Noncontrolled Trial of Monovalent AS03A-Adjuvanted Vaccine for 2009 Pandemic Influenza A(H1N1) in Long-term Dialysis Patients and Transplant Recipients
Article Outline
To the Editor:
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.1 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.2 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 1. Baseline Characteristics
| Transplant Recipients (n = 57) | Dialysis Patients (n = 101) | Healthy Controls (n = 43) | |
|---|---|---|---|
| Age (y) | 53 (23-73) | 71(25-93) | 33(23-62) |
| Sex | |||
| Women | 14(24.6) | 43(42.6) | 31(72.1) |
| Men | 43(75.4) | 58(57.4) | 12(27.9) |
| Race | |||
| White | 56(98.2) | 98(97.0) | 43(100) |
| Black | 1(1.8) | 3(3.0) | 0(0) |
| Type of transplant | |||
| Deceased | 41(71.9) | — | — |
| Living | 16(20.1) | — | — |
| Time since transplant (mo) | 63(4-267) | — | — |
| Dialysis vintage (mo) | — | 45.6(1-190) | — |
| Cause of kidney failure | |||
| Glomerulonephritis | 21(36.8) | 10(9.9) | — |
| Polycystic kidney disease | 13(22.8) | 6(5.9) | — |
| Unknown | 12(21.1) | 21(20.8) | — |
| Vascular nephropathy | 4(7.0) | 29(28.7) | — |
| Interstitial nephritis/reflux | 3(5.3) | 6(5.9) | — |
| Alport syndrome/systemic disease | 3(5.3) | 3(3.0) | — |
| Diabetes mellitus | 1(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 medications | 2.4±0.5 | — | — |
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 2. Antibody Titers, Seroprotection Rates, and Seroconversion Rates
| Transplant Recipients | Dialysis Patients | Healthy Controls | |||||||
|---|---|---|---|---|---|---|---|---|---|
| All | Serostatus at Immunization | All | Serostatus at Immunization | All | Serostatus at Immunization | ||||
| +d | −e | +d | −e | +d | −e | ||||
| No. of patients | 57 | 9 | 48 | 101 | 37 | 64 | 43 | 2 | 41 |
| Antibody titera | |||||||||
| Day 0 | 47.4(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) | 160b | 24.5(20.4-29.5) |
| Day 21 | 182.9(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) | 1,810.2b | 331.1(229.6-477.4) |
| Week 24 | 274.7(191.1-395.1) | 254.0(65.6-984.3) | 277.6(187.5-411.0) | NA | NA | NA | 447.2(297.3-672.8) | 452.6b | 446.6(291.6-684.0) |
| Week 27 | 167.6(112.7-249.2) | NA | 167.6(112.7-249.2) | NA | NA | NA | NA | NA | NA |
| Seroprotection ratec | |||||||||
| Day 0 | 9/57(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 21 | 37/57(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 24 | 35/50(70.0) | 4/6(67.7) | 31/44(70.5) | NA | NA | NA | 26/29(89.7) | 2/2(100) | 24/27(88.9) |
| Week 27 | 10/15(66.7) | NA | 10/15(66.7) | NA | NA | NA | NA | NA | NA |
| Seroconversion rate on day 21c | 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) |
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. |
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.3, 4 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.5 There is ongoing discussion about the role of MMF in the impairment of the humoral response after vaccination.6, 7, 8 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.
Acknowledgements
Support: None.
Financial Disclosure: The authors declare that they have no relevant financial interests.
Supplementary Material
Supplementary Figure S1 (PDF) Geometric mean antibody titers in healthy controls, transplant recipients, and dialysis patients before and after vaccination.
References
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- Decreased antibody response to influenza vaccination in kidney transplant recipients: a prospective cohort study . Am J Kidney Dis . 2009;54(1):112–121
- Cross-reactive antibody responses to the 2009 pandemic H1N1 influenza virus . N Engl J Med . 2009;361(20):1945–1952
- Humoral and cellular immune responses after influenza vaccination in kidney transplant recipients . Am J Transplant . 2009;9(10):2346–2354
- . Suppression of the humoral immune response by mycophenolate mofetil . Nephrol Dial Transplant . 1998;13(1):160–164
- Influenza vaccination is efficacious and safe in renal transplant recipients . Am J Transplant . 2008;8(2):332–337
Originally published online December 23, 2011.
PII: S0272-6386(11)01658-1
doi:10.1053/j.ajkd.2011.11.024
© 2012 National Kidney Foundation, Inc. Published by Elsevier Inc All rights reserved.
