Influenza Vaccination Is Efficacious and Safe in Renal Transplant Recipients

Whether influenza vaccination in solid-organ transplant recipients is efficacious remains a controversial issue. Furthermore, theoretical concerns have been raised regarding the safety of vaccination as it might trigger rejection of the allograft. The present prospective trial is aimed at investigating the antibody response and safety of influenza vaccination in renal transplant recipients (RTR).
A total of 165 RTR and 41 healthy volunteers were vaccinated with a standard trivalent inactivated influenza vaccine. Hemagglutination-inhibiting (HI) antibodies were quantified before and 1 month after vaccination. Seroprotection (SP) and seroresponse (SR) were defined as a titer ≥40 and a 4-fold rise in HI titer, respectively. Similar SR rates were observed in both groups. Postvaccination SP rates in RTR amounted to 92.7%, 78.7% and 82.9% for A/H1N1, A/H3N2 and B, respectively. High baseline SP rates, most probably reflecting frequent preimmunizations, explain partly the high postvaccination SP rates. SR rate was independently and inversely associated with baseline SP rate. Mycophenolate mofetil ( MMF ) usage was associated with a 2.6–5-fold lower SR. Nonetheless, these patients showed good postvaccination SP rates. A booster dose did not enhance SP or SR rates. Influenza vaccination neither affected allograft function nor caused rejection episodes. In conclusion, influenza vaccination is efficacious and safe in renal transplantation.     

Influenza vaccination in heart transplant recipients.

Seventy-nine heart transplant recipients were vaccinated with a trivalent influenza virus vaccine 1996/97 containing the strains A/Singapore/6/86 (H1N1), A/Wuhan/395/95 (H3N2), and B/Beijing/184/93. The proportions of patients with protective levels of antibody (HI > or = 40) after vaccination ranged from 100% (A/Singapore [H1N1]) to 31.6% (B/Beijing) and their mean fold titer increases were lower than those recorded for vaccination of 109 healthy subjects with the same batch of vaccine. The vaccinations were tolerated well and did not result in serious side effects, such as graft rejections. Our findings indicate that influenza vaccination can induce protective antibody levels in a substantial proportion of heart transplant recipients and lend support to the recommendation to vaccinate such patients annually against influenza.     

Influenza virus vaccination in kidney transplant recipients: serum antibody response to different immunosuppressive drugs

Salles MJC, Sens YAS, Boas LSV, Machado CM. Influenza virus vaccination in kidney transplant recipients: serum antibody response to different immunosuppressive drugs.
Clin Transplant 2010: 24: E17–E23. © 2009 John Wiley & Sons A/S.   Abstract: 
Introduction:  This study prospectively accessed the immune response to the inactivated influenza vaccine in renal transplant recipients receiving either azathioprine or mycophenolate mofetil (MMF). Side effects were investigated.
Methods:  Sixty-nine patients received one dose of inactivated trivalent influenza vaccine. Antihemagglutinin (HI) antibody response against each strain was measured before and one to six months after vaccination.
Results:  Geometric mean HI antibody titers for H1N1 and H3N2 strains increased from 2.57 and 2.44 to 13.45 (p = 0.001) and 7.20 (p < 0.001), respectively. Pre- and post-vaccination protection rates for H1N1 and H3N2 increased from 8.7% to 49.3% (p < 0.001); and 36.3% (p < 0.001) and seroconversion rates were 36% and 25.3%, respectively. There was no response to influenza B. The use of MMF reduced the H1N1 and H3N2 protection rates and the seroconversion rate for the H1N1 strain when compared with the use of azathioprine, and subjects transplanted less than 87 months also had inferior antibody response. Adverse events were mild and there were no change on renal function post-vaccination.
Conclusion:  Renal transplant patients vaccinated against influenza responded with antibody production for influenza A virus strains, but not for influenza B. Use of MMF and shorter time from transplantation decreased the immune response to the vaccine.     

Seasonal Maintenance of Influenza Vaccine-Induced Antibody Response in Kidney Transplant Recipients

Background/Aims: Although annual influenza vaccination is recommended for kidney transplant recipients, efficacy as reflected by serum antibody titers has not been well studied beyond 1 month in kidney transplant recipients. Methods: We performed a single-center prospective cohort study of 51 kidney transplant recipients and 102 healthy controls receiving the 2006-2007 influenza vaccine. Anti-hemagglutinin antibody titers to A/H1N1, A/H3N2, and B were measured before and 1 month after vaccination, and again at the end of influenza season. The primary outcome was the proportion of participants maintaining seroprotection (antibody titer ≥1:32) for the duration of the influenza season after influenza vaccination. Results: Median follow-up time was 175 and 155 days in the transplant and control groups, respectively. For types A/H1N1 and B, a similar high proportion of the transplant and control groups (88.5 and 81.6% vs. 83.7 and 74.2% for A/H1N1 and B, respectively) maintained seroprotection. For type A/H3N2, significantly less of the transplant group (66.7%) versus the control group (90%) maintained a protective influenza vaccine response (odds ratio 0.21, 95% confidence interval 0.07-0.64). This difference disappeared in adjusted analyses. Actual geometric mean titers decreased significantly within both groups (p < 0.001) but this did not differ between groups. Conclusions: Once they have developed protective vaccine-induced antibody responses to influenza vaccine, kidney transplant recipients are able to maintain adequate protective levels of antibody compared with healthy controls.     

Influenza vaccination in the organ transplant recipient: review and summary recommendations

Influenza virus causes a spectrum of illness in transplant recipients with a high rate of lower respiratory disease. Seasonal influenza vaccination is an important public health measure recommended for transplant recipients and their close contacts. Vaccine has been shown to be safe and generally well tolerated in both adult and pediatric transplant recipients. However, responses to vaccine are variable and are dependent on various factors including time from transplantation and specific immunosuppressive medication. Seasonal influenza vaccine has demonstrated safety and no conclusive evidence exists for a link between vaccination and allograft dysfunction. Annually updated trivalent inactivated influenza vaccines have been available and routinely used for several decades, although newer influenza vaccination formulations including high-dose vaccine, adjuvanted vaccine, quadrivalent inactivated vaccine and vaccine by intradermal delivery system are now available or will be available in the near future. Safety and immunogenicity data of these new formulations in transplant recipients requires investigation. In this document, we review the current state of knowledge on influenza vaccines in transplant recipients and make recommendations on the use of vaccine in both adult and pediatric organ transplant recipients.     

Influenza Vaccination in Orthotopic Liver Transplant Recipients: Absence of Post Administration ALT Elevation

Influenza vaccination has reduced life-threatening complications from influenza virus infection in adult liver transplant recipients. We evaluated changes in aminotransferase level and immunogenicity of influenza vaccination in liver transplant recipients. Fifty-one liver transplant recipients were administered a standard dose of the 2002-2003 inactivated trivalent influenza vaccine. ALT values were measured at baseline, 1 week and 4-6 weeks postvaccination. Antibody responses to each component of the vaccine were measured at baseline and after 4-6 weeks by a hemagglutination inhibition (HAI) assay. Response was defined as an HAI titer > or = 1: 40 and/or a 4-fold increase in antibody titers from baseline. An ALT elevation was defined as a rise of > or = 50% from baseline. There was no difference in the median rise in ALT value between seroconverters and nonseroconverters. A significant number of recipients developed potentially protective antibody titers (p-value < 0.0001). At less than 4 months post transplantation, 1/7 (14%), at 4-12 months, 6/9 (67%), and after 12 months, 30/35 (86%) subjects responded to the H1 strain. Of 51 recipients, one HCV (-) recipients vaccinated within 3 months of transplantation developed acute cellular rejection. Influenza virus vaccination is not associated with allograft rejection or ALT flares in liver transplant recipients.     

Impairment of the immune response to influenza vaccination in renal transplant recipients by cyclosporine, but not azathioprine

Influenza vaccination has been strongly recommended for immunosuppressed renal transplant recipients. However, immunosuppression may lead to impaired antibody responses. We studied the antibody response to an inactivated trivalent influenza vaccine in 59 renal transplant recipients with life-sustaining kidney function: 21 were on cyclosporine and prednisone, 38 on azathioprine and prednisone. Healthy volunteers (n = 29) and patients on hemodialysis (n = 28) served as controls. Despite comparable renal allograft function, cyclosporine-treated patients had a significantly lower immune response against influenza A viruses than azathioprine-treated patients, whether mean antibody levels, fourfold titer rise, or seroconversion to protective titers was analyzed. No significant differences in antibody responses were found between healthy controls and patients on azathioprine. The patients on hemodialysis showed an impaired response to vaccination. However, in contrast to the cyclosporine-treated patients, booster immunization proved valuable in this group.     

Mycophenolate and lower graft function reduce the seroresponse of kidney transplant recipients to pandemic H1N1 vaccination

In late 2009 transplant organizations recommended that kidney recipients be vaccinated for pandemic H1N1 influenza (pH1N1); however, the vaccine efficacy was unknown. We had offered a monovalent non-adjuvanted pH1N1 vaccine to transplant recipients. Here we compared the pre- and post-vaccination seroresponses of 151 transplant recipients to that of 71 hemodialysis patients and 30 healthy controls. Baseline seroprotection was similar between groups but was significantly different at 1 month (44, 56, and 87%, respectively). Seroconversion was significantly less common for transplant recipients (32%) than dialysis patients (45%) and healthy controls (77%). After adjusting for age and gender, dialysis patients were significantly more likely (2.7-fold) to achieve new seroprotection than transplant recipients. The likelihood of seroprotection in transplant recipients was significantly reduced by mycophenolate use (adjusted odds ratio 0.24), in a dose-dependent manner, and by reduced eGFR (adjusted odds ratio 0.16 for worst to best). Seroprotection and geometric mean antibody titers increased substantially in 49 transplant recipients who subsequently received the 2010 seasonal influenza vaccine. Thus, patients requiring renal replacement therapy had reduced seroresponses to vaccination with the monovalent vaccine compared with healthy controls. Transplant recipient responses were further reduced if they were receiving mycophenolate or had significantly lower graft function.     

Comparing early withdrawal or avoidance of steroids with standard steroid therapy in kidney transplant recipients

This Practice Point commentary discusses the findings and limitations of an open-label, multicenter, prospective trial conducted by Vincenti et al., in which kidney transplant recipients receiving basiliximab, ciclosporin microemulsion, and enteric-coated mycophenolate sodium were randomized to standard corticosteroid therapy, steroid withdrawal 7 days after transplantation, or complete steroid avoidance. The trial failed to show noninferiority of the steroid-sparing arms in terms of calculated glomerular filtration rate at 12 months. In addition, the steroid-sparing groups had an increased cumulative incidence of biopsy-proven acute rejection at 12 months. This commentary highlights the issues to consider when interpreting and generalizing these results, including the under-representation of African Americans in the study population, the short duration of follow-up, and the switching of some patients between steroid-containing and steroid-sparing immunosuppressive regimens. The benefits of steroid-free immunosuppression versus low maintenance doses of steroids in kidney transplant recipients remain unclear.     

H1N1 vaccination in pediatric renal transplant patients

Background

Solid organ transplant recipients undergoing immunosuppressive therapy are considered to be at high risk of serious infectious complications. In 2009, a new influenza pandemic caused serious infections and deaths, especially among children and immunocompromised patients. Herein we have reported the safety and efficacy of a single-shot monovalent whole-virus vaccine against H1N1 infection in the pediatric renal transplant population.

Methods

In November and December 2009, we vaccinated 37 renal transplant children and adolescents and measured their antibody responses. Seroprotection, seroconversion, and seroconversion factors were analyzed at 21 days after vaccination.

Results

None of the vaccinated patients experienced vaccine-related side effects. None of the patients had an H1N1 influenza infection after vaccination. All of the patients showed elevations in antibody titer at 21 days after vaccination. In contrast, only 29.72% of the patients achieved a safe seroprotection level and only 18.75% a safe seroconversion rate. More intense immunosuppressive treatment displayed negative effect on seroprotection and seroconversion, and antibody production significantly increased with age. No other factor was observed to influence seroprotection.

Conclusions

We recommend vaccination of children and adolescent renal transplant recipients against H1N1 virus. However, a single shot of vaccine may not be sufficient; to achieve seroprotection, a booster vaccination and measurement of the antibody response are needed to assure protection of our patients.     

Panel Reactive Antibody Responses Against Influenza Vaccination in Kidney Transplant Recipients

IntroductionSeasonal influenza is an important cause of morbidity and mortality in the post-transplant period; therefore, the influenza vaccination has been recommended for all kidney transplant recipients before the influenza season. However, at least theoretically, the introduction of antigens via vaccines may trigger rejection attacks by causing an antibody response. In this study, we examined the development of de novo panel reactive antibody (PRA) development against the influenza vaccine in kidney transplant recipients.Materials and MethodsOverall, 41 kidney transplant recipients who received the influenza vaccination and 50 kidney transplant recipients (study group) who refused to receive the influenza vaccination (control group) were enrolled in the study. Following basal biochemistry examination, the inactivated trivalent influenza vaccine was administered intramuscularly. Panel reactive antibodies were screened in all patients before and after vaccination on days 30 and 180. The primary outcome variable was development of de novo panel reactive antibodies.ResultsOne patient in the study group developed de novo class I and II PRA at 6 months after vaccination (P > .05), while no antibody development was noted in the control group. Graft dysfunction or biopsy-confirmed rejection was not observed during the follow-up period in both groups.ConclusionThe influenza vaccination is generally effective and safe in solid organ transplant recipients. The vaccination procedure has the potential to trigger antibody development and occurrence of rejection. Therefore, vaccinated kidney transplant recipients should be monitored more carefully with regard to PRA; if the graft deteriorates, a rapid transplant biopsy should be performed.     

Impact of adjuvanted H1N1 vaccine on cell-mediated rejection in heart transplant recipients

During the H1N1 influenza virus pandemic, vaccination of high risk groups including solid-organ transplant recipients was advised. A retrospective case control study of 60 heart transplant patients, 15 having received the H1N1 virus antigen and ASO3 adjuvant vaccine (GlaxoSmithKline, Mississauga, ON, Canada) within 21 days and 45 having not been vaccinated, all undergoing routine surveillance endmyocardial biopsies, was performed. The overall rate of cellular rejection (all grades) was not statistically different between groups; however, acute cellular rejection, ≥grade 2 (1990 ISHLT criteria), was more frequent among those having recently vaccinated (control: 1/45 vs. 6/15, p = 0.001). On multivariate analysis, the only risk factor found to be associated with acute cellular rejection was recent H1N1 viral antigen and adjuvant vaccination (OR 26.5: 95% CI 02.59-270.5). Vaccine adjuvants increase host response to vaccine antigens by immune upregulation potentially increasing risk of rejection in solid-organ transplant recipients. The potential hazard of vaccination this study raises must be weighed with the clear benefit vaccination has proven to be.     

Heterologous Immune Responses to Influenza Vaccine in Kidney Transplant Recipients

Influenza vaccine is known to have suboptimal immunogenicity in transplant recipients. Despite this, influenza vaccine may have the added benefit of inducing a cross‐reactive immune response to viral strains not found in the vaccine. This is termed “heterologous immunity” and has not been assessed previously in transplant patients. Pre‐ and postvaccination sera from kidney transplant recipients (n = 60) immunized with the 2012–2013 adjuvanted or nonadjuvanted influenza vaccine underwent testing by hemagglutination inhibition assay for strains not present in vaccine: A/New Caledonia/20/99 (H1N1), A/Texas/50/2012 (H3N2) and B/Brisbane/60/2008. The geometric mean titer of antibody to heterologous strains increased after vaccine (H1N1: 80.0 to 136.1, p < 0.001; H3N2: 23.3 to 77.3, p < 0.001; B: 13.3 to 19.5, p < 0.001). Seroconversion rates were 16.7%, 41.7%, and 13.3%, respectively. No differences in heterologous response were seen in the adjuvanted versus nonadjuvanted groups. Patients were more likely to seroconvert for a cross‐reactive antigen if they seroconverted for the specific vaccine antigen. Seroconversion to heterologous A/H3N2, for example, was 84.0% for homologous H3N2 seroconverters versus 11.4% for nonseroconverters (p < 0.001). This study provides novel evidence that transplant recipients are able to mount significant cross‐protective responses to influenza vaccine that may be an additional, previously unknown benefit of immunization.     

Natural influenza infection produces a greater diversity of humoral responses than vaccination in immunosuppressed transplant recipients

The humoral immune response to influenza virus infection is complex and may be different compared to the antibody response elicited by vaccination. We analyzed the breadth of IgG and IgA responses in solid organ transplant (SOT) recipients to a diverse collection of 86 influenza antigens elicited by natural influenza A virus (IAV) infection or by vaccination. Antibody levels were quantified using a custom antigen microarray. A total of 120 patients were included: 80 IAV infected (40 A/H1N1 and 40 A/H3N2) and 40 vaccinated. Based on hierarchical clustering analysis, infection with either H1N1 or H3N2 virus showed a more diverse antibody response compared to vaccination. Similarly, H1N1-infected individuals showed a significant IgG response to 27.9% of array antigens and H3N2-infected patients to 43.0% of antigens, whereas vaccination elicited a less broad immune response (7.0% of antigens). Immune responses were not exclusively targeting influenza hemagglutinin (HA) proteins but were also directed against conserved influenza antigens. Serum IgA responses followed a similar profile. This study provides novel data on the breadth of antibody responses to influenza. We also found that the diversity of response is greater in influenza-infected rather than vaccinated patients, providing a potential mechanistic rationale for suboptimal vaccine efficacy in this population.     

Antibody persistence 1 year after pandemic H1N1 2009 influenza vaccination and immunogenicity of subsequent seasonal influenza vaccine among adult organ transplant patients

We investigated the antibody persistence in solid organ transplant (SOT) recipients 1 year after immunization with two doses of monovalent AS03‐adjuvanted influenza A(H1N1)pdm09 vaccine. We also assessed the boosting effect of the seasonal trivalent inactivated vaccine 2010 (TIV/10) that contained the influenza A(H1N1)pdm09 strain. A total of 49 SOT recipients and 11 healthy controls were included. After a blood sample was obtained to assess the persistent immunity, one dose of TIV/10 was administered and another blood sample was collected 1 month after vaccination. A(H1N1)pdm09 antibodies were measured using a haemagglutination inhibition assay. The percentage of SOT recipients with protective titres decreased between 1 month and 10–14 months after the monovalent influenza A(H1N1)pdm09 vaccination, from 79% (n = 38) to 47% (n = 23) (P = 0.02). The corresponding numbers for the control group were 100% and 63%, respectively (P = 0.008). After the TIV/10 boosting dose, the number of SOT recipients with protective titres increased from 47% (n = 23) to 71% (n = 35) (P = 0.2). All the controls reached a protective titre level. The median titre rise was significantly higher among controls when compared to SOT recipients (P = 0.0036). No rejection or adverse events were seen. The results show an obvious need for vaccine boosting doses in the SOT patients. (ClinicalTrials.gov number: NCT01256931).     

Influenza vaccine after pediatric kidney transplant: a Midwest Pediatric Nephrology Consortium study

The main aim of this study was to compare the response to trivalent inactivated influenza vaccine in children who received a kidney transplant and were on steroid-free versus steroid-based immunosuppression. Groups: 1. Kidney transplant recipients on steroid-free immunosuppression (n = 27); 2. Kidney transplant recipients on steroid-based immunosuppression (n = 39); 3. Healthy controls (n = 21). Hemagglutination inhibition titers against 2007–2008 A/H1N1 and A/H3N2 and B strains were measured before and 8 weeks postvaccination. Postvaccination geometric mean titers to A/H1N1 were significantly lower among both transplant groups than controls (p = 0.025 and 0.015, respectively). Postvaccination titers to H3N2 and B strains were not statistically different between groups. Proportions of participants developing seroprotection were not different among groups. Both kidney transplant groups seroconverted less than controls for A/H1N1 (p = 0.0002) and were no different from controls for B. For A/H3N2, the steroid-free group had the weakest seroconversion (p = 0.008), possibly due to mycophenolate-enhanced exposure and a younger age. Overall, children after kidney transplantation demonstrated a good serologic response to the inactivated influenza vaccine although somewhat lower than controls. Steroid-free immunosuppression did not seem to present an advantage in antibody response. Data on inactivated influenza vaccine safety and efficacy was collected and demonstrated absence of acute rejection or laboratory-proven influenza for 6 months postvaccination.     

Influenza vaccination in liver transplant recipients

BACKGROUND: The immunogenicity of the trivalent inactivated influenza split virus vaccine (Infusplit SSW 97/98) containing A/Bayern/07/95 (H1N1)-like (A/Johannesburg/82/96 [NIB-39]), A/Wuhan/359/95 (H3N2)-like (A/Nanchang/933/95 [Resvir-0]), and B/Beijing/184/93-like (B/Harbin/7/94) hemagglutinin antigens was tested in liver transplant recipients (TXL-R). SUBJECTS AND METHODS: Serum antibody titers were determined 21+/-2 days after a single vaccination in 62 adult TXL-R and 59 adult volunteers. RESULTS: Protective postimmunization antibody titers for the three antigens were similar in TXL-R (protection rates 92%, 92%, and 95%) and the comparison group (97%, 100%, and 100%). Adverse reactions were mild and less frequent in TXL-R. A significant decrease of CD8+CD38+ lymphocytes after vaccination was found in TXL-R. No association between antibody response and age, gender, time interval since transplantation, anti-hepatitis B surface antigen immunoprophylaxis, or immunosuppressive medication was detected. CONCLUSION: Our results show that the vaccine is safe and effective and should be recommended to TXL-R.     

Humoral and Cellular Immune Responses after Influenza Vaccination in Kidney Transplant Recipients

It has been speculated that influenza vaccination of renal allograft recipients could be associated with de novo production and/or increased titers of anti-HLA antibodies (HLA-Ab). To directly address this issue, we recruited 66 stable renal transplant recipients and 19 healthy volunteers during the 2005–2006 vaccination campaign. At day 0 and day 30 following vaccination, HLA-Ab were screened and in parallel influenza-specific antibody and T-cell responses were assessed. Humoral postvaccinal responses to A/H1N1 and A/H3N2 strains, but not B strain, were less frequent in transplanted patients than in control subjects. Significant expansion of influenza-specific IFN-γ-producing T cells was observed at similar frequencies in patients and controls. There was no correlation between cellular and humoral postvaccinal responses. No impact of sex, age or immunosuppressive regimen could be evidenced. Vaccination was not associated with any significant change in preexisting or de novo anti-HLA sensitization. No episode of allograft rejection was recorded in any of the patients. Our results suggest that flu vaccination is safe in stable renal transplanted patients. Larger studies are needed for definitive statistical proof of the safety and effectiveness, with regard to the quality of the immune response, of yearly influenza vaccination in immunosuppressed patients.     

The Effect of Sirolimus Therapy on Vaccine Responses in Transplant Recipients

Different immunosuppressant regimens vary in their effects on antibody responses to vaccination. The combination of prednisolone and azathioprine has only a minor effect, whereas the addition of ciclosporin attenuates protective antibody responses to influenza vaccination. The effect of sirolimus, a new immunosuppressant, on vaccine responses has been little studied. Thirty-two hepatic or renal transplant patients randomized to calcineurin inhibitor-based or sirolimus-based immunosuppression were vaccinated against influenza and pneumococcus. Following tri-valent influenza vaccination, a similar rise in antibody titer occurred in sirolimus and calcineurin inhibitor (CNI) treated patients, though sirolimus treated patients developed a 'protective' titer to more influenza antigens. The pneumococcal polysaccharide vaccine was equally effective in both groups. Hence, vaccination guidelines in place for CNI treated patients are likely to be appropriate for transplant recipients maintained on sirolimus.