvaccination as did inactivated virus vaccinees. These observations indicate that live virus vaccines may be a satisfactory alternative to inactivated vaccines for healthy persons.

Chemotherapy and vaccination: a possible strategy for the control of highly virulent influenza virus.

The influenza A virus [A/Chicken/Pennsylvania/1370/83 (H5N2)] that caused up to 80% mortality among chickens provided a model system for testing the efficacy of chemotherapeutic agents against highly virulent influenza virus. Amantadine and rimantadine administered in drinking water were efficacious both prophylactically and therapeutically. However, under conditions simulating natural transmission of virus, amantadine- and rimantadine-resistant viruses arose and were transmitted to other birds in contact with the infected chickens, causing mortality. Simultaneous administration of inactivated H5N2 vaccine and amantadine provided protection. Thus, chemotherapy may be useful in the treatment of a highly pathogenic influenza virus outbreak in humans or other animals when used in combination with vaccine.