Solid organ transplant recipients have a high risk for morbidity and mortality from influenza infection.1-3 In addition to increased rates of lower respiratory infection with influenza, studies have also reported increased acute and chronic allograft rejection after infection, specifically in lung and kidney transplant recipients.4-8 Therefore, solid organ transplant patients are recommended to receive the annual trivalent inactivated influenza vaccine.9-11 However, humoral responses to immunization in this group are suboptimal as compared to immunocompetent persons.12-14 Responses have been dependent on several factors including time from transplantation, use of certain immunosuppression agents, such as mycophenolate mofetil, as well as type of transplant.
Seasonal trivalent inactivated influenza vaccine contains 15 μg antigen from each of 2 A strains and 1 B strain of influenza and is given as a single 0.5-mL intramuscular dose. The selection of vaccine strains is based on analysis of circulating influenza strains and annual recommendations by the World Health Organization. Numerous methods to increase immunogenicity of influenza vaccine in immunocompromised populations have been attempted including the use of booster doses of vaccine within the same season, and the intradermal administration of vaccines. These have not shown to be successful in improving immunogenicity.15-17 The addition of adjuvants to vaccines has the potential to increase the immunogenicity of a given antigen either by nonspecific stimulation of inflammatory cells or by acting as Toll-like receptor agonists. Although the most common adjuvant in vaccines is alum, newer adjuvants, such as MF59, ASO3, and ASO4, have also been approved for clinical use. MF59 is an oil-in-water emulsion that contains squalene and polysorbate-80 and acts via attracting inflammatory cells to the site of injection.18 A common but unproven concern with vaccine adjuvants is whether they have the potential to induce autoimmunity or alloimmunity.19 This issue has been further highlighted by published reports of HLA alloantibody upregulation or allograft rejection in organ transplant patients who received the adjuvanted 2009 pandemic influenza vaccine (containing the ASO3 adjuvant).20-22 An MF59-adjuvanted influenza vaccine is currently available in Europe and Canada for patients older than 65 years (Fluad, Novartis Vaccines, Canada). Immunogenicity data have demonstrated improved antibody response with the adjuvant vaccine versus standard vaccine in those older than 65 years.23,24 If an adjuvanted vaccine were shown to induce greater immunogenicity in transplant recipients without adverse effects on alloupregulation, it would represent a significant advance in the prevention of influenza in this population. However, there are limited data for the immunogenicity and safety of adjuvanted versus standard vaccines in organ transplant recipients. Therefore, we performed a randomized controlled trial to compare the adjuvanted vaccine versus a nonadjuvanted formulation in stable outpatient kidney transplant recipients assessing both the indicated population (age older than 65 years) and the off-label population (age 18-64 years).
MATERIALS AND METHODS
Patient Population and Study Design
The study was conducted at a tertiary care hospital after receiving institutional research ethics board approval. All patients provided written informed consent. Adult kidney transplant recipients attending outpatient clinics were randomized to receive adjuvanted or nonadjuvanted influenza vaccine during the 2012 to 2013 influenza vaccination campaign. Patients were included if they were at least 3 months after transplantation and had not yet received the 2012-2013 influenza vaccine. The study was registered at www.clinicaltrials.gov number NCT01584908.
At enrollment, patients received either adjuvanted or nonadjuvanted seasonal influenza vaccine in a 1:1 ratio. Randomization was done using a computer generated schedule, in blocks of 4 to ensure equal numbers. Once the patient agreed to participate, the treatment assignment was provided by the study coordinating office. Both vaccines contained the same 3 influenza antigens: influenza A/California/7/2009 (H1N1)pdm09 virus, influenza A/Victoria/361/2011 (H3N2)-like virus and influenza B/Wisconsin/1/2010 (Yamagata lineage). The adjuvanted vaccine was Fluad (Novartis, Canada) containing 15 μg antigen of each strain in 0.5 mL volume as well as MF59 adjuvant. The nonadjuvanted vaccine was Agriflu (Novartis) and contained the same amount of antigen and volume but with no MF59. Both vaccines are subunit vaccines and were available in a prefilled syringe. Vaccine was injected into the deltoid muscle of the nondominant arm. Because the study vaccines differed in appearance (the adjuvanted vaccine was milky white and the nonadjuvanted vaccine was clear and colourless), the patient was asked to turn away during vaccine administration. To reduce bias, vaccination was done by an individual who was not assessing adverse events or analyzing study results. Sera were collected 1 month before and after vaccination for strain-specific antibody testing. Demographics, type of transplant, and immunosuppression data were collected. Adverse events data were collected by those not aware of vaccine allocation. Safety data were collected at the following postimmunization times: 24 hours, 48 hours, 7 days, 1 month, and 6 months. All adverse effects were graded as none, mild (no interference in daily activities), moderate (some interference in daily activities), and severe (patient unable to participate in activities of daily living). Patients were followed up for a total of 6 months from enrollment for the development of influenza infection and biopsy-proven allograft rejection.
Sera were stored at −80°C until the day of analysis. The samples underwent hemagglutination inhibition assay for each of the 3 strains in the seasonal vaccine.25 The laboratory staff performing the assay were blinded to vaccine allocation. The test was performed at the Microbiology Services, Colindale, Health Protection Agency, UK using the methods previously described.26 Briefly, serum was incubated with receptor-destroying enzyme (RDE II, Denka Seiken Ltd, Japan) to remove any nonspecific inhibitors of hemagglutination from the sera. Sera were serially diluted and incubated with influenza virus (containing 4 hemagglutination units of virus). This was followed by addition of a suspension of blood cells (0.5% turkey red blood cells for the H1N1 and B strains and 0.5% guinea pig red blood cells for the H3N2 strain). Titers were determined by doubling dilutions of antibody. Sera were tested in duplicate using an initial dilution of 1:10 and a final dilution of 1:2048. Antibody concentrations that were below the lower limit of detection (<10) were assigned a titer of 5 for the purposes of analysis.
Sera collected from those who received adjuvanted vaccine was used for detection of HLA alloantibodies. Sera were tested by Labscreen class I and II single antigen beads (One Lambda, Canoga Park, CA). Samples were tested as per the manufacturer's protocol with the exception of the use of 3.5 μL of beads per well. Beads were acquired on a Luminex 200 instrument and analysis performed using HLA Fusion software. For purposes of the study, we defined a positive specimen as a mean fluorescence intensity greater than 1000. To determine if donor-specific HLA antibodies developed as a result of vaccination, only the postvaccine samples were tested initially. If donor-specific antibodies were detected or if HLA typing was unavailable for the antibodies that were detected, the pretransplant serum was tested to determine if the antibody was already present before vaccination or was de novo postvaccination. De novo donor-specific antibody (DSA) was reported as a result of vaccination if there was no evidence of DSA in the prevaccination sample. If the donor HLA typing was not available for a given HLA locus, de novo HLA antibody was reported as positive if the prevaccine sample did not have any evidence of antibody to the relevant HLA antigen.
Definitions and Statistics
The following variables were used to assess vaccine immunogenicity: seroprotection to a strain was defined as a strain-specific postvaccination titer of 1:40 or greater. Seroconversion was defined as a 4-fold rise or greater in titer from baseline. Seroconversion factor (SCF) was derived by dividing the postimmunization titer by the prevaccine titer. Geometric mean fold rise was calculated as the geometric mean of SCF. If baseline vaccine seroconversion rates are 50%, our study had 70% power to detect a 30% increase in seroconversion, with an α of 0.05. Because of the logistical issues in obtaining adjuvanted vaccine in a timely fashion for the study, we were not able to reach our original sample size of 120 which would have increased study power. Demographics were analyzed using descriptive statistics. The primary endpoint was defined as seroconversion to at least 1 of 3 influenza vaccine antigens. Associations between factors affecting vaccine response and statistical analysis was performed using IBM SPSS version 22.0 (Chicago, IL) and GraphPad Prism version 4.0 (La Jolla, CA). Univariate analyses were performed to determine the most significant factors affecting seroconversion to at least 1 vaccine antigen. These factors included patient age, time from transplant, type of organ transplanted, and immunosuppression. Because the adjuvanted vaccine is licensed for age 65 years or older, an a priori decision was made to separately analyze ages 18 to 64 years and those 65 years or older. For multivariate analysis, a model was constructed using variables that had a P value less than 0.2 on univariate analysis or those that are known to be clinically important in affecting vaccine response. Multivariate analysis was performed using stepwise conditional regression. Statistical significance was defined as a P value less than 0.05.
During October 2012 to December 2012, we enrolled 68 kidney transplant recipients (34 adjuvanted, 34 nonadjuvanted). Baseline characteristics of the cohort were similar between groups and are detailed in Table 1. The overall median time from transplant to vaccination was 8.1 (0.73-33) years. No patient had received antithymocyte globulin or treatment for rejection in 6 months before enrolment. Maintenance immunosuppression was similar in the 2 groups. The majority of patients had received the influenza vaccine during the previous year vaccination campaign.
Of the 68 enrolled patients, 8 did not have either a prevaccination or postvaccination sera collected and were excluded from the immunogenicity analysis (Figure 1). Therefore, for the immunogenicity analysis, 60 patients were analyzed (31 adjuvanted, 29 nonadjuvanted). Overall, no significant differences in immunogenicity between the 2 cohorts were seen (Table 2). Seroconversion to at least 1 of the 3 vaccine antigens was present in 71.0% versus 55.2% of adjuvanted versus nonadjuvanted vaccine recipients (P = 0.21) (odds ratio [OR], 2.0; 95% confidence interval [95% CI], 0.68-5.77) (Figure 2A). Seroconversion to influenza A/H1N1, A/H3N2 and B was 45.2%, 48.4%, 32.3% in adjuvanted vaccine and 48.3%, 34.5%, 24.1%, respectively, for nonadjuvanted vaccine (P = NS).
In a specified a priori analysis based on vaccine licensure criteria, aged 18 to 64 years and 65 years or older were analyzed separately. In the group aged 18 to 64 years (n = 50), significantly more patients met the primary endpoint (seroconversion to at least 1 of 3 vaccine antigens) in the adjuvanted vaccine arm versus the control arm (22/26 [84.6%] vs 14/24 [58.3%], respectively; P = 0.039) (Figure 2B). Vaccine immunogenicity was particularly poor in the group age 65 years or older (n = 10 patients; 5 in adjuvant arm, 5 in control arm). Only 2 of 10 (20%) patients seroconverted to at least 1 antigen (both in the unadjuvanted vaccine group, P = NS).
In the total cohort, baseline seroprotection (before vaccination) to A/H1N1, A/H3N2, and B was present in 55.0%, 81.7%, and 45.0%, respectively, and was not significantly different in the 2 groups. If those seroprotected at baseline were excluded, after nonadjuvanted and adjuvanted vaccination seroconversion rates to A/H1N1 were 8/12 (66.7%) and 7/15 (55.6%) (P = 0.30), for A/H3N2 rates were 2/4 (50%) and 7/7 (100%) (P = 0.11), and for influenza B rates were 5/15(33.3%) and 7/18 (38.9%) (P = 0.74) respectively.
No patient developed documented influenza infection during the 2012 to 2013 season.
Factors Affecting Vaccine Response
Rates of seroconversion were analyzed by time after transplantation as well as immunosuppression and age. In univariate analysis (Table 3), patients receiving mycophenolate mofetil (MMF) had lower likelihood of seroconversion (55.6% vs 86.7% seroconversion on MMF vs no MMF; P = 0.03). Seroconversion rates were especially low in those on MMF of 2 g or greater daily (44.4% vs 71.4%; P = 0.047). Older age was also a significant variable, leading to diminished seroconversion with an odds ratio of 0.95 per year of increasing age (0.90, 0.99). The SCF for A/H1N1 strain was significantly lower in the 65 years or older age group (P < 0.001, Figure 3). Time after transplantation (evaluated as a continuous variable per year of transplant) was not a significant factor in seroconversion rates (OR, 0.93; 95% CI, 0.86-1.02).
In a separate univariate analysis of factors predictive of response within the age 18 to 64 years age group, the significant factors associated with likelihood of seroconversion were use of adjuvanted vaccine (P = 0.039), tacrolimus use (P = 0.012), and use of MMF (P = 0.009). Multivariate analysis showed that only the use of adjuvanted vaccine was significantly associated with seroconversion (OR, 6.10; 95% CI, 1.25-28.6) in the age 18 to 64 years age group.
HLA Alloantibody and Vaccine Safety
We performed single antigen bead testing for HLA antibody initially on postvaccination sera. Testing was done only on samples from 29 patients who had received adjuvanted vaccine and had enough sera remaining once the influenza antibody testing was completed. Seven samples were negative for any HLA antibody and therefore pretransplant samples were not tested. In the remaining 22 sample, because some level of HLA antibody was detectable, a prevaccination test was also performed. In 5 recipients, DSA (MHC class I alone [n = 1], class II alone [n = 2], and both class I and II [n = 2]) was detected. However, no changes in mean fluorescence intensity or pattern of reactivity were seen between the pretransplant and posttransplant samples. In the remaining 17 patients, HLA non-DSA antibodies were present (MHC class I [n = 8], class II [n = 4], and class I and II [n = 5]). However, no significant changes were detected in the postvaccination samples when compared to the prevaccination samples. Over the 6-month follow-up period, there was only 1 episode of acute rejection 3 weeks after receiving the nonadjuvanted vaccine.
Other aspects of vaccine safety were assessed at regular intervals up to 6 months after vaccination in 62 of 68 patients. Within 7 days of immunization, local tenderness was significantly greater in those who received the adjuvanted vaccine (77.4% vs 51.6%; P = 0.034). There were no other significant differences in local and systemic side effects between the 2 groups (Table 4). There were 6 hospitalizations (3 in each vaccine group), all for reasons deemed unrelated to vaccination (1 case each of Clostridium difficile colitis, diabetic ketoacidosis, peritonitis, pneumonia, motor vehicle accident, small cell lung cancer). There was 1 death due to progressive small cell lung cancer in the adjuvanted vaccine group.
We performed a randomized trial using a novel strategy of adjuvanted versus nonadjuvanted influenza vaccine in a cohort of kidney transplant recipients. We found that in the whole cohort, there was a nonsignificant trend towards a greater seroconversion rate in the adjuvanted vaccine group (71% vs 55.2% for nonadjuvanted vaccine; P = 0.21). However, in an a priori analysis of patients age 18–64 years of age, the adjuvanted vaccine group had a higher rate of seroconversion to at least 1 vaccine antigen (84.6% vs 58.3%; P = 0.039). In this age group, in a multivariate analysis controlling for the degree of immunosuppression, adjuvanted vaccine type was the only independent factor associated with improved seroconversion. Both vaccines were safe and well tolerated with a higher rate of local reactions seen with adjuvanted vaccine. No evidence of HLA antibody upregulation was seen in patients receiving adjuvanted vaccine.
We also found that patients receiving MMF, especially at higher doses had a lower likelihood of seroconversion. Highly immunosuppressed patients are likely to have lower vaccine immunogenicity. In our study, no patient received induction therapy in the preceding 12 months or had acute rejection in the previous 3 months; therefore, we were not able to determine the effect of induction or rejection on vaccine response. In addition, all patients were receiving low doses of prednisone and only 1 patient received sirolimus making a detailed analysis of the effect of varying immunosuppression regimens on vaccine response more difficult to perform.
Our study examined vaccine immunogenicity as a primary endpoint rather than the clinical endpoint of influenza infection. Although the latter endpoint would be preferable, a significantly larger sample size would be required. The exact sample size would depend on the attack rate of influenza and the vaccine efficacy in a given season, but would likely require more than 1000 patients to be enrolled to detect a 50% vaccine efficacy difference.
Numerous strategies have been evaluated to improve influenza vaccine immunogenicity in organ transplant recipients. To date, none of these have proven successful. For example, in a study evaluating a high-dose intradermal injection compared to standard dose intramuscular vaccination, seroconversion rates ranged from 17.1% to 37.4%, depending on the vaccine antigen with no significant difference between groups.15 In 2 studies assessing a boosting strategy for influenza vaccine recipients, the booster dose did not significantly increase seroconversion rates achieved after the initial dose.17,27 To our knowledge, this is the first trial in transplant patients to demonstrate an intervention which potentially leads to enhanced immunogenicity.
For several years, adjuvanted vaccines have been proposed as a way to increase immunogenicity in populations that respond poorly to standard influenza vaccines. Recently, 2 novel adjuvants, MF59 (Novartis) and ASO3 (GlaxoSmithKline), have been used in influenza vaccines as a method to increase immunogenicity or to reduce the amount of influenza antigen required to generate a vaccine response. MF59 is an oil-in-water emulsion containing squalene, polysorbate-80 and sorbitan trioleate. The exact immune mechanism of MF59 action is not known; however, the adjuvant is reported to induce chemokine secretion from various inflammatory cells and attract monocytes and dendritic cells to the site of injection.18 The MF59 adjuvanted influenza vaccine has previously been shown to have greater immunogenicity in individuals 65 years or older.23,24 There have been no previous studies with the MF59 adjuvanted seasonal influenza vaccine in kidney transplant recipients. A previous randomized study in 58 heart transplant recipients did not show a significant immunogenicity difference between MF59-adjuvanted vaccine and nonadjuvanted influenza vaccine.28 However, this study did not determine strain-specific antibody titer or HLA alloantibody formation. Although the data with MF59 influenza vaccine are limited, a recent study of CMV vaccination in organ transplant recipients used a MF59-adjuvanted glycoprotein B vaccine which demonstrated an acceptable safety profile.29 HLA alloantibodies were not specifically addressed in this study.
In the overall cohort, we found that higher doses of MMF significantly reduce vaccine seroconversion rates. This has previously been shown by our group and others15,17 and supports the recommendation to optimize immunization once the patient has achieved stable immunosuppression. Other studies have shown that patients who are very early after transplantation have poor vaccine response.15,30 However, this was not seen in the current study likely because our cohort included very few patients who were within the first posttransplant year. We also found older age to be a factor associated with poor immunogenicity. Specifically, transplant patients over 65 years of age had very low rates of seroconversion regardless of type of vaccine. This is consistent with the reduced efficacy of vaccination in older populations due to immunosenescence and its effects on Th2 and Th1 responses.31 Overall responses to the B strain were also low again consistent with previous studies both in the general population and transplant recipients.
The safety of novel adjuvants has been a concern with reports of autoimmunity.32 However, specific adjuvants differ in their mechanism of action and range from local inflammatory effects (eg, oil-in-water emulsions) to stimulation of toll-like receptors (eg, Monophosphoryl A). Although the data with MF59-adjuvant in transplant recipients are limited, a number of investigators have studied the ASO3-adjuvanted pandemic influenza vaccine. Similar to MF59, ASO3 is an oil-in-water emulsion, but it also contains α-Tocopherol which is a potent stimulator of local cytokine and chemokine production. However, studies in transplant patients using ASO3-adjuvanted monovalent influenza A/H1N1 (pandemic) vaccine have failed to demonstrate improved immunogenicity compared to nonadjuvanted vaccine.33-35 One concern, however, is that some previous studies with monovalent ASO3-adjuvanted pandemic influenza vaccine have shown increased alloantibody formation with 11.9% to 17.3% of kidney transplant patients developing new anti-HLA antibodies when tested after immunization.20,21 Another study of heart transplant recipients showed an increased rate of cellular rejection in those that received the ASO3-adjuvanted influenza vaccine compared to nonimmunized controls.22 However, these studies were done during the pandemic and may be confounded due to the possibility of natural influenza infection in patients.36 We found greater local tenderness with the adjuvanted vaccine, an expected finding since MF59 triggers a local inflammatory response. Nevertheless, no significant increase in systemic reactions was noted. Importantly, we did not find any evidence of de novo or nonspecific HLA alloantibody formation in response to adjuvanted vaccine.
Our study has some limitations. For cost reasons, we did not test HLA alloantibody in the nonadjuvanted group. However, there are several studies that have shown no significant changes in alloantibody with nonadjuvanted vaccine15,37,38; the purpose of our study was to determine the safety of adjuvanted vaccine with respect to alloantibody formation. However, our population consisted mostly of stable long-term kidney transplant patients; therefore, the safety of this vaccine early after transplantation is unknown. In addition, another goal of the study was to evaluate the immunogenicity of the vaccine specifically in the 65 years or older age group (ie, approved adjuvant vaccine indication). However, only a minority of our overall cohort fell into this age group (n = 10). Nonetheless, response seemed to be particularly poor for both vaccines in this patient population.
In conclusion, adjuvanted vaccine had similar immunogenicity compared with nonadjuvanted vaccine in the whole cohort. However, a potential benefit was observed in the patients aged 18 to 64 years. We also did not see any evidence of safety concerns with adjuvanted vaccine, especially with regard to HLA alloantibody formation. Therefore, our study suggests that MF59-adjuvanted vaccine could be safely used in transplant recipients as a potential means of improving immunogenicity and should be evaluated further. The age 65-year populations remain a group that responds poorly to either vaccine type, and alternative strategies are needed.
Vaccines for the study were provided by Alberta Public Health.
Adjuvanted influenza vaccine is not FDA approved for use in transplant recipients.
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