Skip to main content
Top
Published in: Journal of Clinical Immunology 3/2011

Open Access 01-06-2011

H5N1 Influenza Vaccine Formulated with AS03A Induces Strong Cross-Reactive and Polyfunctional CD4 T-Cell Responses

Authors: Philippe Moris, Robbert van der Most, Isabel Leroux-Roels, Frédéric Clement, Mamadou Dramé, Emmanuel Hanon, Geert G. Leroux-Roels, Marcelle Van Mechelen

Published in: Journal of Clinical Immunology | Issue 3/2011

Login to get access

Abstract

Objective

Adjuvantation of an H5N1 split-virion influenza vaccine with AS03A substantially reduces the antigen dose required to produce a putatively protective humoral response and promotes cross-clade neutralizing responses. We determined the effect of adjuvantation on antibody persistence and B- and T-cell-mediated immune responses.

Methods

Two vaccinations with a split-virion A/Vietnam/1194/2004 (H5N1, clade 1) vaccine containing 3.75–30 μg hemagglutinin and formulated with or without adjuvant were administered to groups of 50 volunteers aged 18–60 years.

Results

Adjuvantation of the vaccine led to better persistence of neutralizing and hemagglutination-inhibiting antibodies and higher frequencies of antigen-specific memory B cells. Cross-reactive and polyfunctional H5N1-specific CD4 T cells were detected at baseline and were amplified by vaccination. Expansion of CD4 T cells was enhanced by adjuvantation.

Conclusion

Formulation of the H5N1 vaccine with AS03A enhances antibody persistence and induces stronger T- and B-cell responses. The cross-clade T-cell immunity indicates that the adjuvanted vaccine primes individuals to respond to either infection and/or subsequent vaccination with strains drifted from the primary vaccine strain.
Literature
1.
go back to reference Girard MP, Tam JS, Assossou OM, Kieny MP. The 2009 A (H1N1) influenza virus pandemic: a review. Vaccine. 2010;28:4895–902.PubMedCrossRef Girard MP, Tam JS, Assossou OM, Kieny MP. The 2009 A (H1N1) influenza virus pandemic: a review. Vaccine. 2010;28:4895–902.PubMedCrossRef
3.
go back to reference European Agency for Proprietary Medicinal Products. Guideline on influenza vaccine prepared from viruses with the potential to cause a pandemic and intended for use outside of the core dossier context (EMEA/CHMP/VWP/263499/2006). European Agency for the Evaluation of Medicinal Products; 2007. European Agency for Proprietary Medicinal Products. Guideline on influenza vaccine prepared from viruses with the potential to cause a pandemic and intended for use outside of the core dossier context (EMEA/CHMP/VWP/263499/2006). European Agency for the Evaluation of Medicinal Products; 2007.
4.
go back to reference Leroux-Roels I, Leroux-Roels G. Current status and progress of prepandemic and pandemic influenza vaccine development. Expert Rev Vaccines. 2009;8:401–23.PubMedCrossRef Leroux-Roels I, Leroux-Roels G. Current status and progress of prepandemic and pandemic influenza vaccine development. Expert Rev Vaccines. 2009;8:401–23.PubMedCrossRef
5.
go back to reference Food and Drug Administration. Guidance for industry: clinical data needed to support the licensure of pandemic influenza vaccines. 2007. Food and Drug Administration. Guidance for industry: clinical data needed to support the licensure of pandemic influenza vaccines. 2007.
6.
go back to reference European Agency for Proprietary Medicinal Products. Guideline on dossier structure and content for pandemic influenza vaccine marketing authorisation application (CPMP/VEG/4717/03). European Agency for the Evaluation of Medicinal Products; 2004. European Agency for Proprietary Medicinal Products. Guideline on dossier structure and content for pandemic influenza vaccine marketing authorisation application (CPMP/VEG/4717/03). European Agency for the Evaluation of Medicinal Products; 2004.
7.
go back to reference Nicolson C, Major D, Wood JM, Robertson JS. Generation of influenza vaccine viruses on Vero cells by reverse genetics: an H5N1 candidate vaccine strain produced under a quality system. Vaccine. 2005;23:2943–52.PubMedCrossRef Nicolson C, Major D, Wood JM, Robertson JS. Generation of influenza vaccine viruses on Vero cells by reverse genetics: an H5N1 candidate vaccine strain produced under a quality system. Vaccine. 2005;23:2943–52.PubMedCrossRef
8.
go back to reference Webby RJ, Perez DR, Coleman JS, Guan Y, Knight JH, Govorkova EA, et al. Responsiveness to a pandemic alert: use of reverse genetics for rapid development of influenza vaccines. Lancet. 2004;363:1099–103.PubMedCrossRef Webby RJ, Perez DR, Coleman JS, Guan Y, Knight JH, Govorkova EA, et al. Responsiveness to a pandemic alert: use of reverse genetics for rapid development of influenza vaccines. Lancet. 2004;363:1099–103.PubMedCrossRef
9.
go back to reference Banzhoff A, Gasparini R, Laghi-Pasini F, Staniscia T, Durando P, Montomoli E, et al. MF59-adjuvanted H5N1 vaccine induces immunologic memory and heterotypic antibody responses in non-elderly and elderly adults. PLoS ONE. 2009;4:e4384.PubMedCrossRef Banzhoff A, Gasparini R, Laghi-Pasini F, Staniscia T, Durando P, Montomoli E, et al. MF59-adjuvanted H5N1 vaccine induces immunologic memory and heterotypic antibody responses in non-elderly and elderly adults. PLoS ONE. 2009;4:e4384.PubMedCrossRef
10.
go back to reference Bernstein DI, Edwards KM, Dekker CL, Belshe R, Talbot HK, Graham IL, et al. Effects of adjuvants on the safety and immunogenicity of an avian influenza H5N1 vaccine in adults. J Infect Dis. 2008;197:667–75.PubMedCrossRef Bernstein DI, Edwards KM, Dekker CL, Belshe R, Talbot HK, Graham IL, et al. Effects of adjuvants on the safety and immunogenicity of an avian influenza H5N1 vaccine in adults. J Infect Dis. 2008;197:667–75.PubMedCrossRef
11.
go back to reference Leroux-Roels I, Borkowski A, Vanwolleghem T, Drame M, Clement F, Hons E, et al. Antigen sparing and cross-reactive immunity with an adjuvanted rH5N1 prototype pandemic influenza vaccine: a randomised controlled trial. Lancet. 2007;370:580–9.PubMedCrossRef Leroux-Roels I, Borkowski A, Vanwolleghem T, Drame M, Clement F, Hons E, et al. Antigen sparing and cross-reactive immunity with an adjuvanted rH5N1 prototype pandemic influenza vaccine: a randomised controlled trial. Lancet. 2007;370:580–9.PubMedCrossRef
12.
go back to reference Leroux-Roels I, Bernhard R, Gerard P, Drame M, Hanon E, Leroux-Roels G. Broad Clade 2 cross-reactive immunity induced by an adjuvanted clade 1 rH5N1 pandemic influenza vaccine. PLoS ONE. 2008;3:e1665.PubMedCrossRef Leroux-Roels I, Bernhard R, Gerard P, Drame M, Hanon E, Leroux-Roels G. Broad Clade 2 cross-reactive immunity induced by an adjuvanted clade 1 rH5N1 pandemic influenza vaccine. PLoS ONE. 2008;3:e1665.PubMedCrossRef
13.
go back to reference Levie K, Leroux-Roels I, Hoppenbrouwers K, Kervyn AD, Vandermeulen C, Forgus S, et al. An adjuvanted, low-dose, pandemic influenza A (H5N1) vaccine candidate is safe, immunogenic, and induces cross-reactive immune responses in healthy adults. J Infect Dis. 2008;198:642–9.PubMedCrossRef Levie K, Leroux-Roels I, Hoppenbrouwers K, Kervyn AD, Vandermeulen C, Forgus S, et al. An adjuvanted, low-dose, pandemic influenza A (H5N1) vaccine candidate is safe, immunogenic, and induces cross-reactive immune responses in healthy adults. J Infect Dis. 2008;198:642–9.PubMedCrossRef
14.
go back to reference Schwarz TF, Horacek T, Knuf M, Damman HG, Roman F, Drame M, et al. Single dose vaccination with AS03-adjuvanted H5N1 vaccines in a randomized trial induces strong and broad immune responsiveness to booster vaccination in adults. Vaccine. 2009;27:6284–90.PubMedCrossRef Schwarz TF, Horacek T, Knuf M, Damman HG, Roman F, Drame M, et al. Single dose vaccination with AS03-adjuvanted H5N1 vaccines in a randomized trial induces strong and broad immune responsiveness to booster vaccination in adults. Vaccine. 2009;27:6284–90.PubMedCrossRef
15.
go back to reference Stephenson I, Nicholson KG, Hoschler K, Zambon MC, Hancock K, DeVos J, et al. Antigenically distinct MF59-adjuvanted vaccine to boost immunity to H5N1. N Engl J Med. 2008;359:1631–3.PubMedCrossRef Stephenson I, Nicholson KG, Hoschler K, Zambon MC, Hancock K, DeVos J, et al. Antigenically distinct MF59-adjuvanted vaccine to boost immunity to H5N1. N Engl J Med. 2008;359:1631–3.PubMedCrossRef
16.
go back to reference Chu DW, Hwang SJ, Lim FS, Oh HM, Thongcharoen P, Yang PC, et al. Immunogenicity and tolerability of an AS03(A)-adjuvanted prepandemic influenza vaccine: a phase III study in a large population of Asian adults. Vaccine. 2009;27:7428–35.PubMedCrossRef Chu DW, Hwang SJ, Lim FS, Oh HM, Thongcharoen P, Yang PC, et al. Immunogenicity and tolerability of an AS03(A)-adjuvanted prepandemic influenza vaccine: a phase III study in a large population of Asian adults. Vaccine. 2009;27:7428–35.PubMedCrossRef
17.
go back to reference Rümke HC, Bayas JM, de Juanes JR, Caso C, Richardus JH, Campins M, et al. Safety and reactogenicity profile of an adjuvanted H5N1 pandemic candidate vaccine in adults within a phase III safety trial. Vaccine. 2008;26:2378–88.PubMedCrossRef Rümke HC, Bayas JM, de Juanes JR, Caso C, Richardus JH, Campins M, et al. Safety and reactogenicity profile of an adjuvanted H5N1 pandemic candidate vaccine in adults within a phase III safety trial. Vaccine. 2008;26:2378–88.PubMedCrossRef
18.
go back to reference EMEA. European public assessment report for Prepandrix, 2010. EMEA. European public assessment report for Prepandrix, 2010.
19.
go back to reference Baras B, Stittelaar KJ, Simon JH, Thoolen RJMM, Mossman SP, Pistoor FHM, et al. Cross-protection against lethal H5N1 challenge in ferrets with an adjuvanted pandemic influenza vaccine. PLoS ONE. 2008;3:e1401.PubMedCrossRef Baras B, Stittelaar KJ, Simon JH, Thoolen RJMM, Mossman SP, Pistoor FHM, et al. Cross-protection against lethal H5N1 challenge in ferrets with an adjuvanted pandemic influenza vaccine. PLoS ONE. 2008;3:e1401.PubMedCrossRef
20.
go back to reference Doherty PC, Turner SJ, Webby RG, Thomas PG. Influenza and the challenge for immunology. Nat Immunol. 2006;7:449–55.PubMedCrossRef Doherty PC, Turner SJ, Webby RG, Thomas PG. Influenza and the challenge for immunology. Nat Immunol. 2006;7:449–55.PubMedCrossRef
21.
go back to reference Swain SL, Agrewala JN, Brown DM, Jelley-Gibbs DM, Golech S, Huston G, et al. CD4+ T-cell memory: generation and multi-faceted roles for CD4+ T cells in protective immunity to influenza. Immunol Rev. 2006;211:8–22.PubMedCrossRef Swain SL, Agrewala JN, Brown DM, Jelley-Gibbs DM, Golech S, Huston G, et al. CD4+ T-cell memory: generation and multi-faceted roles for CD4+ T cells in protective immunity to influenza. Immunol Rev. 2006;211:8–22.PubMedCrossRef
22.
go back to reference Crotty S, Aubert RD, Glidewell J, Ahmed R. Tracking human antigen-specific memory B cells: a sensitive and generalized ELISPOT system. J Immunol Methods. 2004;286:111–22.PubMedCrossRef Crotty S, Aubert RD, Glidewell J, Ahmed R. Tracking human antigen-specific memory B cells: a sensitive and generalized ELISPOT system. J Immunol Methods. 2004;286:111–22.PubMedCrossRef
23.
go back to reference Maecker HT. Multiparameter flow cytometry monitoring of T cell responses. Methods Mol Biol. 2009;485:375–91.PubMedCrossRef Maecker HT. Multiparameter flow cytometry monitoring of T cell responses. Methods Mol Biol. 2009;485:375–91.PubMedCrossRef
24.
go back to reference Nomura L, Maino VC, Maecker HT. Standardization and optimization of multiparameter intracellular cytokine staining. Cytom A. 2008;73:984–91.CrossRef Nomura L, Maino VC, Maecker HT. Standardization and optimization of multiparameter intracellular cytokine staining. Cytom A. 2008;73:984–91.CrossRef
25.
go back to reference Waldrop SL, Davis KA, Maino VC, Picker LJ. Normal human CD4+ memory T cells display broad heterogeneity in their activation threshold for cytokine synthesis. J Immunol. 1998;161:5284–95.PubMed Waldrop SL, Davis KA, Maino VC, Picker LJ. Normal human CD4+ memory T cells display broad heterogeneity in their activation threshold for cytokine synthesis. J Immunol. 1998;161:5284–95.PubMed
26.
go back to reference Sallusto F, Geginat J, Lanzavecchia A. Central memory and effector memory T cell subsets: function, generation, and maintenance. Annu Rev Immunol. 2004;22:745–63.PubMedCrossRef Sallusto F, Geginat J, Lanzavecchia A. Central memory and effector memory T cell subsets: function, generation, and maintenance. Annu Rev Immunol. 2004;22:745–63.PubMedCrossRef
27.
go back to reference de Bree GJ, Daniels H, Schilfgaarde M, Jansen HM, Out TA, van Lier RA, et al. Characterization of CD4+ memory T cell responses directed against common respiratory pathogens in peripheral blood and lung. J Infect Dis. 2007;195:1718–25.PubMedCrossRef de Bree GJ, Daniels H, Schilfgaarde M, Jansen HM, Out TA, van Lier RA, et al. Characterization of CD4+ memory T cell responses directed against common respiratory pathogens in peripheral blood and lung. J Infect Dis. 2007;195:1718–25.PubMedCrossRef
28.
go back to reference Lanzavecchia A, Sallusto F. Understanding the generation and function of memory T cell subsets. Curr Opin Immunol. 2005;17:326–32.PubMedCrossRef Lanzavecchia A, Sallusto F. Understanding the generation and function of memory T cell subsets. Curr Opin Immunol. 2005;17:326–32.PubMedCrossRef
29.
go back to reference Amanna IJ, Carlson NE, Slifka MK. Duration of humoral immunity to common viral and vaccine antigens. N Engl J Med. 2007;357:1903–15.PubMedCrossRef Amanna IJ, Carlson NE, Slifka MK. Duration of humoral immunity to common viral and vaccine antigens. N Engl J Med. 2007;357:1903–15.PubMedCrossRef
30.
go back to reference Cellerai C, Harari A, Vallelian F, Boyman O, Pantaleo G. Functional and phenotypic characterization of tetanus toxoid-specific human CD4+ T cells following re-immunization. Eur J Immunol. 2007;37:1129–38.PubMedCrossRef Cellerai C, Harari A, Vallelian F, Boyman O, Pantaleo G. Functional and phenotypic characterization of tetanus toxoid-specific human CD4+ T cells following re-immunization. Eur J Immunol. 2007;37:1129–38.PubMedCrossRef
31.
go back to reference Divekar AA, Zaiss DM, Lee FE, Liu D, Topham DJ, Sijts AJ, et al. Protein vaccines induce uncommitted IL-2-secreting human and mouse CD4 T cells, whereas infections induce more IFN-gamma-secreting cells. J Immunol. 2006;176:1465–73.PubMed Divekar AA, Zaiss DM, Lee FE, Liu D, Topham DJ, Sijts AJ, et al. Protein vaccines induce uncommitted IL-2-secreting human and mouse CD4 T cells, whereas infections induce more IFN-gamma-secreting cells. J Immunol. 2006;176:1465–73.PubMed
32.
go back to reference Lee LYH, Ha DLA, Simmons C, de Jong MD, Chau NV, Schumacher R, et al. Memory T cells established by seasonal human influenza A infection cross-react with avian influenza A (H5N1) in healthy individuals. J Clin Invest. 2008;118:3478–90.PubMed Lee LYH, Ha DLA, Simmons C, de Jong MD, Chau NV, Schumacher R, et al. Memory T cells established by seasonal human influenza A infection cross-react with avian influenza A (H5N1) in healthy individuals. J Clin Invest. 2008;118:3478–90.PubMed
33.
go back to reference Wherry EJ, Ahmed R. Memory CD8 T-cell differentiation during viral infection. J Virol. 2004;78:5535–45.PubMedCrossRef Wherry EJ, Ahmed R. Memory CD8 T-cell differentiation during viral infection. J Virol. 2004;78:5535–45.PubMedCrossRef
34.
go back to reference Le Bon A, Tough DF. Type I interferon as a stimulus for cross-priming. Cytokine Growth Factor Rev. 2008;19:33–40.PubMedCrossRef Le Bon A, Tough DF. Type I interferon as a stimulus for cross-priming. Cytokine Growth Factor Rev. 2008;19:33–40.PubMedCrossRef
35.
go back to reference Galli G, Medini D, Borgogni E, Zedda L, Bardelli M, Malzone C, et al. Adjuvanted H5N1 vaccine induces early CD4+ T cell response that predicts long-term persistence of protective antibody levels. Proc Natl Acad Sci USA. 2009;106:3877–82.PubMedCrossRef Galli G, Medini D, Borgogni E, Zedda L, Bardelli M, Malzone C, et al. Adjuvanted H5N1 vaccine induces early CD4+ T cell response that predicts long-term persistence of protective antibody levels. Proc Natl Acad Sci USA. 2009;106:3877–82.PubMedCrossRef
36.
go back to reference Galli G, Hancock K, Hoschler K, DeVos J, Praus M, Bardelli M, et al. Fast rise of broadly cross-reactive antibodies after boosting long-lived human memory B cells primed by an MF59 adjuvanted prepandemic vaccine. Proc Natl Acad Sci USA. 2009;106:7962–7.PubMedCrossRef Galli G, Hancock K, Hoschler K, DeVos J, Praus M, Bardelli M, et al. Fast rise of broadly cross-reactive antibodies after boosting long-lived human memory B cells primed by an MF59 adjuvanted prepandemic vaccine. Proc Natl Acad Sci USA. 2009;106:7962–7.PubMedCrossRef
37.
go back to reference Malherbe L, Mark L, Fazilleau N, Heyzer-Williams LJ, Heyzer-Williams MG. Vaccine adjuvants alter TCR-based selection thresholds. Immunity. 2008;28:698–709.PubMedCrossRef Malherbe L, Mark L, Fazilleau N, Heyzer-Williams LJ, Heyzer-Williams MG. Vaccine adjuvants alter TCR-based selection thresholds. Immunity. 2008;28:698–709.PubMedCrossRef
38.
go back to reference Nurieva RI, Chung Y, Hwang D, Yang XO, Kang HS, Ma L, et al. Generation of T follicular helper cells is mediated by interleukin-21 but independent of T helper 1, 2, or 17 cell lineages. Immunity. 2008;29:138–49.PubMedCrossRef Nurieva RI, Chung Y, Hwang D, Yang XO, Kang HS, Ma L, et al. Generation of T follicular helper cells is mediated by interleukin-21 but independent of T helper 1, 2, or 17 cell lineages. Immunity. 2008;29:138–49.PubMedCrossRef
Metadata
Title
H5N1 Influenza Vaccine Formulated with AS03A Induces Strong Cross-Reactive and Polyfunctional CD4 T-Cell Responses
Authors
Philippe Moris
Robbert van der Most
Isabel Leroux-Roels
Frédéric Clement
Mamadou Dramé
Emmanuel Hanon
Geert G. Leroux-Roels
Marcelle Van Mechelen
Publication date
01-06-2011
Publisher
Springer US
Published in
Journal of Clinical Immunology / Issue 3/2011
Print ISSN: 0271-9142
Electronic ISSN: 1573-2592
DOI
https://doi.org/10.1007/s10875-010-9490-6

Other articles of this Issue 3/2011

Journal of Clinical Immunology 3/2011 Go to the issue