sharon sanders
Editor-in-Chief & President
The Lancet Infectious Diseases 2006; 6:255-256
DOI:10.1016/S1473-3099(06)70443-1
Cytotoxic T-cell immunity as a target for influenza vaccines Arno M?llbacher
a, Mario Lobigs a, Mohammed Alsharifi a and Matthias Regner a
Current vaccines against influenza virus are predominantly ?killed? vaccines, where the infectivity of a virus preparation is inactivated by chemical treatment.1 They function almost exclusively by inducing virus-neutralising antibody. However, due to the frequent antigenic drift and shift of influenza viruses, antibody-based vaccines elicit limited or no protective immunity against newly arising strains?eg, H5N1. The possible beneficial effects of vaccination-induced cytotoxic T (Tc) cell-mediated immunity in ameliorating disease severity of influenza in human beings has been largely ignored. The Tc cell response, in combination with antibodies, is thought to be important in recovery from primary infections with influenza A strains.2,3 Although memory Tc cells cannot provide sterile immunity or prevent infection with a heterologous virus, they may reduce disease severity by lowering the viral burden early after infection, as has been demonstrated in birds challenged with the H5N1 strain.4 The antigenic determinants giving rise to Tc cell immunity are generally not subject to immune evasion by the virus and, in the case of influenza A viruses, are broadly cross-reactive.5 Furthermore, Tc cell immunity is, at least in mice, long-lived.6 Consequently, the ability to induce Tc cell memory is a highly desirable property of a vaccine candidate.
The generation of Tc cell immunity generally requires infection with a live virus. Intriguingly, γ-ray-inactivated (sterile) virus preparations retain the ability to prime Tc cell immunity, which protects against lethal challenge with heterologous influenza A strains.7 This phenomenon has also been observed with alphaviruses and bunyaviruses.8,9 Our original observation of the cross-protective value of γ-ray-inactivated influenza A virus has been confirmed by others, although the authors did not distinguish between the contribution of humoral and cellular immunity.10,11 γ-ray irradiation inactivates virus infectivity by generating strand breaks in the viral genome and, by contrast with chemical treatment with formalin or α-propriolactone (currently used in the production of inactivated influenza virus vaccines), γ-ray irradiation has little impact on the antigenic structure and biological integrity of proteins.12 Thus, the haemagglutinating activity of influenza virus is retained following γ-ray irradiation.11 It has the further advantage of high penetration into biological materials.12
We envisage two (not exclusive) mechanisms for the efficient induction of Tc cell responses by γ-ray-inactivated virus. First, given that the functional domains of the viral surface proteins remain intact, efficient uptake into cells and uncoating of the γ-ray-irradiated virus is likely to take place. This uptake may provide sufficient viral antigen into the cytoplasm of antigen presenting cells for induction of Tc cell immunity. Second, abortive translation of fragmented genomic viral RNA may occur, allowing the priming of virus-specific Tc cell immunity. Defective ribosomal products (prematurely terminated and misfolded gene products) are considered a dominant source of viral antigen for MHC class I antigen presentation.13 In addition to inducing virus-immune Tc cells, γ-ray-inactivated virus may also elicit improved humoral immunity, given that the antigenic structure of γ-irradiated virus remains largely intact.
Although induction of heterotypic immunity by γ-ray-inactivated virus has, so far, only been demonstrated in mouse models for A/strain influenza and several other RNA viruses, the applicability of this approach to human beings is, we believe, worthy of consideration at the present time.
<!--start simple-tail=-->References
1. Stephenson I, Gust I, Kieny MP, Pervikov Y. Development and evaluation of influenza pandemic vaccines. Lancet Infect Dis 2006; 6: 71-72. Full Text | PDF (41 KB) | MEDLINE | CrossRef
2. Karzon D. Cytotoxic T cells in influenza immunity. Semin Virol 1996; 7: 265-271. CrossRef
3. Braciale TJ, Yap KL. Role of viral infectivity in the induction of influenza virus-specific cytotoxic T cells. J Exp Med 1978; 147: 1236-1252. MEDLINE | CrossRef
4. Seo SH, Webster RG. Cross-reactive, cell-mediated immunity and protection of chickens from lethal H5N1 influenza virus infection in Hong Kong poultry markets. J Virol 2001; 75: 2516-2525. MEDLINE | CrossRef
5. Ada GL, Jones PD. The immune response to influenza infection. Curr Top Microbiol Immunol 1986; 128: 1-54. MEDLINE
6. M?llbacher A. The long term maintenance of cytotoxic T cell memory does not require persistence of antigen. J Exp Med 1994; 179: 317-321. MEDLINE | CrossRef
7. M?llbacher A, Ada GL, Hla RT. Gamma-irradiated influenza A virus can prime for a cross-reactive and cross-protective immune response against influenza A virus. Immunol Cell Biol 1988; 66: 153-157.
8. M?llbacher A, Marshall ID, Blanden RV. Cross-reactive cytotoxic T cells to alphavirus infection. Scand J Immunol 1979; 10: 291-296. MEDLINE | CrossRef
9. M?llbacher A, Marshall ID, Ferris P. Classification of Barmah forest virus as an alphavirus using cytotoxic T cell assays. J Gen Virol 1986; 67: 295-299.
10. Pang GT, Clancy RL, O'Reilly SE, Cripps AW. A novel particulate influenza vaccine induces long-term and broad-based immunity in mice after oral immunization. J Virol 1992; 66: 1162-1170. MEDLINE
11. Lidbury BA, Grissell TV, Sizer PJ, Pang GT, Clancy R, Cripps AW. Erythrocytes enhance the immunogenicity of oral vaccination with gamma irradiated influenza virus: increasing the dose of irradiation results in a significant diminution of lung IgA response. Vaccine 1997; 15: 1529-1537. MEDLINE | CrossRef
12. Lowy RJ, Vavrina GA, LaBarre DD. Comparison of gamma and neutron radiation inactivation of influenza A virus. Antiviral Res 2001; 52: 261-273. MEDLINE | CrossRef
13. Yewdell J, Anton LC, Bacik I, Schubert U, Snyder HL, Bennink JR. Generating MHC class I ligands from viral gene products. Immunol Rev 1999; 172: 97-108. MEDLINE | CrossRef
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<!--end simple-tail-->Affiliations
a. Division of Immunology and Genetics, The John Curtin School of Medical Research, Australian National University, Canberra, ACT 0200, Australia
DOI:10.1016/S1473-3099(06)70443-1
Cytotoxic T-cell immunity as a target for influenza vaccines Arno M?llbacher
a, Mario Lobigs a, Mohammed Alsharifi a and Matthias Regner aCurrent vaccines against influenza virus are predominantly ?killed? vaccines, where the infectivity of a virus preparation is inactivated by chemical treatment.1 They function almost exclusively by inducing virus-neutralising antibody. However, due to the frequent antigenic drift and shift of influenza viruses, antibody-based vaccines elicit limited or no protective immunity against newly arising strains?eg, H5N1. The possible beneficial effects of vaccination-induced cytotoxic T (Tc) cell-mediated immunity in ameliorating disease severity of influenza in human beings has been largely ignored. The Tc cell response, in combination with antibodies, is thought to be important in recovery from primary infections with influenza A strains.2,3 Although memory Tc cells cannot provide sterile immunity or prevent infection with a heterologous virus, they may reduce disease severity by lowering the viral burden early after infection, as has been demonstrated in birds challenged with the H5N1 strain.4 The antigenic determinants giving rise to Tc cell immunity are generally not subject to immune evasion by the virus and, in the case of influenza A viruses, are broadly cross-reactive.5 Furthermore, Tc cell immunity is, at least in mice, long-lived.6 Consequently, the ability to induce Tc cell memory is a highly desirable property of a vaccine candidate.
The generation of Tc cell immunity generally requires infection with a live virus. Intriguingly, γ-ray-inactivated (sterile) virus preparations retain the ability to prime Tc cell immunity, which protects against lethal challenge with heterologous influenza A strains.7 This phenomenon has also been observed with alphaviruses and bunyaviruses.8,9 Our original observation of the cross-protective value of γ-ray-inactivated influenza A virus has been confirmed by others, although the authors did not distinguish between the contribution of humoral and cellular immunity.10,11 γ-ray irradiation inactivates virus infectivity by generating strand breaks in the viral genome and, by contrast with chemical treatment with formalin or α-propriolactone (currently used in the production of inactivated influenza virus vaccines), γ-ray irradiation has little impact on the antigenic structure and biological integrity of proteins.12 Thus, the haemagglutinating activity of influenza virus is retained following γ-ray irradiation.11 It has the further advantage of high penetration into biological materials.12
We envisage two (not exclusive) mechanisms for the efficient induction of Tc cell responses by γ-ray-inactivated virus. First, given that the functional domains of the viral surface proteins remain intact, efficient uptake into cells and uncoating of the γ-ray-irradiated virus is likely to take place. This uptake may provide sufficient viral antigen into the cytoplasm of antigen presenting cells for induction of Tc cell immunity. Second, abortive translation of fragmented genomic viral RNA may occur, allowing the priming of virus-specific Tc cell immunity. Defective ribosomal products (prematurely terminated and misfolded gene products) are considered a dominant source of viral antigen for MHC class I antigen presentation.13 In addition to inducing virus-immune Tc cells, γ-ray-inactivated virus may also elicit improved humoral immunity, given that the antigenic structure of γ-irradiated virus remains largely intact.
Although induction of heterotypic immunity by γ-ray-inactivated virus has, so far, only been demonstrated in mouse models for A/strain influenza and several other RNA viruses, the applicability of this approach to human beings is, we believe, worthy of consideration at the present time.
<!--start simple-tail=-->References
1. Stephenson I, Gust I, Kieny MP, Pervikov Y. Development and evaluation of influenza pandemic vaccines. Lancet Infect Dis 2006; 6: 71-72. Full Text | PDF (41 KB) | MEDLINE | CrossRef
2. Karzon D. Cytotoxic T cells in influenza immunity. Semin Virol 1996; 7: 265-271. CrossRef
3. Braciale TJ, Yap KL. Role of viral infectivity in the induction of influenza virus-specific cytotoxic T cells. J Exp Med 1978; 147: 1236-1252. MEDLINE | CrossRef
4. Seo SH, Webster RG. Cross-reactive, cell-mediated immunity and protection of chickens from lethal H5N1 influenza virus infection in Hong Kong poultry markets. J Virol 2001; 75: 2516-2525. MEDLINE | CrossRef
5. Ada GL, Jones PD. The immune response to influenza infection. Curr Top Microbiol Immunol 1986; 128: 1-54. MEDLINE
6. M?llbacher A. The long term maintenance of cytotoxic T cell memory does not require persistence of antigen. J Exp Med 1994; 179: 317-321. MEDLINE | CrossRef
7. M?llbacher A, Ada GL, Hla RT. Gamma-irradiated influenza A virus can prime for a cross-reactive and cross-protective immune response against influenza A virus. Immunol Cell Biol 1988; 66: 153-157.
8. M?llbacher A, Marshall ID, Blanden RV. Cross-reactive cytotoxic T cells to alphavirus infection. Scand J Immunol 1979; 10: 291-296. MEDLINE | CrossRef
9. M?llbacher A, Marshall ID, Ferris P. Classification of Barmah forest virus as an alphavirus using cytotoxic T cell assays. J Gen Virol 1986; 67: 295-299.
10. Pang GT, Clancy RL, O'Reilly SE, Cripps AW. A novel particulate influenza vaccine induces long-term and broad-based immunity in mice after oral immunization. J Virol 1992; 66: 1162-1170. MEDLINE
11. Lidbury BA, Grissell TV, Sizer PJ, Pang GT, Clancy R, Cripps AW. Erythrocytes enhance the immunogenicity of oral vaccination with gamma irradiated influenza virus: increasing the dose of irradiation results in a significant diminution of lung IgA response. Vaccine 1997; 15: 1529-1537. MEDLINE | CrossRef
12. Lowy RJ, Vavrina GA, LaBarre DD. Comparison of gamma and neutron radiation inactivation of influenza A virus. Antiviral Res 2001; 52: 261-273. MEDLINE | CrossRef
13. Yewdell J, Anton LC, Bacik I, Schubert U, Snyder HL, Bennink JR. Generating MHC class I ligands from viral gene products. Immunol Rev 1999; 172: 97-108. MEDLINE | CrossRef
Back to top
<!--end simple-tail-->Affiliations
a. Division of Immunology and Genetics, The John Curtin School of Medical Research, Australian National University, Canberra, ACT 0200, Australia