Guidelines

Bone Marrow Transplantation (2009) 44, 521–526; doi:10.1038/bmt.2009.263

Vaccination of hematopoietic cell transplant recipients

P Ljungman1, C Cordonnier2, H Einsele3, J Englund4, C M Machado5, J Storek6 and T Small7

  1. 1Karolinska University Hospital, Stockholm, Sweden
  2. 2Hopital Henri Mondor, Creteil, France
  3. 3Universitatsklinik Wurzburg Medizinische Klinik und Poliklinik II, Wurzburg, Germany
  4. 4University of Washington/Seattle Children's Hospital and Regional Medical Center, Seattle, WA, USA
  5. 5Institue of Tropical Medicine, Universidade de São Paulo, São Paulo, Brazil
  6. 6Department of Medicine, Oncology, Microbiology and Infectious Diseases, University of Calgary, Calgary, Alberta, Canada
  7. 7Memorial Sloan Kettering Cancer Center, New York, NY, USA

Correspondence: Dr P Ljungman, Department of Hematology, Karolinska University Hospital/Huddinge M54, Stockholm, S-14186, Sweden. E-mail: Per.Ljungman@ki.se; Dr M Tomblyn, Blood & Marrow Transplantation, H Lee Moffitt Cancer Center & Research Institute, 12902 Magnolia Drive FOB 3, Tampa, FL 33612, USA. E-mail: marcie.tomblyn@moffitt.org

Received 20 June 2009; Accepted 20 July 2009.

Keywords:

vaccines, immune recovery, hematopoietic cell transplantation

Vaccination recommendations have previously been developed and published separately by the European Group of Blood and Marrow Transplantation (EBMT) and the Centers for Disease Control (CDC), by the Infectious Diseases Society of America (IDSA) and by the American Society for Blood and Marrow Transplantation (ASBMT).1,786,787 The purpose of the vaccination schedule in these joint updated guidelines is to provide guidance for hematopoietic cell transplant (HCT) centers around the globe.

Antibody titers to vaccine-preventable diseases (for example, tetanus, polio, measles, mumps, rubella) decline during the 1–10 years after allogeneic or autologous HCT788–792 if the recipient is not revaccinated. The clinical relevance of decreased Abs to vaccine-preventable diseases among HCT recipients is not immediately apparent because a limited number of cases of vaccine-preventable diseases are reported among HCT recipients. However, vaccine-preventable diseases still pose risks to the population. In addition, evidence exists that certain vaccine-preventable diseases, such as pneumococcal infection, Haemophilus influenzae type b infection, measles, varicella and influenza, can pose increased risk for HCT recipients.193,309,793–798 Therefore, HCT recipients should be routinely revaccinated after HCT so that they can experience immunity to the same vaccine-preventable diseases as others (Table 5). Although several studies have evaluated the safety and immunogenicity (for example, serological studies of Ab titers after vaccination) of different vaccines in allogeneic HCT recipients, limited and only indirect data were found regarding vaccine efficacy among HCT recipients (that is, whether vaccinated HCT recipients have decreased attack rates of infections compared with unvaccinated HCT recipients).798


For a vaccine to mount a response thought to be clinically relevant (for example, a fourfold rise in specific Ab levels or a rise to a level considered protective), adaptive (T- and B-cell) immunity after transplant must be at least partially reconstituted. B-cell counts, which are typically zero or near zero in the first 1–3 months after HCT, return to normal by 3–12 months after transplant.799,800 In patients treated with rituximab after transplant, B-cell recovery is generally delayed for 6 months after the last dose.801 Regardless of the time to recovery, newly generated B cells often show impaired Ag-specific responses because of a limited capability of naive B cells to undergo somatic mutation and isotype switching during the first year after transplant. T-cell counts are low in the first 1–3 months after transplant (CD4+ counts are typically <200 cells per μl). Thereafter, the recovery of T cells, particularly CD4+ T cells, is influenced by patient age at HCT, by substantial T-cell depletion of the graft and by the presence or absence of chronic GVHD. Most patients <18 years of age at HCT without chronic GVHD will recover CD4+ cell counts of >200 cells per μl by 6–9 months after transplant, whereas adults, particularly those with chronic GVHD, may require >2 years.

Most of the circulating T cells in the first year after transplantation, particularly in adults, are memory/effector T cells, likely derived from T cells infused with the graft and capable of responding to Ags encountered by the donor before transplant. Naive T cells capable of responding to new Ags are generated only at 6–12 months after transplant, earlier in young children and later in older adults. As HCT recipients have varying immune system recovery after HCT, it has been proposed that different vaccination schedules be recommended for recipients of different types of HCT, with the rationale that, for example, autologous HCT patients do not lose immunity as frequently or rapidly as do patients after allogeneic HCT. However, existing evidence suggests that loss of immunity is also common after autologous HCT (particularly in patients who have received multiple courses of chemotherapy before HCT) and that responses to vaccination are similar to those that occur after allogeneic HCT.194,790,791,802–805 It should also be recognized that limited information regarding vaccine immunogenicity exists for patients transplanted with umbilical cord blood or haploidentical grafts, or after reduced-intensity conditioning. Therefore, for the sake of simplicity, the committee has chosen to recommend the same vaccination schedule for all HCT recipients until additional data are published.

T-cell response to vaccines for pathogens encountered before transplant (for example, VZV) can be observed as soon as 1–6 months after transplant. Ab response to vaccines for pathogens encountered before transplant (for example, tetanus toxoid) can be observed at 6–12 months after HCT. T-cell or Ab response to vaccines for pathogens not encountered before transplant (for example, Hepatitis B virus (HBV) in most European and American adults) can usually be observed later (1 year or more after transplant). HCT recipients are similar to young children in that they respond poorly to pure polysaccharide Ags such as those included in the 23-valent polysaccharide pneumococcal vaccine. Pure polysaccharide Ags elicit Ab responses later after HCT than do protein Ags (for example, diphtheria toxoid) or polysaccharide–protein conjugates (for example, Haemophilus influenzae type b capsular polysaccharide conjugated to a carrier protein). GVHD and/or its treatment hampers T-cell and Ab responses to vaccines. As studies have shown that patients with chronic GVHD can mount responses to vaccines and clearly need protection against pneumococci, these guidelines do not recommend postponing vaccination in patients with GVHD with the exception of withholding live vaccines. However, when vaccinating patients with active GVHD, it may be prudent to measure specific Ab levels before and after vaccination to determine their level of protection and need for booster immunizations.

The committee has split the recommendations into different categories. In Table 5, the vaccines are listed for which evidence exists regarding safety and immunogenicity and which are generally recommended to be used in HCT recipients. Since the publication of the previous version of vaccination guidelines, new vaccines have been introduced. In addition, clinicians at HCT centers get questions from patients, family members and health-care workers regarding vaccinations in special situations, such as after disease exposure or before travel to areas endemic for infections not previously considered in these recommendations. Therefore, comments are made regarding these vaccines and situations (Table 6), although very limited or no data exist. Finally, there are situations when vaccination of family members, household contacts and health-care workers is recommended to minimize exposure of vaccine-preventable diseases among HCT recipients (Table 8).



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Donor vaccination

Vaccination of the donor has been shown to improve the post transplant immunity of the patient in the case of tetanus toxoid, 7-valent pneumococcal conjugate vaccine (PCV) and Haemophilus influenzae type b-conjugate vaccines. No recommendations are made regarding donor vaccination because of the practical and ethical difficulties surrounding this issue.

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Serological testing

Hematopoietic cell transplant patients are immunosuppressed to varying degrees and it is therefore prudent to test immunity to some infections before or after vaccination.

Testing before vaccination

Testing for Abs to measles is recommended in adults, with vaccination performed only if the patient is seronegative (CIII) (Table 5). If vaccination against varicella is contemplated, testing of immunity should be carried out and vaccination should be administered to seronegative patients only (CIII) (Table 5).

Testing after vaccination

Testing after vaccination can be indicated either to assess the response to vaccination and the need for additional doses or to check the durability of response during long-term follow-up. Testing to assess the response to vaccination against pneumococcal disease is recommended at 1 month or later after the third or fourth dose of pneumococcal vaccine (BIII) (Table 5). There are different methods for assessment of pneumococcal Ab levels, each having advantages and disadvantages; thus, no specific method can be recommended. Similarly, as a widely accepted definition of adequate response to pneumococcal vaccine is lacking, guidelines for revaccination of nonresponders are not given. Testing to assess the response to HBV vaccination is also recommended. Testing should be carried out 1 month or later after the third vaccine dose (BIII). A second three-dose vaccination schedule is recommended in nonresponders (CIII). The interval between the first and second series has to be determined individually as nonresponsiveness to HBV vaccine can have different causes (for example, chronic GVHD, in which case it may be prudent to revaccinate only after GVHD has abated).

Regular testing of long-term HCT survivors for maintenance of Ab levels is recommended (BIII). Testing should be conducted approximately every 4–5 years to assess for immunity to HBV, measles, tetanus, diphtheria and polio (BIII). Testing for immunity to pneumococcus might reasonably be repeated every 2 years for the first 4 years (BIII). The need for revaccination has to be assessed on an individual basis.

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Comments regarding specific vaccines

Pneumococcal vaccine

There are two types of pneumococcal vaccine: a conjugate vaccine (PCV) and a polysaccharide vaccine (pneumococcal polysaccharide vaccine 23-valent, PPSV23). As with most conjugate vaccines, compared with polysaccharide vaccines, PCV is more immunogenic than PPSV23. However, the spectrum of protection is narrower, as PCV7 covers only seven strains of pneumococci, whereas PPSV23 covers 23 strains. When given during the first year after transplantation, PPSV23 elicits inadequate responses. Four prospective trials show better responses with PCV in HCT recipients;195,797,806,807 thus, PCV is the preferred vaccine. It is likely beneficial to use PPSV23 in the fourth dose (after three doses of PCV) (BII) to broaden the immune response.808 A fourth dose of PCV might increase the response rate in patients with chronic GVHD, who are less likely to respond to PPSV23 (CIII).

If a microbiologically documented pneumococcal infection occurs after pneumococcal vaccination, documenting the serotype of the strain is recommended (BIII) to determine whether the serotype is among those included in the vaccine, which can be indicative of a nonresponse to the vaccine(s). Such patients should receive additional doses of pneumococcal vaccine, with the choice of vaccine (that is, PCV or PPSV23) depending on the documented strain (BIII).

The time after transplant to initiate routine vaccination with PCV is controversial. One trial showed that similar Ab responses with vaccination started at 3 months (early) and 9 months (late) after transplant.808 Thus, early vaccination may be preferred as it may protect against not only late but also early pneumococcal disease. It should be noted that early vaccination may not prime for a PPSV23 boost as efficiently as late vaccination. Furthermore, early vaccination may result in a shorter-lasting Ab response. Therefore, if vaccination is started early, it may be particularly important to determine pneumococcal Ab levels and, if these are ‘low’, revaccinate (BIII).

Diphtheria–tetanus vaccine

There are two general types of diphtheria and tetanus vaccines: those containing ‘full’-dose diphtheria toxoid in combination with tetanus toxoid (DT) and those containing reduced dose diphtheria toxoid (such as Td; the lower case ‘d’ indicates reduced diphtheria toxoid, whereas the tetanus content is essentially the same in TD and Td). Use of reduced diphtheria toxoid vaccines after transplant can be associated with lack of response. Therefore, post transplant patients should be viewed as ‘never vaccinated’ and full toxoid vaccines should be used if possible. The DT vaccine is not approved in individuals >7 years of age in the United States because of its side effects, although experience with adult HCT recipients receiving DT vaccine indicates a lower risk for side effects than in previously vaccinated healthy adults. Adult transplant recipients might have an adequate response to the diphtheria portion of Td. However, whether the response is equal to that of TD has not been studied. Checking diphtheria Ab level after vaccination with Td might therefore be warranted in situations in which an increased risk for diphtheria might be envisaged.

Pertussis vaccine

For the general population, the Advisory Committee on Immunization Practices and the CDC have recommended the use of acellular (rather than whole cell) pertussis vaccine in pediatric vaccination regimens since 1997. Owing to the steady increase in pertussis over the last decade and the licensing of two vaccines containing tetanus, reduced dose diphtheria and reduced dose pertussis (Tdap), the CDC now recommends that adolescents (10–18 years of age) and adults (19–64 years of age) receive a single dose of Tdap to replace their routine adult tetanus and diphtheria toxoids (Td) booster. For adolescents, the preferred age range is 11–12 years. For adults (11–64 years), a single Tdap is recommended to replace their routine Td booster if given greater than or equal to10 years earlier. The recommended interval of 10 years between Td and Tdap was because of concerns of local site reactions. However, for adults who have contact with infants <12 months of age, as well as with health-care workers and those in community outbreaks of pertussis, intervals as short as 2 years after the last Td is now recommended. The aim is to decrease the reservoir of pertussis that affects infants and immunocompromised individuals regardless of age.

Hematopoietic cell transplant recipients may be particularly vulnerable to complications from pertussis because of pulmonary damage from chemotherapy and/or TBI, even in the absence of chronic GVHD. As post transplant patients should be viewed as ‘never vaccinated’ and receive full doses of toxoids, their ‘DT’ vaccine should include full-dose (not reduced dose) acellular pertussis toxoid (DTaP) if available. In the United States, DTaP is available for children <7 years of age. The adult pertussis vaccine used frequently by community physicians, Tdap, contains tetanus toxoid, reduced dose diphtheria toxoid and reduced dose acellular pertussis toxoid. Tdap is different from the DTaP vaccine currently given to babies and young children, as it contains lesser quantities of diphtheria and pertussis proteins and is much less likely than DTaP to cause side effects such as pain, redness and tenderness.

Preliminary data in autologous and allogeneic transplant recipients show that the response to reduced dose pertussis in Tdap is poor, irrespective of when the vaccine is given.809,810 Use of Tdap as the initial tetanus-containing vaccine in adult autologous HCT recipients was associated with lack of response to the tetanus and pertussis portion, suggesting that this vaccine should be used as a booster vaccine rather than as a part of the primary series.810 Vaccines with a higher tetanus and pertussis content may be more immunogenic in HCT recipients and thus should be considered for the initial vaccination.

Influenza vaccine

Lifelong seasonal influenza vaccination with inactivated influenza vaccine is recommended for all HCT candidates and recipients (AII). The time when vaccination should be initiated after HCT depends on the epidemiological situation, but it is likely that the effectiveness is better later after HCT. Whether influenza vaccination is beneficial during the first months after nonmyeloablative conditioning is unknown. If the vaccine is administered earlier than 6 months after HCT, regardless of the conditioning intensity, a second dose could be contemplated (CIII). The live intranasal influenza vaccine should not be used, as an inactivated alternative exists (EIII).

During community outbreaks, HCT recipients who have not yet received a current influenza vaccination should be vaccinated against influenza immediately if they are more than 4 months after HCT (BIII). A second dose can also be given, especially if the first dose is given <6 months after HCT (CIII). For pediatric HCT recipients and candidates who are >6 months old, annual seasonal influenza vaccination is recommended after HCT (BIII). Children <9 years old who are receiving influenza vaccination for the first time require two doses administered 1 month apart (AI).

Varicella vaccines

There are two main varicella vaccines directed against preventing chickenpox (Varivax) or shingles (Zostavax). The difference between these two vaccines is the number of plaque-forming units of attenuated virus. The chickenpox vaccine has lower viral titers and can be used for all HCT recipients who have met the criteria for live virus vaccination. The new shingles vaccine should not be used because of the much higher viral titers.

Hepatitis B vaccine

Vaccination is recommended for HBV surface Ag- or HBV core Ab-positive patients, as vaccination can reduce the risk of reverse seroconversion (BII). For HBV surface Ag- or HBV core Ab-negative HCT patients, recommendations for the general population in their country of residence should be followed.

Meningococcal vaccine

Both polysaccharide-based and conjugate vaccines exist. It is reasonable to assume that, as is true of vaccines against pneumococci and Haemophilus influenzae type b, conjugated meningococcal vaccine will give more stable immune responses than polysaccharide-based vaccines, although no comparative study of the two vaccine types has been conducted.811,812

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