Long-Term Persistence of Cell-Mediated and Humoral Responses to A(H1N1)pdm09 Influenza Virus Vaccines and the Role of the AS03 Adjuvant System in Adults during Two Randomized Controlled Trials

Robbert G van der Most, Frédéric Clément, Julie Willekens, Walthère Dewé, Karl Walravens, David W Vaughn, Geert Leroux-Roels, Robbert G van der Most, Frédéric Clément, Julie Willekens, Walthère Dewé, Karl Walravens, David W Vaughn, Geert Leroux-Roels

Abstract

We investigated the role of AS03A (here AS03), an α-tocopherol oil-in-water emulsion-based adjuvant system, on the long-term persistence of humoral and cell-mediated immune responses to A(H1N1)pdm09 influenza vaccines. In two studies, a total of 261 healthy adults (≤60 years old) were randomized to receive two doses of AS03-adjuvanted vaccine containing 3.75 μg of hemagglutinin (HA) or nonadjuvanted vaccine containing 15 μg of hemagglutinin (in study A) or 3.75 μg of hemagglutinin (in study B) 21 days apart. Hemagglutination inhibition (HI) antibody, memory B-cell, and CD4+/CD8+ T-cell responses were characterized up to 1 year following dose 1. We also assessed the effects of age and seasonal influenza vaccination history. AS03-adjuvanted (3.75 μg HA) vaccine and nonadjuvanted vaccine at 15 μg but not at 3.75 μg HA elicited HI antibody responses persisting at levels that continued to meet European licensure criteria through month 12. At month 12, the geometric mean titer for AS03-adjuvanted vaccine was similar to that for nonadjuvanted (15-μg) vaccine in study A (1:86 and 1:88, respectively) and higher than that for nonadjuvanted (3.75-μg) vaccine in study B (1:77 and 1:35, respectively). A(H1N1)pdm09-specific CD4+ T-cell and B-cell responses were stronger in AS03-adjuvanted groups and persisted only in these groups for 12 months at levels exceeding prevaccination frequencies. Advancing age and a seasonal vaccination history tended to reduce HI antibody and memory B-cell responses and, albeit less consistently, CD4+ T-cell responses. Thus, AS03 seemed to enhance the persistence of humoral and cell-mediated responses to A(H1N1)pdm09 vaccine, allowing for antigen sparing and mitigating potential negative effects of age and previous seasonal vaccination. (These studies have been registered at ClinicalTrials.gov under registration no. NCT00968539 and NCT00989287.).

Keywords: AS03 adjuvant; influenza vaccine; pandemic influenza.

Copyright © 2017 van der Most et al.

Figures

FIG 1
FIG 1
Participant flowcharts for studies A and B. H1N1, A(H1N1)pdm09 vaccine. N, number of participants.
FIG 2
FIG 2
Age-stratified A(H1N1)pdm09-specific HI antibody responses. The GMTs (A), SCRs (B), and SPRs (C) with 95% CIs determined following vaccination with AS03-adjuvanted or nonadjuvanted A(H1N1)pdm09 (H1N1) vaccine containing 3.75 or 15 μg of HA are shown. Dotted lines represent the cutoffs of the CHMP criteria for HI antibody responses in adults 18 to 60 years of age with respect to the SCR (>40%) and SPR (>70%). The data for time zero (day 0) and days 21 and 42 supplement previously published data for the cohorts without age stratification (6). y, years.
FIG 3
FIG 3
A(H1N1)pdm09-specific HI antibody responses stratified by the participants' history of seasonal influenza vaccination. The graphs shown represent the GMTs (A, D), SCRs (B), and SPRs (C) with 95% CIs determined following vaccination with the AS03-adjuvanted or nonadjuvanted A(H1N1)pdm09 (H1N1) vaccine. Data are stratified by the participants' history of seasonal influenza vaccination (Flu/No flu). The GMTs in study A are also stratified by age (D). Dotted lines represent the cutoffs of the CHMP criteria for the HI antibody responses in adults 18 to 60 years of age with respect to the SCR (>40%) and SPR (>70%). Data for time zero (day 0) and days 21 and 42 were reported previously (6) and are shown here for completeness. y, years.
FIG 4
FIG 4
Age-stratified A(H1N1)pdm09-specific CD4+ T-cell responses. The graphs shown represent antigen-specific CD4+ T-cell responses induced by the AS03-adjuvanted or nonadjuvanted A(H1N1)pdm09 (H1N1) vaccine measured after stimulation with H1N1 split antigen (A) or the H1 pool of peptides (B). Data are reported as percentages of A(H1N1)pdm09-specific CD4+ T cells expressing at least two immune markers (IFN-γ, IL-2, TNF-α, or CD40L). Data for time zero (D0), day 21 (D21), and day 42 (D42) in study A supplement previously published data for the cohorts without age stratification (6). y, years. M, month. Q1 and Q3, first and third quartiles. Min and Max, minimum and maximum values.
FIG 5
FIG 5
A(H1N1)pdm09-specific CD4+ T-cell responses stratified by the participants' history of seasonal influenza vaccination and age. The graphs shown represent antigen-specific CD4+ T-cell responses induced by the AS03-adjuvanted or nonadjuvanted A(H1N1)pdm09 (H1N1) vaccine measured after stimulation with H1N1 split antigen (A and B) or the H1 pool of peptides (C). Data are stratified by the participants' history of seasonal influenza vaccination (Flu/No flu; panels A to C) and by age (panel B; study A only) and reported as percentages of A(H1N1)pdm09-specific CD4+ T cells expressing at least two immune markers (IFN-γ, IL-2, TNF-α, or CD40L). Data for time zero (D0), day 21 (D21), and day 42 (D42) in study A supplement previously published data for the cohorts without stratification for seasonal influenza vaccination history (6). y, years. M, month. Q1 and Q3, first and third quartiles. Min and Max, minimum and maximum values.
FIG 6
FIG 6
A(H1N1)pdm09-specific CD8+ T-cell responses in study B. The graphs shown represent antigen-specific CD8+ T-cell responses induced by the AS03-adjuvanted or nonadjuvanted A(H1N1)pdm09 (H1N1) vaccine measured after stimulation with H1N1 split antigen. Data are stratified either by age (A) or by the participants' history of seasonal influenza vaccination (Flu/No flu; B) and reported as percentages of A(H1N1)pdm09-specific CD8+ T cells expressing at least two immune markers (IFN-γ, IL-2, TNF-α, or CD40L). y, years. M, month. Q1 and Q3, first and third quartiles. Min and Max, minimum and maximum values.
FIG 7
FIG 7
A(H1N1)pdm09-specific memory B-cell responses in study B. The graphs shown represent the frequencies of antigen-specific memory B cells in the total number of IgG-producing memory B cells induced by the AS03-adjuvanted or nonadjuvanted A(H1N1)pdm09 (H1N1) vaccine. The data are stratified either by age (A) or by the participants' history of seasonal influenza vaccination (Flu/No flu; B), y, years. M, month. Q1 and Q3, first and third quartiles. Min and Max, minimum and maximum values.

References

    1. Huijskens E, Rossen J, Mulder P, van Beek R, van Vugt H, Verbakel J, Rimmelzwaan G, Koopmans M, Peeters M. 2011. Immunogenicity, boostability, and sustainability of the immune response after vaccination against influenza A virus (H1N1) 2009 in a healthy population. Clin Vaccine Immunol 18:1401–1405. doi:10.1128/CVI.05046-11.
    1. Nolan T, McVernon J, Skeljo M, Richmond P, Wadia U, Lambert S, Nissen M, Marshall H, Booy R, Heron L, Hartel G, Lai M, Basser R, Gittleson C, Greenberg M. 2010. Immunogenicity of a monovalent 2009 influenza A(H1N1) vaccine in infants and children: a randomized trial. JAMA 303:37–46. doi:10.1001/jama.2009.1911.
    1. Roman F, Vaman T, Kafeja F, Hanon E, Van Damme P. 2010. AS03A-adjuvanted influenza A (H1N1) 2009 vaccine for adults up to 85 years of age. Clin Infect Dis 51:668–677. doi:10.1086/655830.
    1. Morel S, Didierlaurent A, Bourguignon P, Delhaye S, Baras B, Jacob V, Planty C, Elouahabi A, Harvengt P, Carlsen H, Kielland A, Chomez P, Garçon N, Van Mechelen M. 2011. Adjuvant system AS03 containing α-tocopherol modulates innate immune response and leads to improved adaptive immunity. Vaccine 29:2461–2473. doi:10.1016/j.vaccine.2011.01.011.
    1. Peeters M, Regner S, Vaman T, Devaster JM, Rombo L. 2012. Safety and immunogenicity of an AS03-adjuvanted A(H1N1)pmd09 vaccine administered simultaneously or sequentially with a seasonal trivalent vaccine in adults 61 years or older: data from two multicentre randomised trials. Vaccine 30:6483–6491. doi:10.1016/j.vaccine.2012.07.081.
    1. Roman F, Clément F, Dewé W, Walravens K, Maes C, Willekens J, De Boever F, Hanon E, Leroux-Roels G. 2011. 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 18:835–843. doi:10.1128/CVI.00480-10.
    1. Vesikari T, Richardus JH, Berglund J, Korhonen T, Flodmark CE, Lindstrand A, Silfverdal SA, Bambure V, Caplanusi A, Dieussaert I, Roy-Ghanta S, Vaughn DW. 2015. Immunogenicity and safety of a trivalent inactivated influenza vaccine in children 6 months to 17 years of age, previously vaccinated with an AS03-adjuvanted A(H1N1)pdm09 vaccine: two open-label, randomized trials. Pediatr Infect Dis J 34:774–782. doi:10.1097/INF.0000000000000709.
    1. Furman D, Jojic V, Kidd B, Shen-Orr S, Price J, Jarrell J, Tse T, Huang H, Lund P, Maecker HT, Utz PJ, Dekker CL, Koller D, Davis MM. 2013. Apoptosis and other immune biomarkers predict influenza vaccine responsiveness. Mol Syst Biol 9:659. doi:10.1038/msb.2013.15.
    1. van der Most RG, Roman FP, Innis B, Hanon E, Vaughn DW, Gillard P, Walravens K, Wettendorff M. 2014. Seeking help: B cells adapting to flu variability. Sci Transl Med 6:246ps8. doi:10.1126/scitranslmed.3008409.
    1. Yang WH, Dionne M, Kyle M, Aggarwal N, Li P, Madariaga M, Godeaux O, Vaughn DW. 2013. Long-term immunogenicity of an AS03-adjuvanted influenza A(H1N1)pdm09 vaccine in young and elderly adults: an observer-blind, randomized trial. Vaccine 31:4389–4397. doi:10.1016/j.vaccine.2013.07.007.
    1. Wu J, Zhong X, Li CK, Zhou JF, Lu M, Huang KY, Dong M, Liu Y, Luo F-J, Du N, Chui C, Liu LQ, Smith NM, Li B, Shi NM, Song LF, Gao Y, Wang DY, Wang X, Zhu WF, Yan Y, Li Z, Chen JT, McMichael AJ, Yin WD, Xu XN, Shu Y. 2011. Optimal vaccination strategies for 2009 pandemic H1N1 and seasonal influenza vaccines in humans. Vaccine 29:1009–1016. doi:10.1016/j.vaccine.2010.11.058.
    1. European Medicines Agency Committee for Human Medicinal Products. 2007. Guideline on influenza vaccines 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 Medicines Agency, London, United Kingdom: .
    1. Nicholson KG, Abrams KR, Batham S, Clark TW, Hoschler K, Lim WS, Medina MJ, Nguyen-Van-Tam JS, Read RC, Warren FC, Zambon M. 2011. 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 11:91–101. doi:10.1016/S1473-3099(10)70296-6.
    1. Langley JM, Frenette L, Chu L, McNeil S, Halperin S, Li P, Vaughn D. 2012. A randomized, controlled non-inferiority trial comparing A(H1N1)pmd09 vaccine antigen, with and without AS03 adjuvant system, co-administered or sequentially administered with an inactivated trivalent seasonal influenza vaccine. BMC Infect Dis 12:279. doi:10.1186/1471-2334-12-279.
    1. Jackson LA, Chen WH, Stapleton JT, Dekker CL, Wald A, Brady RC, Edupuganti S, Winokur P, Mulligan MJ, Keyserling HL, Kotloff KL, Rouphael N, Noah DL, Hill H, Wolff MC. 2012. 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 206:811–820. doi:10.1093/infdis/jis427.
    1. Ohfuji S, Fukushima W, Deguchi M, Kawabata K, Yoshida H, Hatayama H, Maeda A, Hirota Y. 2011. Immunogenicity of a monovalent 2009 influenza A (H1N1) vaccine among pregnant women: lowered antibody response by prior seasonal vaccination. J Infect Dis 203:1301–1308. doi:10.1093/infdis/jir026.
    1. Andrews NJ, Walker WT, Finn A, Heath PT, Collinson AC, Pollard AJ, Snape MD, Faust SN, Waight PA, Hoschler K, Sheasby L, Waddington C, Kerridge S, Chalk J, Reiner A, John T, Fletcher M, Allen R, Fineman N, Wilkins S, Casey M, Michaelis L, Oeser C, Okike I, Ladhani S, Miller E. 2011. Predictors of immune response and reactogenicity to AS03B-adjuvanted split virion and non-adjuvanted whole virion H1N1 (2009) pandemic influenza vaccines. Vaccine 29:7913–7919. doi:10.1016/j.vaccine.2011.08.076.
    1. Choi YS, Baek YH, Kang W, Nam SJ, Lee J, You S, Chang DY, Youn JC, Choi YK, Shin EC. 2011. Reduced antibody responses to the pandemic (H1N1) 2009 vaccine after recent seasonal influenza vaccination. Clin Vaccine Immunol 18:1519–1523. doi:10.1128/CVI.05053-11.
    1. Plennevaux E, Sheldon E, Blatter M, Reeves-Hoché MK, Denis M. 2010. Immune response after a single vaccination against 2009 influenza A H1N1 in USA: a preliminary report of two randomised controlled phase 2 trials. Lancet 375:41–48. doi:10.1016/S0140-6736(09)62026-2.
    1. Uno S, Kimachi K, Kei J, Miyazaki K, Oohama A, Nishimura T, Ibaragi K, Odoh K, Kudo Y, Kino Y. 2011. Effect of prior vaccination with a seasonal trivalent influenza vaccine on the antibody response to the influenza pandemic H1N1 2009 vaccine: a randomized controlled trial. Microbiol Immunol 55:783–789. doi:10.1111/j.1348-0421.2011.00381.x.
    1. Van Damme P, Kafeja F, Bambure V, Hanon E, Moris P, Roman F, Gillard P. 2013. 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 9:1512–1522. doi:10.4161/hv.24504.
    1. Roy-Ghanta S, van der Most R, Li P, Vaughn DW. 2014. Responses to A(H1N1)pdm09 influenza vaccines in participants previously vaccinated with seasonal influenza vaccine: a randomized, observer-blind, controlled study. J Infect Dis 210:1419–1430. doi:10.1093/infdis/jiu284.
    1. Kim JH, Skountzou I, Compans R, Jacob J. 2009. Original antigenic sin responses to influenza viruses. J Immunol 183:3294–3301. doi:10.4049/jimmunol.0900398.
    1. Kim JH, Davis WG, Sambhara S, Jacob J. 2012. Strategies to alleviate original antigenic sin responses to influenza viruses. Proc Natl Acad Sci U S A 109:13751–13756. doi:10.1073/pnas.0912458109.
    1. Ndifon W. 2015. A simple mechanistic explanation for original antigenic sin and its alleviation by adjuvants. J R Soc Interface 12:20150627. doi:10.1098/rsif.2015.0627.
    1. Roman F, Vaman T, Gerlach B, Markendorf A, Gillard P, Devaster JM. 2010. 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 28:1740–1745. doi:10.1016/j.vaccine.2009.12.014.
    1. Greenberg ME, Lai MH, Hartel GF, Wichems CH, Gittleson C, Bennet J, Dawson G, Hu W, Leggio C, Washington D, Basser RL. 2009. Response to a monovalent 2009 influenza A (H1N1) vaccine. N Engl J Med 361:2405–2413. doi:10.1056/NEJMoa0907413.
    1. Ikematsu H, Nagai H, Kawashima M, Kawakami Y, Tenjinbaru K, Maeda A, Li P, Gillard P, Roman F. 2010. Immunogenicity and safety of a novel AS03A-adjuvanted H1N1 2009 pandemic influenza vaccine in adults in Japan. Hum Vaccin 6:888–893. doi:10.4161/hv.6.11.12851.
    1. Sobolev O, Binda E, O'Farrell S, Lorenc A, Pradines J, Huang Y, Duffner J, Schulz R, Cason J, Zambon M, Malim MH, Peakman M, Cope A, Capila I, Kaundinya GV, Hayday AC. 2016. Adjuvanted influenza-H1N1 vaccination reveals lymphoid signatures of age-dependent early responses and of clinical adverse events. Nat Immunol 17:204–213. doi:10.1038/ni.3328.
    1. Ferguson M, Risi G, Davis M, Sheldon E, Baron M, Li P, Madariaga M, Fries L, Godeaux O, Vaughn D. 2012. 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 205:733–744. doi:10.1093/infdis/jir641.
    1. Khurana S, Chearwae W, Castellino F, Manischewitz J, King LR, Honorkiewicz A, Rock MT, Edwards KM, Del Giudice G, Rappuoli R, Golding H. 2010. Vaccines with MF59 adjuvant expand the antibody repertoire to target protective sites of pandemic avian H5N1 influenza virus. Sci Transl Med 2:15ra5. doi:10.1126/scitranslmed.3000624.
    1. Khurana S, Verma N, Yewdell JW, Hilbert AK, Castellino F, Lattanzi M, Del Giudice G, Rappuoli R, Golding H. 2011. MF59 adjuvant enhances diversity and affinity of antibody-mediated immune response to pandemic influenza vaccines. Sci Transl Med 3:85ra48. doi:10.1126/scitranslmed.3002336.
    1. Kumar R, Burns EA. 2008. Age-related decline in immunity: implications for vaccine responsiveness. Expert Rev Vaccines 7:467–479. doi:10.1586/14760584.7.4.467.
    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. 2009. Cross-reactive antibody responses to the 2009 pandemic H1N1 influenza virus. N Engl J Med 361:1945–1952. doi:10.1056/NEJMoa0906453.
    1. He XS, Holmes TH, Zhang C, Mahmood K, Kemble GW, Lewis DB, Dekker CL, Greenberg HB, Arvin AM. 2006. Cellular immune responses in children and adults receiving inactivated or live attenuated influenza vaccines. J Virol 80:11756–11766. doi:10.1128/JVI.01460-06.
    1. Furman D, Hejblum BP, Simon N, Jojic V, Dekker CL, Thiébaut R, Tibshirani RJ, Davis MM. 2014. Systems analysis of sex differences reveals an immunosuppressive role for testosterone in the response to influenza vaccination. Proc Natl Acad Sci U S A 111:869–874. doi:10.1073/pnas.1321060111.
    1. Klein SL, Pekosz A. 2014. Sex-based biology and the rational design of influenza vaccination strategies. J Infect Dis 209(Suppl 3):S114–S119. doi:10.1093/infdis/jiu066.
    1. Klein SL, Flanagan KL. 2016. Sex differences in immune responses. Nat Rev Immunol 16:626–638. doi:10.1038/nri.2016.90.
    1. Bollaerts K, Shinde V, Dos Santos G, Ferreira G, Bauchau V, Cohet C, Verstraeten T. 2016. Application of probabilistic multiple-bias analyses to a cohort- and a case-control study on the association between Pandemrix™ and narcolepsy. PLoS One 11:e0149289. doi:10.1371/journal.pone.0149289.
    1. Sturkenboom MC. 2015. The narcolepsy-pandemic influenza story: can the truth ever be unraveled? Vaccine 33(Suppl 2):B6–B13. doi:10.1016/j.vaccine.2015.03.026.
    1. European Centre for Disease Prevention and Control. 2012. Narcolepsy in association with pandemic influenza vaccination—a multi-country European epidemiological investigation. ECDC, Stockholm, Sweden: .
    1. Barker CI, Snape MD. 2014. Pandemic influenza A H1N1 vaccines and narcolepsy: vaccine safety surveillance in action. Lancet Infect Dis 14:227–238. doi:10.1016/S1473-3099(13)70238-X.
    1. European Medicines Agency. 2015. Pandemrix—European public assessment report (EPAR) EMA/691037/2013. Annex I: summary of product characteristics. Accessed 2 October 2016.
    1. Hehme NW, Künzel W, Petschke F, Türk G, Raderecht C, van Hoecke C, Sänger R. 2002. Ten years of experience with the trivalent split-influenza vaccine, Fluarix™. Clin Drug Investig 22:751–769. doi:10.2165/00044011-200222110-00004.
    1. Crotty S, Aubert RD, Glidewell J, Ahmed R. 2004. Tracking human antigen-specific memory B cells: a sensitive and generalized ELISPOT system. J Immunol Methods 286:111–122. doi:10.1016/j.jim.2003.12.015.
    1. Moris P, van der Most R, Leroux-Roels I, Clement F, Dramé M, Hanon E, Leroux-Roels GG, Van Mechelen M. 2011. H5N1 influenza vaccine formulated with AS03A induces strong cross-reactive and polyfunctional CD4 T-cell responses. J Clin Immunol 31:443–454. doi:10.1007/s10875-010-9490-6.

Source: PubMed

Sponsors and Collaborators

Medical Conditions

Drug Interventions

3
Subscribe