Update on Immunizations in Solid Organ Transplant Recipients: What Clinicians Need to Know
* Corresponding author: Robin Avery, firstname.lastname@example.org
Vaccine-preventable diseases remain a major source of morbidity and mortality in transplant recipients. Since the publication of the American Society of Transplantation's guidelines for vaccination of solid organ transplant recipients in 2004 (1), several new vaccines have been licensed. Transplant clinicians have been inundated by questions from patients and colleagues regarding the utility and safety of these vaccines in transplant candidates and recipients. In addition, new data has appeared regarding utility of some established vaccines, lack of rejection after vaccination and newer adjuvant strategies. Literature published between 2004 and 2007 was reviewed in a Medline search. Guidelines from the Centers for Disease Control and Prevention's Advisory Committee on Immunization Practices are reviewed and summarized, with particular attention to vaccines for human papillomavirus, varicella and varicella-zoster, tetanus-reduced diphtheria-acellular pertussis (Tdap) and hepatitis B, as well as conjugated meningococcal and conjugated pneumococcal vaccines. Although randomized controlled trials in transplant recipients have not been performed for most new licensed vaccines, preliminary recommendations can be formulated based on current data and guidelines. Further studies will be important to determine the indications and optimal timing of newer immunizations and immunization strategies.
In recent years, new licensed vaccines have extended the realm of vaccine-preventable diseases. As there are already a number of comprehensive reviews on standard vaccines for transplant candidates and recipients (1–11) and for potential travelers (12), the current review will focus on new developments in this field. Recently licensed vaccines include the human papillomavirus (HPV) vaccine (13), the zoster vaccine (14), the rotavirus vaccine (15) and the adolescent-adult tetanus-reduced diphtheria-acellular pertussis (Tdap) vaccine (16,17). In addition, new strategies for hepatitis B vaccination after liver transplantation will be discussed (18–23). The availability of conjugated meningococcal and pneumococcal vaccines has been a welcome development given suboptimal immunogenicity of standard vaccines in some studies (24–29).
Despite the burden of illness due to vaccine-preventable diseases in transplant recipients, licensed vaccines remain underutilized, as demonstrated in a 1997 national survey of bone marrow transplant centers (30). Guidelines for revaccination after hematopoietic stem cell transplantation have been published by the Centers for Disease Control and Prevention (CDC), the Infectious Diseases Society of America (IDSA) and the American Society for Blood and Marrow Transplantation (ASBMT) (31). The American Society of Transplantation's (AST) Guidelines for the Prevention and Management of Infectious Complications of Solid Organ Transplantation included tables of recommended vaccinations for transplant candidates and recipients (1). However, there continues to be a gap between guidelines and practice.
One reason for this gap could be concern that immunizations might trigger allograft rejection (32), although most large studies in the past have not shown an increase in rejection rates after standard immunizations. Several recent studies provide additional data in support of the lack of excess incidence of rejection and the general safety of vaccinations in organ transplant recipients (33–37).
Vaccination coverage of health-care workers, including those caring for transplant patients, is often suboptimal as well (38). The 2007 National Patient Safety Goals of the Joint Commission (http://www.jointcommission.org) includes ‘Reduce influenza and pneumococcal disease’ as Goal #10. It is an excellent time to put systems in place for vaccination of solid organ transplant recipients and candidates according to established guidelines. In addition, these guidelines should be revised as new vaccines are licensed and additional information becomes available.
Human Papillomavirus (HPV) Vaccine
HPV is the most common sexually transmitted disease in the US, causing 6.2 million new infections per year (13). HPV types 6 and 11 cause approximately 90% of genital warts (condylomata) (13). Although many infections are asymptomatic, high-risk HPV types are involved in the pathogenesis of 99% of cervical cancers as well as other anogenital cancers (13). High-risk types 16 and 18 are associated with 70% of cervical cancers (13).
In 2006, a quadrivalent HPV vaccine was licensed in the US for girls and women ages 9–26. This vaccine utilizes the L1 major capsid protein of HPV for types 6, 11, 16 and 18, and is not a live vaccine (13). The Advisory Committee on Immunization Practices (ACIP) has recommended that all girls ages 11–12 be vaccinated, with catch-up vaccination for those up to age 26; the series is three doses at 0, 2 and 6 months. The vaccine appears to be highly effective for prevention of persistent infection and cervical cancer due to the vaccine strains (13). The vaccine is most efficacious when administered before sexual debut and before acquisition of one or more of the vaccine strains of HPV (13); nonetheless, some benefit may be gained from protection against the other strains in a patient with preexisting infection.
Transplant recipients with anogenital HPV infection are at 20–100-fold increased risk of cervical intraepithelial neoplasia and other anogenital malignancies (39). In addition, transplant recipients are at high risk for HPV-related warts and skin cancers. As of the present time, no published studies of immunogenicity of this vaccine in transplant recipients and candidates are yet available. Since it is not live, it could theoretically be given after transplantation. For optimal response, it is advisable to administer the HPV vaccine to pretransplant candidates according to current guidelines (nonpregnant female transplant candidates between the ages of 9 and 26). The recommended gender and age recommendations will likely broaden when further data on the vaccine's efficacy in transplant recipients and candidates becomes available.
Varicella-Zoster (Shingles) Vaccine
Herpes zoster (shingles) represents the reactivation of varicella-zoster virus (VZV) acquired during primary varicella infection earlier in life. Clinical manifestations in transplant recipients vary from a painful, blistering, uni- or multi-dermatomal eruption to a severe, sometimes fatal form with cutaneous and/or visceral dissemination (40). Presentation with abdominal pain and without rash is a particularly challenging diagnostic dilemma.
A new zoster vaccine (Zostavax) has been approved in the US for prevention of herpes zoster (shingles), and is distinct from the standard varicella vaccine (Varivax). The new zoster vaccine is live-attenuated, uses higher titers of the vaccine strain of virus than are used in the Varivax, and is designed to stimulate a boost in waning immunity in the elderly population. A randomized trial of over 38 000 adults demonstrated a reduction in herpes zoster of >50% (14). Provisional ACIP recommendations call for a single dose of zoster vaccine for individuals ages 60 and above, whether or not they report a prior episode of herpes zoster, unless a contraindication exists (41). According to licensing information, contraindications include immunodeficiency states and immunosuppressive therapy, as well as pregnancy and active tuberculosis (42). Because it is a live vaccine, posttransplant recipients should not receive the zoster vaccine. Further data are awaited regarding whether it is efficacious in preventing posttransplant zoster when administered to varicella-seropositive pretransplant candidates not receiving immunosuppressive therapy. Varicella-seronegative pretransplant candidates should continue to receive the standard varicella vaccine (Varivax) according to current guidelines (1).
Varicella vaccine, a live-attenuated vaccine, was traditionally considered contraindicated in posttransplant patients (1). Given the risk of primary varicella in seronegative transplant patients, every effort should be made to vaccinate seronegative patients prior to transplant. Despite these efforts, however, some patients will still be found to be seronegative after transplantation.
There are several recent studies which suggest that varicella vaccine (Varivax) may be safely administered to certain transplant recipients. Weinberg et al. immunized 16 VZV-naïve pediatric kidney and liver transplant recipients with varicella vaccine, but none were early posttransplant (range 257–2045 days posttransplant) (43). Four developed fever and four developed rashes, of whom three received acyclovir. None developed elevated liver enzymes. Evidence of humoral and cellular immunity developed in 86–87%. Subsequent varicella exposures did not result in chickenpox (43). Khan et al. immunized 26 pediatric liver recipients with measles, mumps, rubella vaccine (MMR) and with varicella vaccine and noted seroconversion in 73% and 64.5%, respectively (18 and 7 children required booster doses of vaccine, respectively) (44). Adverse events were similar to those in the general population (44). On the other hand, Kraft and Shaw reported varicella infection due to the Oka vaccine strain requiring i.v. acyclovir therapy in a heart transplant recipient who had received varicella vaccine as part of a preemployment protocol (45). In addition, Levitsky et al. described a liver transplant recipient, previously seronegative for varicella, who received postexposure varicella vaccine and required hospitalization twice for cutaneous varicella infection (46). In summary, there is growing evidence that varicella vaccine may be safe, particularly, in seronegative pediatric transplant recipients who are not in the early posttransplant phase and who are clinically stable, but case reports suggest that the vaccine is not necessarily safe for all posttransplant patients. Larger studies would be helpful to identify the population of transplant recipients in whom varicella vaccine is indicated.
Tetanus Toxoid-Reduced Diphtheria Toxoid-Acellular Pertussis (Tdap) Vaccine
Tetanus, diphtheria and pertussis immunization is part of the routine vaccination series for infants and young children, but until recently adolescents and adults received only booster doses of tetanus-diphtheria (Td) vaccine. However, pertussis immunity wanes 5–10 years after initial immunization, and >25 000 cases of pertussis were reported in the US in 2005 (17). Pertussis, caused by Bordetella pertussis, is an acute respiratory infection characterized by severe paroxsyms of cough; deaths can occur, particularly, in young infants. It is quite likely that pertussis in adults is under-reported. In 2005, the Tdap vaccine was licensed in the US for persons 11–64 years of age. Currently, the ACIP recommends a single dose of Tdap as a booster for adults whose last Td was >10 years ago, for health-care workers and for persons who are in close contact with infants <12 months of age. Tdap can be given as little as 2 years (or shorter intervals) after Td vaccine in high-risk persons (17).
There is little information on the incidence or severity of pertussis in transplant recipients, although Ner et al. reported two pediatric lung recipients with pneumonia due to B. bronchoseptica (an animal-associated Bordetella which causes ‘kennel cough’) (47). In accordance with ACIP guidelines for the general public, it would make sense to vaccinate transplant candidates with Tdap during the pretransplant evaluation when the clinician would otherwise administer a Td booster. Tdap is not a live vaccine and therefore could theoretically be given to posttransplant patients, though its efficacy in this population is unknown.
Hepatitis B Vaccine After Liver Transplantation
For recommendations concerning hepatitis B vaccination in other transplant-related settings, the reader is referred to the AST ID Guidelines (1,48) and for prevention of donor-derived hepatitis B virus (HBV), to the helpful review by Chung, Feng and Delmonico (49). Liver transplantation performed for hepatitis-B-related cirrhosis is generally accompanied by long-term prophylaxis with hepatitis B immune globulin (HBIg) and/or lamivudine to prevent recurrence of HBV infection. However, administration of HBIg long-term is extremely costly, and resistance to lamivudine can occur. Therefore, considerable effort has been directed toward vaccinating posttransplant liver recipients with HBV vaccine with the goal of truncating prophylaxis. While vaccine efficacy in these studies has often been suboptimal (21,22), recent work involving adjuvants has produced more promising results. Bienzle et al. vaccinated 20 liver recipients with five doses of one of two HBV vaccines using novel adjuvants between 0 and 18 weeks posttransplant; three additional doses were administered to those who did not seroconvert (50). Using this regimen, 16/20 (80%) seroconverted and were able to discontinue HBIg (50). In a subsequent study, 11 of these responders were revaccinated with double-dose conventional HBV vaccine and anti-HBs titers increased significantly (19). Larger studies are awaited with interest.
Meningococcal Conjugate Vaccine
Immunogenicity of polysaccharide vaccines is limited under the age of 2 years; consequently, conjugated vaccines have been developed against Pneumococcus, H. influenzae and most recently N. meningitidis. Annually, 1400–2800 cases per year of meningococcal disease occur, with peaks in infancy and in adolescence (51). The meningococcal conjugate vaccine (MCV 4) was approved for use in 2005 for ages 11–55. Like the previous meningococcal polysaccharide vaccine (MPSV 4), it confers protection against meningococcal types A, C, Y and W-135, but not type B (51). The previous vaccine was immunogenic in individuals over the age of 2, but titers wane after 2–3 years especially in children. Recently the ACIP has recommended that all 11–12-year-olds be immunized with MCV 4 at their preadolescent visit (51). In addition, incoming college freshmen who will be living in dormitories are at higher risk and should be offered the vaccine. For high-risk individuals ages 2–10 or >55, MPSV 4 should be administered (51).
As yet, no comparative data on efficacy of MCV 4 and MPSV 4 in transplant candidates and recipients has been reported. It is reasonable to follow the guidelines for the general population as neither vaccine is a live vaccine. A pretransplant candidate in the 11–18-year-old age group would be particularly important to vaccinate.
Pneumococcal Conjugate Vaccine
The traditional pneumococcal vaccine is a 23-valent polysaccharide vaccine (PPV23), which is not immunogenic in children under the age of 2. The 7-valent pneumococcal conjugate vaccine (PCV7) was licensed in 2000 for infants 2 months and older, with a recommended primary dosing series of 2, 4, 6 and 12–15 months (52). As immunogenicity of the pneumococcal polysaccharide vaccine is not always optimal in solid organ recipients (24–26), Kumar et al. conducted a randomized controlled trial of a single dose of PPV23 versus PCV7 in 60 renal transplant recipients (53). Vaccine response rate was improved for two serotypes and mean titers were higher for two serotypes in the PCV7 group, but functional antibody responses were not significantly different (53). In a follow-up study of the same patients, titers declined significantly after 3 years with both PPV23 and PCV7; the authors concluded that PCV7 does not improve durability of response (28). However, studies with administration of booster doses would be of interest.
Lin et al. assessed the safety and immunogenicity of the currently recommended schedule of pneumococcal vaccinations in pediatric solid organ transplant recipients who had not received a primary series in infancy (29). Transplant recipients between the ages of 2 and 18 years received two doses of PCV7 followed by one dose of PPV23; age-matched controls received one dose of PCV 7 then PPV23. Although significant rises in serotype-specific pneumococcal antibodies were observed in both groups, transplant recipients had lower antibody responses, and heart transplant recipients had a lower response than liver recipients. These responses to PCV7 serotypes were not boosted by the 2nd PCV7 or the PPV23 vaccine. More studies are needed to determine the optimal number of doses and interval between doses in this population.
Rotavirus is the most common cause of serious childhood gastroenteritis resulting in up to 70 000 hospitalizations per year in the United States alone. A human-bovine reassortant live-attenuated rotavirus vaccine, RotaTeq, was licensed for use in children between the ages of 6 and 32 weeks. A previous rhesus-based rotavirus vaccine was withdrawn from the market 1 year after approval due to an association with intussusception (54). Data on the current vaccine are insufficient with respect to efficacy and safety in immunocompromised hosts, and the vaccine is listed as a precaution by the ACIP but not a contraindication (55). However, because of the significant age restrictions, (first dose must be administered by 12 weeks of life and last dose by 32 weeks), it is likely to be most useful for pediatric candidates. Shedding after the first dose can occur between 1 and 15 days. Shedding has not been found after the 2nd and 3rd doses of vaccine. There are currently no data on the risk of household transmission of the vaccine strain of virus. It would appear reasonable for infants living in the household of transplant recipients to receive the vaccine to prevent wild-type rotavirus, which would pose more of a threat to transplant recipients; however, transplant recipients should be advised to use good hand washing techniques after changing the diapers of vaccinated children.
Vaccines and the Pretransplant Evaluation
The importance of the pretransplant evaluation as a time for reassessment of the candidate's vaccine status cannot be over-emphasized. Gasink et al. found that only 62.4% of lung transplant candidates reported prior pneumococcal vaccination, despite anticipation of 100% coverage due to underlying lung disease (56). Transplant centers should develop systems to screen for prior vaccination and to update vaccination status in transplant candidates. In high-risk populations such as lung transplant candidates, humoral immune surveys including pneumococcal, measles, hepatitis B surface antibody and other serologic titers provide additional information on the adequacy of prior vaccinations, and can serve as a guide to the need for booster doses pretransplant (57).
Lack of Association Between Influenza Vaccine and Rejection
Clinicians' reluctance to administer vaccines to transplant recipients stems from a variety of factors, including fear of precipitating allograft rejection. Anecdotal reports are common but there is little firm evidence of this association. In a study of a two-dose series of influenza vaccine in heart transplant recipients by Blumberg et al., 4/14 vaccine recipients compared with 1/14 controls had episodes of rejection (p = .326) (32). Most previous studies had shown a lack of association between influenza vaccine and rejection (58,59).
Several recent studies provide additional evidence of the safety of influenza vaccination after transplant. Studies by Burbach et al. (33) and Lawal et al. (35) involved 62 and 51 liver transplant recipients, respectively, and demonstrated the safety of influenza immunization in this population. Neither excess rejection nor elevation of ALT levels was documented (35).
In heart recipients, Magnani et al. performed a randomized trial of two different influenza vaccines (36). Flu symptoms were reported by 33% and 29% of patients in the vaccinated groups, as compared with 61% of the nonvaccinated control group. No differences in rejection were noted (36). Kimball et al. studied 29 vaccinated heart recipients and found no increase in alloantibodies nor changes in lymphocyte subpopulations and no excess rejection (34). The largest study to date, a multi-institutional study by White-Williams et al. of 3601 patients, revealed a disparity of practices. Of 28 centers, 5 required patients to be 12 months posttransplant, 1 center 6 months and 1 center 3 months posttransplant before administering influenza vaccine, while 3 centers did not administer influenza vaccine at all (37). There were no differences in overall rejection rates, nor in rejection episodes by month, between centers with different vaccination policies (37). The authors concluded that influenza vaccine can safely be administered to heart recipients (37).
Vaccine Compliance Among Health-Care Workers
The other side to the under-utilization of licensed vaccines in transplant recipients is the suboptimal immunization rates in health-care workers themselves. In one study in a tertiary-care hospital, only 18% of health-care workers were fully immunized according to current guidelines (60). Only half had received influenza vaccine in the preceding 12 months (60). Systems must be created to provide positive incentives to individual health-care workers and to groups providing direct care, to create a circle of protection around the transplant recipient.
Halpern et al. conducted a survey of transplant surgeons, receiving 347 responses (56% response rate) (38). Of surgeons for whom vaccination was indicated, 22.5% had received less than the recommended three doses of HBV vaccine. Of the 27.3% of surgeons reporting at least one needlestick while operating on an HBV-infected patient, 14.9% were inadequately vaccinated (38). This study underscores the need for emphasizing adequate vaccination for transplant clinicians as well as for patients. Health-care workers should receive, at minimum, yearly influenza vaccination, a full three-dose HBV vaccine series and measles, mumps, rubella and varicella vaccination (unless already immune). In addition, a single dose of Tdap (see above) should be given according to current guidelines (17). True vaccine contraindications occur in only a very small percentage of the general population; a fear of becoming ill after immunization is both irrational and potentially detrimental to the individuals themselves and to the patients for whom they provide care.
In summary, the last several years have witnessed significant changes in the area of licensed vaccines. The HPV vaccine, zoster vaccine and tetanus-reduced diphtheria-acellular pertussis (Tdap) vaccine have been introduced. For these newer vaccines, additional data on efficacy in transplant candidates and (for the HPV and Tdap vaccines) transplant recipients, will be welcome. Additional data has been reported concerning the safety of live-attenuated varicella vaccine in some transplant recipients. The use of adjuvants has produced promising results in some studies of HBV vaccination after liver transplantation. Conjugated meningococcal and pneumococcal vaccines have been developed to enhance immunogenicity and may confer slight advantages in adult recipients. Further evidence has been provided regarding the safety of influenza vaccination and lack of association with rejection. Finally, the issue of adequate immunization of health-care workers, including transplant clinicians, has been highlighted. The adequate immunization of the transplant candidate, transplant recipient and transplant clinician should be a prominent goal of transplant centers in accordance with increasing emphasis on patient safety and adherence to existing guidelines.