Long-term immunogenicity of an AS03-adjuvanted influenza A(H1N1)pdm09 vaccine in young and elderly adults: an observer-blind, randomized trial

William H Yang, Marc Dionne, Michael Kyle, Naresh Aggarwal, Ping Li, Miguel Madariaga, Olivier Godeaux, David W Vaughn, William H Yang, Marc Dionne, Michael Kyle, Naresh Aggarwal, Ping Li, Miguel Madariaga, Olivier Godeaux, David W Vaughn

Abstract

Background: This study (NCT00979602) evaluated the immunogenicity and relative protective efficacy of one dose of influenza A(H1N1)pdm09 vaccine with or without AS03 (an α-tocopherol oil-in-water emulsion based Adjuvant System).

Methods: Four thousands and forty-eight healthy adults aged ≥ 18 years were randomized (1:1) to receive one dose of either the adjuvanted split virion (3.75 μg hemagglutinin antigen [HA]/AS03) or non-adjuvanted (15 μg HA) vaccine. Hemagglutination inhibition [HI] antibody response was evaluated before vaccination and at Days 21, 42 and 182 (Month 6). Safety of the study vaccines was evaluated during the entire study duration.

Results: At Day 21, both study vaccines induced HI immune responses meeting the US regulatory criteria in subjects 18-64 years (seroprotection rate [SPR]: 98.0% [97.1-98.6]; seroconversion rate [SCR]: 89.7% [88.0-91.2] in the AS03-adjuvanted group; SPR: 91.4% [89.9-92.8]; SCR: 74.6% [72.3-76.9] in the non-adjuvanted group) and >64 years of age (SPR: 86.0% [82.5-89.0]; SCR: 75.3% [71.1-79.2] in the AS03-adjuvanted group; SPR: 69.1% [64.6-73.3]; SCR: 56.7% [52.0-61.3] in the non-adjuvanted group). The AS03-adjuvanted vaccine induced higher HI geometric mean titers than the non-adjuvanted vaccine at all time points. At Month 6, only subjects 18-64 years of age from both vaccine groups still met the US regulatory criteria (SPR: 82.1% [80.0-84.1]; SCR: 62.3% [59.6-64.8] in the AS03-adjuvanted group; SPR: 75.3% [72.9-77.5]; SCR: 53.7% [51.0-56.4] in the non-adjuvanted group). Protective efficacy was not evaluated due to low number of RT-qPCR-confirmed A(H1N1)pdm09 influenza cases. Through Month 12, 216 serious adverse events (in 157 subjects: 84 in the AS03-adjuvanted and 73 in the non-adjuvanted group) and 12 potentially immune mediated diseases (5 in the AS03-adjuvanted and 7 in the non-adjuvanted group) were reported.

Conclusion: A single dose of either adjuvanted or non-adjuvanted influenza A(H1N1)pdm09 vaccine induced protective HI antibody levels against the A/California/7/2009 strain that persisted through Month 6 in the 18-64 years population.

Keywords: ATP; Adjuvant; BARDA; BMI; Biomedical Advanced Research and Development Authority; CBER; CHMP; CI; Center for Biologics Evaluation & Research; Committee for Medicinal Products for Human Use; GMFR; GMT; H1N1; HA; HHS; HI; ILIs; Influenza; Influenza-Like-Illnesses; Pandemic; RVP; SAEs; SCR; SD; SPR; TVC; United States Department of Health and Human Services; VEI; Vaccine; WHO; World Health Organization; according to protocol; body mass index; confidence interval; geometric mean fold rise; geometric mean titer; hemagglutination inhibition; hemagglutinin; pIMDs; potential immune mediated diseases; respiratory viral panel; serious adverse events; seroconversion rate; seroprotection rate; standard deviation; total vaccinated cohort; vaccine effectiveness improvement.

Copyright © 2013 The Authors. Published by Elsevier Ltd.. All rights reserved.

Figures

Fig. 1
Fig. 1
Participant flow diagram.
Fig. 2
Fig. 2
Geometric mean titers for influenza A(H1N1)pdm09 hemagglutination inhibition antibodies by age strata at Days 21 (A) and 182 (Month 6) (B) (according to protocol cohort for immunogenicity). Footnotes: HI, hemagglutination inhibition; GMTs, geometric mean titers; ATP, according to protocol.
Fig. 3
Fig. 3
The incidence of solicited local (A) and general (B) adverse events reported during the 7-day post-vaccination period (total vaccinated cohort).

References

    1. Clark T.W., Pareek M., Hoschler K., Dillon H., Nicholson K.G., Groth N. Trial of influenza A(H1N1) 2009 monovalent MF59-adjuvanted vaccine. N Engl J Med. 2009;361:2424–2435.
    1. Liang X.F., Wang H.Q., Wang J.Z., Fang H.H., Wu J., Zhu F.C. Safety and immunogenicity of 2009 pandemic influenza A H1N1 vaccines in China: a multicentre, double-blind, randomised, placebo-controlled trial. Lancet. 2010;375:56–66.
    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 2009–2010 influenza season: a multicentre, randomised controlled trial. Lancet. 2010;375:49–55.
    1. Madhun A.S., Akselsen P.E., Sjursen H., Pedersen G., Svindland S., Nøstbakken J.K. An adjuvanted pandemic influenza H1N1 vaccine provides early and long term protection in health care workers. Vaccine. 2011;29:266–273.
    1. Dawood F.S., Jain S., Finelli L., Shaw M.W., Lindstrom S., Garten R.J., Virus Investigation Team Novel Swine-Origin Influenza A(H1N1). Emergence of a novel swine-origin influenza A(H1N1) virus in humans. N Engl J Med. 2009;360:2605–2615. [erratum in: N Engl J Med 2009;361(1):102]
    1. Garten R.J., Davis C.T., Russell C.A., Shu B., Lindstrom S., Balish A. Antigenic and genetic characteristics of swine-origin 2009 A(H1N1) influenza viruses circulating in humans. Science. 2009;325:197–201.
    1. Katz J., Hancock K., Veguilla V., Zhong W., Lu X.H., Sun H. Serum cross-reactive antibody response to a novel influenza A(H1N1) virus after vaccination with seasonal influenza vaccine. MMWR Morb Mortal Wkly Rep. 2009;58:521–524.
    1. Hancock K., Veguilla V., Lu X., Zhong W., Butler E.N., Sun H. Cross-reactive antibody responses to the 2009 pandemic H1N1 influenza virus. N Engl J Med. 2009;361:1945–1952.
    1. World Health Organization (WHO). Global Alert and Response (GAR). Pandemic influenza A(H1N1) 2009 virus vaccine – conclusions and recommendations from the October 2009 meeting of the immunization Strategic Advisory Group of Experts, ; December 04, 2009 [accessed 16.11.11].
    1. World Health Organization (WHO), WHO recommendations on pandemic (H1N1) 2009 vaccines. Pandemic (H1N1) 2009: briefing note 2, ; July 13, 2009 [accessed 16.11.11].
    1. Jackson L.A., Chen W.H., Stapleton J.T., Dekker C.L., Wald A., Brady R.C. Immunogenicity and safety of varying dosages of a monovalent 2009 H1N1 influenza vaccine given with and without AS03 Adjuvant System in healthy adults and older persons. J Infect Dis. 2012;206:811–820.
    1. Morel S., Didierlaurent A., Bourquiqon P., Delhaye S., Baras B., Jacob V. Adjuvant System AS03 containing α-tocopherol modulates innate immune response and leads to improved adaptive immunity. Vaccine. 2011;29:2461–2473.
    1. Garcon N., Vaughn D.W., Didierlaurent A.M. Development and evaluation of AS03, an Adjuvant System containing α-tocopherol and squalene in an oil-in-water emulsion. Expert Rev Vaccines. 2012;11:349–366.
    1. Chu D.W.S., Hwang S.J., Lim F.S., Oh H.M., Thongcharoen P., Yang P.C. Immunogenicity and tolerability of an AS03A-adjuvanted prepandemic influenza vaccine: a phase III study in a large population of Asian adults. Vaccine. 2009;27:7428–7435.
    1. Nagai H., Ikematsu H., Tenjinbaru K., Maeda A., Dramé M., Roman F.P. A phase II, open-label, multicentre study to evaluate the immunogenicity and safety of an adjuvanted prepandemic (H5N1) influenza vaccine in healthy Japanese adults. BMC Infect Dis. 2010;10:338.
    1. Leroux-Roels I., Bernhard R., Gérard 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.
    1. Roman F., Vaman T., Gerlach B., Markendorf A., Gillard P., Devaster J.M. Immunogenicity and safety in adults of one dose of influenza A H1N1v 2009 vaccine formulated with and without AS03(A)-trial. Adjuvant: preliminary report of an observer-blind, randomized controlled trial. Vaccine. 2010;28:1740–1745.
    1. Roman F., Clement F., Dewe W., Walravens K., Maes C., Willekens J. Effect on cellular and humoral immune responses of the AS03 Adjuvant System in an A/H1N1/2009 influenza virus vaccine administered to adults during two randomized controlled trials. Clin Vaccine Immunol. 2011;18:835–843.
    1. Ikematsu H., Nagai H., Kawashima M., Kawakami Y., Tenjinbaru K., Maeda A. Immunogenicity and safety of a novel AS03A-adjuvanted H1N1 2009 pandemic influenza vaccine in adults in Japan. Hum Vaccin. 2010;6:888–893.
    1. WHO Expert Committee on Biological Standardization: 56th report, Geneva, World Health Organization. Annex 5: WHO biosafety risk assessment and guidelines for the production and quality control of human influenza pandemic vaccines, ; 2007 [accessed 19.04.13].
    1. US Food and Drug Administration (FDA) for Industry, Clinical data needed to support the licensure of pandemic influenza vaccines. US Food and Drug Administration, ; May 2007 [accessed 16.11.10].
    1. European Committee for Proprietary Medicinal Products (CHMP), 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, January 24, 2007.
    1. Hehme N.W., Künzel W., Petschke F., Gisela T., Carmen R., Christian van H. Ten years of experience with the trivalent split-influenza vaccine, Fluarix™. Clin Drug Invest. 2002;22:751–769.
    1. Vesikari T., Beran J., Durviaux S., Stainier I., El Idrissi M., Walravens K. Use of real-time polymerase chain reaction (rtPCR) as a diagnostic tool for influenza infection in a vaccine efficacy trial. J Clin Virol. 2012;53:22–28.
    1. Pabbaraju K., Wong S., Tokaryk K.L., Fonseca K., Drews S.J. Comparison of the Luminex xTAG Respiratory Viral Panel with xTAG Respiratory Viral Panel Fast for diagnosis of respiratory virus infections. J Clin Microbiol. 2011;49:1738–1744.
    1. Gadsby N.J., Hardie A., Claas E.C.J., Templeton K.E. Comparison of the Luminex Respiratory Virus Panel Fast Assay with In-House Real-Time PCR for respiratory viral infection diagnosis. J Clin Microbiol. 2010;48:2213–2216.
    1. Mahmud S., Hammond G., Elliott L., Hilderman T., Kurbis C., Caetano P. Effectiveness of the pandemic H1N1 influenza vaccines against laboratory-confirmed H1N1 infections: population-based case–control study. Vaccine. 2011;29:7975–7981.
    1. Skowronski D.M., de Serres G., Crowcroft N.S., Janjua N.Z., Boulianne N., Hottes T.S. Association between the 2008 and 2009 seasonal influenza vaccine and pandemic H1N1 illness during spring–summer 2009: four observational studies from Canada. PLoS Med. 2010;7:e1000258.
    1. van Buynder P.G., Dhaliwal J.K., van Buynder J.L., Couturier C., Minville-Leblanc M., Garceau R. Protective effect of single-dose adjuvanted pandemic influenza vaccine in children. Influenza Other Respi Viruses. 2010;4:171–178.
    1. Andrews N., Waight P., Yung C.F., Miller E. Age-specific effectiveness of an oil-in-water adjuvanted pandemic (H1N1) 2009 vaccine against confirmed infection in high risk groups in England. J Infect Dis. 2011;203:32–39.
    1. Ikematsu H., Tenjinbaru K., Li P., Madan A., Vaughn D. Evaluation of immune response following one dose of an AS03A-adjuvanted H1N1 2009 pandemic influenza vaccine in Japanese adults 65 years of age or older. Hum Vaccin Immunother. 2012;8:1119–1125.
    1. Ferguson M., Risi G., Davis M., Sheldon E., Baron M., Li P. Safety and long-term humoral immune response in adults after vaccination with an H1N1 2009 pandemic influenza vaccine with or without AS03 adjuvant. J Infect Dis. 2012;205:733–744.
    1. Ikematsu H., Nagai H., Kawashima M., Kawakami Y., Tenjinbaru K., Li P. Characterization and long-term persistence of immune response following two doses of an AS03A-adjuvanted H1N1 influenza vaccine in healthy Japanese adults. Hum Vaccin Immunother. 2012;8:1–7.
    1. Nicholson K.G., Abrams K.R., Batham S., Clark T.W., Hoschler K., Lim W.S. Immunogenicity and safety of a two-dose schedule of whole-virion and AS03A-adjuvanted 2009 influenza A(H1N1) vaccines: a randomised, multicentre, age-stratified, head-to-head trial. Lancet Infect Dis. 2011;11:91–101.
    1. Nolan T., McVernon J., Skeljo M., Richmond P., Wadia U., Lambert S. Immunogenicity of a monovalent 2009 Influenza A(H1N1) vaccine in infants and children: a randomized trial. JAMA. 2010;303:37–46.
    1. Nolan T., Richmond P.C., Formica N.T., Höschler K., Skeljo M.V., Stoney T. Safety and immunogenicity of a prototype adjuvanted inactivated split-virus infl uenza A (H5N1) vaccine in infants and children. Vaccine. 2008;26:6383–6391.
    1. Andrews N.J., Walker W.T., Finn A. Predictors of immune response and reactogenicity to AS03B-adjuvanted split virion and nonadjuvanted whole virion H1N1 (2009) pandemic influenza vaccines. Vaccine. 2011;29:7913–7919.
    1. Ohfuji S., Fukushima W., Deguchi M. Immunogenicity of a monovalent 2009 influenza A(H1N1) vaccine among pregnant women: lowered antibody response by prior seasonal vaccination. J Infect Dis. 2011;203:1301–1308.
    1. Ohmit S.E., Petrie J.G., Malosh R.E., Cowling B.J., Thompson M.G., Shay D.K., Monto A.S. Influenza vaccine effectiveness in the community and the household. Clin Infect Dis. 2013 [Epub ahead of print]
    1. McElhaney J.E., Beran J., Devaster J.M., Esen M., Launay O., Leroux-Roels G. AS03-adjuvanted versus non-adjuvanted inactivated trivalent influenza vaccine against seasonal influenza in elderly people: a phase 3 randomised trial. Lancet Infect Dis. 2013 [Epub ahead of print]
    1. Mahmud S.M., van Caeseele P., Hammond G., Kurbis C., Hilderman T., Elliott L. No association between 2008 and 2009 influenza vaccine and influenza A(H1N1)pdm09 virus infection, Manitoba, Canada, 2009. Emerg Infect Dis. 2012;18:801–810.
    1. Talbot H.K., Coleman L.A., Crimin K., Zhu Y., Rock M.T., Meece J. Association between obesity and vulnerability and serologic response to influenza vaccination in older adults. Vaccine. 2012;30:3937–3943.
    1. Sheridan P.A., Paich H.A., Handy J., Karlsson E.A., Hudgens M.G., Sammon A.B. Obesity is associated with impaired immune response to influenza vaccination in humans. Int J Obesity (Lond) 2011:1–6. [Epub]
    1. Saitoh A., Tamura S., Nagai A., Tsuchida N., Sako M., Maekawa T. Clinical evaluation of an AS03-adjuvanted pandemic influenza H1N1 2009 vaccine in children (preliminary report) J Jap Pediatr Soc. 2011;115:578–584. [Japanese]
    1. Clark T.W., Pareek M., Hoschler K., Dillon H., Nicholson K.G., Groth N., Stephenson I. Trial of 2009 influenza A(H1N1) monovalent MF59-adjuvanted vaccine. N Engl J Med. 2009;361:2424–2435.
    1. Wu J., Li W., Wang H.Q., Chen J.T., Lv M., Zhou J.C. A rapid immune response to 2009 influenza A(H1N1) vaccines in adults: a randomized, double-blind, controlled trial. J Infect Dis. 2010;202:675–680.
    1. McElhaney J.E., Zhou X., Talbot H.K., Soethout E., Bleackley R.C., Granville D.J. The unmet need in the elderly: how immunosenescence, CMV infection, co-morbidities and frailty are a challenge for the development of more effective influenza vaccines. Vaccine. 2012;30:2060–2067.
    1. Talbot H.K.B., Libster R., Edwards K.M. Influenza vaccination for older adults. Human Vaccin Immunother. 2012;8:1–6.
    1. van Damme P., Kafeja F., Bambure V., Hanon E., Moris P., Roman F. Long-term persistence of humoral and cellular immune responses induced by an AS03A-adjuvanted H1N1 2009 influenza vaccine: an open-label, randomized study in adults aged 18–60 years and older. Hum Vaccin Immunother. 2013;9 [Epub ahead of print]

Source: PubMed

Sponsors et collaborateurs

Les conditions médicales

Interventions en matière de drogue

3
S'abonner