Poor seroprotection but allosensitization after adjuvanted pandemic influenza h1n1 vaccine in kidney transplant recipients

Transplant Infectious Disease, ISSN 1398-2273 Poor seroprotection but allosensitization afteradjuvanted pandemic influenza H1N1 vaccine inkidney transplant recipients T. Fairhead, E. Hendren, K. Tinckam, C. Rose, C.H. Sherlock, L.
Shi, N.S. Crowcroft, J.B. Gubbay, D. Landsberg, G. Knoll, J. Gill, D.
Kumar. Poor seroprotection but allosensitization after adjuvanted pandemic influenza H1N1 vaccine in kidney transplant recipients.
Transpl Infect Dis 2012. All rights reserved D. Kumar61Ottawa Hospital Research Institute, University of Ottawa, Abstract: Background. Seasonal and pandemic influenza virus Ottawa, Ontario, Canada, 2Division of Nephrology, University infections in renal transplant patients are associated with poor of British Columbia, Vancouver, British Columbia, Canada, outcomes. During the pandemic of 2009–2010, the AS03-adjuvanted 3Laboratory Medicine Program and Division of Nephrology, monovalent H1N1 influenza vaccine was recommended for University Health Network, Toronto, Ontario, Canada, transplant recipients, although its immunogenicity in this population Departments of Pathology and Laboratory Medicine, was unknown. We sought to determine the safety and University of British Columbia and Providence Health Care,Vancouver, British Columbia, Canada, 5Public Health Ontario, immunogenicity of an adjuvant-containing vaccine against pandemic Toronto, Ontario, Canada, 6Alberta Institute for Transplant influenza A H1N1 2009 (pH1N1) administered to kidney transplant Sciences, University of Alberta, Edmonton, Alberta, Canada recipients.
Methods. We prospectively enrolled 124 adult kidney transplantrecipients in the fall of 2009 at two transplant centers. Cohort 1(n = 42) was assessed before and after pH1N1 immunization, whileCohort 2 (n = 82) was only assessed post immunization. Humoralresponse was measured by the hemagglutination inhibition assay.
Vaccine safety was assessed by adverse event reporting, graftfunction, and human leukocyte antigen (HLA) alloantibodymeasurements.
Results. Cohort 1 had a low rate of baseline seroprotection topH1N1 (7%) and a low rate of seroprotection after immunization(31%). No patient <6 months post transplant (n = 5) achieved Key words: Influenza; vaccination; kidneytransplantation; anti-HLA antibodies; H1N1 seroprotection. Seroprotection rate was greater in patients receivingdouble as compared with triple immunosuppression (80% vs. 24%, P = 0.01). In Cohort 2, post-immunization seroprotection was 35%.
Dr Todd Fairhead, MD, MSc, Kidney Research Institute, In both cohorts, no confirmed cases of pH1N1 infection occurred.
University of Ottawa, Room 2517, 451 Smyth Road, No difference was seen in estimated glomerular filtration rate before (54.3 mL/min/1.73 m2) and after (53.8 mL/min/1.73 m2) immunization, and no acute rejections had occurred after immunization at last follow-up. In Cohort 1, 11.9% of patients developed new anti-HLA antibodies.
Conclusion. An adjuvant-containing vaccine to pH1N1 provided poorseroprotection in renal transplant recipients. Receiving triple Received 17 January 2012, revised 20 April 2012, immunosuppression was associated with a poor seroresponse.
21 June 2012, accepted for publication 4 July 2012 Vaccination appeared safe, but some patients developed new anti-HLA antibodies post vaccination. Alternative strategies to improve Transplantation is the treatment of choice for end-stage a higher morbidity and mortality compared with the kidney disease, but infections continue to be a leading general population (1). There is also a reported complication after solid organ transplantation. In increased incidence of allograft rejection during or kidney transplant patients, influenza is associated with after influenza infection (2, 3). Thus, strategies to Fairhead et al: H1N1 vaccination in kidney transplantation prevent seasonal influenza infection in kidney trans- study the safety and immunogenicity of an adjuvant- containing vaccine against pH1N1. The study was The American Society of Transplantation (AST) approved by the research ethics board of each institution.
recommends seasonal influenza vaccination for renal Informed consent was obtained from all participants.
transplant recipients; however, there are conflictingdata regarding its immunogenicity (4). In transplantrecipients, influenza vaccine seroresponse appears to be lower than that seen in the general population, butprevious studies are confounded by small study size, All renal transplant recipients were encouraged to a high baseline rate of seroprotection, and use of receive immunization with the inactivated pH1N1 historical immunosuppression regimens (5–7). A vaccine in addition to the seasonal influenza vaccine theoretical concern also exists about possible sensi- as per the AST/Transplantation Society guidance on tization and graft rejection after vaccination, either novel influenza A/H1N1 (13). Patients were recruited caused by non-specific immune activation or by between October 2009 and January 2010. Patients induction of cross-reactivity to transplant antigens were eligible for enrollment if they (i) were  18 (8). In North America, physicians have avoided the years of age, (ii) were >1 month from the time of use of novel adjuvant-containing vaccines in kidney transplant, (iii) had stable renal function (<20% transplant recipients because of this perceived risk variability between last 2 creatinine measurements), and (iv) had chosen to receive the pH1N1 influenza A new reassortant influenza A/H1N1 strain emerged vaccine. Patients were excluded if they were (i) in Mexico during the spring of 2009 and rapidly spread ineligible to receive the vaccine, (ii) were being to the rest of North America and rest of the world.
treated for an active infection or rejection, (iii) were Minimal pre-existing seroprotection to pandemic influ- undergoing active treatment for malignancy, or (iv) enza A H1N1 2009 (pH1N1) was present in the general had a known allergic reaction to eggs or to prior population, and pregnant women and immunosup- pressed individuals (including transplant recipients) All enrolled patients received a single dose (0.5 mL) were identified at particular risk for development of severe disease after exposure to this novel influenza Ontario, Canada) intramuscularly. The vaccine con- variant (11, 12). Canadian public health authorities set tained the ASO3 adjuvant consisting of DL-a-tocopherol out a broad immunization campaign targeting at-risk 11.86 mg, squalene 10.69 mg, and polysorbate-80 populations in Canada in the fall of 2009 using an 4.86 mg in addition to 3.75 lg of hemagglutinin derived adjuvant-containing pH1N1 influenza vaccine. This from A/California/7/2009 (pH1N1) strain. The vaccine unique situation allowed for the study of influenza contained 5 lg of thimerosol preservative.
vaccine efficacy in kidney transplant recipients under Enrolled patients were divided into 2 cohorts.
conditions of low baseline seroprotection and for the Patients in Cohort 1 were recruited at the Ottawa study of the safety of an adjuvant-containing vaccine.
Hospital Renal Transplant program. Pre-vaccination We sought to determine the safety and immunoge- sera were collected within 7 days before immuniza- nicity of an adjuvant-containing vaccine against pH1N1 in a renal transplant population. This dual center 30–45 days after vaccination. At the same time, observational study examined 2 cohorts of patients.
patients also completed a questionnaire regarding Cohort 1 was designed to test humoral response to adverse affects of vaccination and the presence of vaccine, while Cohort 2 examined prevalent seropro- infectious symptoms post vaccination. Patients were tection. Cohort 1 provided information about vaccine followed for 6 months post vaccination for the devel- opment of influenza infection and adverse events.
Patients in Cohort 2 were recruited from both sites.
Only post-vaccination sera were available from these We conducted a prospective cohort study of adultkidney transplant recipients followed by the Ottawa Hospital Renal Transplant Program (Ottawa, Ontario,Canada) and the St. Paul’s Hospital Renal Transplant Antibody titers against pH1N1 were determined using Program (Vancouver, British Columbia, Canada) to the hemagglutination inhibition assay as reported Transplant Infectious Disease 2012: 0: 1–9 Fairhead et al: H1N1 vaccination in kidney transplantation previously (14). Samples from Cohort 1 were tested against pH1N1 influenza A/H1N1/California/07/2009and A/Brisbane/59/07 for potential cross-reactivity at thePublic Health Ontario Laboratory, Toronto, ON, Cohorts 1 and 2 consisted of 42 and 82 patients, Canada. Samples from Cohort 2 were tested against respectively. Patient characteristics are reported in H1N1 influenza A/H1N1/California/07/2009 at the Table 1. Both groups were similar in characteristics with respect to age, gender, cause of underlying renal Vancouver, BC, Canada. There was good agreement disease, time from transplantation, and baseline renal for seropositivity between these laboratories (data function (Table 1). Subtle differences existed between not shown). Antibody titers of  1:40 were consid- Cohort 1 and Cohort 2. Cohort 2 contained a higher ered seroprotective and a 4-fold or greater increase percentage of non-Caucasian participants (41% vs. 7%) in antibody titers from baseline was considered as an appropriate seroconversion response (15). Kid- immunosuppressive therapy (45% vs. 12%). The ney function was reported as serum creatinine in variation in immunosuppression reflects differences in clinical practice between the two participating Modification of Diet in Renal Disease (MDRD)equation (16).
Detection of anti-human leukocyte antigen (HLA) antibodies was done on the LuminexTM platform forthose who had both pre- and post-vaccination serum In Cohort 1, baseline seroprotection against pH1N1 samples (Cohort 1 only). Antibody screening utilized was low at 3/42 (7%) patients (Table 2), Post vaccina- the Lifecodes Class I and II ID Bead Assay (Gen- tion, 13/42 (31%) achieved a seroprotective titer and Probe Inc, Stamford, Connecticut, USA) in accor- 12/42 (29%) met the criteria for seroconversion. In dance with the manufacturer recommended method.
Cohort 2, only post-vaccination serology was done.
With valid results for positive and negative control Similar seroprotection rates of 29/82 (35%) were beads, the assay was considered positive if one or reached. Combining Cohorts 1 and 2, 42/124 (34%) more beads had mean fluorescence intensity of achieved seroprotection. No patient had cross-reactive  600. All sera that screened positive were subse- antibody to influenza A/Brisbane. Post vaccination, no quently tested with LabScreen Single Antigen Class I and II Beads (One Lambda, Canoga Park, California, occurred, nor was oseltamivir prescribed in either USA) as necessary, in accordance with the manufac- turer recommended method. Based on the labora- Age and baseline GFR were not predictive of tory’s internal validation data, a test bead was seroconversion after vaccination. In Cohort 1, patients considered positive for HLA antibody if the positive receiving triple-drug immunosuppression had a lower and negative control beads were valid, and the test seroconversion rate than patients receiving double- bead normalized mean fluorescence intensity was drug immunosuppression (8/37 vs. 4/5; P = 0.01,  1000. Donor-specific antibody (DSA) was classified Table 3A). The ability to mount an antibody response if the antibody identified was specific to the donor was not influenced by newer immunosuppressive HLA A, B, C, DRB1, DQB1 typing, as determined at agents including tacrolimus, mycophenolic acid, or sirolimus. Although not statistically significant, it isimportant to note that no patient in Cohort 1,vaccinated within 6 months of receiving a kidney transplant, achieved seroprotection against pH1N1influenza.
Baseline categorical variables were summarized with When Cohorts 1 and 2 were combined, age, lower 2-proportions testing using the Fisher exact test.
renal function, new immunosuppressive agents, or Continuous baseline variables were evaluated for normality and were summarized using the Student prevalence of seroprotection against pH1N1 influenza t-test. Statistical analysis was performed using Graph- (Table 3B). Fewer patients within 6 months of pad Prism statistical software, version 5.02 (GraphPad transplant achieved protective pH1N1 antibody titers; Software, La Jolla, California, USA).
however, this did not reach statistical significance.
Transplant Infectious Disease 2012: 0: 1–9 Fairhead et al: H1N1 vaccination in kidney transplantation Patient characteristics of Cohort 1 and 2 Values expressed as number (percent).
The ArepanrixTM vaccine was well tolerated by kidney transplant recipients. Reported side effects were minor and none required medical attention (Table 4). In all kidney transplant recipients from both cohorts, pre- and post-vaccination measurements of renal function were available. No statistically significant increase was seen in serum creatinine or eGFR after receiving the ArepanrixTM vaccine. No cases of either biopsy-proven acute rejection or suspected rejection occurred in the total cohort of 124 transplant recipients in the 6 months We also determined the presence of anti-HLA anti- bodies before and after vaccination in all participants in Cohort 1. Of the 42 patients, we observed an increase in anti-HLA antibodies in 5 (11.9%) transplant recipients (Table 5). Of the 5 individuals with newly identifiedanti-HLA antibodies, all were female, aged 35–72 years.
Median time from transplantation was 101 months (range, 13–262 months). In all 5 individuals, multiple anti-HLA antibodies were identified on the LuminexÒ platform. Two of the 5 had pre-existing anti-HLA antibodies pre-vaccination, while the remaining 3 patients were unsensitized prior to immunization.
These 3 patients developed newly identified DSAs, while the remaining 2 patients developed new non- specific anti-HLA antibodies. Only 1 of 5 showed aseroresponse to vaccination, indicating that a positive Values expressed as mean ± SD, median (range) or number reaction to vaccination was not required to develop anti- HLA antibodies. Four of the 5 patients have remained eGRF, estimated glomerular filtration rate; N/A not available; SD,standard deviation.
well after 18 months post immunization, with noevidence of rejection, and no increase in serum creatinine or unexplained increase in proteinuria.
Transplant Infectious Disease 2012: 0: 1–9 Fairhead et al: H1N1 vaccination in kidney transplantation Odds of developing an antibody response to H1N1 vaccination B. Cohorts 1 + 2: Seroprevalence, n = 124 GFR, glomerular filtration rate; CI, confidence interval.
Adverse effects of H1N1 vaccination in Cohort 1 Patient 4 showed a small rise in creatinine post vaccinationthat has been slowly progressive over the past 18 months.
She developed significant albuminuria at 6 months postvaccination, and a renal biopsy performed 18 months post vaccination was suspicious for chronic antibody-mediated rejection; however, C4d staining for complement deposi- tion was negative (Banff score: g0, i1, t0, v0, ah1, cg2, ci1, ct1, cv1, and mm1). In addition, a repeat screen for DSA was negative at 18 months, including loss of the DSA thathad been present at 1 month post vaccination. It is interesting to note that 2 patients developed identical anti-HLA-A antibodies (A2, 11, 24, 29). Anti-HLA-DQ2, DQ6, and DQ9 were also represented in more than 1 *Hospitalizations for gout, bacterial sepsis; no H1N1 sero-conversion.
We sought to determine the safety and immunogenicity of an AS03 adjuvant-containing vaccine against pH1N1 Transplant Infectious Disease 2012: 0: 1–9 Fairhead et al: H1N1 vaccination in kidney transplantation De novo anti-human leukocyte antigen (HLA) antibody production after H1N1 vaccination 1Donor DQ type 7/8.
2No Donor DQ identification performed.
3Possible, see text for details.
Tx, transplantation; DSA, donor-specific antibody.
administered to renal transplant recipients. We found population (19). A case-control study done in Canada, that immunogenicity was poor, with both cohorts using a sentinel surveillance system, estimated the achieving only a 31–35% seroprotection rate and with effectiveness of ArepanrixTM to be 93% in the general a 29% seroconversion rate seen in Cohort 1. Despite the population (20). Our reported seroconversion rate of poor humoral immunity, we did not find any significant 29% is lower than that of the general population, but local or systemic adverse events. We did find the similar to most other reports of immunosuppressed development of de novo donor-specific HLA antibody in organ transplant recipients who have received pH1N1 3/42 (7.1%) patients. However, there did not appear vaccine. For example, in a prospective observational to be any clinical consequences, with the majority trial of 60 renal transplant patients, Brakemeier et al.
of patients remaining stable with regard to renal (21) demonstrated a seroresponse rate of 34.5% with a similar ASO3-adjuvanted pH1N1 vaccine, as compared with a 90% response in healthy controls. In a cohort of subsequent worldwide vaccination effort allowed a 47 heart transplant recipients, similar in age and time unique opportunity to study the efficacy of immuniza- from transplant as those in our study, who also received tion in a population with minimal baseline seroprotec- the AS03 adjuvant-containing pH1N1 vaccine, Meyer tion. Indeed, only 7% of the transplant population et al. (22) reported a seroresponse rate of 32%. Esposito showed baseline protection against the pH1N1 strain.
et al. (23) reported a seroconversion rate of 25% at This low baseline rate was consistent with baseline 30 days in pediatric transplant recipients after receipt of seroprotection seen in Canada during the pandemic an MF59-adjuvanted pH1N1 vaccine, as compared with (17). Previous studies suggested a higher baseline 100% in healthy controls. In a trial of solid organ seroprevalence in older individuals, secondary to a transplant patients receiving a non-adjuvanted inacti- remote exposure against a similar influenza strain (18).
vated whole virion vaccine against pH1N1, <30% of However, we did not find a higher rate of baseline patients demonstrated seroconversion (24). Two trials seroprotection among transplant recipients >70 years have reported higher seroconversion rates after immu- of age, although the number of patients was small nization with an ASO3-adjuvanted pH1N1 vaccine than what we observed. Manuel et al. (25) reported a The AS03-adjuvanted pH1N1 vaccine has a reported seroconversion rate of 52% using the hemagglutination seroprotection rate of up to 98.2% in the general inhibition assay; however, baseline seroprotection was Transplant Infectious Disease 2012: 0: 1–9 Fairhead et al: H1N1 vaccination in kidney transplantation considerably higher at 24% in this population. Hansen however, reports have been published associating et al. (26) observed a seroconversion rate of 58% in adjuvanted vaccines with HLA alloantibody formation.
kidney transplant recipients 3 weeks after immuniza- In one study of kidney transplant recipients, Katarinis tion; however, the hemagglutination inhibition assay et al. (32) showed that 12–17% of patients developed was not used to determine antibody titers. Overall, HLA alloantibody after an AS03-containing influenza protection of immunosuppressed solid organ recipients vaccine. Although most of the reported anti-HLA against pH1N1 after vaccination was uniformly poor, as antibodies had significantly declined or disappeared at compared with the general population.
6 months, 1 patient suffered an acute antibody-medi- The response of kidney transplant recipients to ated rejection and 1 developed a thrombotic microan- influenza vaccination has been variable in the literature.
giopathy. Our study also shows that 5/42 (11.9%) Vaccine-specific variables such as differing immunoge- patients developed de novo HLA alloantibody. Of these nicities of the specific influenza strain variants con- 5 individuals, 1 recipient displayed evidence of graft tained within a given vaccine, and the presence or dysfunction that was related to chronic antibody-med- absence of a vaccine adjuvant may play a role in the iated rejection. In a prospective observational trial to development of protective antibody titers. In addition, test the efficacy of pH1N1 vaccination, similar to our patient variables such as the baseline seroprotection, own, 5.6% of patients developed de novo DSAs, with 2 age, time from transplant, and historical vs. modern individuals developing acute antibody-mediated rejec- immunosuppression regimens may play a role in tion and 1 having allograft failure (21). In addition, a vaccine responsiveness. One of the main factors case-control study in heart transplant patients showed a preventing effective immunization in kidney transplant significantly increased risk of rejection after the AS03 recipients appears to be the effect of immunosuppres- vaccine (33). These observations are concerning and sive medications. In our cohort, patients maintained on suggest that adjuvant-containing vaccines may increase triple immunosuppressive agents as compared with two the risk of developing de novo DSAs and subsequent agents, had a lower likelihood of vaccine response antibody-mediated rejection. A recent editorial high- (odds ratio for developing an antibody response was lighted the difficulty in proving the association of 0.07; 95% confidence interval 0.01–0.71; Table 3A). Use immunization with development of anti-HLA antibodies of both tacrolimus and mycophenolic acid was associ- and antibody-mediated rejection (10). As hypothesized ated with lower odds of developing an antibody by Colvin (34), a significant amount of exposure to DSA response, although statistical significance was not and time may be required before development of achieved. This finding is consistent with other studies, complement C4d deposition in the allograft and where patients taking mycophenolic acid derivatives subsequent antibody-mediated rejection. Further study have been shown to have lower immune responses and follow-up of patients who develop de novo anti-HLA depending on drug dosing (21, 27, 28). Those patients antibodies is warranted, to better define risk, especially within 6 months of transplantation have also been as DSA is known to correlate with graft outcome (35).
recognized as a group that may not respond to In summary, we show a poor response rate to influenza vaccination (29). In our Cohort 1, no patient adjuvanted pH1N1 vaccine in a cohort of kidney within 6 months of receiving a transplant (typically the transplant recipients. Strategies to improve the immu- nogenicity of influenza vaccine and further study on the developed a seroprotective response.
safety of adjuvanted vaccines in this population are Minimal safety data are available on AS03-containing needed. Annual seasonal vaccination for transplant vaccines in kidney transplant recipients. Our study recipients and their close contacts should continue to provides evidence of the safety of the ASO3-adjuvanted vaccine in the kidney transplant population. In ourstudy, no serious adverse events occurred and no acutetransplant rejections were observed in 6 months ofpost-vaccination follow-up. It has previously been pos- tulated that vaccinating kidney transplant recipientsmay lead to non-specific up-regulation of humoral Thanks: We wish to thank the clinical trials team at the immunity, potentially leading to renal allograft rejec- Kidney Research Centre (Ottawa) and the Ottawa tion. Both Candon et al. (30) and Danziger-Isakov et al.
Hospital Transplant Clinic staff for their assistance.
(31) have shown no evidence of de novo anti-HLA Financial support: A portion of this research was antibodies after seasonal influenza vaccination, thus funded by an undirected research grant from Roche.
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Transplant Infectious Disease 2012: 0: 1–9 Fairhead et al: H1N1 vaccination in kidney transplantation Potential conflicts of interest: D.K. has received Available at http://www.ema.europa.eu/docs/en_GB/document_ research support from Hoffmann-LaRoche and Sanofi library/Scientific_guideline/2009/09/WC500003945.pdf Pasteur. The authors have no further conflicts of 16. National Kidney Foundation. K/DOQI Clinical practice guidelines for chronic kidney disease: evaluation classification stratification.
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Jørgen K. Larsen - Finsen Laboratory - Publications Møller U, Larsen JK, Faber M: The influence of injected tritiated thymidine on the mitotic circadian rhythm in the epithelium of the hamster cheek pouch. Cell Tissue Kinet 7: 213-239, 1974. Hart Hansen O, Pedersen T, Larsen JK: A method to study cell proliferation kinetics in human gastric mucosa. Gut 16: 23-27, 1975. Krøll J, Larsen JK,

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