Long-term booster schedules with AS03A-adjuvanted heterologous H5N1 vaccines induces rapid and broad immune responses in Asian adults

BMC Infectious Diseases

François Roman²  Karl Walravens²  Mamadou Dramé⁶  Fong Seng Lim⁷  Prasert Thongcharoen⁵  Pan-Chyr Yang³  Shinn-Jang Hwang¹  Daniel Wai Sing Chu⁴  Paul Gillard⁸ 

[1] Department of Family Medicine, Taipei Veterans General Hospital and National Yang-Ming University, School of Medicine, Taipei, Taiwan;GlaxoSmithKline Vaccines, Rixensart, Belgium;College of Medicine, National Taiwan University, Taipei, Taiwan;Department of Medicine, Queen Mary Hospital Hong Kong, Hong Kong, China;Faculty of Medicine, Mahidol University, Nakon Pathom, Thailand;GlaxoSmithKline Vaccines, King of Prussia, PA, USA;National Healthcare Group Polyclinics, Singapore, Republic of Singapore;GlaxoSmithKline Vaccines, Wavre, Belgium

关键词: Prime–boost;    AS03_A-adjuvant;    Pandemic influenza;    H5N1;   

Others  :  1134343
DOI  :  10.1186/1471-2334-14-142

 received in 2013-11-08, accepted in 2014-03-06,  发布年份 2014

【 摘 要 】

Background

The pandemic potential of avian influenza A/H5N1 should not be overlooked, and the continued development of vaccines against these highly pathogenic viruses is a public health priority.

Methods

This open-label extension booster study followed a Phase III study of 1206 adults who had received two 3.75 μg doses of primary AS03_A-adjuvanted or non-adjuvanted H5N1 split-virus vaccine (A/Vietnam/1194/2004; clade 1) (NCT00449670). The aim of the extension study was to evaluate different timings for heterologous AS03_A-adjuvanted booster vaccination (A/Indonesia/5/2005; clade 2.1) given at Month 6, 12, or 36 post-primary vaccination. Immunogenicity was assessed 21 days after each booster vaccination and the persistence of immune responses against the primary vaccine strain (A/Vietnam) and the booster strain (A/Indonesia) was evaluated up to Month 48 post-primary vaccination. Reactogenicity and safety were also assessed.

Results

After booster vaccination given at Month 6, HI antibody responses to primary vaccine, and booster vaccine strains were markedly higher with one dose of AS03_A-H5N1 booster vaccine in the AS03_A-adjuvanted primary vaccine group compared with two doses of booster vaccine in the non-adjuvanted primary vaccine group. HI antibody responses were robust against the primary and booster vaccine strains 21 days after boosting at Month 12 or 36. At Month 48, in subjects boosted at Month 6, 12, or 36, HI antibody titers of ≥1:40 against the booster strain persisted in 39.2%, 61.2%, and 95.6% of subjects, respectively. Neutralizing antibody responses and cell-mediated immune responses also showed that AS03_A-H5N1 heterologous booster vaccination elicited robust immune responses within 21 days of boosting at Month 6, 12, or 36 post-primary vaccination. The booster vaccine was well tolerated, and no safety concerns were raised.

Conclusions

In Asian adults primed with two doses of AS03_A-adjuvanted H5N1 pandemic influenza vaccine, strong cross-clade anamnestic antibody responses were observed after one dose of AS03_A-H5N1 heterologous booster vaccine given at Month 6, 12, or 36 after priming, suggesting that AS03_A-adjuvanted H5N1 vaccines may provide highly flexible prime–boost schedules. Although immunogenicity decreased with time, vaccinated populations could potentially be protected for up to three years after vaccination, which is likely to far exceed the peak of the a pandemic.

【 授权许可】

   
2014 Gillard et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

Figure 3.

Figure 4.

Figure 5.

【 参考文献 】

• [1]World Health Organization: Cumulative Number Of Confirmed Human Cases For Avian Influenza A(H5n1) Reported To Who, 2003–2013. 2013. http://www.who.int/influenza/human_animal_interface/EN_GIP_20130705CumulativeNumberH5N1cases_2.pdf webcite
• [2]Liu D, Shi W, Shi Y, Wang D, Xiao H, Li W, Bi Y, Wu Y, Li X, Yan J, Liu W, Zhao G, Yang W, Wang Y, Ma J, Shu Y, Lei F, Gao GF: Origin and diversity of novel avian influenza A H7N9 viruses causing human infection: phylogenetic, structural, and coalescent analyses. Lancet 1926–1932, 2013:381.
• [3]World Health Organization: Antigenic And Genetic Characteristics Of Zoonotic Influenza Viruses And Development Of Candidate Vaccine Viruses For Pandemic Preparedness. 2013. http://www.who.int/influenza/vaccines/virus/201302_h5h7h9_vaccinevirusupdate.pdf webcite
• [4]Leroux-Roels I, Borkowski A, Vanwolleghem T, Drame M, Clement F, Hons E, Devaster JM, Leroux-Roels G: Antigen sparing and cross-reactive immunity with an adjuvanted rH5N1 prototype pandemic influenza vaccine: a randomised controlled trial. Lancet 2007, 370:580-589.
• [5]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.
• [6]Ferguson NM, Cummings DA, Fraser C, Cajka JC, Cooley PC, Burke DS: Strategies for mitigating an influenza pandemic. Nature 2006, 442:448-452.
• [7]Jennings LC, Monto AS, Chan PK, Szucs TD, Nicholson KG: Stockpiling prepandemic influenza vaccines: a new cornerstone of pandemic preparedness plans. Lancet Infect Dis 2008, 8:650-658.
• [8]Langley JM, Frenette L, Ferguson L, Riff D, Sheldon E, Risi G, Johnson C, Li P, Kenney R, Innis B, Fries L: Safety and cross-reactive immunogenicity of candidate AS03-adjuvanted prepandemic H5N1 influenza vaccines: a randomized controlled phase 1/2 trial in adults. J Infect Dis 2010, 201:1644-1653.
• [9]Langley JM, Risi G, Caldwell M, Gilderman L, Berwald B, Fogarty C, Poling T, Riff D, Baron M, Frenette L, Sheldon E, Collins H, Shepard M, Dionne M, Brune D, Ferguson L, Vaughn D, Li P, Fries L: Dose-sparing H5N1 A/Indonesia/05/2005 pre-pandemic influenza vaccine in adults and elderly adults: a phase III, placebo-controlled, randomized study. J Infect Dis 2011, 203:1729-1738.
• [10]Leroux-Roels G: Prepandemic H5N1 influenza vaccine adjuvanted with AS03: a review of the pre-clinical and clinical data. Expert Opin Biol Ther 2009, 9:1057-1071.
• [11]Schwarz TF, Horacek T, Knuf M, Damman HG, Roman F, Drame M, Gillard P, Jilg W: 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, 27:6284-6290.
• [12]Gillard P, Caplanusi A, Knuf M, Roman F, Walravens K, Moris P, Drame M, Schwarz TF: An assessment of prime-boost vaccination schedules with AS03A -adjuvanted prepandemic H5N1 vaccines: a randomized study in European adults. Influenza Other Respi Viruses 2013, 7:55-65.
• [13]Chu DW, Hwang SJ, Lim FS, Oh HM, Thongcharoen P, Yang PC, Bock HL, Drame M, Gillard P, Hutagalung Y, Tang H, Teoh YL, Ballou R: Immunogenicity and tolerability of an AS03(A)-adjuvanted prepandemic influenza vaccine: a phase III study in a large population of Asian adults. Vaccine 2009, 27:7428-7435.
• [14]Hehme N, Engelmann H, Kuenzel W, Neumeier E, Saenger R: Immunogenicity of a monovalent, aluminum-adjuvanted influenza whole virus vaccine for pandemic use. Virus Res 2004, 103:163-171.
• [15]Kendal A, Pereira M, Skehel J: Hemagglutination Inhibition. In Concepts And Procedures For Laboratory-Based Influenza Surveillance. Edited by Kendal AP, Pereira MS, Skehel JJ. Atlanta: Centers for Disease Control and Prevention and Pan-American Health Organization; 1982:B17-35.
• [16]Rowe T, Abernathy RA, Hu-Primmer J, Thompson WW, Lu X, Lim W, Fukuda K, Cox NJ, Katz JM: Detection of antibody to avian influenza A (H5N1) virus in human serum by using a combination of serologic assays. J Clin Microbiol 1999, 37:937-943.
• [17]Stephenson I, Wood JM, Nicholson KG, Charlett A, Zambon MC: Detection of anti-H5 responses in human sera by HI using horse erythrocytes following MF59-adjuvanted influenza A/Duck/Singapore/97 vaccine. Virus Res 2004, 103:91-95.
• [18]Reed L, Muench H: A simple method of estimating fifty percent endpoints. Am J Hyg 1938, 27:493-497.
• [19]Díez-Domingo J, Garcés-Sanchez M, Baldó J-M, Planelles M, Ubeda I, JuBert A, Marés J, Moris P, Garcia-Corbeira P, Dramé M, Gillard P: Immunogenicity and safety of H5N1 a/Vietnam/1194/2004 (clade 1) AS03-adjuvanted pre-pandemic candidate influenza vaccines in children aged 3 to 9 years: a phase II, randomized, open, controlled study. Pediatr Infec Dis J 2010, 29:e35-e46.
• [20]Maecker H, Maino V, Picker L: Immunofluorescence analysis of T-Cell responses in health and disease. J Clin Immun 2000, 20:391-399.
• [21]Waldrop S, Davis K, Maino V, Picker L: Normal human CD4+ memory T cells display broad heterogeneity in their activation threshold for cytokine synthesis. J Immunol 1998, 161:5284-5295.
• [22]Katz JM, Lim W, Bridges CB, Rowe T, Hu-Primmer J, Lu X, Abernathy RA, Clarke M, Conn L, Kwong H, Lee M, Au G, Ho YY, Mak KH, Cox NJ, Fukuda K: Antibody response in individuals infected with avian influenza A (H5N1) viruses and detection of anti-H5 antibody among household and social contacts. J Infect Dis 1999, 180:1763-1770.
• [23]Leroux-Roels I, Roman F, Forgus S, Maes C, De Boever F, Drame M, Gillard P, van der Most R, Van Mechelen M, Hanon E, Leroux-Roels G: Priming with AS03(A)-adjuvanted H5N1 influenza vaccine improves the kinetics, magnitude and durability of the immune response after a heterologous booster vaccination: an open non-randomised extension of a double-blind randomised primary study. Vaccine 2010, 28:849-857.
• [24]Roman F, Vaman T, Kafeja F, Hanon E, Van Damme P: AS03(A)-adjuvanted influenza a (H1N1) 2009 vaccine for adults up to 85 years of Age. Clin Infect Dis 2009, 2010(51):668-677.
• [25]Swain SL, Agrewala JN, Brown DM, Jelley-Gibbs DM, Golech S, Huston G, Jones SC, Kamperschroer C, Lee WH, McKinstry KK, Roman E, Strutt T, Weng : CD4+ T-cell memory: generation and multi-faceted roles for CD4+ T cells in protective immunity to influenza. Immunol Rev 2006, 211:8-22.
• [26]Moris P, van der Most R, Leroux-Roels I, Clement F, Drame M, Hanon E, Leroux-Roels GG, Van Mechelen M: H5N1 influenza vaccine formulated with AS03 A induces strong cross-reactive and polyfunctional CD4 T-cell responses. J Clin Immunol 2011, 31:443-454.