REVIEW URRENT C OPINION
Immunizations following solid-organ transplantation Deepali Kumar
Purpose of review To highlight the latest evidence for the use of key vaccines that are recommended in organ transplant candidates and recipients. Recent findings Influenza vaccine is the best studied vaccine; factors affecting immunogenicity of this vaccine include time from transplant, use of mycophenolate mofetil and type of transplant. Newer formulations of influenza vaccine are available, but data for these are limited. Updated recommendations include giving conjugated pneumococcal vaccine to adult transplant candidates and recipients followed by the polysaccharide vaccine to increase serotype coverage. Human papillomavirus vaccine should also be given to transplant recipients, although the immunogenicity may be suboptimal. Quadrivalent meningococcal conjugate vaccine needs to be given in special circumstances such as to patients who are starting eculizumab therapy. Live vaccines in general are contraindicated, although increasing safety data are emerging for Varicella vaccine. Herpes Zoster vaccine may be offered prior to transplant, although the utility of this strategy regarding protection from shingles after transplant is not known. Newer vaccines such as inactivated zoster vaccine and vaccines for the prevention of cytomegalovirus are under study. Summary Immunization for organ transplant recipients is an important part of pretransplant evaluation and the long-term care of the transplant recipient. Keywords Herpes Zoster, influenza, pneumococcus, vaccine
INTRODUCTION Vaccine-preventable diseases cause morbidity and mortality in organ transplant recipients. Prevention with vaccines is key to reducing complications. However, it is important to be aware of the types of vaccines, timing and effectiveness or immunogenicity of these vaccines in the transplant setting, as well as the vaccine responses with a variety of immunosuppressives. There are special considerations for pediatric transplant recipients as well. In general, there are no large-scale vaccine efficacy studies in the transplant population and most studies rely on measuring laboratory correlates of protection. Key vaccines include influenza, pneumococcal, human papillomavirus (HPV), and live vaccines such as Varicella Zoster, Measles–Mumps– Rubella (MMR) and Herpes Zoster. Here, we discuss these key vaccines recommended for transplant recipients, their updated formulations and recommendations for use (Table 1).
GENERAL PRINCIPLES OF IMMUNIZATION IN SOLID-ORGAN TRANSPLANTATION In general, humoral and cellular responses to vaccines after transplantation are suboptimal.
Therefore, when possible, it is important to immunize patients while they are awaiting transplant. This can best be done as part of a comprehensive pretransplant evaluation. Vaccine responses in persons on hemodialysis or with chronic liver disease are not as optimal as in healthy individuals, but are in general better than after transplantation. For example, in a study by McCashland et al. [1], liver transplant candidates received pneumococcal polysaccharide vaccine (PPV). Although patients had a significant increase in antibody levels initially, titers significantly declined by 3 months after liver transplant. Studies with influenza vaccine have also shown that humoral responses are greater in hemodialysis patients compared with transplant recipients [2,3].
Transplant Infectious Diseases and Multi-Organ Transplant Program, University Health Network, Toronto, Ontario, Canada Correspondence to Deepali Kumar, MD, MSc, FRCPC, 11-PMB-174, 585 University Avenue, Toronto, ON, Canada M5G 2N2. Tel: +1 416 340 4241; fax: +1 416 340 4043; e-mail: [email protected] Curr Opin Infect Dis 2014, 27:329–335 DOI:10.1097/QCO.0000000000000078
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KEY POINTS Vaccine-preventable diseases cause morbidity and mortality in transplant patients. Immunization should be evaluated prior to transplant when possible as well as updated during the long-term care of the transplant recipient. Inactivated influenza vaccine should be administered annually. Pneumococcal conjugate vaccine (13 valent) should be used for adult immunization followed by pneumococcal polysaccharide vaccine (23 valent). Live vaccines are generally contraindicated after transplant, although there are increasing data regarding the safety of Varicella vaccine.
INFLUENZA VACCINE Influenza illness can be severe in transplant patients and commonly leads to lower respiratory tract infection and rarely extrapulmonary complications such as myocarditis and myositis [4]. During the 2009 pandemic of influenza A/(H1N1)pdm09, a multicenter review of influenza illness showed a hospitalization rate of 71% and death in 4% of transplant patients [5]. In addition to the direct effects of viral infection, influenza infection has also been associated with allograft dysfunction as well as acute and chronic rejection in lung transplant recipients [6–9]. Influenza vaccine is the most common method of illness prevention and in general receives the greatest attention in the literature as it is an annual vaccine. The standard influenza vaccine is a trivalent inactivated formulation containing two A
strains and one B strain of circulating influenza. The specific strains change annually based on the recommendations by the World Health Organization. In the near future, quadrivalent vaccines containing an additional B strain will become available in many areas. Immunogenicity to influenza vaccine is measured by seroprotection (a strain-specific titer of 1 : 40 by hemagglutination inhibition assay) and seroconversion (a four-fold rise in titer compared with prevaccination values). In transplant recipients, immunogenicity varies greatly from 15 to 95% [10]. The variability in vaccine response is likely because of the heterogeneity of studies that involve various types of transplant and a variety of immunosuppressives. The American Society of Transplantation recommends influenza vaccine to be given to organ transplant recipients starting at 3–6 months after transplantation; other guidelines however, recommend that vaccine can be given as early as 1 month after transplant [11,12,13 ]. Time from transplant is shown to be an important factor affecting immunogenicity; therefore, although some patients may respond, earlier vaccination may not be as immunogenic [14]. For example, studies have shown that vaccination after 6 months to 1 year after transplant is more immunogenic than earlier vaccination [15,16 ]; however, it is unclear whether the greater immunogenicity obtained when administering vaccine later after transplant translates into improved protection. For example, Hurst et al. [17] studied a large United States Renal Data System (USRDS) database of kidney transplant recipients. Patients who received influenza vaccine in the first year after transplant had better graft survival at 3 years. Approximately 43% of those who received &&
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Table 1. Recommended routine vaccines for organ transplant recipients Vaccine
Pretransplant
Posttransplant
Influenza (inactivated)
þ
þ
Pneumococcal PCV13 followed by PPV23
þ
þ
Hepatitis A
Comments Limited data for adjuvanted or high-dose vaccines Routine for those with underlying liver disease
Hepatitis B
þ
þ
Double-dose vaccine for transplant recipients
HPV
þ
þ
Immunogenicity data with quadrivalent vaccine. No data with bivalent vaccine.
Tetanus, diphtheria, polio, acellular pertussis
þ
þ
Hemophilus influenza B
þ
þ
Meningococcal – quadrivalent conjugate
þ
þ
Measles–Mumps–Rubella
þ
–
Varicella Zoster
þ
þ/–
Herpes Zoster
þ
–
Based on risk factors and prior to eculizumab Safety shown in small studies and careful patient selection No safety data after transplant. Contains much greater PFU of Varicella Zoster virus than Varicella vaccine
PCV13, pneumococcal conjugate vaccine 13-valent; PFU, plaque-forming units; PPV23, pneumococcal polysaccharide vaccine 23-valent. HPV, Human Papillomavirus Vaccine.
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Immunizations following solid-organ transplantation Kumar
vaccine in the first year were immunized in the first 6 months after transplant. The use of mycophenolate mofetil (MMF) is also a well known factor leading to diminished immunogenicity [3,18]. A recent study found that higher doses of MMF of at least 2 g daily reduced the seroconversion rate of influenza vaccine [16 ]. The mechanism of this is likely because of inhibition of influenza-specific responses in B and T cells (Egli, Kumar, unpublished observation). Type of transplant is also an important factor in predicting immunogenicity; studies in lung transplant recipients consistently show lower immunogenicity rates than those in kidney transplant [19,20]. Given the poor immunogenicity of the standard inactivated influenza vaccine, investigators have attempted to find alternative methods to improve immunogenicity. This has included giving two or three doses of vaccine in the same season, or boosting the initial vaccination with a lower dose intradermal booster [18,20–24]. However, these methods have not been found to substantially increase immunogenicity. An intradermal delivery system for influenza vaccine has also been developed; intradermal vaccines take advantage of the greater number of dendritic cells present in the dermis as these act as potent antigen-presenting cells. A randomized trial of high-dose intradermal vaccine vs. standard dose intramuscular vaccine in 212 organ transplant recipients did not find a difference in immunogenicity between the two groups [16 ]. An adjuvanted formulation of influenza vaccine, containing MF59 adjuvant, has been available in Europe for several years. Adjuvants are molecules that, when combined with a vaccine antigen, can enhance the immunogenicity of the antigen. The adjuvant attracts a greater number of inflammatory cells to the site of immunization, thereby enhancing vaccine response [25 ,26]. In transplantation, there are limited data on adjuvanted seasonal influenza vaccine; however, an adjuvanted pandemic vaccine that used the ASO3 adjuvant system was widely used in the clinical setting and studied during the 2009 influenza A pandemic. In studies to date, adjuvanted pandemic influenza vaccine does not appear to have greater immunogenicity compared with standard vaccine [27–31]. High-dose vaccines containing four times the standard antigen have also become available and data suggest that these have improved efficacy in the older age groups [32]; however, there are no safety and immunogenicity data for this formulation in transplantation. &&
function. The mechanisms by which this may occur include molecular mimicry and bystander activation. Several investigators have studied this by determination of human leukocyte antigen (HLA) alloantibody upregulation after vaccination. In studies done with seasonal influenza vaccine, there have been no definitive reports of HLA alloantibody upregulation. Many recent studies dealing with the immunogenicity of influenza vaccine have included the assessment of HLA alloantibodies [16 ,33]. However, no specific association has been noted for seasonal influenza vaccine. Particular attention was paid to this phenomenon during the 2009 influenza A/H1N1 pandemic, during which time monovalent influenza vaccine with the ASO3 adjuvant system was available in Europe and Canada. Some studies showed greater rates of HLA alloantibody upregulation after immunization with this vaccine [34,35], although this did not translate into clinical allograft dysfunction. A case–control study in heart transplant recipients during the pandemic also showed a higher rate in cellular rejection after those that were immunized vs. nonimmunized controls [36]. In summary, studies that have shown HLA alloantibody upregulation are those done with adjuvanted vaccine during the pandemic. These studies are difficult to interpret primarily because of lack of appropriate controls and the potential for patients to have influenza infection during the study period. &&
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INFLUENZA VACCINE AND ALLOGRAFT FUNCTION It has been anecdotally suggested that influenza vaccine may have an adverse effect on allograft
PNEUMOCOCCAL VACCINE Pneumococcal disease after organ transplant has a relative risk of up to 13 times greater than the general population [37]. Therefore, pneumococcal vaccine is recommended for transplant candidates and recipients. Both 13-valent conjugated vaccine (PCV13) and 23-valent polysaccharide vaccine (PPV23) are available for use. Recently, PCV13 was recommended by the Advisory Committee of Immunization practices in the United States and by the National Advisory Committee on Immunization in Canada for use in transplanted adults [38 ,39]. Studies in the transplant population with the 7-valent conjugate vaccine (PCV7) show marginally increased serotype-specific immunity. In a pilot randomized controlled trial of PCV7 vs. PPV23 in 60 kidney transplant patients, there was a trend to greater response rates with PCV7 (response to at least one serotype was 73% with PCV7 vs. 53% with PPV23, P ¼ 0.11) [40]. Subsequently, a long-term follow-up of these patients showed that pneumococcal titers returned to baseline in 3 years regardless of the type of vaccine [41]. A prime-boost strategy has been suggested in immunocompromised persons. In this strategy, pneumococcal conjugate vaccine (PCV) is given initially followed after an
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interval (usually 8 weeks) by PPV. In theory, the T-dependent response elicited by PCV should create antibodies of high avidity as well as memory B cells. The follow-up immunization with PPV can then stimulate memory B cells to produce high levels of specific antibody. The immunogenicity of pneumococcal vaccination using this strategy has been explored in several studies. However, the boosting effect with PPV for the serotypes in PCV has not been found to occur in the organ transplant setting [42–44]. Nevertheless, the administration of PPV23 provides additional serotype coverage over PCV13.
LIVE-ATTENUATED VACCINES (VARICELLA AND MEASLES–MUMPS–RUBELLA) In general, live-attenuated vaccines are not recommended after transplantation because of the possibility of vaccine-related viral disease. For example, inadvertent administration of varicella vaccine to a seronegative heart transplant recipient has been reported to cause disseminated varicella [45]. Therefore, live vaccines are generally suggested to be given at least 4 weeks prior to transplant. However, in carefully performed studies, investigators have administered varicella vaccine to seronegative children after transplantation [46 ,47,48]. Many of these studies are done in long-term transplant recipients who are receiving low doses of immunosuppression. Adverse events have been uncommon, suggesting that vaccine could safely be given after transplant. However, the selection of patients to receive Varicella vaccine after transplant as well as the risks and benefits of the vaccine need to be carefully considered and should only be performed in select patients with careful monitoring and availability of antivirals in case of complications. There are no studies of MMR vaccine administration after organ transplant. There are no specific antivirals for measles, mumps or rubella, and MMR vaccine is contraindicated after transplant. In cases of inadvertent immunization or exposure to wildtype measles, passive immunization with immune globulin can be used to decrease the risk of disease. &&
units of attenuated zoster virus. The Shingles Prevention Study, done in immunocompetent persons at least 60 years of age, showed that it is 51% effective in the prevention of Herpes Zoster and 67% effective in the prevention of postherpetic neuralgia [52]. A subsequent study showed greater effectiveness of the vaccine in a younger 50–59-year-old population [53]. Current guidelines suggest that the vaccine is contraindicated after transplant. However, it can be administered prior to transplant. A period of up to 4 weeks should elapse, however, before transplantation takes place. The effectiveness or immunogenicity of pretransplant vaccination in the prevention of posttransplant Herpes Zoster disease is not known. Trials to determine the immunogenicity of Herpes Zoster vaccine before transplant are ongoing. In addition, inactivated formulations of Herpes Zoster vaccine are undergoing clinical trials and these may be useful in the posttransplant setting.
HUMAN PAPILLOMAVIRUS VACCINE Transplant recipients are thought to be at greater risk of HPV-related cervical cancer and anogenital warts than the general population, given the reduced cancer surveillance from immunosuppression [54]. However, other studies indicate that the risk is similar to that of the general population [55,56]. A recent large review of U.S. transplant recipients showed an increased incidence of HPVrelated cancers (e.g. vulvar, anal and penile cancer), although the incidence of cervical cancer was similar to that of the general population [57 ]. Studies in the general population show benefit of HPV vaccine in girls and women aged 9–45 as well as boys and men aged 9–26 [58–60]. Therefore, HPV vaccine should also be offered to transplant candidates and recipients in the standard three-dose schedule. In eight transplant adolescents who received the complete HPV vaccine series and had results available 1 month after the last dose, all developed seroconversion to the four HPV types [61]. Another study in 47 transplanted adults aged 18–35 years, using the quadrivalent HPV vaccine, showed immunogenicity ranging from 52.6 to 68.4% [62 ]. This study also showed that shorter time from transplant and lung transplantation were the factors contributing to decreased immunogenicity. Therefore, despite receiving vaccine, transplant recipients should be counseled to continue to have annual cervical screening. A bivalent vaccine containing ASO4-adjuvant and HPV types 16 and 18 is also available. However, there are no data regarding the safety and immunogenicity of this vaccine in transplant recipients. &
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HERPES ZOSTER VACCINE Herpes Zoster, caused by the reactivation of Varicella Zoster virus, occurs in up to 20% patients after transplant [49–51]. In the recent years, a Herpes Zoster vaccine has been authorized for the prevention of shingles. The currently available vaccine (Zostavax, Merck Vaccines) is a live-attenuated vaccine containing at least 19 400 plaque forming 332
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Immunizations following solid-organ transplantation Kumar
OTHER VACCINES All transplant candidates and recipients should be immunized against hepatitis B and have serology to determine the response. Ideally, this should take place prior to transplantation. In general, high-dose vaccine (40 mg dose for adults) is suggested for optimum response [13 ]. Accelerated schedules if transplantation is imminent are also options [63]. Those who fail to respond to the vaccine series can have a second attempt at vaccination. Studies have also found intradermal hepatitis B vaccination to be successful in those who do not respond to repeated intramuscular doses [64]. Nonresponders should be counseled as to their risk of hepatitis B and receive appropriate prophylaxis if exposure occurs. Meningococcal vaccine is indicated for routine use in transplant recipients with risk factors for invasive meningococcal disease such as splenectomy and travel. All transplant patients starting on therapy with complement inhibitors such as eculizumab must be immunized with quadrivalent meningococcal conjugate vaccine prior to treatment [65]. Persons with liver disease should receive hepatitis A vaccine in addition to other routine vaccines. Transplant recipients should also be up-to-date with other vaccines such as tetanus, acellular pertussis and Hemophilus influenza B. &&
HEALTHCARE WORKERS AND CLOSE CONTACTS As the immunogenicity of vaccines is suboptimal in transplant recipients, it is of critical importance that persons in contact with the transplant patients be fully immunized. Annual influenza vaccine is one of the most important immunizations for contacts. Similarly, children of transplant recipients should receive all indicated vaccines including live-attenuated vaccines such as rotavirus vaccine, MMR and varicella vaccine. Live-attenuated influenza vaccine can be given to children of organ transplant recipients if injectable vaccine is not an acceptable option. In all cases of live vaccine administration, strict handwashing is important to prevent transmission.
TRAVEL VACCINES For transplant recipients who wish to travel, it is important for the healthcare provider to start planning immunizations well in advance. Routine immunizations need to be up-to-date. Travelspecific immunizations need to be individualized depending on the area of travel. However, in general, live vaccines such as oral typhoid and oral polio vaccine should not be given. The injectable forms of
these vaccines are inactivated and can be used for transplant recipients. For travel to an area where yellow fever is endemic, a waiver is usually required as the yellow fever vaccine is live-attenuated. However, a recent survey in Brazil reported 19 cases of yellow fever vaccination after organ transplant [66]. Although there were no significant reactions, this practice cannot be widely recommended because of the small numbers of patients studied. Interestingly, a recent study reported that almost all persons who were immunized with yellow fever vaccine prior to transplant had protective antibody titers at a median of 3 years after transplant and antibodies were detectable at a median of 13 years after immunization, suggestive of long-term protection [67 ]. &
CONCLUSION Organ transplant recipients have a greater lifetime risk of vaccine-preventable diseases than the general population. Several vaccines are recommended for transplant recipients, although the immunogenicity of most vaccines is suboptimal. Therefore, a review of immunizations is an important part of the pretransplant evaluation and in the long-term care of the transplant recipient. It is important that transplant patients be immunized to reduce the risk of disease. In the future, newer vaccines such as those for cytomegalovirus and inactivated Herpes Zoster vaccines will likely play a greater role. Acknowledgements None. Conflicts of interest D.K. has received research grants from Roche, Merck, Astellas and honoraria from Roche, Merck, Pfizer and Oxford Immunotec.
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Immunizations following solid-organ transplantation Kumar 59. Garland SM, Hernandez-Avila M, Wheeler CM, et al. Quadrivalent vaccine against human papillomavirus to prevent anogenital diseases. N Engl J Med 2007; 356:1928–1943. 60. Munoz N, Manalastas R Jr, Pitisuttithum P, et al. Safety, immunogenicity, and efficacy of quadrivalent human papillomavirus (types 6, 11, 16, 18) recombinant vaccine in women aged 24–45 years: a randomised, double-blind trial. Lancet 2009; 373:1949–1957. 61. Gomez-Lobo V, Whyte T, Kaufman S, et al. Immunogenicity of a prophylactic quadrivalent human papillomavirus L1 virus-like particle vaccine in male and female adolescent transplant recipients. Pediatr Transplant 2014; 18:310– 315. 62. Kumar D, Unger ER, Panicker G, et al. Immunogenicity of quadrivalent human && papillomavirus vaccine in organ transplant recipients. Am J Transplant 2013; 13:2411–2417. This is the first study of HPV vaccination in transplant recipients which shows that shorter time from transplant and having a lung transplant significantly diminish the immunogenicity of the vaccine.
63. Feng L, Niu Y, Chen H, et al. Immunogenicity of different hepatitis B virus vaccination schedules in liver transplant recipients. Hepatol Res 2013; 43:495–501. 64. Choy BY, Peiris JS, Chan TM, et al. Immunogenicity of intradermal hepatitis B vaccination in renal transplant recipients. Am J Transplant 2002; 2:965–969. 65. Struijk GH, Bouts AH, Rijkers GT, et al. Meningococcal sepsis complicating eculizumab treatment despite prior vaccination. Am J Transplant 2013; 13:819–820. 66. Azevedo LS, Lasmar EP, Contieri FL, et al. Yellow fever vaccination in organ transplanted patients: is it safe? A multicenter study. Transpl Infect Dis 2012; 14:237–241. 67. Wyplosz B, Burdet C, Francois H, et al. Persistence of yellow fever vaccine& induced antibodies after solid organ transplantation. Am J Transplant 2013; 13:2458–2461. This study shows that yellow fever vaccine antibodies persist in the long term even in organ transplant recipients and further shows the benefit of pretransplant vaccination.
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Immunizations following solid-organ transplantation Deepali Kumar
Purpose of review To highlight the latest evidence for the use of key vaccines that are recommended in organ transplant candidates and recipients. Recent findings Influenza vaccine is the best studied vaccine; factors affecting immunogenicity of this vaccine include time from transplant, use of mycophenolate mofetil and type of transplant. Newer formulations of influenza vaccine are available, but data for these are limited. Updated recommendations include giving conjugated pneumococcal vaccine to adult transplant candidates and recipients followed by the polysaccharide vaccine to increase serotype coverage. Human papillomavirus vaccine should also be given to transplant recipients, although the immunogenicity may be suboptimal. Quadrivalent meningococcal conjugate vaccine needs to be given in special circumstances such as to patients who are starting eculizumab therapy. Live vaccines in general are contraindicated, although increasing safety data are emerging for Varicella vaccine. Herpes Zoster vaccine may be offered prior to transplant, although the utility of this strategy regarding protection from shingles after transplant is not known. Newer vaccines such as inactivated zoster vaccine and vaccines for the prevention of cytomegalovirus are under study. Summary Immunization for organ transplant recipients is an important part of pretransplant evaluation and the long-term care of the transplant recipient. Keywords Herpes Zoster, influenza, pneumococcus, vaccine
INTRODUCTION Vaccine-preventable diseases cause morbidity and mortality in organ transplant recipients. Prevention with vaccines is key to reducing complications. However, it is important to be aware of the types of vaccines, timing and effectiveness or immunogenicity of these vaccines in the transplant setting, as well as the vaccine responses with a variety of immunosuppressives. There are special considerations for pediatric transplant recipients as well. In general, there are no large-scale vaccine efficacy studies in the transplant population and most studies rely on measuring laboratory correlates of protection. Key vaccines include influenza, pneumococcal, human papillomavirus (HPV), and live vaccines such as Varicella Zoster, Measles–Mumps– Rubella (MMR) and Herpes Zoster. Here, we discuss these key vaccines recommended for transplant recipients, their updated formulations and recommendations for use (Table 1).
GENERAL PRINCIPLES OF IMMUNIZATION IN SOLID-ORGAN TRANSPLANTATION In general, humoral and cellular responses to vaccines after transplantation are suboptimal.
Therefore, when possible, it is important to immunize patients while they are awaiting transplant. This can best be done as part of a comprehensive pretransplant evaluation. Vaccine responses in persons on hemodialysis or with chronic liver disease are not as optimal as in healthy individuals, but are in general better than after transplantation. For example, in a study by McCashland et al. [1], liver transplant candidates received pneumococcal polysaccharide vaccine (PPV). Although patients had a significant increase in antibody levels initially, titers significantly declined by 3 months after liver transplant. Studies with influenza vaccine have also shown that humoral responses are greater in hemodialysis patients compared with transplant recipients [2,3].
Transplant Infectious Diseases and Multi-Organ Transplant Program, University Health Network, Toronto, Ontario, Canada Correspondence to Deepali Kumar, MD, MSc, FRCPC, 11-PMB-174, 585 University Avenue, Toronto, ON, Canada M5G 2N2. Tel: +1 416 340 4241; fax: +1 416 340 4043; e-mail: [email protected] Curr Opin Infect Dis 2014, 27:329–335 DOI:10.1097/QCO.0000000000000078
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KEY POINTS Vaccine-preventable diseases cause morbidity and mortality in transplant patients. Immunization should be evaluated prior to transplant when possible as well as updated during the long-term care of the transplant recipient. Inactivated influenza vaccine should be administered annually. Pneumococcal conjugate vaccine (13 valent) should be used for adult immunization followed by pneumococcal polysaccharide vaccine (23 valent). Live vaccines are generally contraindicated after transplant, although there are increasing data regarding the safety of Varicella vaccine.
INFLUENZA VACCINE Influenza illness can be severe in transplant patients and commonly leads to lower respiratory tract infection and rarely extrapulmonary complications such as myocarditis and myositis [4]. During the 2009 pandemic of influenza A/(H1N1)pdm09, a multicenter review of influenza illness showed a hospitalization rate of 71% and death in 4% of transplant patients [5]. In addition to the direct effects of viral infection, influenza infection has also been associated with allograft dysfunction as well as acute and chronic rejection in lung transplant recipients [6–9]. Influenza vaccine is the most common method of illness prevention and in general receives the greatest attention in the literature as it is an annual vaccine. The standard influenza vaccine is a trivalent inactivated formulation containing two A
strains and one B strain of circulating influenza. The specific strains change annually based on the recommendations by the World Health Organization. In the near future, quadrivalent vaccines containing an additional B strain will become available in many areas. Immunogenicity to influenza vaccine is measured by seroprotection (a strain-specific titer of 1 : 40 by hemagglutination inhibition assay) and seroconversion (a four-fold rise in titer compared with prevaccination values). In transplant recipients, immunogenicity varies greatly from 15 to 95% [10]. The variability in vaccine response is likely because of the heterogeneity of studies that involve various types of transplant and a variety of immunosuppressives. The American Society of Transplantation recommends influenza vaccine to be given to organ transplant recipients starting at 3–6 months after transplantation; other guidelines however, recommend that vaccine can be given as early as 1 month after transplant [11,12,13 ]. Time from transplant is shown to be an important factor affecting immunogenicity; therefore, although some patients may respond, earlier vaccination may not be as immunogenic [14]. For example, studies have shown that vaccination after 6 months to 1 year after transplant is more immunogenic than earlier vaccination [15,16 ]; however, it is unclear whether the greater immunogenicity obtained when administering vaccine later after transplant translates into improved protection. For example, Hurst et al. [17] studied a large United States Renal Data System (USRDS) database of kidney transplant recipients. Patients who received influenza vaccine in the first year after transplant had better graft survival at 3 years. Approximately 43% of those who received &&
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Table 1. Recommended routine vaccines for organ transplant recipients Vaccine
Pretransplant
Posttransplant
Influenza (inactivated)
þ
þ
Pneumococcal PCV13 followed by PPV23
þ
þ
Hepatitis A
Comments Limited data for adjuvanted or high-dose vaccines Routine for those with underlying liver disease
Hepatitis B
þ
þ
Double-dose vaccine for transplant recipients
HPV
þ
þ
Immunogenicity data with quadrivalent vaccine. No data with bivalent vaccine.
Tetanus, diphtheria, polio, acellular pertussis
þ
þ
Hemophilus influenza B
þ
þ
Meningococcal – quadrivalent conjugate
þ
þ
Measles–Mumps–Rubella
þ
–
Varicella Zoster
þ
þ/–
Herpes Zoster
þ
–
Based on risk factors and prior to eculizumab Safety shown in small studies and careful patient selection No safety data after transplant. Contains much greater PFU of Varicella Zoster virus than Varicella vaccine
PCV13, pneumococcal conjugate vaccine 13-valent; PFU, plaque-forming units; PPV23, pneumococcal polysaccharide vaccine 23-valent. HPV, Human Papillomavirus Vaccine.
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Immunizations following solid-organ transplantation Kumar
vaccine in the first year were immunized in the first 6 months after transplant. The use of mycophenolate mofetil (MMF) is also a well known factor leading to diminished immunogenicity [3,18]. A recent study found that higher doses of MMF of at least 2 g daily reduced the seroconversion rate of influenza vaccine [16 ]. The mechanism of this is likely because of inhibition of influenza-specific responses in B and T cells (Egli, Kumar, unpublished observation). Type of transplant is also an important factor in predicting immunogenicity; studies in lung transplant recipients consistently show lower immunogenicity rates than those in kidney transplant [19,20]. Given the poor immunogenicity of the standard inactivated influenza vaccine, investigators have attempted to find alternative methods to improve immunogenicity. This has included giving two or three doses of vaccine in the same season, or boosting the initial vaccination with a lower dose intradermal booster [18,20–24]. However, these methods have not been found to substantially increase immunogenicity. An intradermal delivery system for influenza vaccine has also been developed; intradermal vaccines take advantage of the greater number of dendritic cells present in the dermis as these act as potent antigen-presenting cells. A randomized trial of high-dose intradermal vaccine vs. standard dose intramuscular vaccine in 212 organ transplant recipients did not find a difference in immunogenicity between the two groups [16 ]. An adjuvanted formulation of influenza vaccine, containing MF59 adjuvant, has been available in Europe for several years. Adjuvants are molecules that, when combined with a vaccine antigen, can enhance the immunogenicity of the antigen. The adjuvant attracts a greater number of inflammatory cells to the site of immunization, thereby enhancing vaccine response [25 ,26]. In transplantation, there are limited data on adjuvanted seasonal influenza vaccine; however, an adjuvanted pandemic vaccine that used the ASO3 adjuvant system was widely used in the clinical setting and studied during the 2009 influenza A pandemic. In studies to date, adjuvanted pandemic influenza vaccine does not appear to have greater immunogenicity compared with standard vaccine [27–31]. High-dose vaccines containing four times the standard antigen have also become available and data suggest that these have improved efficacy in the older age groups [32]; however, there are no safety and immunogenicity data for this formulation in transplantation. &&
function. The mechanisms by which this may occur include molecular mimicry and bystander activation. Several investigators have studied this by determination of human leukocyte antigen (HLA) alloantibody upregulation after vaccination. In studies done with seasonal influenza vaccine, there have been no definitive reports of HLA alloantibody upregulation. Many recent studies dealing with the immunogenicity of influenza vaccine have included the assessment of HLA alloantibodies [16 ,33]. However, no specific association has been noted for seasonal influenza vaccine. Particular attention was paid to this phenomenon during the 2009 influenza A/H1N1 pandemic, during which time monovalent influenza vaccine with the ASO3 adjuvant system was available in Europe and Canada. Some studies showed greater rates of HLA alloantibody upregulation after immunization with this vaccine [34,35], although this did not translate into clinical allograft dysfunction. A case–control study in heart transplant recipients during the pandemic also showed a higher rate in cellular rejection after those that were immunized vs. nonimmunized controls [36]. In summary, studies that have shown HLA alloantibody upregulation are those done with adjuvanted vaccine during the pandemic. These studies are difficult to interpret primarily because of lack of appropriate controls and the potential for patients to have influenza infection during the study period. &&
&&
&
INFLUENZA VACCINE AND ALLOGRAFT FUNCTION It has been anecdotally suggested that influenza vaccine may have an adverse effect on allograft
PNEUMOCOCCAL VACCINE Pneumococcal disease after organ transplant has a relative risk of up to 13 times greater than the general population [37]. Therefore, pneumococcal vaccine is recommended for transplant candidates and recipients. Both 13-valent conjugated vaccine (PCV13) and 23-valent polysaccharide vaccine (PPV23) are available for use. Recently, PCV13 was recommended by the Advisory Committee of Immunization practices in the United States and by the National Advisory Committee on Immunization in Canada for use in transplanted adults [38 ,39]. Studies in the transplant population with the 7-valent conjugate vaccine (PCV7) show marginally increased serotype-specific immunity. In a pilot randomized controlled trial of PCV7 vs. PPV23 in 60 kidney transplant patients, there was a trend to greater response rates with PCV7 (response to at least one serotype was 73% with PCV7 vs. 53% with PPV23, P ¼ 0.11) [40]. Subsequently, a long-term follow-up of these patients showed that pneumococcal titers returned to baseline in 3 years regardless of the type of vaccine [41]. A prime-boost strategy has been suggested in immunocompromised persons. In this strategy, pneumococcal conjugate vaccine (PCV) is given initially followed after an
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interval (usually 8 weeks) by PPV. In theory, the T-dependent response elicited by PCV should create antibodies of high avidity as well as memory B cells. The follow-up immunization with PPV can then stimulate memory B cells to produce high levels of specific antibody. The immunogenicity of pneumococcal vaccination using this strategy has been explored in several studies. However, the boosting effect with PPV for the serotypes in PCV has not been found to occur in the organ transplant setting [42–44]. Nevertheless, the administration of PPV23 provides additional serotype coverage over PCV13.
LIVE-ATTENUATED VACCINES (VARICELLA AND MEASLES–MUMPS–RUBELLA) In general, live-attenuated vaccines are not recommended after transplantation because of the possibility of vaccine-related viral disease. For example, inadvertent administration of varicella vaccine to a seronegative heart transplant recipient has been reported to cause disseminated varicella [45]. Therefore, live vaccines are generally suggested to be given at least 4 weeks prior to transplant. However, in carefully performed studies, investigators have administered varicella vaccine to seronegative children after transplantation [46 ,47,48]. Many of these studies are done in long-term transplant recipients who are receiving low doses of immunosuppression. Adverse events have been uncommon, suggesting that vaccine could safely be given after transplant. However, the selection of patients to receive Varicella vaccine after transplant as well as the risks and benefits of the vaccine need to be carefully considered and should only be performed in select patients with careful monitoring and availability of antivirals in case of complications. There are no studies of MMR vaccine administration after organ transplant. There are no specific antivirals for measles, mumps or rubella, and MMR vaccine is contraindicated after transplant. In cases of inadvertent immunization or exposure to wildtype measles, passive immunization with immune globulin can be used to decrease the risk of disease. &&
units of attenuated zoster virus. The Shingles Prevention Study, done in immunocompetent persons at least 60 years of age, showed that it is 51% effective in the prevention of Herpes Zoster and 67% effective in the prevention of postherpetic neuralgia [52]. A subsequent study showed greater effectiveness of the vaccine in a younger 50–59-year-old population [53]. Current guidelines suggest that the vaccine is contraindicated after transplant. However, it can be administered prior to transplant. A period of up to 4 weeks should elapse, however, before transplantation takes place. The effectiveness or immunogenicity of pretransplant vaccination in the prevention of posttransplant Herpes Zoster disease is not known. Trials to determine the immunogenicity of Herpes Zoster vaccine before transplant are ongoing. In addition, inactivated formulations of Herpes Zoster vaccine are undergoing clinical trials and these may be useful in the posttransplant setting.
HUMAN PAPILLOMAVIRUS VACCINE Transplant recipients are thought to be at greater risk of HPV-related cervical cancer and anogenital warts than the general population, given the reduced cancer surveillance from immunosuppression [54]. However, other studies indicate that the risk is similar to that of the general population [55,56]. A recent large review of U.S. transplant recipients showed an increased incidence of HPVrelated cancers (e.g. vulvar, anal and penile cancer), although the incidence of cervical cancer was similar to that of the general population [57 ]. Studies in the general population show benefit of HPV vaccine in girls and women aged 9–45 as well as boys and men aged 9–26 [58–60]. Therefore, HPV vaccine should also be offered to transplant candidates and recipients in the standard three-dose schedule. In eight transplant adolescents who received the complete HPV vaccine series and had results available 1 month after the last dose, all developed seroconversion to the four HPV types [61]. Another study in 47 transplanted adults aged 18–35 years, using the quadrivalent HPV vaccine, showed immunogenicity ranging from 52.6 to 68.4% [62 ]. This study also showed that shorter time from transplant and lung transplantation were the factors contributing to decreased immunogenicity. Therefore, despite receiving vaccine, transplant recipients should be counseled to continue to have annual cervical screening. A bivalent vaccine containing ASO4-adjuvant and HPV types 16 and 18 is also available. However, there are no data regarding the safety and immunogenicity of this vaccine in transplant recipients. &
&&
HERPES ZOSTER VACCINE Herpes Zoster, caused by the reactivation of Varicella Zoster virus, occurs in up to 20% patients after transplant [49–51]. In the recent years, a Herpes Zoster vaccine has been authorized for the prevention of shingles. The currently available vaccine (Zostavax, Merck Vaccines) is a live-attenuated vaccine containing at least 19 400 plaque forming 332
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Immunizations following solid-organ transplantation Kumar
OTHER VACCINES All transplant candidates and recipients should be immunized against hepatitis B and have serology to determine the response. Ideally, this should take place prior to transplantation. In general, high-dose vaccine (40 mg dose for adults) is suggested for optimum response [13 ]. Accelerated schedules if transplantation is imminent are also options [63]. Those who fail to respond to the vaccine series can have a second attempt at vaccination. Studies have also found intradermal hepatitis B vaccination to be successful in those who do not respond to repeated intramuscular doses [64]. Nonresponders should be counseled as to their risk of hepatitis B and receive appropriate prophylaxis if exposure occurs. Meningococcal vaccine is indicated for routine use in transplant recipients with risk factors for invasive meningococcal disease such as splenectomy and travel. All transplant patients starting on therapy with complement inhibitors such as eculizumab must be immunized with quadrivalent meningococcal conjugate vaccine prior to treatment [65]. Persons with liver disease should receive hepatitis A vaccine in addition to other routine vaccines. Transplant recipients should also be up-to-date with other vaccines such as tetanus, acellular pertussis and Hemophilus influenza B. &&
HEALTHCARE WORKERS AND CLOSE CONTACTS As the immunogenicity of vaccines is suboptimal in transplant recipients, it is of critical importance that persons in contact with the transplant patients be fully immunized. Annual influenza vaccine is one of the most important immunizations for contacts. Similarly, children of transplant recipients should receive all indicated vaccines including live-attenuated vaccines such as rotavirus vaccine, MMR and varicella vaccine. Live-attenuated influenza vaccine can be given to children of organ transplant recipients if injectable vaccine is not an acceptable option. In all cases of live vaccine administration, strict handwashing is important to prevent transmission.
TRAVEL VACCINES For transplant recipients who wish to travel, it is important for the healthcare provider to start planning immunizations well in advance. Routine immunizations need to be up-to-date. Travelspecific immunizations need to be individualized depending on the area of travel. However, in general, live vaccines such as oral typhoid and oral polio vaccine should not be given. The injectable forms of
these vaccines are inactivated and can be used for transplant recipients. For travel to an area where yellow fever is endemic, a waiver is usually required as the yellow fever vaccine is live-attenuated. However, a recent survey in Brazil reported 19 cases of yellow fever vaccination after organ transplant [66]. Although there were no significant reactions, this practice cannot be widely recommended because of the small numbers of patients studied. Interestingly, a recent study reported that almost all persons who were immunized with yellow fever vaccine prior to transplant had protective antibody titers at a median of 3 years after transplant and antibodies were detectable at a median of 13 years after immunization, suggestive of long-term protection [67 ]. &
CONCLUSION Organ transplant recipients have a greater lifetime risk of vaccine-preventable diseases than the general population. Several vaccines are recommended for transplant recipients, although the immunogenicity of most vaccines is suboptimal. Therefore, a review of immunizations is an important part of the pretransplant evaluation and in the long-term care of the transplant recipient. It is important that transplant patients be immunized to reduce the risk of disease. In the future, newer vaccines such as those for cytomegalovirus and inactivated Herpes Zoster vaccines will likely play a greater role. Acknowledgements None. Conflicts of interest D.K. has received research grants from Roche, Merck, Astellas and honoraria from Roche, Merck, Pfizer and Oxford Immunotec.
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This publication shows the safety of live varicella vaccine in children after transplantation. 47. Weinberg A, Horslen SP, Kaufman SS, et al. Safety and immunogenicity of Varicella-Zoster virus vaccine in pediatric liver and intestine transplant recipients. Am J Transplant 2006; 6:565–568. 48. Danerseau AM, Robinson JL. Efficacy and safety of Measles, Mumps, Rubella and Varicella live viral vaccines in transplant recipients receiving immunosuppressive drugs. World J Pediatr 2008; 4:254–258. 49. Gourishankar S, McDermid JC, Jhangri GS, Preiksaitis JK. Herpes Zoster infection following solid organ transplantation: incidence, risk factors and outcomes in the current immunosuppressive era. Am J Transplant 2004; 4:108– 115. 50. Manuel O, Kumar D, Singer LG, et al. Incidence and clinical characteristics of Herpes Zoster after lung transplantation. J Heart Lung Transplant 2008; 27:11–16. 51. Fuks L, Shitrit D, Fox BD, et al. 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Madeleine MM, Finch JL, Lynch CF, et al. HPV-related cancers after solid organ & transplantation in the United States. Am J Transplant 2013; 13:3202–3209. This is a large review on the epidemiology of HPV-related diseases in transplantation and shows the benefit of cervical screening practices. 58. Giuliano AR, Palefsky JM, Goldstone S, et al. Efficacy of quadrivalent HPV vaccine against HPV Infection and disease in males. N Engl J Med 2011; 364:401–411.
Volume 27 Number 4 August 2014
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Immunizations following solid-organ transplantation Kumar 59. Garland SM, Hernandez-Avila M, Wheeler CM, et al. Quadrivalent vaccine against human papillomavirus to prevent anogenital diseases. N Engl J Med 2007; 356:1928–1943. 60. Munoz N, Manalastas R Jr, Pitisuttithum P, et al. Safety, immunogenicity, and efficacy of quadrivalent human papillomavirus (types 6, 11, 16, 18) recombinant vaccine in women aged 24–45 years: a randomised, double-blind trial. Lancet 2009; 373:1949–1957. 61. Gomez-Lobo V, Whyte T, Kaufman S, et al. Immunogenicity of a prophylactic quadrivalent human papillomavirus L1 virus-like particle vaccine in male and female adolescent transplant recipients. Pediatr Transplant 2014; 18:310– 315. 62. Kumar D, Unger ER, Panicker G, et al. Immunogenicity of quadrivalent human && papillomavirus vaccine in organ transplant recipients. Am J Transplant 2013; 13:2411–2417. This is the first study of HPV vaccination in transplant recipients which shows that shorter time from transplant and having a lung transplant significantly diminish the immunogenicity of the vaccine.
63. Feng L, Niu Y, Chen H, et al. Immunogenicity of different hepatitis B virus vaccination schedules in liver transplant recipients. Hepatol Res 2013; 43:495–501. 64. Choy BY, Peiris JS, Chan TM, et al. Immunogenicity of intradermal hepatitis B vaccination in renal transplant recipients. Am J Transplant 2002; 2:965–969. 65. Struijk GH, Bouts AH, Rijkers GT, et al. Meningococcal sepsis complicating eculizumab treatment despite prior vaccination. Am J Transplant 2013; 13:819–820. 66. Azevedo LS, Lasmar EP, Contieri FL, et al. Yellow fever vaccination in organ transplanted patients: is it safe? A multicenter study. Transpl Infect Dis 2012; 14:237–241. 67. Wyplosz B, Burdet C, Francois H, et al. Persistence of yellow fever vaccine& induced antibodies after solid organ transplantation. Am J Transplant 2013; 13:2458–2461. This study shows that yellow fever vaccine antibodies persist in the long term even in organ transplant recipients and further shows the benefit of pretransplant vaccination.
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