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The contribution of systemic and pulmonary immune effectors to vaccine-induced protection from H5N1 influenza virus infection.

ABSTRACT: Live attenuated influenza vaccines (LAIVs) are effective in providing protection against influenza challenge in animal models and in preventing disease in humans. We previously showed that LAIVs elicit a range of immune effectors and that successful induction of pulmonary cellular and humoral immunity in mice requires pulmonary replication of the vaccine virus. An upper respiratory tract immunization (URTI) model was developed in mice to mimic the human situation, in which the vaccine virus does not replicate in the lower respiratory tract, allowing us to assess the protective efficacy of an H5N1 LAIV against highly pathogenic H5N1 virus challenge in the absence of significant pulmonary immunity. Our results show that, after one dose of an H5N1 LAIV, pulmonary influenza-specific lymphocytes are the main contributors to clearance of challenge virus from the lungs and that contributions of influenza-specific enzyme-linked immunosorbent assay (ELISA) antibodies in serum and splenic CD8(+) T cells were negligible. Complete protection from H5N1 challenge was achieved after two doses of H5N1 LAIV and was associated with maturation of the antibody response. Although passive transfer of sera from mice that received two doses of vaccine prevented lethality in naive recipients following challenge, the mice showed significant weight loss, with high pulmonary titers of the H5N1 virus. These data highlight the importance of mucosal immunity in mediating optimal protection against H5N1 infection. Understanding the requirements for effective induction and establishment of these protective immune effectors in the respiratory tract paves the way for a more rational and effective vaccine approach in the future.

SUBMITTER: Lau YF

PROVIDER: S-EPMC3347357 | biostudies-other | 2012 May

REPOSITORIES: biostudies-other

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The contribution of systemic and pulmonary immune effectors to vaccine-induced protection from H5N1 influenza virus infection.

Lau Yuk-Fai YF Wright Amber R AR Subbarao Kanta K

Journal of virology 20120229 9

Live attenuated influenza vaccines (LAIVs) are effective in providing protection against influenza challenge in animal models and in preventing disease in humans. We previously showed that LAIVs elicit a range of immune effectors and that successful induction of pulmonary cellular and humoral immunity in mice requires pulmonary replication of the vaccine virus. An upper respiratory tract immunization (URTI) model was developed in mice to mimic the human situation, in which the vaccine virus does ...[more]

PMID: 22379093

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Project description:Aim:The need for non-parenteral administration of inactivated avian influenza virus of H5N1 subtype (AIV-H5N1) vaccine is paramount. Here, we provide preliminary data on the immune response of chicken and mice after intranasal administration of AIV-H5N1-inactivated vaccine with ISCOMS, Inmunair (INM), and combined ISCOMS and INM as an adjuvant. Materials and Methods:The AIV isolate of A/Chicken/Denpasar/01/2004 (H5N1) was cultivated in specific pathogen-free chicken eggs and inactivated with formaldehyde. The vaccine preparation was added with those adjuvants for intranasal administration and aluminum hydroxide for subcutaneous injection. The chicken and mouse were vaccinated at the age of 3 weeks or 1 month and repeated 2 weeks thereafter. In one experiment, chicken was injected with Newcastle disease virus (NDV) at the same time with AIV vaccine. The sera were collected at one (serum 1) and 2 w (serum 2) after booster vaccination. The anti-AIV-H5 and NDV antibodies in chicken sera were detected using hemagglutination inhibition (HI) assay. Mouse IgG anti-AIV-H5N1 antibody was detected using ELISA. Results:The result shows that the geometric mean titers (GMTs) of chicken sera of intranasal vaccinated with inactivated AIV-H5N1 vaccine with mixed ISCOM- INM as adjuvant were <20.0 and 22.7 unit HI-unit (HIU) in serum 1 and serum 2, respectively. The GMTs of the positive control group were 23.7 and 25.7 HIU in serum 1 and serum 2, respectively. The result of the second experiment shows that IgG anti-AIV-H5N1 was detected in mouse sera. In the third experiment, the GMTs of anti-NDV in chicken vaccinated subsequently with inactivated NDV vaccine and AIV-H5N1 with mixed ISCOMS-INM administrated intranasally and aluminum hydroxide adjuvant administrated through subcutaneous injection as well as positive control group receiving NDV vaccine only were 28.0, 28.0, and 27.4 HIU in serum 1 while were 29.6, 29.2, and 28.2 HIU in serum 2, respectively. Conclusion:Intranasal administration of inactivated AIV-H5N1 vaccine-induced a systemic immune response in chicken and mice after adding ISCOMS and/or INM as adjuvants. The adjuvant and the intranasal administration caused no immunosuppressive effect on the chicken immune response to NDV vaccine.

Project description:During the past decade, a number of H5 subtype influenza vaccines have been developed and tested in clinical trials, but most of them induced poor serum antibody responses prompting the evaluation of novel vaccination approaches. One of the most promising ones is a "prime-boost" strategy, which could result in the induction of prompt and robust immune responses to a booster influenza vaccine following priming with homologous or heterologous vaccine strains. In our study we evaluated immunogenicity of an adjuvanted A(H5N1) inactivated influenza vaccine (IIV) in healthy adult subjects who received A(H5N2) live attenuated influenza vaccine (LAIV) 1.5 years earlier and compared this with a group of naïve subjects. We found that priming with A(H5N2) LAIV induced a long-lasting B-cell immunological memory against influenza A(H5N1) virus, which was brought on by more prompt and vigorous antibody production to a single dose of A(H5N1) IIV in the primed group, compared to the naïve controls. Thus, by day 28 after the first booster dose, the hemagglutination inhibition and neutralizing (MN) antibody titer rises were 17.2 and 30.8 in the primed group, compared to 2.3 and 8.0 in the control group, respectively. The majority (79%) of the primed individuals achieved seroprotective MN antibody titers at 7 days after the first dose of the IIV. All LAIV-primed volunteers had MN titers ? 1:40 by Day 28 after one dose of IIV, whereas only 58% subjects from the naïve control group developed similar immune responses at this time point. The second A(H5N1) IIV dose did not increase the immune response in the LAIV-primed group, whereas 2 doses of IIV were required for naïve volunteers to develop significant immune responses. These findings were of special significance since Russian-based LAIV technology has been licensed to WHO, through whom the vaccine has been provided to vaccine manufacturers in India, China and Thailand - countries particularly vulnerable to a pandemic influenza. The results of our study will be useful to inform the development of vaccination strategies in these countries in the event of a pandemic.

Project description:Age-related changes in T-cell function are associated with a loss of influenza vaccine efficacy in older adults. Both antibody and cell-mediated immunity plays a prominent role in protecting older adults, particularly against the serious complications of influenza. High dose (HD) influenza vaccines induce higher antibody titers in older adults compared to standard dose (SD) vaccines, yet its impact on T-cell memory is not clear. The aim of this study was to compare the antibody and T-cell responses in older adults randomized to receive HD or SD influenza vaccine as well as determine whether cytomegalovirus (CMV) serostatus affects the response to vaccination, and identify differences in the response to vaccination in those older adults who subsequently have an influenza infection. Older adults (≥65years) were enrolled (n=106) and randomized to receive SD or HD influenza vaccine. Blood was collected pre-vaccination, followed by 4, 10 and 20weeks post-vaccination. Serum antibody titers, as well as levels of inducible granzyme B (iGrB) and cytokines were measured in PBMCs challenged ex vivo with live influenza virus. Surveillance conducted during the influenza season identified those with laboratory confirmed influenza illness or infection. HD influenza vaccination induced a high antibody titer and IL-10 response, and a short-lived increase in Th1 responses (IFN-γ and iGrB) compared to SD vaccination in PBMCs challenged ex vivo with live influenza virus. Of the older adults who became infected with influenza, a high IL-10 and iGrB response in virus-challenged cells was observed post-infection (week 10 to 20), as well as IFN-γ and TNF-α at week 20. Additionally, CMV seropositive older adults had an impaired iGrB response to influenza virus-challenge, regardless of vaccine dose. This study illustrates that HD influenza vaccines have little impact on the development of functional T-cell memory in older adults. Furthermore, poor outcomes of influenza infection in older adults may be due to a strong IL-10 response to influenza following vaccination, and persistent CMV infection.

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The contribution of systemic and pulmonary immune effectors to vaccine-induced protection from H5N1 influenza virus infection.

Publications

The contribution of systemic and pulmonary immune effectors to vaccine-induced protection from H5N1 influenza virus infection.

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