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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.
easing some of the theoretical concerns. More recently,
(J.G., University of British Columbia).
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
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C O M M U N I Q U E D E P R E S S E OFI Private Equity Capital signe un accord pour acquérir Gault & Frémont, le leader français de l’emballage pour la boulangerie-viennoiserie-pâtisserie (BVP) OFI Private Equity Capital signe un accord pour acquérir la société Gault & Frémont auprès de LBO France et des actionnaires financiers BNP Développement et Osny Finance. Fondé
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,