Vaccinations Against Infectious Diseases in Hematopoietic Stem Cell Transplant Recipients

ABSTRACT: Blood and marrow transplantation, a curative treatment for a variety of serious diseases, induces a period of sustained immunosuppression predisposing recipients to opportunistic infections. Both for the protection of the individual transplant recipient and as a matter of public health policy, the US Centers for Disease Control and Prevention (CDC) has developed guidelines for the use of vaccination in the prevention of infectious disease following transplantation. This review examines the primary clinical research supporting vaccination policies in this target population. Widely accepted recommendations for transplant recipients based on scientific data are sparse, as few large studies have been conducted in this population. Anecdotal reports, expert advice, summaries, and limited series involving less than 50 patients using surrogate end points form the basis of the scientific literature, with the result being a wide variation in practice. Although based largely on inadequate scientific data, the CDC recommendations offer a pragmatic approach to the prevention of opportunistic disease in hematopoietic transplant recipients and serve as a useful starting point for standardization of practice while defining the direction of future studies in transplant recipients and other immunocompromised hosts.

Blood and marrow stem cell transplantation is a potentially curative treatment for a variety of hematologic malignancies, marrow failure syndromes, immunodeficiency states, and selected solid tumors. This aggressive treatment induces a period of sustained immunosuppression predisposing transplant recipients to opportunistic infections. Strategies for the prevention of these infections include the judicious use of prophylactic antibiotics and both active and passive immunization.[1]

Recently, both the US Centers for Disease Control and Prevention (CDC)[2] and the European Group for Bone Marrow Transplantation[ 3,4] issued recommendations for infectious disease immunization of hematopoietic stem cell transplant recipients. As increasing numbers of transplant recipients survive and return to the community setting, it becomes incumbent upon primary care physicians to ensure appropriate vaccination both for the protection of transplant recipients and as a matter of community public health.

Causes of Altered Immunity Following Transplantation

Transplant recipients become severely immunocompromised following high-dose therapy.[5] The transplant conditioning (chemoradiotherapy) regimen is the major contributor to early immune dysfunction. High-dose therapy causes damage to skin, gastrointestinal mucosa, and respiratory tract linings, permitting direct entry of pathogens. Alterations in protective barrier secretions (including immunoglobulin [Ig]A and saliva) may persist for months after treatment. The conditioning regimen also causes severe myelosuppression and a brief period of absolute neutropenia.

Engraftment of neutrophils, typically within 10 to 30 days after stem cell infusion, restores significant phagocytic function and considerably reduces the risk of bacterial infection. However, long-lasting immune impairment, primarily as a result of the depression of cellular immunity (lymphoid lineage driven), persists for months even in the absence of additional immunosuppressive medications or graft-vs-host reactions. These impairments are characterized by deficiencies in total immunoglobulin levels, IgG subclass concentrations, and in vitro B-cell and T-cell function.[6-8]

The incorporation of highly immunosuppressive medications into the conditioning regimens (permitting nonmyeloablative transplantation)[9] and the expanding role of posttransplant immunotherapy [10] may further affect immune recovery. The use of cytokines (hematopoietic growth factors) may also influence recovery. For example, granulocyte colonystimulating factor (G-CSF, Neupogen) appears to polarize recovering T lymphocytes toward a tolerance phenotype.[11]

Graft Characteristics

The rate of immunologic reconstitution also depends on characteristics of the hematopoietic graft including the stem cell source. Neutrophil recovery occurs most rapidly with peripheral blood stem cells, less rapidly with marrow, and slowest with umbilical cord cells. A more rapid neutrophil recovery after blood stem cell transplant is associated with a decrease in early mortality from infectious causes, compared to bone marrow stem cell sources among recipients of allogeneic transplants.[12] Lymphoid recovery also differs by stem cell source, leading to qualitative differences in immune function. Peripheral blood stem cell transplant recipients achieve faster recovery of total lymphocyte counts, total T cells (CD3), CD8, and CD4 cells, compared to marrow recipients.[13]

Among allogeneic transplant recipients, the use of marrow vs peripheral blood was associated with a 1.7-fold increase in documented infections, which was greatest for fungal infections, intermediate for bacterial infections, and least for viral infections.[14] Among autologous transplant recipients, one study comparing peripheral blood stem cell recovery to bone marrow recovery noted that 47% of blood and 29% of marrow recipients maintained immunity against tetanus.[15] However, a recent comparative study of vaccine responses to influenza, pneumococcal polysaccharide, and tetanus toxoid vaccines found no differences in serologic outcomes among allogeneic sibling marrow, autologous marrow, and autologous blood stem cell transplant recipients, thus supporting a broader vaccination policy.[16]

In addition, there are major differences in immune reconstitution between allogeneic and autologous transplant recipients. Although patients who undergo autologous transplant reconstitute the immune system more rapidly, significant impairment may occur among patients with lymphoid malignancies or recipients of grafts who have undergone ex vivo pharmacologic purging to remove tumor cells or CD34 selection (which reduces T-cell content).[17] Among allogeneic recipients, passive transfer of immune function from the donor may be beneficial but transient, and recipients are at risk of developing immune deregulation caused by disparity between the donor and recipient (commonly known as graft-vs-host disease [GVHD]). Patients who develop chronic GVHD experience significantly delayed lymphoid recovery (lasting for years), which may contribute to an excess of infections and delayed response to vaccinations. Recipients of mismatched or haploidentical allografts and those receiving immature cord blood grafts may experience extreme delays in immune recovery.

Late Infections

Although the conditioning regimen, type of transplant, and underlying disease affect the rate of immune reconstitution, all transplant recipients are at increased risk of late infection. In a study of 818 recipients of autografts and 1,007 recipients of allografts, 6.2% developed a late infection that required hospitalization 3 months or more following the transplant. The most common infectious pathogens were cytomegalovirus (n = 19), pneumococcus (n = 15), pneumocystis (n = 12), aspergillosis (n = 8), and pseudomonas (n = 7).[18] In a series of 244 autologous peripheral blood stem cell transplants, 64 (26%) developed an infection after engraftment. Varicella zoster virus (VZV, n = 36) and pneumonia (n = 16) were most common.

Risk factors for late infections in these autograft recipients included the administration of total-body irradiation (odds ratio [OR]: 2.5), previous use of fludarabine (Fludara, OR: 2.5), and a diagnosis of myeloma (OR: 2.6).[19] In the allogeneic setting, a 1982 series of 98 patients noted that approximately one-third of long-term survivors had three or more infections. Of the 244 infections in this series, 62 were of pulmonary origin (23 bacterial pneumonia, 25 bronchitis, 7 interstitial pneumonia), 49 cutaneous (including 29 VZV), 84 involving the ear, nose, and throat, 17 systemic (including 11 bacterial sepsis), and 15 ophthalmologic.[20]

In a more recent series of 151 allogeneic-related donor recipients, 67% had a late infection, and among 98 unrelated transplant recipients, 81% had a late infection (P = .015). Bacterial infections were most common, causing 52% of events (52% of these were gram-positive). Viruses caused 37%, and fungi were involved in 11%. Sixty-seven percent of the infections occurred between day 50 and 6 months, with 43% occurring between days 50 and 100; 22% occurred between 3 and 6 months, 26% between 6 months and 1 year, and 8% beyond 1 year. Of the 367 late infections, 103 were lifethreatening.[ 21]

Vaccinations to Prevent Infections

Recommendations exist for the prevention of common infections by vaccination in healthy individuals, but these measures are greatly underutilized in adult populations. The value and use of vaccines in immunocompromised populations are even more unclear. Widely accepted vaccine recommendations for transplant patients based on scientific data are sparse, as few large studies have been conducted in this population. Anecdotal reports, "expert" advice, summaries, and limited series involving fewer than 50 patients form the basis of the scientific literature.[22-25a] This has resulted in wide variations in vaccination practices among transplant centers.

Recent survey data from Europe[3] and the United States[1] indicate that substantial numbers of allogeneic and autologous transplant recipients are not immunized against common preventable infections. For example, among patients in centers that participated in the National Marrow Donor Program, only 50% to 90% received immunization against influenza, pneumococcus, or tetanus.

One potential explanation for this lack of vaccination among transplant recipients is the use of multiple medical providers; ie, patients return from the specialized transplant centers to their local physicians before the appropriate time for vaccination. It is also possible that with multiple providers, immunizations have been administered but have not been properly recorded in all medical records. In addition, most transplant patients rely heavily on their medical oncologist for general medical care, and these physicians may not be as well equipped to provide vaccinations as primary care specialists. This disjointed care reduces standardization and makes tracking of the true incidence of late infections problematic. Moreover, there is the mistaken perception that the "well" transplant patient does not require vaccination and that the "sick" patient will not benefit from it.

To address these issues, the European Group for Bone Marrow Transplantation issued recommendations for vaccination practices in 1995 and updated them in 1999.[3,4] In October 2000, the CDC, in conjunction with the Infectious Diseases Society of America and the American Society of Blood and Marrow Transplantation (and endorsed by the American Academy of Pediatrics and the International Society of Hematotherapy and Graft Engineering) issued guidelines for the prevention of opportunistic infections in hematopoietic stem cell recipients.[2] This document addresses multiple phases of infection control including the appropriate use of antibiotics, hospital infection control policies, home environment issues, and stem cell safety issues.

The CDC recommendations for vaccinations are listed in Tables 1 through 4. The complete recommendations, citations, and evidence-based strength of ratings are available on the Internet at www.cdc.gov/mmwr/PDF/RR/RR4910.pdf. In the following section, we critically review these recommendations for adult recipients of hematopoietic transplant. Although, as described above, immunologic reconstitution occurs at differing times based on the type of transplant, the CDC guidelines are similar for all types of transplants, emphasizing a pragmatic approach that standardizes administration.

Streptococcus pneumoniae

• CDC Recommendations-The CDC recommends use of the 23-valent polysaccharide vaccine at 12 and 24 months posttransplant.

• Discussion-Streptococcus pneumoniae is a major cause of late posttransplant infection. A review of 1,329 transplant patients (1973-1997) noted pneumococcal sepsis in 31 (2.3%) at a median of 10 months, with 7 fatalities (0.5%). Late infections developed in 4% of 5-year survivors and 6% of 10-year survivors, with all episodes occurring in recipients of allografts or autografts following total-body irradiation. In a 2002 prospective survey over a 3.5-year period, the incidence of early and late pneumococcal infections was estimated at 2.03/1,000 and 8.63/ 1,000, respectively, with an overall mortality rate of 20%.[27]

Based on the prevalence and seriousness of pneumococcal infections, many transplant centers recommend lifelong penicillin prophylaxis for allograft recipients with a history of chronic GVHD.[28] Because it is a major cause of infection, the development of early effective preventive strategies could have an important clinical impact. Although antibodies against pneumococcus are noted in most adult transplant patients prior to high-dose therapy, antibody levels decline dramatically in allogeneic recipients, with few who develop chronic GVHD retaining protective antibody levels at 1 year. In contrast, recipients of autologous marrow grafts tend to maintain existing antibodies.[29]

• Timing of Vaccination-In 1983, the first study of posttransplant vaccination with a 14-valent polysaccharide pneumococcal vaccine was performed in 39 allogeneic recipients. Impaired responses were noted in all, with male sex, corticosteroid therapy, and early vaccination having a negative effect. Of the 27 patients vaccinated before 7 months, 5 were unprotected and subsequently developed pneumococcal infection. Patients vaccinated after longer periods posttransplant developed evidence of antibody response to at least two strains.[30] Similarly, late vaccination with the 14-valent vaccine (after 18 months) achieved suboptimal but protective responses in allogeneic recipients without GVHD.[31]

The timing of posttransplant pneumoccocus vaccination has been briefly explored. As noted above, vaccination with the 14-valent polysaccharide product before 7 months did not appear to be efficacious, whereas after 24 months, vaccination yielded acceptable responses in most patients. A recent trial of the currently licensed 23-valent vaccine noted poor overall responses, but failed to show major differences in response between a 12- and 24-month schedule. Unfortunately, in this recent series, only 19% of recipients achieved protective levels at 24 months.[32]

• Donor Immune Status-A randomized comparison involving 45 allogeneic patients vaccinated at either 8 or 20 months with the 23-valent product also found poor responses in both groups. The authors did not note any benefit to delaying vaccination. Interestingly, responses were correlated with donor immune status against pneumococcus.[33] However, a subsequent trial was unable to confirm an effect with pretransplant immunization of the donor on subsequent recipient response to the 23-valent pneumococcus vaccine. Doses administered at 12 and 24 months yielded postvaccination antibody concentrations of 0.80:0.99 μg/mL (12 month) and 1.06:0.96 μg/mL (24 month) in the donor immunized and nonimmunized groups, respectively.[34]

Vaccination of the donor to elicit protective antibody responses to subsequent doses of vaccine represents a novel strategy to improve response. In a randomized trial, 67% of transplant recipients whose donors received a single dose of the heptavalent pneumococcal conjugate vaccine achieved protective immunoglobulin levels following a first dose of vaccine administered at 3 months posttransplant. The response rate in patients whose donors had not been vaccinated was 36%. Both groups achieved greater than 60% response rates with a three-dose series (3, 6, 12 months) of this vaccine.[35]

• Preventive Strategies-Given the risks of posttransplant pneumococcal infection, the development of effective preventive strategies would be of clinical value. Unfortunately, the current polysaccharide vaccine (23-valent) is T-cell-independent and not highly immunogenic. Moreover, this vaccine does not cover 20% of the commonly encountered pathogenic pneumococcal strains. The covalent linkage of the polysaccharide pneumococcal antigens to a protein (such as tetanus or diphtheria toxoid) results in a more immunogenic vaccine capable of eliciting a T-cell-dependent response that is stronger and more durable.

Unfortunately, studies of an early heptavalent polysaccharide-protein conjugate vaccine did not improve on the results achieved with the current 23-valent polysaccharide vaccine in allogeneic recipients.[36] Studies of a recently released 7-valent conjugate vaccine (Prevnar) administered alone or in sequence with the 23-valent nonconjugated vaccines are ongoing.

• Conclusions-In summary, the available studies suggest that the current polysaccharide 23-valent pneumococcal vaccine results in a suboptimal response in most allogeneic transplantation patients. Recognizing this, the CDC recommends a second vaccination at 24 months to provide an additional opportunity to achieve an immunologic response among those who failed to respond to the first dose. The timing of the vaccination also appears important, with few responses noted in those vaccinated before 6 months. However, clinical trials have not demonstrated a significant benefit to delaying vaccination, as responses remain poor and the key time frame for infection is early.

There are minimal data on the use of pneumococcal vaccines in the autologous marrow setting, and nearly no data on the use of these vaccines in blood stem cell or purged transplants. Moreover, the basis for the recommendations for this and most of the other vaccines is almost exclusively the surrogate laboratory end points of antibody levels rather than the clinical end point of disease prevention.

The value of vaccinations in decreasing disease severity in the transplant population has also not been addressed. Basic response data are needed for these populations and would be useful in establishing a baseline for newer more immunogenic vaccines and/or adjuvant vaccine trials. Although the CDC recommends that the polysaccharide 23-valent vaccine be administered at 12 and 24 months, data generated by clinical trials suggest that patients should be followed closely for infection and considered for antibiotic prophylaxis during the initial critical year posttransplant (and possibly lifelong in allogeneic recipients).

Haemophilus influenzae type b

• CDC Recommendations-Use of the conjugate vaccine is recommended at 12, 14, and 24 months posttransplant.

• Discussion-Haemophilus influenzae type b is a major infectious pathogen after the third month posttransplant. Similar to pneumococcus, responses to traditional polysaccharide vaccines among immunocompetent individuals (including infants) with H influenzae b infections were disappointing and spurred the development of more immunogenic products. The conjugate vaccines covalently link polysaccharide antigens to proteins such as meningococcus, tetanus, or diphtheria toxoid, resulting in a T-cell-dependent response that is much stronger. The currently licensed H influenzae b conjugate vaccines have been able to induce adequate immunity in infants and individuals with primary IgG2 deficiency.

Protective levels of antibody against H influenzae b decline following transplant but can be regained with vaccination. A randomized trial in 40 allogeneic transplant recipients demonstrated the superiority of the conjugate approach. Before immunization, only three patients (8%) had protective antibody levels (defined as ≥ 1 μg/mL). Using a highly variable schedule of vaccination, ranging from the fourth month to later than 18 months, one dose of conjugate vaccine resulted in a 70% response rate. A second dose increased the response rate to 85%. There was no clear association between response and the presence of GVHD, time of vaccination, or concurrent immunosuppressive medications.[37]

• Timing of Vaccination-The timing of conjugate vaccination was recently explored in 45 allogeneic transplant patients. Patients received immunization at either 6 or 18 months posttransplant. The authors noted similar results at both times (60% and 67%, respectively), and therefore, recommended the earlier schedule in light of the more common time of infection within the first year posttransplant.[ 25] A second study used multiple dose schedules and noted that patients who began vaccination at 3 and 6 months achieved higher titers of protective antibodies at 12 and 24 months, compared to patients who began vaccination at 12 months. However, the proportion of patients achieving protective levels of antibodies was similar in all groups.[38]

The type of transplant may also affect antibody response to H influenzae b. In the allogeneic setting, the immune status of the donor influences antibody response in the recipient. Vaccination of donors in one study increased responses. Following vaccination at 3, 6, 12, and 24 months, the percentage of recipients with protective antibody levels of 1 μg/mL at 3, 12, and 24 months posttransplant in a cohort with concurrent donor immunization was 97%, 92%, and 92%, respectively, compared to 55%, 37%, and 47% in a cohort without donor immunization.[26]

In the autologous setting, vaccination prior to the marrow harvest may elicit a protective late response.[ 39] Additionally, antibody levels are higher and achieved earlier in recipients of peripheral blood stem cell grafts compared to recipients of autologous bone marrow. The 17 peripheral blood stem cell and 10 bone marrow transplant patients received vaccinations at 3, 6, 12, and 24 months posttransplant. The percentage of patients with protective antibody levels in the peripheral blood stem cell group at 6, 12, and more than 12 months was 44%, 25%, and 75%, compared to 24%, 17%, and 43% in the bone marrow cohort.[40]

• Conclusions-The conjugate H influenzae b vaccines are immunogenic during the posttransplant period. As with pneumococcal vaccination, timing of the vaccine may be important, and unlike pneumococcus, adequate responses may be achieved within the critical first year. Donor or preautologous harvest vaccinations may also be beneficial. However, the CDC guidelines do not address these issues. Similar to pneumococcus, use of prophylactic antibiotics in allogeneic transplant recipients, especially those with chronic GVHD, should be considered.

Tetanus, Diphtheria, and Pertussis

• CDC Recommendations-Vaccination with combined tetanus/diphtheria toxoids is recommended at 12, 14, and 24 months. Postexposure tetanus vaccination, with or without concomitant tetanus immunoglobulin, is recommended at any time. Revaccination every 10 years thereafter is similar to guidelines for the general public. Pertussis vaccine is not recommended in adults.

• Discussion-Although the risk of infection with tetanus is low, lifethreatening infection by tetanus is preventable. Both allogeneic and autologous transplant recipients experience a gradual loss of protective antibodies that can be restored with vaccination. In 37 allogeneic recipients known to be seropositive against tetanus before transplant, 19 (51%) lost immunity by 1 year and none who did not undergo vaccination retained immunity at 2 years posttransplant.[ 41] Although passive transfer of tetanus immunity from donor to recipient has been suggested (and therefore might be protective early following transplant), the recipient's pretransplant antibody levels (and not the donor's) most strongly influenced residual tetanus antibody levels at the 1 year evaluation. Three-dose primary immunization beginning at 1-year posttransplant restored immunity in all studied allogeneic patients, and chronic GVHD did not alter response.

In an attempt to move the vaccination schedule forward before the expected loss of protective antibody, a randomized trial noted similar results with a three-vaccine schedule at 6, 8, and 14 months, compared to a delayed schedule of 18, 20, and 26 months.[42] A second timing study noted improved antibody titers against tetanus in a cohort that received early vaccinations starting at either 3 or 6 months posttransplant, compared to a cohort starting vaccination at 1 year.[31]

Autograft recipients also experience a gradual decline in protective tetanus antibodies. Among 90 patients, only 29% of those who received autologous marrow rescue and 47% of those who received blood stem cells had immunity against tetanus at 1 year (P = NS). No cases of spontaneous recovery were reported among patients who were seronegative prior to transplant. Similar to allograft recipients, a three-dose series starting at 1 year posttransplant was capable of restoring immunity in all patients.[43] As with the H influenzae b conjugate vaccines, immune response to vaccination appears more rapid among recipients of autologous blood stem cells compared to bone marrow rescue. Vaccination starting at 3 months resulted in earlier and higher titers of tetanus-protective antibody levels among blood stem cell recipients.[33]

Although rare in the United States, diphtheria remains a public health problem worldwide with periodic epidemics and high fatality rates. As with tetanus, immunity against diphtheria wanes during the first year. Only two-thirds of allograft recipients and 40% of those with chronic GVHD retain immunity.[44] In one study, at 1 year, 55% had detectable antibodies, with the mean only barely above protective levels. All patients with protective levels at 1 year had been immune before transplant and had received marrow from a seropositive donor.[45] Vaccination in adults following either autologous or allogeneic transplant has not been well studied, although in children, multiple doses are required to restore immunity (21% restored following one dose compared to 86% with three doses).[46]

Pertussis is an unusual infection in adults, and vaccination is not routine in the general population above the age of 6 to 7 years. No data exist on the effectiveness of (or need for) pertussis vaccination in adults posttransplant.

• Conclusions-Immunity against tetanus gradually declines following allogeneic and autologous transplant but can be restored with vaccination. Although data demonstrate significant loss of protective antibody during the first year and the efficacy of early vaccination, the CDC recommends a three-vaccine series starting at 12 months. The rarity of clinical infection during the first year and the pragmatic nature of vaccine scheduling probably justifies this recommendation. Postexposure vaccination, with or without concomitant immunoglobulin, is advised at any time following transplantation to protect against active disease.

Diphtheria titers also decline and may be restored (as extrapolated from pediatric data) with a multidose vaccine regimen. Vaccinating adults against pertussis is not recommended.

Polio

• CDC Recommendations-Inactivated polio vaccine is recommended at 12, 14, and 24 months. Oral polio vaccine is contraindicated. Inactivated polio vaccine is preferable for household contacts; exposure to household recipients of oral live vaccine should be minimized for 4 to 6 weeks.

• Discussion-Poliomyelitis is a rare infection in the United States, with no naturally occurring (wildtype) cases reported in the past decade and only a handful of vaccine-related (oral live vaccine) cases. Nonetheless, even in developed countries, sporadic outbreaks continue and efforts to eradicate polio worldwide are ongoing. Despite the low incidence of the disease, the CDC recommends vaccination of all transplant recipients with the inactivated polio vaccine-the only polio vaccine currently available in the United States.

Three studies in adult patients have documented a gradual loss of protective antibody against polio following allogeneic transplant. In aggregate, only 60% to 80% of allogeneic recipients retained immunity at 1 year, and four- to eightfold decreases in antibody titers were common.[ 47-49] Similarly, nearly 20% of autologous bone marrow recipients lost immunity against at least one strain of polio by the first year posttransplant, and unimmunized patients continued to experience gradual declines in antibody titers during years 2 and 3.[50]

Vaccination is capable of restoring protective levels of antibodies. Among 45 allogeneic recipients randomized to receive inactivated polio vaccines at 6, 8, and 14 months (early group) or at 18, 20, and 26 months posttransplant (late group), both schedules were found to be equally immunogenic with 44 patients achieving protective levels 1 and 22 months postvaccination. Acute GVHD accelerated the decrease of poliovirus antibody titers prior to vaccination, but neither acute nor chronic GVHD influenced responsiveness to the vaccine.[51]

Similarly, high response rates with two doses beginning at a median of 16 months posttransplant (immunity restored against 89% to 98% of serotypes) were reported in a second study.[41] However, an earlier study in allogeneic patients noted only an 8% to 57% response rate to three strains of poliovirus with one vaccine dose, which improved to a 14% to 59% response rates with a threedose schedule.

Chronic GVHD in this study was felt to adversely affect response when all three vaccines were completed within 14 months, but GVHD patients who received additional late dosing (24-36 months) achieved protective titers.[40] Among autologous transplant recipients, a three-dose schedule restored immunity against three serotypes of polio in 83% to 100% of patients with an earlier response to the type 2 poliovirus followed by responses to types 1 and 3. These responses were similar to those seen after primary immunization of healthy individuals.[43] It is important to note that in all of these studies administration of the inactivated vaccine appeared to be safe with no severe adverse reactions.

• Conclusions-The literature documents a progressive loss of protective antibody titers against poliovirus. Among autologous transplant and allogeneic transplant recipients without GVHD, three doses of inactivated vaccine given during the first year posttransplant are capable of restoring immunity. Among allogeneic recipients with chronic GVHD, reduced early responses support a delayed schedule of administration extending 2 to 3 years following transplant.

The CDC has recommended a later schedule to coincide with vaccination against other pathogens. Given the rarity of this infection, a more pragmatic approach appears justified. A better question to ask, in the absence of any wild-type infections in the United States, is whether this population requires vaccination against polio at all.

Hepatitis A and B

• CDC Recommendations-In light of limited data, hepatitis A vaccine is not rated and is currently considered not routinely indicated. Intramuscular immunoglobulin is recommended for those traveling to endemic areas and for postexposure prophylaxis. Hepatitis B vaccine is recommended at 12, 14, and 24 months for individuals ≤ 18 years old and those with risk factors. Two doses of hepatitis B immunoglobulin 1 month apart are recommended for percutaneous or mucosal exposure.

• Discussion-Hepatitis A vaccination has limited value in the general immunocompetent population, except for those engaged in high-risk behaviors or frequent international travel, or at high risk of fulminant complications due to chronic liver disease. Likewise, routine vaccination should have a minimal role in the transplant population. To date, there is limited clinical experience documenting the efficacy or safety of hepatitis A vaccination among transplant recipients, although theoretically, individuals with chronic GVHD of the liver might potentially benefit from vaccination.

Currently, the licensed vaccines are conventional inactivated wholevirus vaccines prepared from virus propagated in cell culture, and thus, should be safe. Hepatitis A immunoglobulin is recommended for transplant recipients who anticipate exposure to hepatitis A (such as travel to endemic areas) or as postexposure prophylaxis. Intramuscular immunoglobulin is much less expensive and provides immediate protection.[52] Likewise, the CDC guidelines recommend hepatitis A vaccination of household contacts of the transplant recipient only if they fall into a highrisk cohort, and not by virtue of their relationship to a transplant recipient.

Current vaccines against hepatitis B are subunit vaccines produced by recombinant DNA technology. Although highly immunogenic in healthy individuals (> 95% develop immunity with three doses), the response among immune incompetent individuals is significantly less. Using an older virally inactivated vaccine, one-quarter of cancer patients who received chemotherapy failed to respond.[53] There is limited experience with the recombinant vaccine following transplant, and the current CDC recommendations mirror those for the general public. One older report noted poor responses among allogeneic recipients.[54]

• Timing of Vaccination-Because hematopoietic stem cell transplant patients are at risk of developing transfusion-related hepatitis (either from an infected marrow donor or from blood transfusions following transplantation), interest has focused on administering vaccinations prior to transplant. In the autologous transplant setting, 48 patients were immunized against hepatitis B with a series of three injections (with the first two injections completed by 30 days posttransplant). Seroconversion occurred in 33 patients (69%) and was persistent in 19 (59%).[55] This transient protection may be sufficient, as most autologous recipients decrease their blood exposures within 1 to 2 months of transplant.

Among 24 allogeneic transplant recipients of infected donors (hepatitis B surface antigen [HbsAg]-positive marrow), seroconversion occurred in 22%, but only 5.5% became chronic carriers. Severe liver failure was more likely to develop in recipients of a marrow donor also positive for anti-hepatitis B e antigen (28% vs 0%). Because less severe liver disease developed after transplant in previously "immune" recipients (pretransplant anti-hepatitis B s antibodies), passive prophylaxis of recipients with anti-hepatitis B immunoglobulin (BayHep B, Nabi HB) or intravenous immunoglobulin could be considered when the donor is HBsAg-positive and the recipient not previously immune.[56,57]

Transplant candidates who are already HBsAg-positive are at risk for reactivation of virus and liver dysfunction following transplantation. Vaccination of the donor has been proposed as a method of adoptive immune transfer to facilitate clearance of the recipient's chronic carrier state. Long-term follow-up has shown persistent anti-hepatitis B s antibodies in 22 of 35 recipients of bone marrow from actively immunized donors.[58]

Passive immunization with hepatitis B immunoglobulin using a twodose schedule 1 month apart is recommended by the CDC for immunocompromised individuals who have percutaneous or permucosal exposure.

• Conclusions-Vaccination against hepatitis A is not routinely recommended by the CDC, and to date, there are few data on the efficacy of posttransplant vaccination. Individuals at risk are recommended to receive passive immunization with intramuscular gammaglobulin (BayGam).

The issues surrounding hepatitis B vaccination are more complex. Currently, there is a national consensus on vaccinating all children, but efforts in the adult population are focused on those at high risk. In the absence of good efficacy data, the CDC recommended hepatitis vaccination of high-risk bone marrow transplant populations (possibly including individuals with liver disease caused by chronic GVHD) analogous to that of immunocompetent populations. Clinical reports, but not the CDC, support active vaccination of the marrow donor if the recipient is infected as a means of clearing the carrier state, and conversely, using passive immunoglobulin if the donor is infected.

Influenza A

• CDC Recommendations-Lifelong, seasonal administration is recommended, beginning before transplant and resuming ≤ 6 months following transplant.

• Discussion-Influenza A infections have not been well studied in the marrow transplant population. Although it is recognized that influenza A predisposes the immunocompromised host to bacterial superinfection, the incidence of influenza infections and the value of preventive vaccination are unknown. Severe life-threatening infections may occur during the early aplastic phase of transplantation.[59,60]

A study in 48 patients, including 35 T-cell-depleted allogeneic recipients and 13 autologous marrow recipients, has been reported. Patients received two doses of the influenza vaccine (1 month apart) at various schedules. No patient who received a vaccination before 6 months responded adequately. Protective titers were achieved after one dose in 13% vaccinated between 7 and 24 months, and in 64% to 71% of those vaccinated after 2 years. The two-dose schedule only marginally improved response rates.[61]

The potential role of immune adjuvants, which has improved responses to influenza vaccines in elderly populations, has not been fully explored. One preliminary report of the addition of granulocyte-macrophage colony-stimulating factor (GM-CSF, Leukine) to early vaccination (between 4 to 12 months posttransplant) found no benefit, with only approximately 30% of patients responding with or without the immune stimulant.[ 62] Based on limited data, the CDC recommends lifelong seasonal immunization, but emphasizes the potential role of concurrent chemoprophylaxis with amantadine or rimantadine (Fludamine) during a nosocomial or community outbreak. The value of neuraminidase inhibitors (zanimivir [Relenza] and oseltamivir [Tamiflu]) for prophylaxis and ribavirin (Rebetol, Virazole) for treatment is unknown in this population.

Given the lack of data and the efficacy of influenza A vaccination in early transplant recipients, efforts to minimize transmission are paramount. Individuals with upper respiratory tract symptoms should avoid close contact with transplant patients. The guidelines recommend vaccination of family members and close household contacts for the first 2 years following transplant. During influenza outbreaks, family members should be offered chemoprophylaxis for 2 weeks until the immunologic response to the vaccine is complete. Additionally, health-care providers, especially those in contact with recipients of hematopoietic stem cell transplants, should be encouraged to receive annual influenza vaccines.

Mumps, Measles, and Rubella

• CDC Recommendations-Live vaccine is recommended at 24 months posttransplant. Intramuscular immunoglobulin is recommended at any time for individuals exposed to measles and not previously vaccinated.

• Discussion-The success of routine childhood measles, mumps, and rubella (MMR) vaccination in the United States has resulted in limited outbreaks in the general population and among transplant recipients. However, the majority of transplant recipients lose their immunity to these pathogens. In a longitudinal study in 124 allogeneic transplant patients who had survived at least 2 years posttransplant, the calculated probabilities of being immune to measles at 3, 5, and 7 years were 47%, 27%, and 20%, respectively. Likewise, a loss of protective immunity at similar time points for mumps was 37%, 12%, and 6%. For rubella, the corresponding probabilities were 47%, 33%, and 28%.[63]

A longitudinal study in 63 autologous bone marrow transplant recipients also noted a progressive loss of immunity; 12% who were known to be seropositive against measles prior to transplant became seronegative at 1 year. Corresponding rates for mumps and rubella at 1 year were 18% and 6%. Interestingly, most of the adult patients who acquired their pretransplant immunity via the occurrence of natural disease maintained immunity, in contrast to the higher rates of seronegativity among children who received pretransplant vaccinations.[64]

• Clinical Experience-Although MMR is a live vaccine, clinical experience has demonstrated that it can be administered to transplant recipients. A total of 20 seronegative allogeneic bone marrow recipients without active chronic GVHD or ongoing immunosuppression were vaccinated (17 at 2 years and 3 at 3 years posttransplant). The vaccine was efficacious with a 77% seroconversion rate for measles, 64% for mumps, and 75% for rubella. The corresponding rates of seroconversion for normal controls were 90%, 86%, and 100%, respectively. No early or late side effects were reported.[65]

Among pediatric allogeneic bone marrow transplant recipients without ongoing GVHD vaccinated at least 2 years posttransplant, 77% achieved seropositivity against measles, 87% against mumps, and 91% against rubella without serious adverse effects.[ 66] Vaccinations in the autologous setting have also been safe, although responses to measles vaccination have been suboptimal.

In autologous recipients who are seronegative to measles, a preexisting T-cell response (cellular-mediated immunity) has been correlated with an impaired B-cell (humoral) response to the vaccination. Both Th1 and Th2 cytokine production appear to be increased by stimulation of the measles antigen with retained cellular-mediated immunity to measles. However, the Th1 response appears to be stronger possibly leading to an increase in interferon-gamma production after vaccination and thus a downregulation of clinical antibody production.[67]

After a 1997 outbreak of measles in Brazil, eight cases of measles were confirmed among 122 nonvaccinated bone marrow transplant patients.[ 68] Subsequently, transplant physicians in Australia initiated early MMR vaccination (median: 13 months posttransplant) in autologous and non-GVHD allogeneic transplant recipients. Protective antibody titers against rubella were achieved by 91%, but only 46% achieved responses against measles. No adverse outcomes were noted.[69] Thus, during a community outbreak of measles, it may be possible to safely administer earlier vaccinations.

Vaccination of household contacts is recommended for all persons over 1 year old who are not pregnant or immunocompromised, similar to the CDC recommendations for the general public. To date, there is no evidence of person-to-person transmission of the live-attenuated vaccine-strain viruses, except a single case of rubella strain from a nursing mother to her infant. No special household contact precautions are advised.

Meningococcus

• CDC Recommendations-Meningococcal vaccine (Menomune) is not rated because of limited data.

• Discussion-Neisseria meningitidis is a major cause of bacterial meningitis worldwide, although reports of infection in adults following transplant are rare. Because immune response to polysaccharide proteins after transplant is poor (as noted above with pneumococcal and H influenza vaccines), it has been assumed that transplant patients might be at risk of N meningitidis infection but that vaccine response might also be inadequate. In the absence of published data, the CDC could not recommend vaccination. However, the CDC guidelines call for an evaluation of the risks/benefits of administering the meningococcal vaccine during an outbreak and to individuals who live in endemic areas.

Recently, Finnish investigators studied the efficacy of a tetravalent polysaccharide meningiococcal vaccine.[ 70] A total of 44 allogeneic recipients were randomized to vaccination at either 8 or 20 months posttransplant. Only 14% of the early group and 10% of the late group had residual protective levels of antibodies prior to vaccination, confirming a loss of antibody with transplantation. One month following vaccination, 76% to 84% of individuals achieved protective antibody levels, although 6 months after vaccination, the antibodies fell by one-half.

The schedule of administration-early vs late-had little effect. Chronic GVHD also did not appear to impair vaccine responsiveness. Rather, because of functional asplenia caused by chronic GVHD, the authors stressed that this population may be particularly vulnerable to infection, and thus, may benefit from vaccination.[ 70] A potentially more immunogenic conjugate vaccine is currently in development.

Lyme Disease

• CDC Recommendations-Vaccination against Lyme disease is not rated because of limited data.

• Discussion-No data regarding the efficacy or safety of vaccination against lyme disease are available at this time. This vaccine has been withdrawn from general use.

Rabies

• CDC Recommendations-Vaccination against rabies is not rated because of limited data.

• Discussion-Routine administration of the rabies vaccine is not recommended for the general public. Although immunogenicity and safety data are absent, the CDC guidelines permit individuals with potential occupational exposures (ie, animal handlers) to be vaccinated prior to exposure, with the caution that vaccination might best be delayed for 12 to 24 months. Postexposure use of human rabies immunoglobulin (BayRab, Imogam) and vaccine is recommended using a standard schedule (days 0, 3, 7, 14, and 28 postexposure).

Respiratory Syncytial Virus Immunoglobulin and Monoclonal Antibody

• CDC Recommendations-Use of respiratory syncytial virus (RSV) immunoglobulin (RespiGam) and monoclonal antibody (palivizumab, Synagis) is acceptable in transplant recipients.

• Discussion-Community-acquired RSV is a potentially lethal infection following hematopoietic stem cell transplant. A prospective study conducted at 37 European centers identified infections in 2.2% of 819 allogeneic and 0.17% of 1,154 autologous transplant recipients, with a total mortality of 25% within 28 days of diagnosis.[71] Because of the high fatality rates from RSV pneumonia among transplant recipients, the CDC deems the use of passive antibody treatment at the onset of upper or lower respiratory symptoms acceptable until controlled clinical trials can be completed. Preventive measures are advisable, including contact isolation of any individual suspected to be infected and avoidance of visits by individuals with upper respiratory tract symptoms.

Varicella-Zoster Virus Live Vaccine

• CDC Recommendations-Varicella virus vaccine (Varivax) is contraindicated for transplant recipients but recommended for family and household contacts. Varicella-zoster virus (VZV) immunoglobulin is recommended for exposures.

• Discussion-Primary infection with VZV (chickenpox) is uncommon in adult transplant recipients. By contrast, reactivation of VZV (shingles) is one of the most common and distressing late infections in this population. In a series of 151 patients who underwent allogeneic transplant, survived at least 3 months, and were maintained on prophylactic antiviral therapy (ganciclovir [Cytovene] or acyclovir) for the first 6 months following bone marrow transplant, the cumulative incidence of VZV was 13% at 12 months and 32% at 24 months. No patient developed VZV while receiving antiviral therapy, but there appeared to be rapid onset following cessation of the drug.[72]

Similar results were noted in a consecutive series of 100 adult allogeneic recipients, 59% of whom developed VZV by 2 years, including one fatal case and one case of encephalitis.[ 73] Although antiviral therapy delays infection, which may be beneficial for those with ongoing GVHD, prolonged chemoprophylaxis also delays reconstitution of VZVspecific immunity. The need for better long-term strategies including vaccination or immune stimulation is obvious.

• Vaccination Studies-The usefulness of the live-attenuated VZV vaccine in bone marrow transplant patients-adult or pediatric-is largely unknown. Similar to most other live vaccines, the CDC guidelines consider the vaccine contraindicated in transplant recipients. In one study in 15 children vaccinated 12 to 23 months after bone marrow transplant, 8 of 9 previously seronegative subjects achieved seroconversion. Although no clinical cases of VZV were observed, late administration of the vaccine past the critical time frame for usual reactivation makes the data difficult to interpret.[74]

As part of a larger trial in pediatric acute lymphoblastic leukemia patients, 21 autologous transplant recipients received vaccination. All had been in remission for at least 1 year, had no detectable antibodies against VZV, and had at least 700/ mm3 circulating lymphocytes. Active chemotherapy (ie, maintenance treatment) was withheld for the 2 weeks surrounding the vaccination. The most common adverse effect was the development of a rash 2 to 6 weeks postvaccination. The 5% of leukemic children who no longer received treatment (n = 64) and the 50% who continued to receive maintenance therapy (n = 511) also experienced a maculopapular vesicular rash that resembled a mild form of chickenpox. Children who developed more than 50 lesions or had a rash for more than 7 days were treated with acyclovir.

Three transplant recipients (14%) subsequently developed clinical VZV infection, compared to 1.9% of 527 leukemic children without a transplant history (P = .01); clinical disease occurred in 4.1% of those with the rash and 0.7% of those without a rash (P = .02).[75]

Given the prevalence of VZV infections after bone marrow transplant, a variety of innovative vaccination strategies have been explored. An investigational heat-inactivated vaccine may hold promise, allowing earlier vaccination. A recent randomized trial noted a significant reduction in the incidence of VZV infection with a four-dose vaccine schedule administered before and during the first 90 days following transplantation. In 111 autologous transplant recipients, VZV infection developed in 7 of 53 (13%) vaccinated patients compared with 19 of 58 (33%) unvaccinated patients (P = .01).[76] An early three-dose trial (at 1, 2, and 3 months after bone marrow transplant) reduced the clinical severity of VZV, but the incidence of viral reactivation remained unchanged.[77] A second approach involves transfer of immunity by vaccinating the donor. A decrease in VZV infections was noted in one trial in which donors had been immunized 2 to 4 weeks prior to stem cell harvest.[78]

• Conclusions-Although the majority of VZV disease in adults following bone marrow transplant is caused by reactivation of endogenous VZV, transplant recipients (regardless of their serologic status) are encouraged to avoid contact with individuals with active VZV. Wildtype VZV has a high transmission rate (over 80%), and clinical disease can be severe. In contrast, studies have suggested that the transmission rate for the live vaccine strain is approximately 20% to 25% and that the clinical rash is typically milder with lower rates of severe disease. Therefore, the CDC recommends that household contacts who do not already have a history of VZV disease or who are seronegative receive vaccination (ideally at least 6 weeks prior to the patient's high-dose conditioning regimen). To date, there are no reports of serious adverse effects among transplant patients exposed to vaccinated household contacts.

Exposures to active chickenpox, shingles, or a vaccine-associated rash by a VZV-seronegative bone marrow transplant recipient (during the 24 months following transplant, or longer if still on immunosuppressants) should be treated with varicella immunoglobulin as soon as possible (ideally within 96 hours) to prevent disease. The similar use of varicella immunoglobulin in exposed seropositive bone marrow transplant recipients is recommended by some researchers, and the CDC guidelines concur in light of the potential severity of disease.

Given the frequency of posttransplant shingles, the development of better strategies to prevent reactivation are needed. Whether the efforts of the CDC to vaccinate healthy children will lead to a future generation of cancer patients less prone to reactivation remains unknown.

Rotovirus

• CDC Recommendations-Rotovirus vaccination is not recommended for any person in the United States.

• Discussion-This vaccine is currently being withdrawn from use in the United States. Intussusception was reported with substantially increased frequency among infants during the first 2 weeks following rotovirus vaccination.

Bacillus Calmette-Gurin

• CDC Recommendations-Use of bacillus Calmette-Gurin (BCG) vaccine (TICE BCG) is contraindicated before 24 months posttransplant.

• Discussion-BCG vaccine is a live-attenuated strain that is rarely used in the United States except in infants exposed to mothers with active pulmonary tuberculosis. As a live vaccine, it is contraindicated during the first 24 months posttransplant. Concerns about disseminated or fatal disease with early use in immunocompromised transplant recipients and the lack of data on its efficacy and/or safety with delayed use preclude administration. The European Group for Blood and Marrow Transplantation cautions against the use of live vaccines, including BCG, in individuals with chronic GVHD.

The CDC recommends that bone marrow transplant candidates be screened for tuberculosis exposure and that skin testing be performed (although results may not be reliable). A full 9-month course of isoniazid is recommended for individuals who have been substantially exposed, or who have a positive skin test but have received no previous treatment. The transplant need not be canceled or delayed due to a positive skin test. The 2-month regimen of pyrazinamide/ rifampin is not recommended due to limited data on safety and efficacy and concerns regarding substantial drug interactions between rifampin and many common transplant-related medications.

Cholera

• CDC Recommendations-Vaccination against cholera is not indicated.

• Discussion-No data regarding safety, immunogenicity, or efficacy in transplant recipients exist.

Japanese B Encephalitis

• CDC Recommendations-Use of this vaccine is not rated because of limited data.

• Discussion-No data regarding safety, immunogenicity, or efficacy in transplant recipients exist.

Plague

• CDC Recommendations-The vaccine for plague is not rated because of limited data.

• Discussion-No data regarding safety, immunogenicity, or efficacy in transplant recipients exist. The vaccine is no longer available in the United States.

Smallpox and Anthrax

• CDC Recommendations-Smallpox and anthrax vaccines are not rated.

• Discussion-Recent tragic events renewed interest in vaccinations against potential agents of biologic terrorism. The role of vaccination against these pathogens in immunocompromised transplant recipients remains unknown but is the subject of discussions.

Typhoid

• CDC Recommendations and Discussion-The oral live-attenuated vaccine is contraindicated during the first 24 months posttransplant. Similar to other live-attenuated vaccines, early use of the oral typhoid vaccine while the patient is still immunocompromised is not recommended by the CDC, and the safety and efficacy of delayed use are unknown. The intramuscular preparation is not rated, as no data regarding safety, immunogenicity, or efficacy in transplant recipients exists.

Yellow Fever

• CDC Recommendations and Discussion-Similar to other live-attenuated vaccines, early use of the yellow fever vaccine (YF-Vax) while the patient is still immunocompromised is not recommended by the CDC, and the safety and efficacy of delayed use are unknown.

Strategies to Improve Vaccination Efficacy

A variety of strategies might be considered to improve the efficacy of the vaccination and reduce late infectious complications. As noted above, pretransplant vaccination of the allogeneic donor may permit temporary adoptive transfer of antigen-specific immunity that might be augmented through a secondary response with early booster vaccination. This strategy has been shown to be feasible with tetanus, H influenzae b, hepatitis B, and Pseudomonas aeruginosa but not pneumococcus.

Cytokines, including GM-CSF, interleukin-2 (IL-2, Proleukin), and interferon-alpha, have entered small clinical trials. Freund's adjuvant (aluminum salts and mineral oil) has not been fully explored in this patient population. Finally, the transfer of T-cell clones against specific antigens (such as cytomegalovirus or Epstein-Barr virus) is gaining experience in patients at high risk.

Public and health-care awareness of the issues surrounding vaccination practices in adult populations (transplant and otherwise) is of paramount importance. Strategies that encourage compliance with appropriate administration of vaccines (and tracking of adverse outcomes) will have a greater effect on outcomes. Simple patient reminder cards sent by the transplant center, or other recall systems, should be standard practice for this population.

Summary

The immunization schedule recommended by the CDC represents a pragmatic approach that incorporates much of the current literature. Its hallmark is the uniformity of vaccine administration at 12, 14, and 24 months with reduced attention to type of transplant, GVHD status (excepting live vaccines), or other major effectors of immune reconstitution. From a public policy standpoint, these guidelines allow for the broadest coverage of the ever-increasing population of long-term transplant survivors. However, these recommendations are based largely on small single-center studies that, in general, used surrogate end points and, unfortunately, did not adequately address some of the critical middle time frame (100 days to 1 year) infections such as pneumococcus, H influenzae b, and varicella-zoster.

As additional studies are conducted-especially studies detailing differences in immune recovery between various stem cell sources and the role of immune adjuvants and donor vaccination strategies-these guidelines will need further revision. However, for now, the adoption of a uniform health policy across the United States represents a major step forward in an arena that formerly was dominated by local chaotic practices.

Financial Disclosure:The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.

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