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Keywords:

  • Consensus;
  • immunogenicity;
  • respiratory virus

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Influenza Vaccination
  5. Immunogenicity of Vaccine in Organ Transplantation
  6. Influence of Immunosuppressive Regimen
  7. Timing of Influenza Vaccination
  8. Effects of Vaccination Including Allograft Dysfunction
  9. Pediatric Issues
  10. Summary
  11. Disclosure
  12. References

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.


Abbreviations: 
ACIP

Advisory Committee on Immunization Practices

AST

American Society of Transplantation

DSA

donor specific antibody

HA

hemagglutinins

HCV

hepatitis C virus

IL

interleukin

LAIV

live attenuated influenza vaccine

MMF

mycophenolate mofetil

NA

neuraminidases

SOT

solid organ transplant

TIV

trivalent inactivate influenza vaccine

WHO

World Health Organization

Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Influenza Vaccination
  5. Immunogenicity of Vaccine in Organ Transplantation
  6. Influence of Immunosuppressive Regimen
  7. Timing of Influenza Vaccination
  8. Effects of Vaccination Including Allograft Dysfunction
  9. Pediatric Issues
  10. Summary
  11. Disclosure
  12. References

Influenza is an orthomyxovirus with three types, A, B or C. Influenza A viruses are further classified into subtypes on the basis of their surface hemagglutinins (HA, H1–16) and neuraminidases (NA, N1–9); additionally, two antigenically distinct B viruses have been described (Yamagata and Victoria lineages). Antigenic drift occurs when there are minor changes in individual amino acids of the HA or NA that develop over time and allow the virus to evade existing humoral immunity (1). Such antigenic drift accounts for the need to update component viruses in influenza vaccines over time. Alternatively, antigenic shift occurs when major changes in HA or NA structure occur either by genetic reassortment or major mutation to result in an entirely novel strain; this often results in a pandemic, as the world recently experienced with the emergence of the novel A/H1N1 virus in 2009 (2).

Influenza can cause significant morbidity and mortality in solid organ transplant (SOT) recipients. Potential risk factors for severe illness include recent augmentation of immune suppression (i.e. short interval between transplant and onset of infection or recent treatment for rejection), lymphopenia, infancy, diabetes and delay in initiation of antiviral therapy (3).

During the winter, influenza has been reported to be responsible for up to 42% of upper and 48% of lower respiratory tract infections in SOT recipients (3–5); available data suggest that between 1% and 4% of SOT patients are infected annually (6,7). Once infected, transplant recipients are known to develop increased viral loads and prolonged shedding, which increases the potential for disease dissemination. In lung transplant recipients, influenza may also mediate acute allograft rejection and bronchiolitis obliterans syndrome (7–12). Mortality secondary to influenza may be as high as 23% in infected pediatric SOT recipients but may be reduced through early use of antiviral therapy (3,6,13).

In this document, we review the current state of knowledge on influenza vaccines and related outcomes in transplant recipients, thereby making recommendations on vaccine use in adult and pediatric organ transplant recipients. The writing group consists of specialists in transplant-related infections in adults and children and well as experts on influenza infections and related vaccine issues. The review was facilitated by a literature search of the English language (1990–2011). Evidence was rated using the GRADE system (14). The recommendations are presented in Table 1.

Table 1.  Recommendations for influenza vaccine graded according to strength of recommendation and quality of evidence
  1. WHO = World Health Organization; ACIP = Advisory Committee on Immunization Practices; AST = American Society of Transplantation; LAIV = live attenuated influenza vaccine; HCW = health care workers.

  2. 1Excluding vaccine-related history of Guillain-Barre syndrome.

• Seasonal inactivated influenza vaccine should be recommended for annual administration in pre- and posttransplant recipients (recommendation supported by WHO, ACIP, AST) (strong, moderate)  The benefit of vaccination outweighs any theoretical safety concerns related to rejection1
• LAIV is not recommended for posttransplant recipients (strong, moderate)
• Influenza vaccine should be given no earlier than 3 months after transplantation or intensified immunosuppression for rejection (weak, moderate)  During periods of pandemic or high influenza activity, vaccine can be given as early as 1 month posttransplant although incomplete protection may be achieved (strong, low)  If influenza activity is still significant, a reasonable approach is to re-immunize children and adults who received early vaccination (i.e. at < 3 months posttransplant) (weak, low)
• There are insufficient data to recommend  High-dose influenza vaccine  Adjuvanted vaccine  Intradermal vaccine  Booster doses of vaccine within the same season
• Close contacts of transplant patients should be immunized (strong, moderate)  Inactivated vaccine is preferred if available (strong, low)
• HCW including those working with transplant patients should be immunized (strong, moderate)  Inactivated vaccine is preferred if available (strong, low)
• Organs from donors that recently received LAIV (in the past 7 days) (including lung transplant donors) can be transplanted (strong, low)
• Influenza vaccination for children should follow the standard age and dose recommendation  At this time, vaccine dosing and the number of doses should follow age-appropriate recommendations as for nontransplant patients. Vaccine is not approved for administration to children younger than 6 months of age. Two doses 4 weeks apart are recommended for children younger than 9 years of age who have not been previously vaccinated against influenza. (strong, high)
• Persons with known severe allergic reactions to chicken or egg protein should not receive influenza vaccine; it can be considered to give vaccine under the supervision of an allergy expert (strong, high)

Influenza Vaccination

  1. Top of page
  2. Abstract
  3. Introduction
  4. Influenza Vaccination
  5. Immunogenicity of Vaccine in Organ Transplantation
  6. Influence of Immunosuppressive Regimen
  7. Timing of Influenza Vaccination
  8. Effects of Vaccination Including Allograft Dysfunction
  9. Pediatric Issues
  10. Summary
  11. Disclosure
  12. References

Annual influenza vaccination is the most effective method of preventing influenza virus infection and the associated complications (15). Influenza vaccines have been commercially available since 1945 in the United States. Globally, significant influenza vaccine production capability exists in Asia, Australia, Europe and North America. Annual vaccine composition is dependent on circulating influenza viruses and is based on recommendations from the World Health Organization and the Food and Drug Administration. Immunization recommendations vary from country to country, and range from universal influenza vaccination for all persons aged >6 months in the United States to vaccination of only those with high-risk conditions. The majority of influenza vaccines are derived from viruses grown in the allantoic cavity of embryonated chicken eggs; however, cell culture-based influenza vaccines have been licensed for use outside the United States.

There are two types of influenza vaccines: trivalent inactivated influenza vaccines (TIV) and live attenuated influenza vaccine (LAIV). Both types contain three strains of influenza (A/H1N1, A/H3N2 and B) selected for their anticipated circulation during the upcoming influenza season. TIV contains inactivated viruses that are incapable of replication in the host and is approved for use in all persons aged >6 months (Table 2). The amount of antigen in TIV varies by age (7.5 μg antigen/virus for ages 6 months to <3 years) and 15 μg antigen/virus for those >3 years of age. In addition to this, a higher dose (60 μg antigen/virus) vaccine has recently been licensed for use in those >65 years. Although the majority of TIV is administered by intramuscular injection, a newly licensed, intradermal preparation (16) has been approved for use for persons 18–59 years of age, with dosage level of 9 μg of hemagglutinin per viral strain. A 15 μg intradermal vaccine is also available for those ≥60 years. In addition to TIV, a quadrivalent inactivated vaccine formulation containing two influenza A and two influenza B strains, is under development. For persons receiving oral anticoagulation therapy, intramuscular administration of TIV is safe provided a fine needle is used and firm pressure is applied to the site (17).

Table 2.  Formulations of influenza vaccine
Vaccine (type, route)1Strength per antigenAge groupComments
  1. TIV = trivalent inactivated influenza vaccine; LAIV = live attenuated influenza vaccine; FFU = fluorescent focus units.

  2. 1Trade names used are most common ones in North America; similar vaccines may be known by various trade names elsewhere.

TIV – intramuscular (various manufacturers)7.5 μg<36 monthsTwo doses required for first-time vaccinees
TIV– intramuscular (various manufacturers)15 μg≥36 monthsCommonly used in adults pre- and posttransplant; several studies to support use
TIV – intramuscular Fluzone High Dose®60 μg≥65 yearsStudies ongoing in immunocompromised
TIV – intradermal Intanza®9 μg18–59 yearsNot studied posttransplant
TIV – intradermal Intanza®15 μg≥60 yearsStudies ongoing in SOT
TIV – intramuscular MF59 adjuvanted Fluad®15 μg≥65 yearsSmall studies in adult heart transplant and pediatric kidney transplant
LAIV – intranasal spray FluMist®106.5–7.5 FFU for each of 3 influenza strains per 0.2 mL dose2–49 years 2–59 years (Canada)Contraindicated posttransplant (see recommendations)

The LAIV is administered intranasally by spray and can cause mild respiratory symptoms related to viral replication (15). LAIV is contraindicated in immunocompromised and asthmatic individuals and is recommended only for healthy, nonpregnant individuals aged 2–49 years. This vaccine should not be used in transplant recipients. Although the vaccine virus is cold-adapted and should not replicate at body temperature, a theoretical risk of dissemination and transmission exists. Immunization of household contacts and health care workers serving transplant patients is clearly a priority. It is preferable to administer TIV to those in close contact with transplant recipients.

Inactivated influenza vaccines containing adjuvants are also available in many countries. Adjuvants can increase immunogenicity of vaccine antigens allowing for lower antigen doses. Examples include oil-in-water emulsion adjuvants such as MF59 (Novartis, Basel, Switzerland) and ASO3 (GlaxoSmithKline, London, United Kingdom) used in both seasonal and the pandemic H1N1 vaccines.

Requirements for licensure of influenza vaccines include demonstration in adults of (i) >70% seroprotection; (ii) >40% seroconversion or (iii) a seroconversion factor >2.5 (18). In general, seroprotection is measured by serum hemagglutination inhibition antibody (HAI) titers. HAI titers in the range of 1:32 or 1:40 are considered seroprotective (i.e. required to confer 50% protection against infection; Ref. 19) and higher titers are likely associated with more protection (15,20). The majority of healthy children and adults have robust responses after TIV; however, lower responses are documented in the elderly population and individuals with impaired immune systems. In addition, it is documented that children under nine require two vaccine doses to achieve protective antibody titers the first year they receive vaccine (21,22). Vaccine efficacy can be as high as 75–90% in healthy adults, but lower vaccine efficacy rates are seen in the young and elderly individuals (15).

Immunogenicity of Vaccine in Organ Transplantation

  1. Top of page
  2. Abstract
  3. Introduction
  4. Influenza Vaccination
  5. Immunogenicity of Vaccine in Organ Transplantation
  6. Influence of Immunosuppressive Regimen
  7. Timing of Influenza Vaccination
  8. Effects of Vaccination Including Allograft Dysfunction
  9. Pediatric Issues
  10. Summary
  11. Disclosure
  12. References

SOT recipients have demonstrated variable, albeit acceptable, responses to influenza vaccine. This variability may be due to several factors including, type of transplant, time from transplant, varying immunosuppressive regimens, and the different study endpoints (i.e. seroprotection vs. seroconversion). Overall responses have ranged from 15% to 93% (Table 3) with lower responses seen in lung transplant and greater responses several years after kidney transplant. For example, in one study, kidney transplant recipients who were 3–10 years posttransplant had 93% seroprotection rate to H1N1 antigen after vaccination (23). However, based on limited comparative data, it does not appear that responses can be reliably predicted based on the organ transplanted (24). Preexisting antibody and strain variation also confound immune responses. Although investigators have generally evaluated humoral responses to individual vaccine components by HAI assays, some investigators have also assessed antigen-specific T-cell responses. Data are more limited for vaccine efficacy and the prevention of laboratory confirmed influenza. However, at least one study suggests that the pandemic 2009 H1N1 vaccine was effective at preventing influenza in vaccinated lung transplant recipients (25). In addition, another recent study of Medicare patients that received kidney transplants suggests that influenza vaccine was associated with a lower rate of rejection and death (26).

Table 3.  Selected studies of influenza vaccine responses in adult organ transplant recipients
First author/year (ref #)Number of patients/organMode of vaccine/adjuvantHumoral responsesCellular responsesImpact of immunosuppressiveComments
  1. Pediatric studies summarized in text. TIV = trivalent inactivated vaccine; GMT = geometric mean titer; HCV = hepatitis C virus; IL = interleukin; DSA = donor specific antibody; MMF = mycophenolate mofetil; RCT = randomized controlled trial.

Blumberg/1996 (24)34 heart, 8 lung 13 kidney, 13 liver 1st year  23 heart second year vs. healthy controlsIntramuscular TIV/no adjuvantDecreased magnitude of GMT rise and seroprotection for SOTNot testedNo association with immunosuppressives2 consecutive years.  Response varied with viral strain  No impact of organ transplanted on response  No benefit to booster for heart transplant
Smith/1998 (40)38 kidney vs. 20 healthy controlsIntramuscular TIV/no adjuvantOverall similar response in both groups but controls had better responses to H3N2Not testedLower response for MMF vs. azathioprine (p < 0.05)No effect of a booster vaccine
Fraund/1999 (27)79 heart vs. healthy controlsIntramuscular TIV/no adjuvantDecreased magnitude of GMT rise and seroprotection for SOTNot testedNo associationResponse varied with vaccine strain  No graft rejection
Sanchez-Fructuoso/2000 (38)49 kidney vs. 37 healthy controlsIntramuscular TIV/no adjuvantTrend to lower responses in kidney transplant groupNot testedTrend to lower responses in MMF 
Mazzone/2001 (28)  Mazzone/2004 (35)43 lung vs. healthy controlsIntramuscular TIV/no adjuvantDecreased GMT and seroprotection for SOTNo increase in IL-2, IL-10, Interferon- gamma, or Granzyme B postimmunizationResponse lower with cyclosporine than tacrolimus (p = 0.042) 
Birdwell/2009 (29)53 kidney vs. healthy controlsIntramuscular TIV/no adjuvantDecreased GMT and seroprotection for transplantNot testedAll transplant patients on tacrolimus-based regimenVaried with viral strain. Reduced response if <6 months posttransplant
Gaeta/2009 (30)16 liver vs. 42 cirrhotics (23 compensated)Intramuscular TIV/no adjuvantDecreased GMT rise compared with compensated cirrhotics; equivalent seroprotectionNot testedNo associationVaried with viral strain
Lawal/2004 (31)51 liver, 25 with HCV, 26 without HCVIntramuscular TIV/ no adjuvantSimilar GMT and seroprotectionNot testedNo reported associationImproved response ≥4 months posttransplant; no rise in ALT observed after vaccine
Hayney/2004 (41)68 lung, 35 healthy controlsIntramuscular TIV/no adjuvantResponse 43% transplant vs 63% control (p < 0.05)Not testedMMF associated with poor response (p = 0.01); sirolimus associated with better response (p = 0.02)Most common underlying disease was cystic fibrosis
Manuel/2007 (32)60 lung transplantIntramuscular TIV followed by intradermal booster TIV/ no adjuvantIncreased GMT following first vaccine, no significant benefit from intradermal boosterNot testedBetter response with basiliximab 
Willcocks/2007(45)23 kidney, 9 liverIntramuscular TIV/no adjuvantGMTs significantly higher following vaccineNot testedGMT similar between sirolimus and CNI but sirolimus patients had protective titer to more influenza antigens 
Scharpe/2008 (23)165 renal vs healthy controlsIntramuscular TIV/no adjuvantComparable seroprotectionNot testedMMF associated with 2.6- to 5-fold lower responseNo benefit from booster
Salles/2010 (39)69 kidneyIntramuscular TIV/no adjuvantGMTs and seroconversion significantly greater postvaccine for influenza ANot testedSignificantly lower responses with MMF to influenza ANo response to influenza B
Manuel/2011 (70)85 lungRCT of intramuscular vs. low dose intradermal TIV/no adjuvantPoor response in both groups (14%–19%)Not testedHigh rate of thymoglobulin/tacrolimus and MMF usage in both groups 
Keshtkar-Jahromi/2008 (33)40 kidney vs. healthy controlsIntramuscular TIV/no adjuvantComparable GMT and seroprotectionNot testedReduced response to A/H1N1 in mycophenolate vs azathioprine (p < 0.05) 
Magnani/2005 (34)58 heart – randomized trialIntramuscular TIV, compared MF59-adjuvant vs nonadjuvant vs no vaccineNo difference with adjuvantNot testedNo association reportedUsed ELISA measurement, not specific to influenza strain  No difference in rejection rates between groups
Candon/2009 (61)66 kidney vs. 19 healthy controlsIntramuscular TIV/ no adjuvantLower GMT and seroresponse in transplant vs. healthy controlsCellular immunity comparable in both groupsNo difference in response for immunosuppressive therapiesNo new DSA postvaccination
Schuurmans/2011 (25)168 lung (148 vaccinated vs. 20 without vaccine)Intramuscular pandemic H1N1 influenza vaccine with AS03 adjuvant, 115 with booster doseNot testedNot testedNone reportedReduced H1N1 influenza in vaccine recipients
Manuel/2011 (71)29 SOT vs. 30 healthy controlsIntramuscular pandemic H1N1 vaccine with ASO3 adjuvant52% seroconversion in SOT compared to 77% controls at day 49Not testedLower responses in those on “triple immunosuppression” rather than dual or monotherapy87% seroconversion in HIV+ cohort
Brakemeier/2011 (63)60 kidney vs. 22 healthy controlsIntramuscular pandemic H1N1 vaccine with ASO3 adjuvant34.5% seroprotection compared to 91% controlsNot testedNo association with immunosuppressive regimenA booster dose given to 19 transplant patients showed only one additional patient benefitted from the booster; 5% had new DSA postvaccination
Meyer/2011 (72)47 heartIntramuscular pandemic H1N1 vaccine with ASO3 adjuvant32% seroprotectionNot testedNo association with immunosuppressive regimen 

Despite variable immune responses, most studies demonstrate that transplant recipients do mount a humoral immune response influenza vaccine, supporting recommendations for yearly influenza vaccine. Compared with healthy controls, however, they are less likely to respond to all serotypes and the level of seroprotection is usually reduced (23,24,27–31). Strategies to improve vaccine response include intradermal administration (32,33), additional doses (24,32), or the use of adjuvants (34). However, booster doses given in the same influenza season have not shown significantly increased responses. Additional data comparing humoral and cellular responses in transplant recipients compared with healthy controls are needed (28,35–37).

Influence of Immunosuppressive Regimen

  1. Top of page
  2. Abstract
  3. Introduction
  4. Influenza Vaccination
  5. Immunogenicity of Vaccine in Organ Transplantation
  6. Influence of Immunosuppressive Regimen
  7. Timing of Influenza Vaccination
  8. Effects of Vaccination Including Allograft Dysfunction
  9. Pediatric Issues
  10. Summary
  11. Disclosure
  12. References

Studies assessing the effects of specific immunosuppressive regimens on responses to influenza vaccine have been conflicting (Table 2). Several studies have assessed the effects of mycophenolate mofetil (MMF) on immune responses, with two reports finding comparable responses to azathioprine (33,38), whereas others have found diminished antibody responses in MMF-treated patients (39–41). In a recent trial of 165 kidney recipients, Scharpe et al. found that although MMF was associated with a 2.6- to 5-fold lower seroresponse rate, patients still had acceptable levels of seroprotection after immunization (23).

Most studies have shown a reduction in vaccine response in patients treated with cyclosporine-based regimens when compared with tacrolimus or azathioprine (28,42,43). Another early study, however, found no association between vaccine responses and cyclosporine levels in pediatric liver recipients (44).

Effects of sirolimus have been assessed by Hayney et al., who found improved vaccine responses in lung recipients on sirolimus (41), and by Willcocks et al., who found similar rises in antibody titer between sirolimus-treated and calcineurin inhibitor-treated liver and kidney recipients, with sirolimus-treated patients developing protective titers to more influenza antigens (45).

Limited information is available on the effects of monoclonal and polyclonal antibodies and vaccine immunogenicity. There are no published data on the effects of rituximab on vaccine responses in solid organ transplantation; extrapolation from studies in patients with rheumatologic disorders suggests that responses are diminished but not abrogated (46). In allogeneic hematopoietic stem cell transplant recipients, rituximab given in the year prior to vaccination was associated with significantly less seroprotection (47). Information is also lacking on the effects of alemtuzumab or antilymphocyte therapy on immunization responses in this setting.

Timing of Influenza Vaccination

  1. Top of page
  2. Abstract
  3. Introduction
  4. Influenza Vaccination
  5. Immunogenicity of Vaccine in Organ Transplantation
  6. Influence of Immunosuppressive Regimen
  7. Timing of Influenza Vaccination
  8. Effects of Vaccination Including Allograft Dysfunction
  9. Pediatric Issues
  10. Summary
  11. Disclosure
  12. References

Optimal timing of vaccination after SOT is likely to be very important in enhancing the immunologic response but there are very few trials that address this question. Many programs defer immunizations early after transplantation and most vaccine trials exclude patients who are less than two to six months posttransplant. The potent immunosuppression given at the time of organ transplant is likely to result in muted immunologic response to vaccination for at least several months. One early study of mixed organ transplant recipients showed no difference in the time after transplant in vaccine nonresponders versus responders (24). Conversely, a series of 51 liver transplant recipients found vaccine responses corresponded with the length of time after transplant with H1 strain responses of 1/7 (14%) within 4 months of transplant, 6/9 (67%) within 4–12 months, and 30/35 (86%) within 12 months posttransplant; overall, more than 55% of the subjects vaccinated 4–12 months posttransplantation had adequate seroconversion to the three strains of the influenza vaccine (31). This was confirmed by a more recent study that showed significantly lower antibody titers in kidney transplant recipients vaccinated within 6 months of transplantation when compared to healthy controls (29). However, responses were similar to healthy controls if transplant patients were vaccinated after six months.

In the absence of strong data to inform the clinical decision of vaccine timing, programs have developed local protocols, leading to variability among sites. A recent survey of 239 kidney transplant programs demonstrated that the majority of respondents began posttransplant vaccination within the first six months, with 42% of programs giving influenza vaccine within the first 3 months, 43% at 3–6 months, 13% at 6–12 months, and 3% waiting till more than 12 months after transplant (48). Guidelines from the American Society of Transplantation Infectious Diseases Community of Practice suggest that vaccination should be restarted at 3–6 months after transplant (49). During pandemic H1N1, expert guidelines suggested that transplant recipients receive H1N1 vaccine as soon as one month after transplant (50). Further studies are needed regarding optimal timing of influenza vaccine after organ transplantation.

Effects of Vaccination Including Allograft Dysfunction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Influenza Vaccination
  5. Immunogenicity of Vaccine in Organ Transplantation
  6. Influence of Immunosuppressive Regimen
  7. Timing of Influenza Vaccination
  8. Effects of Vaccination Including Allograft Dysfunction
  9. Pediatric Issues
  10. Summary
  11. Disclosure
  12. References

Influenza vaccine has generally been safe and well tolerated in transplant recipients. The safety profile of influenza vaccination does not appear significantly different from healthy controls in the published literature. However, one case of Guillain-Barré syndrome in a liver transplant recipient and another case of rhabdomyolysis leading to renal failure and kidney retransplantation after influenza vaccination have been reported (51,52).

It has also anecdotally been suggested that influenza immunization may be associated with early allograft rejection or allo-sensitization of patients after transplant. This is based on studies of T-cell responses to viral infections especially herpesviruses which establish latency unlike influenza that causes acute lytic infection without persistence. For example, CD8+ T cells that recognize viral peptides of Epstein-Barr virus and herpes simplex virus in association with self-MHC antigens may also cross-react with allo-MHC antigens. There is no specific evidence for this with inactivated viral vaccines such as influenza vaccine. (53–55). Another mechanism that could explain an increase in graft rejection following infection or vaccination is “heterologous immunity” which describes the development of alloreactive T cells in the absence of direct exposures to alloantigens (56). In an effort to evaluate the association between vaccination and alloreactivity, Danziger-Isakov et al. looked at postvaccination alloresponses in healthy volunteers and transplant recipients (57). In this study, both groups had increased T-cell responses to a panel of stimulators 2–4 weeks postvaccination, with lower responses among the transplant patients. However, these waned over 12 weeks, and no clinical rejection was seen in any of the transplant recipients in this study.

Humoral responses to HLA antigens following immunization have also been explored and may arise either from molecular mimicry between viral antigens and allo-HLA molecules or as a result of bystander activation. No clinical evidence for rejection or graft dysfunction following immunization has been reported in studies that have specifically looked at this outcome (31,34,58–60). Three studies have investigated the development of donor specific antibodies (DSA) after vaccination. One showed low-titer DSA in 3/66 previously stable kidney transplants but without evidence of acute rejection following immunization (61). Two studies using ASO3 adjuvanted vaccine were performed during the 2009 H1N1 influenza pandemic; one reported the development of anti-HLA antibodies after two doses of adjuvanted influenza vaccine in 20 of 151 (13.2%) of kidney transplant patients compared to a rate of 6% in historical controls (62). DSA was present in 8.6%. Another showed a rate of 5% for new DSA postsingle dose influenza immunization (63). In both studies, no clinical association between influenza vaccination and acute rejection was reported. This was a relatively high rate of alloantibody formation and may have been specific to the adjuvant or due to widespread infection during the pandemic.

Overall, preliminary data indicate areas for additional investigation but most importantly no convincing epidemiologic links between allograft dysfunction and vaccination has been found in studies of inactivated influenza vaccine given to transplant recipients. Given the potential risks of influenza infection in SOT, influenza vaccine should be administered to SOT recipients.

Pediatric Issues

  1. Top of page
  2. Abstract
  3. Introduction
  4. Influenza Vaccination
  5. Immunogenicity of Vaccine in Organ Transplantation
  6. Influence of Immunosuppressive Regimen
  7. Timing of Influenza Vaccination
  8. Effects of Vaccination Including Allograft Dysfunction
  9. Pediatric Issues
  10. Summary
  11. Disclosure
  12. References

The pediatric age group is unique in that two doses of vaccine are recommended for first time vaccinees under the age of 9. In addition, although LAIV elicits good responses in immunocompetent children, it should not be given to immunosuppressed children posttransplant. Compared to studies in adult transplant recipients, studies of influenza vaccine safety, immunogenicity, and efficacy in pediatric transplant recipients are very limited. Some of these studies were performed in the 1990s when immunosuppressive regimens differed significantly from current use. Nonetheless, taken together these studies have provided insight into the use and benefit of influenza vaccination in children undergoing organ transplantation as well as the need for future studies.

Studies of seasonal influenza vaccination in pediatric liver transplant recipients demonstrated seroprotective responses ranging from 38% to 71% depending on the influenza antigen used (64). Similarly, recent reports in pediatric kidney transplant recipients show variable seroprotective responses ranging from 31% to 85% depending on the vaccine strain (65,66). In a cohort of children postliver transplant, Mack et al. reported that younger age and shorter posttransplant time were factors for poorer vaccine response. In addition, there was no substantial increase in seroprotection with a second dose (67–72%). Similar to studies in immune competent individuals, responses to influenza A strains in pediatric transplant recipients are generally superior to responses to influenza B strains. Madan and colleagues looked at both cellular and humoral responses in a cohort of long-term pediatric liver transplant recipients (mean 52.3 months after transplant) and showed similar seroprotection and seroconversion, but decreased interferon gamma production compared to healthy sibling controls (64).

Data on pandemic vaccine responses in pediatric transplant patients are also available. Goldschmidt et al. retrospectively evaluated the acceptance and adverse events attributable to the use of an adjuvanted 2009 H1N1 vaccination in pediatric liver transplant recipients in Germany (67). Although measurements of seroresponse were not performed as part of this study, they noted the rates of H1N1 infection to be significantly higher in unvaccinated patients compared to vaccinated individuals (25% vs. 4%, p < 0.01). In pediatric kidney transplant recipients, Esposito et al. reported 81–100% seroprotection after administration of 2009 A/H1N1 MF59-adjuvanted influenza vaccine (66). Haller et al. found an increase from 66.6% to 89.5% after a second dose of vaccine against influenza A/pH1N1/09, concluding that two doses should be considered in transplant recipients in the pandemic setting. A small study looked at responses to the adjuvanted vaccine in five pediatric heart transplant recipients who were early (5–23 weeks) posttransplant (68). Despite recent induction therapy with antilymphocyte globulin, three of the five transplant recipients developed seroprotective titers after the adjuvanted vaccine. Importantly, significant side effects from vaccination including acute rejection were not found in studies of seasonal or pandemic influenza vaccines in the pediatric population.

Results of pediatric studies to date are limited by several important factors. Available studies focused mainly on pediatric kidney and liver transplant recipients, with a paucity of data from pediatric heart, and none from pediatric lung or intestine recipients. Also many of the studies were performed during periods of time when immunosuppressive regimens differed substantially from currently used immunosuppression. Many study patients are greater than 1–2 years posttransplant and data on immunogenicity and effectiveness of influenza vaccination for children closer to the time of transplantation remains limited. This is especially important for those in the first year after transplantation when the risk for developing more severe influenza disease is greater. Therefore, studies are needed to specifically understand the surrogate markers of immune responsiveness to ascertain the ability of individual patients to respond to immunizations.

Despite these limitations, results from published papers suggest that, at least for those patients 1 year or more from transplant, the use of influenza vaccine is associated with rates of seroresponse that are close to if not equal to immunocompetent children. Further, there does not appear to be any increased likelihood of developing vaccine-associated adverse events. In particular, none of the published studies found an association between influenza vaccination and an increased rejection rate. Many centers initiate vaccination in the early posttransplant period; a review by Benden and colleagues of 16 international pediatric lung transplant centers noted that while most centers waited 3 or more months to vaccinate, over a third of centers were willing to immunize earlier than 3 months during influenza season (69). Earlier immunization was frequently practiced during the 2009 pandemic influenza season as well (68).

Summary

  1. Top of page
  2. Abstract
  3. Introduction
  4. Influenza Vaccination
  5. Immunogenicity of Vaccine in Organ Transplantation
  6. Influence of Immunosuppressive Regimen
  7. Timing of Influenza Vaccination
  8. Effects of Vaccination Including Allograft Dysfunction
  9. Pediatric Issues
  10. Summary
  11. Disclosure
  12. References

In summary, influenza vaccine responses in adult and pediatric organ transplant recipients are quite variable and dependent on time from transplant and the immunosuppressive regimen in use; however, the benefit of vaccinating these vulnerable patients is clearly documented. Summary recommendations using the GRADE system are outlined in Table 1. This system takes into consideration the strength of recommendation, and quality of evidence. As outlined in Table 1, several important areas for further study in transplantation include data for newer formulations of influenza vaccine, the differential effects of various immunosuppressive regimens such as antithymocyte globulin and alemtuzumab on vaccine responses, and vaccine responses in the pediatric transplant population. In addition, strategies to improve immunogenicity are needed. Nevertheless, the benefits of influenza vaccine are clear from an individual and public health perspective and vaccination should be offered to all transplant candidates, recipients and their contacts.

Disclosure

  1. Top of page
  2. Abstract
  3. Introduction
  4. Influenza Vaccination
  5. Immunogenicity of Vaccine in Organ Transplantation
  6. Influence of Immunosuppressive Regimen
  7. Timing of Influenza Vaccination
  8. Effects of Vaccination Including Allograft Dysfunction
  9. Pediatric Issues
  10. Summary
  11. Disclosure
  12. References

The authors of this manuscript have the following conflicts of interest to disclose as defined by the American Journal of Transplantation:

D.K.: Hoffmann-LaRoche, Adamas (research grant); Sanofi-Pasteur (research support); M.I.: Research support (paid to University): ADMA, BioCryst, GlaxoSmithKline, Roche, ViraCor; Paid consultation: Abbott, Abbott Molecular, Astellas, Crucell, ViraCor; Unpaid consultation: Biota, Cellex, Clarassance, GlaxoSmithKline, NexBio, Roche, Toyama; Paid member of DSMB: NexBio; N.B.H.: Grants support from Sanofi Pasteur and Pfizer; data safety monitoring board for Novartis; M.G.: Chimerix-co-investigator, Bristol-Myers Squibb – Advisory Panel; K.E.: No conflicts. L.D.I.: Research support for clinical trials (paid to institution): Chimerix, Pfizer, Roche; R.K.A.: Research support (paid to institution): Roche, Schering-Plough, Medimmune, Viropharma, Chimerix; M.G.M.: Hoffmann-LaRoche, Chimerix, (research grant), Sanofi-Pasteur (research support); E.A.B.: None; C.N.K.: None; G.M.: None; U.D.A.: Hoffman la Roche (Unrestricted grant for Divisional educational activities); Pfizer (participant in multicenter research; advisory board member); ADMA (participant in multicenter research).

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Influenza Vaccination
  5. Immunogenicity of Vaccine in Organ Transplantation
  6. Influence of Immunosuppressive Regimen
  7. Timing of Influenza Vaccination
  8. Effects of Vaccination Including Allograft Dysfunction
  9. Pediatric Issues
  10. Summary
  11. Disclosure
  12. References