Flexibility of interval between vaccinations with AS03A-adjuvanted influenza A (H1N1) 2009 vaccine in adults aged 18-60 and >60 years: a randomized trial

Xavier Duval, Adrian Caplanusi, Henri Laurichesse, Dominique Deplanque, Pierre Loulergue, Tejaswini Vaman, Odile Launay, Paul Gillard, Xavier Duval, Adrian Caplanusi, Henri Laurichesse, Dominique Deplanque, Pierre Loulergue, Tejaswini Vaman, Odile Launay, Paul Gillard

Abstract

Background: Flexibility of vaccination schedule and lower antigen content can facilitate pandemic vaccine coverage. We assessed the immune response and safety of AS03-adjuvanted A/California/7/2009 H1N1 pandemic vaccine containing half of the registered adult haemagglutinin (HA) antigen content, administered as a two-dose schedule at intervals of 21 days or 6 months in both young and elderly adults.

Methods: In this open-label randomized trial, healthy adults aged 18-60 years (N = 163) and >60 years (N = 143) received AS03A-adjuvanted A/California/7/2009 H1N1 vaccine containing 1.9 μg HA on Day 0. A second dose was given on Day 21 (n = 177) or Day 182 (n = 106). Haemagglutination-inhibition (HI) antibody responses were analyzed on Days 0, 21, 42, 182, 364 and additionally on Day 203 for subjects vaccinated on Day 182. Solicited and unsolicited adverse events were recorded.

Results: The HI antibody response in both age strata 21 days after the first dose met and exceeded all regulatory acceptance criteria although the results suggested a lower response in the older age stratum (geometric mean titres [GMTs] for HI antibodies of 420.5 for subjects aged 18-60 years and 174.4 for those >60 years). A second dose of AS03A adjuvanted A/H1N1/2009 vaccine induced a further increase in antibody titres and the response was similar whether the second dose was administered at 21 days (GMTs of 771.8 for 18-60 years and 400.9 for >60 years) or 6 months (GMTs of 708.3 for 18-60 years and 512.1 for >60 years) following the first dose. Seroprotection rates remained high at 6 months after one dose or two doses while at 12 months rates tended to be higher for the 6 month interval schedule (93.3% for 18-60 years and 80.4% for >60 years) than the 21 day schedule (82.3% for 18-60 years and 50.0% for >60 years). Reactogenicity/safety profiles were similar for both schedules, there was no evidence of an increase in reactogenicity following the second dose.

Conclusions: The results indicate that flexibility in the dosing interval for AS03A adjuvanted vaccine may be possible. Such flexibility could help to reduce the logistic stress on delivery of pandemic vaccination programmes.

Trial registration: ClinicalTrials.gov, NCT00975884.

Figures

Figure 1
Figure 1
Trial Profile.
Figure 2
Figure 2
Geometric mean titres (with 95% confidence intervals) for haemagglutination inhibition antibodies against A/California/7/2009 in adults aged 18 to 60 years and in adults >60 years (per-protocol immunogenicity cohorts). Group A = Vaccination on Day 0 and Day 21; Group B = Vaccination on Day 0 and Day 182.

References

    1. Nidom CA, Takano R, Yamada S, Sakai-Tagawa Y, Daulay S, Aswadi D, Suzuki T, Suzuki Y, Shinya K, Iwatsuki-Horimoto K, Muramoto Y, Kawaoka Y. Influenza A (H5N1) viruses from pigs, Indonesia. Emerg Infect Dis. 2010;16(10):1515–23. doi: 10.3201/eid1610.100508.
    1. Fiore AE, Shay DK, Broder K, Iskander JK, Uyeki TM, Mootrey G, Bresee JS, Cox NJ. Prevention and control of seasonal influenza with vaccines: recommendations of the Advisory Committee on Immunization Practices (ACIP), 2009. MMWR. 2009;58(RR-8):1–52.
    1. Fedson DS, Dunhill P. Commentary: from scarcity to abundance: pandemic vaccines and other agents for ‘have not’ countries. J Public Health Policy. 2007;28:322–340. doi: 10.1057/palgrave.jphp.3200147.
    1. Leroux-Roels I, Borkowski A, Vanwolleghem T, Dramé M, Clement F, Hons E, Devaster JM, Leroux-Roels G. Antigen sparing and cross-reactive immunity with an adjuvanted rH5N1 prototype pandemic influenza vaccine. Lancet. 2007;370:580–89. doi: 10.1016/S0140-6736(07)61297-5.
    1. Leroux-Roels I, Bernhard R, Gerard P, Dramé 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. doi: 10.1371/journal.pone.0001665.
    1. Baras B, Stittelaar KJ, Simon JH, Thoolen RJ, Mossman SP, Pistoor FH, van Amerongen G, Wettendorff MA, Hanon E, Osterhaus AD. Crossprotection against lethal H5N1 challenge in ferrets with an adjuvanted pandemic influenza vaccine. PLoS One. 2008;3:e1401. doi: 10.1371/journal.pone.000140.
    1. Rumke HC, Bayas JM, de Juanes JM, Caso C, Richardus JH, Campins M, Rombo L, Duval X, Romanenko V, Schwarz TF, Fassakhov R, Abad-Santos F, von Sonnenburg F, Dramé M, Sänger R, Ballou WR. Safety and reactogenicity profile of an adjuvanted H5N1 pandemic candidate vaccine in adults within a phase III safety trial. Vaccine. 2008;26:2378–88. doi: 10.1016/j.vaccine.2008.02.068.
    1. Chu DW, Hwang SJ, Lim FS, Lin Oh HM, Thongcharoen P, Yang PC, Bock HL, Dramé M, Gillard P, Hutagalung Y, Tang H, Teoh YL, Ballou RW. on behalf of the H5N1 Flu Study Group for Hong Kong, Singapore, Taiwan and Thailand. Immunogenicity and tolerability of an AS03-adjuvanted prepandemic influenza vaccine. A phase III study in a large population of Asian adults. Vaccine. 2009;27:7428–35. doi: 10.1016/j.vaccine.2009.07.102.
    1. EPAR product information: updated 27/02/2012. Available at: .
    1. Roman F, Vaman T, Kafeja F, Hanon E, Van Damme P. AS03A-adjuvanted influenza A (H1N1) 2009 vaccine in adults aged up to 85 years. Clin Infect Dis. 2010;51(6):668–677. doi: 10.1086/655830.
    1. Gillard P, Caplanusi A, Knuf M, Roman F, Walravens K, Moris P, Dramé M, Schwarz TF. An assessment of prime-boost vaccination schedules with AS03(A)-adjuvanted prepandemic H5N1 vaccines: a randomized study in European adults. Infl Other Resp Viruses. 2012. Epub.
    1. Greenberg ME, Lai MH, Hartel GF, Wichems CH, Gittleson C, Bennet J, Dawson G, Hu W, Leggio C, Washington D, Basser RL. Response to a monovalent 2009 influenza A (H1N1) vaccine. N Engl J Med. 2009;361:2405–13. doi: 10.1056/NEJMoa0907413.
    1. Clark TW, Pareek M, Hoschler K, Dillon H, Nicholson KG, Groth N, Stephenson I. Trial of 2009 influenza A (H1N1) monovalent MF59-adjuvanted vaccine. N Engl J Med. 2009;361:2424–35. doi: 10.1056/NEJMoa0907650.
    1. Plennevaux E, Sheldon E, Blatter M, Reeves-Hoché MK, Denis M. Immune response after a single vaccination against 2009 influenza A H1N1 in USA: a preliminary report of two randomised controlled phase 2 trials. Lancet. 2010;375:41–8. doi: 10.1016/S0140-6736(09)62026-2.
    1. Vajo Z, Tamas F, Sinka L, Jankovics I. Safety and immunogenicity of a 2009 pandemic influenza A H1N1 vaccine when administered alone or simultaneously with the seasonal influenza vaccine for the 2009–10 influenza season: a multicentre, randomised controlled trial. Lancet. 2010;375:49–55. doi: 10.1016/S0140-6736(09)62039-0.
    1. EPAR Product information: updated 14/06/2012. Available at .
    1. Schwarz TF, Horacek T, Knuf M, Damman HG, Roman F, Mamadou Dramé M, Gillard P, Jilg W. Single dose vaccination with AS03-adjuvanted H5N1 vaccinesin a randomized trial induces strong and broad immune responsiveness to booster vaccination in adults. Vaccine. 2009;27:6284–90. doi: 10.1016/j.vaccine.2009.01.040.
    1. Guideline on influenza vaccines prepared from viruses with the potential to cause a pandemic and intended to be used outside of the core dossier context (EMEA/CHMP/VWP/263499/ 2006) European Agency for the Evaluation of Medicinal Products; 2007.
    1. Availability of a candidate reassortant vaccine virus for the novel Influenza A (H1N1) vaccine development X-179A. 2009. Accessed May 2011, at .)
    1. Hehme NW, Künzel W, Petschke F, Türk G, Raderecht C, van Hoecke C, Sänger R. Ten years of experience with the trivalent split-influenza vaccine, Fluarix™. Clin Drug Invest. 2002;22:751–69. doi: 10.2165/00044011-200222110-00004.
    1. Roman F, Vaman T, Gerlach B, Markendorf A, Gillard P, Jeanne-Marie Devaster JM. Immunogenicity and safety in adults of one dose of influenza A H1N1v 2009 vaccine formulated with and without AS03A-adjuvant: Preliminary report of an observer-blind, randomised trial. Vaccine. 2010;28:1740–45. doi: 10.1016/j.vaccine.2009.12.014.
    1. Roman F, Clément F, Dewé W, Walravens K, Maes C, Willekens J, De Boever F, Hanon E, Leroux-Roels G. Effect on cellular and humoral immune responses of the AS03 Adjuvant System in an A/H1N1/2009 influenza vaccine administered to adults during two randomised controlled trials. Clin Vaccine Immunol. 2011;18:835–43. doi: 10.1128/CVI.00480-10.
    1. Deng Y, Jing Y, Campbell AE, Gravenstein S. Age-related impaired type 1 T cell responses to influenza: reduced activation ex vivo, decreased expansion in CTL culture in vitro, and blunted response to influenza vaccination in vivo in the elderly. J Immunol. 2004;172:3437–46.
    1. Goodwin K, Viboud C, Simonsen L. Antibody response to influenza vaccination in the elderly: a quantitative review. Vaccine. 2006;24:1159–69. doi: 10.1016/j.vaccine.2005.08.105.
    1. McElhaney JE, Dutz JP. Better influenza vaccines for older people: what will it take? JID. 2008;198:632–4. doi: 10.1086/590435.
    1. O’Hagan DT. MF59 is a safe and potent vaccine adjuvant that enhances protection against influenza virus infection. Expert Rev Vaccines. 2007;6:699–710. doi: 10.1586/14760584.6.5.699.
    1. Heijmans S, De Meulemeester M, Reynders P, Giet D, Demanet E, Devresse PY, Icardi G, Dramé M, Roman F, Gillard P. Immunogenicity profile of a 3.75 μg hemagglutinin pandemic rH5N1 split virion AS03A-adjuvanted vaccine in the elderly. J Infect Dis . 2011;203:1054–62. doi: 10.1093/infdis/jiq174.
    1. Hancock K, Veguilla V, Lu X, Zhong W, Butler EN, Sun H, Liu F, Dong L, DeVos JR, Gargiullo PM, Brammer TL, Cox NJ, Tumpey TM, Katz JM. Cross-reactive antibody responses to the 2009 pandemic H1N1 influenza virus. N Engl J Med. 2009;361:1945–52. doi: 10.1056/NEJMoa0906453.
    1. Skountzou I, Koutsonanos DG, Kim JH, Powers R, Satyabhama L, Masseoud F, Weldon WC, Martin Mdel P, Mittler RS, Compans R, Jacob J. Immunity to pre-1950 H1N1 influenza viruses confers cross-protection against the pandemic swine-origin 2009 A (H1N1) influenza virus. J Immunol. 2010;185(3):1642–9. doi: 10.4049/jimmunol.1000091.
    1. Ferguson M, Risi G, Davis M, Sheldon E, Baron M, Li P, Madariaga M, Fries L, Godeaux O, Vaughn D. Safety and Long-term humoral immune response in adults after vaccination with an H1N1 2009 pandemic influenza vaccine with or without AS03 Adjuvant. JID. 2012;205:733–744. doi: 10.1093/infdis/jir641.

Source: PubMed

Sponsors and Collaborators

Medical Conditions

Drug Interventions

3
Subscribe