Noncontrolled Trial of Monovalent AS03A-Adjuvanted Vaccine for 2009 Pandemic Influenza A(H1N1) in Long-term Dialysis Patients and Transplant Recipients

Abstract

Vaccination is an important means to reduce the risk of influenza infection. Vaccination strategies against 2009 pandemic influenza A(H1N1) include widely used adjuvanted monovalent influenza vaccines.1Morel S. Didierlaurent A. Bourguignon P. et al.Adjuvant system AS03 containing α-tocopherol modulates innate immune response and leads to improved adaptive immunity.Vaccine. 2011; 29: 2461-2473Crossref PubMed Scopus (320) Google Scholar This report summarizes the efficacy and safety of an AS03A-adjuvanted H1N1 vaccine in patients with end-stage renal disease with and without kidney transplant.Between November 2009 and February 2010, we inoculated 57 transplant recipients at least 3 months after kidney transplant, 101 dialysis patients, and 43 healthy controls (Table 1). Approval of the institutional review board and informed consent from all participants were obtained. Each participant was vaccinated with the adjuvanted monovalent split-virus inactivated vaccine against influenza H1N1 (2009) virus (Pandemrix; GlaxoSmithKline, www.gsk.com). Virion neutralizing antibody titers were determined with a colorimetric microneutralization assay before vaccination and 3 and 24 weeks after vaccination.2Grund S. Adams O. Wählisch S. Schweiger B. Comparison of hemagglutination inhibition assay, an ELISA-based micro-neutralization assay and colorimetric microneutralization assay to detect antibody responses to vaccination against influenza A H1N1 2009 virus.J Virol Methods. 2011; 171: 369-373Crossref PubMed Scopus (46) Google Scholar Seroprotection was defined as an antibody titer of 1:160 or higher, and seroconversion, as a 2-fold increase in titer from baseline in addition to an antibody titer of 1:160 or higher 3 weeks after vaccination.Table 1Baseline CharacteristicsTransplant Recipients (n = 57)Dialysis Patients (n = 101)Healthy Controls (n = 43)Age (y)53 (23-73)71 (25-93)33 (23-62)Sex Women14 (24.6)43 (42.6)31 (72.1) Men43 (75.4)58 (57.4)12 (27.9)Race White56 (98.2)98 (97.0)43 (100) Black1 (1.8)3 (3.0)0 (0)Type of transplant Deceased41 (71.9)—— Living16 (20.1)——Time since transplant (mo)63 (4-267)——Dialysis vintage (mo)—45.6 (1-190)—Cause of kidney failure Glomerulonephritis21 (36.8)10 (9.9)— Polycystic kidney disease13 (22.8)6 (5.9)— Unknown12 (21.1)21 (20.8)— Vascular nephropathy4 (7.0)29 (28.7)— Interstitial nephritis/reflux3 (5.3)6 (5.9)— Alport syndrome/systemic disease3 (5.3)3 (3.0)— Diabetes mellitus1 (1.8)26 (25.7)—Kidney function Serum creatinine (mg/dL)1.81 ± 0.7—— eGFR (mL/min/1.73 m2)42.3 ± 15.1——Dialysis data No. of sessions/wk—3 ± 0.5— Session length (h)—4.27 ± 0.3— Kt/V—1.3 ± 0.3— No. of immunosuppressive medications2.4 ± 0.5——Note: Continuous values given as mean ± standard deviation or median (range); categorical variables as number (percentage). Conversion factor for serum creatinine in mg/dL to μmol/L, ×88.4.Abbreviation: eGFR, MDRD (Modification of Diet in Renal Disease)–estimated glomerular filtration rate. Open table in a new tab Of 57 transplant recipients, 37 (64.9%) showed seroprotection 3 weeks after vaccination. Nine patients (15.8%) had an antibody titer of 1:160 or higher even before vaccination; seroconversion occurred in 30 patients (52.6%). Antibody titers for H1N1 increased significantly 3 weeks postvaccination (Table 2; Fig S1, available as online supplementary material). After 6 months, the seroprotection rate was 70.0%. Fifteen transplant recipients who remained seronegative received a second vaccination; of these, 10 (66.7%) showed seroprotection 3 weeks later. The retrospective analysis of antibody titers before the second vaccination showed that 7 of these 10 patients had achieved seroprotection in the meantime (between 3 weeks and 6 months after the first vaccination). Kidney transplant function remained stable (serum creatinine levels, 1.81 ± 0.69 mg/dL [160 ± 61 μmol/L] prevaccination and 1.76 ± 0.65 mg/dL [155.58 ± 57.46 μmol/L] postvaccination; P = 0.1). There was no episode of transplant rejection or other severe side effects. Patients using mycophenolate mofetil (MMF) had significantly lower seroprotection and seroconversion rates than patients without MMF (48.4% vs 84.6% [P = 0.003] and 38.7% vs 69.2% [P = 0.02], respectively). We did not see significant differences in clinical characteristics between patients with and without seroprotection and seroconversion.Table 2Antibody Titers, Seroprotection Rates, and Seroconversion RatesTransplant RecipientsDialysis PatientsHealthy ControlsAllSerostatus at ImmunizationAllSerostatus at ImmunizationAllSerostatus at Immunization+dAntibody titer ≥1:160 at the time of immunization;−eAntibody titer <1:160 at the time of immunization.+dAntibody titer ≥1:160 at the time of immunization;−eAntibody titer <1:160 at the time of immunization.+dAntibody titer ≥1:160 at the time of immunization;−eAntibody titer <1:160 at the time of immunization.No. of patients57948101376443241Antibody titeraUnless otherwise indicated, geometric mean antibody titer is shown, with 95% confidence interval in parentheses, if available; Day 047.4 (36.1-62.3)274.4 (130.5-576.8)34.1 (28.4-41.0)82.2 (65.2-103.8)265.4 (217.1-324.5)41.8 (33.8-51.7)26.7 (21.6-33.1)160bMean;24.5 (20.4-29.5) Day 21182.9 (120.4-277.8)548.7 (274.2-1098.2)148.9 (93.7-236.5)275.9 (215.3-353.6)483.4 (330.8-706.2)228.8 (163.7-319.8)358.3 (248.3-517.0)1,810.2bMean;331.1 (229.6-477.4) Week 24274.7 (191.1-395.1)254.0 (65.6-984.3)277.6 (187.5-411.0)NANANA447.2 (297.3-672.8)452.6bMean;446.6 (291.6-684.0) Week 27167.6 (112.7-249.2)NA167.6 (112.7-249.2)NANANANANANASeroprotection ratecValues in parentheses are percentages; Day 09/57 (15.8)9/9 (100)0/48 (0)37/101(36.6)37/37 (100)0/64 (0)2/43 (4.7)2/2 (100)0/41 (0) Day 2137/57 (64.9)9/9 (100)28/48 (58.3)83/101 (82.2)35/37 (94.6)48/64 (75.0)35/43 (81.4)2/2 (100)33/41 (80.5) Week 2435/50 (70.0)4/6 (67.7)31/44 (70.5)NANANA26/29 (89.7)2/2 (100)24/27 (88.9) Week 2710/15 (66.7)NA10/15 (66.7)NANANANANANASeroconversion rate on day 21cValues in parentheses are percentages;30/57 (52.6)3/9 (33.3)27/48 (56.3)43/101 (42.6)9/37 (24.3)34/64 (53.1)35/43 (81.4)2/2 (100)33/41 (80.5)Abbreviation: NA, not available.a Unless otherwise indicated, geometric mean antibody titer is shown, with 95% confidence interval in parentheses, if available;b Mean;c Values in parentheses are percentages;d Antibody titer ≥1:160 at the time of immunization;e Antibody titer <1:160 at the time of immunization. Open table in a new tab Of 101 dialysis patients, 82.2% showed seroprotection 3 weeks postvaccination. However, a high proportion (36.6%) showed seroprotection before vaccination; the seroconversion rate of this group was 42.6% (Table 2). No severe side effects were recorded.Our analysis of the efficacy of H1N1 vaccination in patients with end-stage renal disease with and without kidney transplant showed an impaired vaccination response compared with healthy controls, but the seroprotection rate in our transplant recipients is similar to the findings with nonadjuvanted vaccines reported by other groups.3Salles M.J.C. Sens Y.A.S. Boas L.S.V. Machado C.M. Influenza virus vaccination in kidney transplant recipients: serum antibody response to different immunosuppressive drugs.Clin Transplant. 2010; 24: E17-E23Crossref PubMed Scopus (70) Google Scholar, 4Birdwell K.A. Ikizler M.R. Sannella E.C. et al.Decreased antibody response to influenza vaccination in kidney transplant recipients: a prospective cohort study.Am J Kidney Dis. 2009; 54: 112-121Abstract Full Text Full Text PDF PubMed Scopus (92) Google Scholar Therefore, our data provide proof of principle that even in immunocompromised patients, a reduction of the antigen dose is possible with an AS03A-adjuvanted vaccine. The relatively high seroprotection rate in our dialysis patients (82.2%) 3 weeks after vaccination might be attributed to the higher seroprotection rate at baseline (36.6%). This could be due to the older age of this cohort (median age, 71 vs 53 years for transplant recipients), which has been shown to be associated with higher prevaccination titers.5Hancock K. Veguilla V. Lu X. et al.Cross-reactive antibody responses to the 2009 pandemic H1N1 influenza virus.N Engl J Med. 2009; 361: 1945-1952Crossref PubMed Scopus (1092) Google Scholar There is ongoing discussion about the role of MMF in the impairment of the humoral response after vaccination.6Candon S. Thervet E. Lebon P. et al.Humoral and cellular immune responses after influenza vaccination in kidney transplant recipients.Am J Transplant. 2009; 9: 2346-2354Crossref PubMed Scopus (93) Google Scholar, 7Smith K.G. Isbel N.M. Catton M.G. Leydon J.A. Becker G.J. Walker R.G. Suppression of the humoral immune response by mycophenolate mofetil.Nephrol Dial Transplant. 1998; 13: 160-164Crossref PubMed Scopus (158) Google Scholar, 8Scharpé J. Evenepoel P. Maes B. et al.Influenza vaccination is efficacious and safe in renal transplant recipients.Am J Transplant. 2008; 8: 332-337Crossref PubMed Scopus (143) Google Scholar Our data indicate a negative impact of MMF on the vaccination response in transplant patients, with significantly lower seroprotection and seroconversion rates. Aside from this, no other confounding factors to the vaccination response were found in transplant recipients or dialysis patients.We found that the antibody titers obtained 3 weeks postvaccination were maintained at 6 months after vaccination in healthy controls and transplant recipients. An intriguing point is that 7 of 15 (43.8%) transplant recipients who did not show seroprotection 3 weeks after vaccination showed seroprotection 6 months postvaccination. This suggests that: (1) transplant patients should be vaccinated as soon as the vaccine is available because of a possibly delayed response to vaccination, and (2) studies assessing the efficacy of a vaccine that include immunosuppressed patients should extend the period of immune response measurement beyond 3 or 4 weeks postvaccination.In conclusion, our data suggest that H1N1 influenza vaccination in end-stage renal disease patients with and without kidney transplant is safe and well tolerated and suggest that transplant patients may have a delayed response to vaccination, which implies that they should be vaccinated as soon as the vaccine is available. Vaccination is an important means to reduce the risk of influenza infection. Vaccination strategies against 2009 pandemic influenza A(H1N1) include widely used adjuvanted monovalent influenza vaccines.1Morel S. Didierlaurent A. Bourguignon P. et al.Adjuvant system AS03 containing α-tocopherol modulates innate immune response and leads to improved adaptive immunity.Vaccine. 2011; 29: 2461-2473Crossref PubMed Scopus (320) Google Scholar This report summarizes the efficacy and safety of an AS03A-adjuvanted H1N1 vaccine in patients with end-stage renal disease with and without kidney transplant. Between November 2009 and February 2010, we inoculated 57 transplant recipients at least 3 months after kidney transplant, 101 dialysis patients, and 43 healthy controls (Table 1). Approval of the institutional review board and informed consent from all participants were obtained. Each participant was vaccinated with the adjuvanted monovalent split-virus inactivated vaccine against influenza H1N1 (2009) virus (Pandemrix; GlaxoSmithKline, www.gsk.com). Virion neutralizing antibody titers were determined with a colorimetric microneutralization assay before vaccination and 3 and 24 weeks after vaccination.2Grund S. Adams O. Wählisch S. Schweiger B. Comparison of hemagglutination inhibition assay, an ELISA-based micro-neutralization assay and colorimetric microneutralization assay to detect antibody responses to vaccination against influenza A H1N1 2009 virus.J Virol Methods. 2011; 171: 369-373Crossref PubMed Scopus (46) Google Scholar Seroprotection was defined as an antibody titer of 1:160 or higher, and seroconversion, as a 2-fold increase in titer from baseline in addition to an antibody titer of 1:160 or higher 3 weeks after vaccination. Note: Continuous values given as mean ± standard deviation or median (range); categorical variables as number (percentage). Conversion factor for serum creatinine in mg/dL to μmol/L, ×88.4. Abbreviation: eGFR, MDRD (Modification of Diet in Renal Disease)–estimated glomerular filtration rate. Of 57 transplant recipients, 37 (64.9%) showed seroprotection 3 weeks after vaccination. Nine patients (15.8%) had an antibody titer of 1:160 or higher even before vaccination; seroconversion occurred in 30 patients (52.6%). Antibody titers for H1N1 increased significantly 3 weeks postvaccination (Table 2; Fig S1, available as online supplementary material). After 6 months, the seroprotection rate was 70.0%. Fifteen transplant recipients who remained seronegative received a second vaccination; of these, 10 (66.7%) showed seroprotection 3 weeks later. The retrospective analysis of antibody titers before the second vaccination showed that 7 of these 10 patients had achieved seroprotection in the meantime (between 3 weeks and 6 months after the first vaccination). Kidney transplant function remained stable (serum creatinine levels, 1.81 ± 0.69 mg/dL [160 ± 61 μmol/L] prevaccination and 1.76 ± 0.65 mg/dL [155.58 ± 57.46 μmol/L] postvaccination; P = 0.1). There was no episode of transplant rejection or other severe side effects. Patients using mycophenolate mofetil (MMF) had significantly lower seroprotection and seroconversion rates than patients without MMF (48.4% vs 84.6% [P = 0.003] and 38.7% vs 69.2% [P = 0.02], respectively). We did not see significant differences in clinical characteristics between patients with and without seroprotection and seroconversion. Abbreviation: NA, not available. Of 101 dialysis patients, 82.2% showed seroprotection 3 weeks postvaccination. However, a high proportion (36.6%) showed seroprotection before vaccination; the seroconversion rate of this group was 42.6% (Table 2). No severe side effects were recorded. Our analysis of the efficacy of H1N1 vaccination in patients with end-stage renal disease with and without kidney transplant showed an impaired vaccination response compared with healthy controls, but the seroprotection rate in our transplant recipients is similar to the findings with nonadjuvanted vaccines reported by other groups.3Salles M.J.C. Sens Y.A.S. Boas L.S.V. Machado C.M. Influenza virus vaccination in kidney transplant recipients: serum antibody response to different immunosuppressive drugs.Clin Transplant. 2010; 24: E17-E23Crossref PubMed Scopus (70) Google Scholar, 4Birdwell K.A. Ikizler M.R. Sannella E.C. et al.Decreased antibody response to influenza vaccination in kidney transplant recipients: a prospective cohort study.Am J Kidney Dis. 2009; 54: 112-121Abstract Full Text Full Text PDF PubMed Scopus (92) Google Scholar Therefore, our data provide proof of principle that even in immunocompromised patients, a reduction of the antigen dose is possible with an AS03A-adjuvanted vaccine. The relatively high seroprotection rate in our dialysis patients (82.2%) 3 weeks after vaccination might be attributed to the higher seroprotection rate at baseline (36.6%). This could be due to the older age of this cohort (median age, 71 vs 53 years for transplant recipients), which has been shown to be associated with higher prevaccination titers.5Hancock K. Veguilla V. Lu X. et al.Cross-reactive antibody responses to the 2009 pandemic H1N1 influenza virus.N Engl J Med. 2009; 361: 1945-1952Crossref PubMed Scopus (1092) Google Scholar There is ongoing discussion about the role of MMF in the impairment of the humoral response after vaccination.6Candon S. Thervet E. Lebon P. et al.Humoral and cellular immune responses after influenza vaccination in kidney transplant recipients.Am J Transplant. 2009; 9: 2346-2354Crossref PubMed Scopus (93) Google Scholar, 7Smith K.G. Isbel N.M. Catton M.G. Leydon J.A. Becker G.J. Walker R.G. Suppression of the humoral immune response by mycophenolate mofetil.Nephrol Dial Transplant. 1998; 13: 160-164Crossref PubMed Scopus (158) Google Scholar, 8Scharpé J. Evenepoel P. Maes B. et al.Influenza vaccination is efficacious and safe in renal transplant recipients.Am J Transplant. 2008; 8: 332-337Crossref PubMed Scopus (143) Google Scholar Our data indicate a negative impact of MMF on the vaccination response in transplant patients, with significantly lower seroprotection and seroconversion rates. Aside from this, no other confounding factors to the vaccination response were found in transplant recipients or dialysis patients. We found that the antibody titers obtained 3 weeks postvaccination were maintained at 6 months after vaccination in healthy controls and transplant recipients. An intriguing point is that 7 of 15 (43.8%) transplant recipients who did not show seroprotection 3 weeks after vaccination showed seroprotection 6 months postvaccination. This suggests that: (1) transplant patients should be vaccinated as soon as the vaccine is available because of a possibly delayed response to vaccination, and (2) studies assessing the efficacy of a vaccine that include immunosuppressed patients should extend the period of immune response measurement beyond 3 or 4 weeks postvaccination. In conclusion, our data suggest that H1N1 influenza vaccination in end-stage renal disease patients with and without kidney transplant is safe and well tolerated and suggest that transplant patients may have a delayed response to vaccination, which implies that they should be vaccinated as soon as the vaccine is available. Support: None. Financial Disclosure: The authors declare that they have no relevant financial interests. Supplementary Material Download .pdf (.02 MB) Help with pdf files Supplementary Figure S1 (PDF)Geometric mean antibody titers in healthy controls, transplant recipients, and dialysis patients before and after vaccination. Download .pdf (.02 MB) Help with pdf files Supplementary Figure S1 (PDF)Geometric mean antibody titers in healthy controls, transplant recipients, and dialysis patients before and after vaccination.