Vaccination of Immunocompromised Hosts

Pneumococcal Vaccines

Pneumococci are important causes of infection in patients with cancer especially those with hematological malignancies. A recent epidemiological study from Denmark showed that the incidence of invasive pneumococcal disease was more than 32 times higher in individuals with hematological cancer compared to individuals without cancer (415.4 vs 12.7/100.000 person years) and five times higher in patients with nonhematological cancer (70.9 vs 12.7 person years). Furthermore, the case fatality rate was significantly higher (adjusted RR 9.53 (8.85–10.27) vs 1.78 (1.70–1.87) for hematological and nonhematological cancers, respectively). Patients with B-cell malignancies such as chronic lymphocytic leukemia (CLL), non-Hodgkin and Hodgkin lymphomas, and multiple myeloma are at especially increased risk.

Early studies were performed with the polysaccharide-based vaccine (PPSV23). In patients with multiple myeloma, less than 40% obtained “protective” antibody levels after vaccination with PPSV23. The response to the same vaccine in patients with Hodgkin lymphoma varied with the time of vaccination relative to therapy. Patients immunized after chemo- and/or radiotherapy have a severe impairment of the antibody response. ^, In contrast, good responses to PPSV23 can be obtained if immunizations are performed before therapy is initiated. ^, In addition, the response in children with Hodgkin lymphoma was poorer if immunizations were performed after as compared to before splenectomy. Repeated vaccinations with PPSV23 given before and then after splenectomy in patients with Hodgkin lymphoma were able to induce increased antibody responses and were not associated with serious side-effects.

Pneumococcal conjugate vaccines (PCVs) have also been studied in patients with hematological malignancies. Molrine et al. showed that a single dose of the PCV7 gave suboptimal responses in patients who had been treated for Hodgkin’s disease. CLL patients responded to PCV7 but the response rates were lower than in controls and were worse late in the course of the disease. Administering a single dose of the 13-valent PCV (PCV13) early after the diagnosis in patients with CLL resulted in an immune response in only 58% of CLL patients compared to 100% of healthy controls. Svensson et al. showed in a randomized trial superior response after one dose of PCV13 compared to PPSV23 in treatment naïve CLL patients. However, the proportions of patients responding to at least 8 of 12 analyzed pneumococcal subtypes were only 39.6% and 21.5% in PCV13 and PPSV23 vaccinated patients, respectively. Mustafa et al. showed similar responses in patients with multiple myeloma and healthy controls after one dose of PCV 13 but the multiple myeloma patients had rapidly waning specific antibody levels.

Few studies have been performed in patients with solid cancers. Choi et al. compared in a randomized study, immunization with PCV13 given before or at 2 weeks after starting adjuvant chemotherapy in patients with gastric or colorectal cancer and showed good immune responses to one dose of PCV13 with no differences in immune response between the two groups. Children seem to respond well to PCV13 especially after completing cancer therapy. Hung et al. showed that children vaccinated after completing therapy responded better than those vaccinated during active immunosuppressive therapy although both groups had significant responses. The risk for side effects was low. Thus, children are likely to benefit from pneumococcal vaccination given early after diagnosis of their malignancy. Repeated doses are probably necessary to achieve a stable protective immune response at least in patients with hematological malignancies, but this has not been studied.

This prime-boost strategy has been successfully used in patients with sickle cell anemia and HIV infection. The booster dose of PPSV23 broadens the coverage of additional pneumococcal serotypes and is recommended by the Centers for Disease Control and Prevention’s Advisory Committee on Immunization Practices (ACIP). ^, In a noncontrolled follow-up study to the study by Molrine and colleagues, Chan and colleagues showed that priming with PCV7 improved the response to the PPSV23 in patients with previously treated Hodgkin lymphoma. Top et al. studied children, who had completed treatment for ALL, and found good responses with the prime-boost strategy that were retained at 12 months postvaccination. It is still unclear how effective this strategy is in patients with hematological malignancies. Renaud et al. showed good responses in multiple myeloma patients receiving first PCV13 followed by PPSV23 with 65% of patients developing responses to at least two of four analyzed subtypes. A study in patients with CLL on the other hand showed poor efficacy of PPSV23 given five years after PCV7.

Despite the high risk of invasive pneumococcal disease, the uptake of vaccination was reported to be very low in a recent Danish cohort study. Immunization against pneumococcal infections is strongly recommended as early as possible after diagnosis and preferably before therapy is initiated, at least in patients with hematological malignancies. ^,

Haemophilus Influenzae Type B Vaccine

Severe infections with Haemophilus influenzae type b (Hib) in cancer patients are quite rare. However, children with leukemia are at a six-fold greater risk for Hib infection compared to normal children. However, immunization with a conjugated Hib vaccine resulted in lower antibody responses than in normal children, and a booster dose was ineffective. Longer duration and intensity of antileukemic chemotherapy were also associated with a poor response. ^, Children undergoing therapy for solid tumors also have lower than normal responses to vaccination with a Hib vaccine.

Very limited data are available regarding the risk for severe Hib infections and the response to vaccination in adult patients with cancer. Patients with multiple myeloma had antibody responses comparable to those of healthy adults. Molrine and colleagues showed that 99% of patients with Hodgkin lymphoma in whom therapy had been discontinued responded to Hib vaccination. In contrast, patients with CLL responded rather poorly to Hib conjugate vaccine with response rates around 50%. ^,

Influenza Vaccine

Patients with cancer are more likely to die during hospitalization for influenza especially if elderly and having co-morbid conditions. The morbidity in adult patients is highest in patients with hematological malignancies especially those with acute leukemia. Patients with lung cancer had the highest influenza-related case-fatality rates among patients with solid tumors. Influenza disease might interrupt scheduled chemotherapy with a negative impact on ultimate disease outcome. Earle showed that in patients with colorectal cancer, patients who were immunized had fewer chemotherapy interruptions and were more likely to survive 1 year. Efficacy data in adult patients with solid tumors are still limited. Rousseau compared responses to two doses of AS03A-adjuvanted influenza vaccine in patients receiving different types of cancer therapy and showed that two doses were needed to obtain a seroprotective response in these patients with better responses in patients receiving targeted therapies or low-intensity chemotherapy compared to more intensive regimens. In a study of lung cancer patients, the vaccination response was similar to that of healthy controls. Patients with breast cancer vaccinated during ongoing chemotherapy had significantly lower responses than healthy controls, but these cancer patients responded better if vaccinated early rather than late after chemotherapy.

The immunogenicity and safety of influenza vaccination in patients receiving checkpoint inhibitors have been investigated in several studies. Läubli et al. studied lung cancer patients receiving PD-1 blockade and showed that more than 60% of patients developed protective antibodies but also demonstrated a risk of immune-related adverse events. Bersanelli et al. found in a retrospective study a positive effect on survival in checkpoint inhibitor treated patients receiving influenza vaccination. Furthermore, Chong et al. found in a retrospective review of patients treated with PD-1 blockade no increase in incidence or severity of immune-related adverse events. Desage et al. performed a systematic review and showed that influenza vaccination could result in a high rate of seroconversion but also an increased risk for immune-related side effects. Currently published information supports that influenza vaccination has a positive risk-benefit balance in patients receiving checkpoint inhibitors.

Most studies show that adult patients with hematological malignancies respond poorly to vaccination. In a study of patients with multiple myeloma, the response rate to one dose of vaccine was 19%. Similar results have been seen in patients with lymphoma. In a study of patients with NHL, 32 patients were vaccinated half with ongoing therapy (type not specified) and half without therapy. The immune responses were similar between the groups although the responses trended to be stronger in patients without ongoing therapy but lower than in healthy controls. Another and larger study from the same group gave similar results comparing previously treated (within 2 months of vaccination) with untreated patients and controls.

It may be possible to improve responses by giving repeated doses. Adults with lymphoma receiving a two-dose schedule showed responses of approximately 30% after one dose and approximately 45% after two doses. In a study of patients with multiple myeloma, two doses gave good seroconversion and seroprotection rates against H1N1 and H3N2 serotypes (27% and 34% seroconversion after first dose; 63% and 54% after the second dose, respectively) while the responses to influenza B were less. However, two studies failed to show an enhanced response after the second dose in patients with various hematological malignancies or CLL. De Lavallade and colleagues reported results of two doses of an adjuvanted pandemic H1N1 vaccine in patients with chronic myeloid leukemia and B-cell malignancies compared to one dose given to healthy controls. The study showed improved seroconversion rates after the second compared to the first dose (39–68% in B-lymphoid malignancies; 85–95% in chronic myeloid leukemia) although lower than in healthy controls. The response rates were better in patients with an interval from chemotherapy of at least 12 months. Branagan et al. used a high-dose trivalent vaccine in patients with plasma cell disorders and found high seroprotection rates (65% to all three strains) after two doses.

Patients having received anti-CD20 antibodies as part of their therapy regimen respond very poorly to influenza vaccination for prolonged periods after the end of anti-CD20 therapy. None of 67 lymphoma patients responded to adjuvanted H1N1 vaccine within the first 6 months after the conclusion of rituximab therapy. Furthermore, in lymphoma patients who had completed a rituximab-containing regimen, the response to influenza vaccine was even further impaired if they patients had been treated with fludarabine. A recent systematic review-and meta-analysis showed strongly decreased responses for at least 6 months following anti-CD20 treatment. In contrast, heavily pretreated patients with multiple myeloma treated with daratumumab had a high response rate to influenza vaccination.

Studies of influenza vaccination in children with acute lymphoblastic leukemia (ALL) show that the proportion of children reaching “protective” antibody levels varied between 45% and 100% for the different influenza subtypes in the vaccines. A Cochrane review analyzing influenza vaccination in children with cancer summarized that immune responses were weaker in children receiving chemotherapy than in those who had completed chemotherapy and in healthy controls. In a study of children with solid tumors or lymphoma, who were given one or two doses of vaccine, the overall results regardless of chemotherapy were lower with only 38% achieving protective antibody levels to all three influenza strains. It has been reported that an antibody titer protective in healthy controls failed to prevent influenza in 24% of children with cancer, but the possibility exists that the severity of the infection may have been reduced by the vaccine. ^, Vaccination against pH1N1 was studied in a group of 54 children with different types of malignancies. The seroconversion rate was 44%; significantly lower in univariate analysis in children with hematological malignancies compared to those with solid tumors and in children with ongoing chemotherapy. In multivariate analysis, children with ongoing chemotherapy had lower responses (p = .05) with a trend for lower responses in children with hematological malignancies (p = .10). In a retrospective study of 498 children with leukemia, Sykes and collaborators found no reduction in laboratory confirmed influenza or influenza-like illness in children having received trivalent-influenza vaccine and recommended alternative strategies to protect such children against influenza. One way to improve outcome would be to immunize with a vaccine containing higher doses of influenza antigen. McManus and coworkers performed a randomized trial comparing standard and high-dose influenza vaccine and found no difference in either immunogenicity or toxicity. However, the study had limited power to reliably detect differences.

Despite the lower serological responses in cancer patients, a systematic review showed that vaccinated cancer patients had a reduced risk for influenza like illness, while a Cochrane review found lower mortality in influenza vaccinated patients but no difference in infection-related outcomes. A more recent Cochrane review stated that the benefits outweigh the risks when vaccinating adults against influenza. Yearly influenza vaccination with the trivalent or quadrivalent inactivated vaccine is recommended for cancer patients. Despite these recommendations, the uptake of vaccination is limited and strongly influenced by the attitude of treating oncologists. However, it must be recognized that the protection is likely to be low in those patients who are at highest risk of severe complications. Elting and colleagues reported that influenza in acute leukemia patients undergoing chemotherapy was commonly nosocomially acquired. Immunization of family members and hospital staff is therefore recommended. Only limited data exist with the live attenuated vaccine given to mild to moderately immunocompromised children with cancer. Currently live attenuated vaccine is not recommended in immunocompromised patients.

COVID-19 Vaccines

Cancer patients are at an increased risk for severe COVID-19 although the risk varies between different populations. Elderly cancer patients are especially vulnerable. Existing data support variability between different patient groups in the likelihood of response to COVID-19 vaccination. Addeo et al. reported 94% seroconversion after two doses of one of the two licensed mRNA vaccines in cancer patients but significantly lower responses in patients with hematological malignancies. Herzog Tzarfati et al. showed in a cohort study including 315 patients with hematological malignancies that 74.6% developed a response to two doses of BNT162b2 vaccine, which was significantly lower than in healthy controls (99.1%; p <.0001). The responses differ between different types of malignancy with lymphoid malignancies responding significantly lower than patients with myeloid malignancies (examples: CLL 47%; multiple myeloma 76%; myeloproliferative disorders 84%, and MDS 94%). Age, time from last treatment, and type of treatment influenced the likelihood of seroconversion. Maneikis studied a large mixed cohort of patients with hematological malignancies receiving the BNT162b2 vaccine and compared the results to a cohort of health care workers and showed lower antibody titers in patients with malignancies. Age and type of received therapy strongly influenced the responses with patients treated with anti-CD20 and Bruton tyrosine kinase inhibitors having the poorest responses. Herishanu and coworkers vaccinated 52 patients with CLL with two doses of the BNT162b2 mRNA COVID-19 vaccine and showed a 52% response rate compared to 100% in healthy controls. Patients having received anti-CD20 based therapy respond very poorly to COVID-19 vaccination. Waissengrin and coworkers presented early safety data in patients on check-point blockade receiving BNT162b2 mRNA vaccine and concluded that the vaccine could be given safely without inducing severe immune activation phenomena.

Tetanus Toxoid, Diphtheria Toxoid, and Inactivated Poliovirus Vaccine

The protection against tetanus, diphtheria, and poliovirus is frequently low in cancer patients undergoing chemotherapy. Hammarström and colleagues showed that 41% of nontransplanted acute leukemia patients were not protected against tetanus. Risk factors for loss of immunity were ALL versus acute myelogenous leukemia, more advanced disease, and increasing age. Einarsdottir et al. showed that patients with leukemia or lymphoma lost protective immunity to tetanus during chemotherapy (24% post vs 12% pretherapy). The same tendency was seen for immunity to diphtheria but there was no difference for poliovirus types 1 or 3. In children treated for cancer, the antibody titers against tetanus, diphtheria, and poliovirus were lower than in an age-matched healthy population. ^, The loss of specific immunity is related to the intensity of given chemotherapy. Children with high-risk ALL were more likely to become nonimmune to tetanus and diphtheria than were patients with low- or standard risk ALL. Antibody titers against tetanus were shown to be reduced after completion of chemotherapy. In contrast, Nordoy and colleagues reported that treatment of low-grade NHL patients with radioimmunotherapy did not influence specific immunity to tetanus.

The responses to diphtheria toxoid and tetanus toxoid vaccinations in adult cancer patients have not been systematically studied. Most children respond well to vaccination after completed chemotherapy for malignancies. ^{, ,} However, children treated for high-risk ALL had poor responses (22% protected against tetanus; 56% against diphtheria). Stenvik and colleagues reported on 14 children with leukemia, who were given a booster dose of vaccine, with 12 of 14 responding. No data exist regarding the vaccination of adults with cancer.

Despite the absence of data, it seems logical to recommend an investigation of poliovirus immunity and booster immunization for cancer patients traveling to or residing in areas of the world that are still endemic for poliovirus although these now are very few. Inactivated poliovirus vaccine is the only vaccine that should be used in immunocompromised patients as paralytic disease can result in the immunocompromised patients and transmission of the live vaccine strain has occurred after immunization. In the United States and in most countries in Europe, only inactivated polio vaccine is available.

Hepatitis B Virus Vaccine

Hepatitis B virus (HBV) infection is a major cause of morbidity in many parts of the world. Several studies have been performed regarding the efficacy of HBV vaccination particularly in children with acute leukemia. The results are summarized in Table 70.2 . Few studies have been performed in adult cancer patients. Immune responses were shown to be lower in patient receiving Bruton tyrosine kinase inhibitors compared to treatment naïve patients with CLL. An accelerated schedule with double-dose vaccine was shown to improve seroprotection in patients ongoing chemotherapy.

Recombinant Herpes Zoster Vaccine

Many cancer patients are older and therefore potentially eligible for vaccination against herpes zoster. Until recently, the only available vaccines against varicella zoster virus have been live, attenuated vaccines carrying the risk of life-threatening side effects in severely immunocompromised patients. ^, An adjuvanted, recombinant zoster vaccine (RZV) has been licensed and has shown promising results in cancer patients. Vink et al. studied in a randomized, placebo-controlled trial the efficacy and safety of RZV in patients with solid tumors. RZV elicited stronger anti-glycoprotein E (gE) responses and T cell responses compared to placebo recipients without an increase in side effects. The gE responses were stronger in patients receiving the vaccine before starting chemotherapy than in those receiving RZV during chemotherapy. Similarly, Dagnew et al. were able to show in a randomized, placebo-controlled trial that RZV induced gE responses in a high proportion of patients with hematological malignancies.

Other Non-live (Nonreplicating) Vaccines

Vaccinations could be considered against pertussis and meningococci, although it is important to assess if there is an increased risk for severe infection in cancer patients. Age-group-appropriate vaccination against meningococci should be performed according to national guidelines. There are also vaccines for cancer patients living in certain areas of the world or to those traveling to these areas. These include hepatitis A vaccine and vaccines against tickborne encephalitis and Japanese encephalitis. Although there are limited data regarding serological responses to these vaccines, the risk for significant side effects should be similar to the normal healthy population as they are nonreplicating agents.

The number of long-term survivors after cancer treatment is increasing. These patients might be at increased risk for late complications driven by human papillomavirus infections. The immune response to existing papillomavirus vaccines have not been systematically studied in cancer patients although patients have been vaccinated as part of their age-appropriate routine schedules. Despite this lack of information human papillomavirus vaccination should be considered especially in survivors after cancer during childhood to be given at the appropriate and recommended age. ^,

Varicella Vaccine

Primary varicella has previously caused high mortality in children with cancer. With the increased use of acyclovir prophylaxis and treatment, the risk for severe disease seems to have decreased. A recent analysis estimated the mortality to be 0.057% with the mortality varying between regions (0.027% in North America, 0.041% in Asia, and 0.08% in Europe). The existing vaccine is live, attenuated, and based on the Oka strain. The vaccine was shown to be effective and safe in children with leukemia who were in remission but it should be recognized that the type of leukemia therapy was less intensive in the 1980s. The rate of varicella infection in vaccinees was 8%, but all infected children had mild disease. The frequency of side effects from the vaccine is low, and breakthrough vaccine disease can usually be treated effectively with acyclovir. ^, However, there have been fatal vaccine-associated infections reported. Cakir and colleagues investigated single dose versus double dose of varicella vaccine and found a much higher rate of seroconversion (29% vs 75%) and better persistence of specific antibodies in patients receiving a double dose. Furthermore, reinfections in previously vaccinated children with cancer have been reported and might become an increasing problem in the future with more adult cancer and leukemia patients having been vaccinated during childhood, The risk for herpes zoster after vaccination is lower than after natural varicella disease. ^, In a small, randomized study, varicella vaccine was given to children with newly diagnosed cancer before starting chemotherapy. There was a high rate of seroconversion and no severe side effects were found, but the number of included patients was low.

Household exposure to varicella is associated with more severe varicella disease. An option is to immunize healthy seronegative family members when the child with cancer is undergoing intensive therapy and a live vaccine cannot be given. Diaz and colleagues showed that the attenuated varicella vaccine virus cannot be isolated from oropharyngeal secretions of immunized siblings. None of the children with cancer showed clinical or serologic evidence of vaccine virus transmission. Immunization with the varicella vaccine is indicated in seronegative patients with cancer when the cancer chemotherapy schedule allows safe immunization, but it would generally not be indicated to interrupt maintenance therapy to allow vaccination considering the relatively low risk for severe and fatal varicella with available antiviral therapy.

Live Zoster Vaccine

Current recommendations are not to vaccinate during cancer therapy. With the introduction of RZV, the indication for using a live-attenuated zoster vaccine is weak based on safety concerns since there are reports of deaths due to the attenuated vaccine strain. ^,

Measles, Mumps, and Rubella Vaccine

Measles disease in cancer patients has a high mortality. Kaplan and colleagues reviewed 27 published cases, among whom 20 (74%) developed pneumonitis and eight (30%) died. The clinical consequences of rubella and mumps infections in cancer patients appear to be of less significance.

Loss of immunity to measles is common in children previously vaccinated with measles, mumps, and rubella (MMR) and then treated for leukemia and other cancers. ^, Risk factors for loss of measles immunity include younger age and female gender in leukemia patients and younger age in other childhood malignancies. Immunization with the live attenuated vaccine has been contraindicated because of the risk of severe side effects in cancer patients undergoing chemotherapy. Koochakzadeh and colleagues studied MMR vaccination 3–12 months after cessation of therapy and reported that it was safe and gave high response rates to mumps (80–100%) but lower responses rates (50–71%) to rubella and measles (41–63%). Immunization with live attenuated MMR vaccine should be considered in seronegative cancer patients who are not receiving active chemotherapy and in epidemiologic situations when the risk for measles is high.

Other Live Vaccines

Very limited data exist on immunization with bacille Calmette-Guérin (BCG), yellow fever, and rotavirus vaccines in cancer patients. The use of these live vaccines is not recommended during active cancer therapy.

Pneumococcal Vaccines

Pneumococcal infections can be fatal in HSCT patients especially in patients with chronic GVHD. Immunization with the PPSV23 can elicit antibody responses from 6 months after HSCT in patients without GVHD but was shown to be ineffective in patients with chronic GVHD. ^{, , ,} In particular, the specific immunoglobulin (Ig) G2 responses have been poor. ^, Children given PPSV23 developed short-lived responses and low avidity antibody, in contrast to adults. Thus, responses to vaccination with PPSV23 are suboptimal in many patients.

PCV7 has been evaluated in several studies in HSCT patients including those with chronic GVHD. Kumar and colleagues conducted a randomized study of one dose of either PPSV23 or PCV7 given to donors before and to recipients 6 months after the HSCT and showed that PCV7 improved the likelihood of an immune response in the recipients compared to PPSV23, but neither approach was optimally effective. Molrine and colleagues performed a randomized study with the PCV7 comparing pretransplant vaccination of patients and their donors with no vaccination. All patients were given three doses of the vaccine at 3, 6, and 12 months after transplantation. Most patients (72–100% for the different serotypes) developed protective antibody levels at 12 months after HSCT. There was also an improved response (67% vs 36%) to the first dose of PCV7 when compared to the polysaccharide vaccine. Cordonnier and colleagues compared early (starting at 3 months) with late (starting at 9 months) vaccination with three doses of PCV7 and showed that good protection could be achieved as early as 3 months after HSCT. Furthermore, PCV7 increased the functional antibodies assessed by an opsonophagocytic assay. However, there was a tendency for patients who were immunized early and for patients with chronic GVHD to have a shorter duration of immunity. It was also shown that a dose of PPSV23 given 9 months after the first PCV7 dose increased the response rates and extended the serotype coverage. Long-term protection has been studied at a median of 9.3 years after transplantation after varying vaccine schedules, but all patients had received at least one dose of PCV and a majority had received at least three PCV doses as currently recommended. Fifty percent of patients were protected to all seven analyzed serotypes while 70% were protected against five of seven serotypes. This shows that seroprotection ought to be regularly assessed to define the need of booster doses. Studies also have been performed in children showing good immune responses. ^, The degree of immunological reconstitution has been shown to influence the immune response.

The current recommendations are to start vaccination with three doses of PCV13 at 3 to 4 months after HSCT followed by either a PPSV23 dose in patients without chronic GVHD or PCV13 in patients with chronic GVHD. ^{, ,} A prospective but uncontrolled trial studied the effect of four doses of the PCV13 and showed very strong immune responses to the fourth dose although associated with more side effects. In this study, there was no beneficial effect of a subsequent dose of PPSV23, but this dose was probably given too early after the fourth PCV dose. It is also likely necessary to give additional pneumococcal vaccine doses during follow-up to maintain immunity to pneumococci but the exact schedule needs to be defined by further studies. There is also a PCV10 vaccine available but this has not been studied in HSCT recipients and new conjugated vaccines covering additional serotypes are under development.

Introduction of PCV has reduced the risk for invasive pneumococcal infection after allogeneic HSCT. It was shown in a retrospective cohort study that the introduction of PCV decreased the risk for invasive pneumococcal disease in allogeneic HSCT recipients compared to patients receiving PPSV23. The current recommendations are to start vaccination with three doses of PCV at 3–4 months after HSCT followed by either a PPSV23 dose in patients without or a PCV dose in patients with chronic GVHD. ^{, ,}

Haemophilus Influenzae Type B Vaccine

Immunization with Hib conjugate vaccines can elicit protective immune responses. ^{, ,} It has been reported that time after transplantation is important for the immune response to Hib vaccine in transplanted children. ^, A good immune response could be elicited when the donor was immunized before transplantation and the recipient at 3 months after transplantation. Immunization with a Hib vaccine is indicated in all allogeneic HSCT recipients. ^{, ,}

Influenza Vaccine

Influenza A and B infections can be severe and life threatening in HSCT recipients ^{, ,} and can occur up to several years after HSCT. ^, The time after HSCT is important for vaccine efficacy, with patients vaccinated later having better responses in most, ^{, , ,} but not all studies.

Ambati and colleagues conducted a prospective, randomized study of the impact of pretransplantation immunization of the donor or the recipient followed by influenza vaccination of the patient at 6 months after HSCT and showed an impact on antibody levels. It is, however, possible that an earlier posttransplantation dose would have increased the immune response. Furthermore, T-cell responses after influenza vaccination can be elicited as early as 3–4 months after HSCT. ^, Ryan et al. performed a prospective study in children and compared HSCT recipients to age-matched controls. An immune response could be elicited in most, but was lower than in age-matched controls.

During and after the H1N1 pandemic, several studies were performed in HSCT recipients. Issa and colleagues studied 82 patients vaccinated a median of 19 months after transplantation (min–max 2.5–94 months) with one dose of unadjuvanted influenza vaccine. Protective titers were found in 51% of the patients with better responses seen in patients vaccinated later after HSCT (odds ratio [OR], 1.79/year) and poorer responses if the patient had received rituximab during the last year. There was no effect by conditioning or chronic GVHD. Engelhard and colleagues studied 55 patients vaccinated a median of 27 months after HSCT (1–290 months) with two doses of an AS03-adjuvanted vaccine (Pandemrix, GlaxoSmithKline). The protection rate after two doses was 48.7% and the seroconversion rate 41.9%. Factors influencing seroconversion were the absolute lymphocyte count (OR, 3.04) and donor type (OR, 14.0) with better responses in patients receiving grafts from human leukocyte antigen–identical donors but with no effect of time after HSCT on response. De Lavaillade and colleagues studied 26 allogeneic HSCT recipients receiving two doses of the same adjuvanted vaccine at a median time from HSCT of 39 months (min–max 6–127 months). The seroprotection rates were 45% after one and 73% after two doses, but significantly lower than found in healthy controls. The only factor influencing the response was time after HSCT. T-cell responses to influenza were also observed in 40% of the patients. Dhédin and colleagues reported comparable immune responses after two doses of adjuvanted pH1N1 vaccine to those seen after natural infection when analyzed 6 months after vaccination. All four studies reported that the vaccines were safe. Dhédin and colleagues reported, however, that four patients developed worsening chronic GVHD possibly induced by the vaccine.

Despite suboptimal serological responses, clinical effectiveness of vaccination might be provided, since protective antibody levels are poorly defined. Machado et al. found that influenza vaccination performed at least 6 months after SCT had an 80% efficacy in preventing influenza. Kumar et al. showed in a prospective cohort study that influenza vaccination the current season reduced the risk for disease severity such as pneumonia and requirement for admission to an intensive care unit. Piñana et al. showed in similarly designed cohort study that influenza vaccination reduced the risk for lower respiratory tract influenza disease and need for hospital admission. Thus, there is a substantial clinical benefit of regular influenza vaccination of HSCT recipients.

Influenza vaccination with the inactivated vaccine is recommended for all allogeneic HSCT recipients starting at 6 months after HSCT and as early as 4 months after HSCT during a community outbreak. Previously unimmunized children 6 months to 8 years of age should be given a second dose of vaccine. The live attenuated influenza vaccine should not be used in HSCT recipients. Another recommended strategy is to immunize family members and hospital staff, thereby reducing the risk for transmission of the infection to the immunocompromised individual. ^{, , ,}

COVID-19 Vaccines

COVID-19 is associated with high morbidity and mortality after allogeneic HSCT. A couple of cohort studies have been presented so far. The results of the studies show that approximately 75% of patients respond to two doses of vaccine. Shorter time after transplantation and ongoing immunosuppression were identified as predictors for poor response. However, important possible toxicities were noted including cytopenias and induction or worsening of GVHD. ^, A prospective clinical trial has recently been concluded at Karolinska University Hospital, Stockholm, Sweden and preliminary data support the observations in these cohort studies regarding the effect of time from transplant and the risk for worsening GVHD. Further studies are therefore needed.

Hepatitis B Virus Vaccine

Severe primary HBV infections are rare after HSCT unless an HBV-positive donor is used for a seronegative recipient. Loss of preexisting immunity is quite common and can result in virus reemergence with or without signs of hepatitis. Immunization early after HSCT is likely to be ineffective unless the donor is immunized. Jaffe and colleagues based start of vaccination on grade of immune competence. 292 patients were vaccinated of whom 187 (64%) seroconverted, a rate lower than in age matched controls. Older age and history of chronic GVHD were associated with lower responses. In another study, the rate of seroconversion after vaccination was higher when the patient, the donor, or both had been vaccinated before HSCT. The immunization of the marrow donor allows a transfer of immunity to the recipient ^, and can be long lasting especially if the recipient also is vaccinated. Chronic GVHD is associated with weaker responses and the need for additional doses. ^, Another important issue is to prevent HBV seroreversion in seropositive individuals. Vaccinated patients are significantly less likely to experience HBV reactivation compared to unvaccinated controls ^, HBV seropositive patients and seronegative patients receiving grafts from HBV seropositive donors should receive antiviral prophylaxis until vaccinations can be given after HSCT to prevent seroreversion and viral replication. Vaccination is recommended after allogeneic HSCT preferably with double-dose vaccine. ^{, ,}

Tetanus Toxoid, Diphtheria Toxoid, and Inactivated Poliovirus Vaccines

Several studies of immunization with these vaccines have been published. ^{, ,} The vaccination of allogeneic HSCT recipients with three doses of tetanus toxoid, diphtheria toxoid, and inactivated poliovirus vaccine is recommended to obtain stable protective immunity. ^{, , ,} Different factors, including chronic GVHD, can negatively influence strength of responses. Gerritsen and colleagues immunized children before bone marrow transplantation (BMT) followed by revaccination as early as 6 weeks after BMT. Thirty percent of the patients responded to early immunization. The inactivated poliovirus vaccine should be used. It has been shown that robust and lasting immune responses to poliovirus vaccine can be obtained when immunizations are started at 6 months after HSCT. It was shown that more than 90% of allogeneic HSCT recipients remained protected against poliovirus at 10 years after vaccination with a three dose schedule. Because posttransplantation patients should be viewed as “never vaccinated” they should receive full doses of toxoids, DT vaccine, and not with the vaccines normally used for booster doses to adults. ^{, ,}

HSCT patients might be vulnerable to pertussis although the documentation for severe infections is limited. ^, In young children, it is logical to vaccinate against pertussis together with diphtheria, and tetanus since many available vaccines include the pertussis component (diphtheria, tetanus, and acellular pertussis [DTaP]) as well as the Hib and inactivated polio vaccine components. The immune response to tetanus, diphtheria, and pertussis (Tdap) is poorer than to DTaP. Pertussis vaccination can be considered in older children and adults, but then it is most likely more effective to use a vaccine with higher pertussis content (P), although these vaccines are not licensed for adults. ^{, ,}

Human Papillomavirus Vaccine

HSCT patients are prone to develop papillomavirus complications such as cervical dysplasia. Stratton et al. showed that strong immune responses can be elicited in HSCT recipients by the quadrivalent HPV vaccine without significant side effects. It would be logical to vaccinate HPV seronegative individuals to prevent acquisition of HPV but whether vaccination of already HPV infected HSCT recipients would result in a clinical benefit is unknown, but this could be a topic for future studies.

Cytomegalovirus Vaccines

CMV is one of the most important pathogens encountered by patients after HSCT. Vaccines based on new vaccine technologies, such as DNA plasmid based vaccines, subcomponent vaccines, and vaccines using other viral vectors, are currently in clinical development. A Phase II study of a DNA plasmid vaccine containing plasmids for glycoprotein B and pp65 elicited T-cell responses and reduced the rate of CMV DNAemia. ^, However, a Phase III study failed to reach the primary endpoint. Other vaccines are also in development including a poxvirus vectored vaccine, which showed promising results in a randomized, Phase II study.

Other Non-live Vaccines

Vaccination with a meningococcal polysaccharide vaccine can elicit good responses in HSCT recipients against both serogroups A and C. Mahler and colleagues studied the tetravalent conjugated meningococcal vaccine in 46 patients, mainly children, at a median of more than 2 years after HSCT. The response rate to the different serotypes varied between 30% and 52%. Seven of 46 patients (15%) responded to all serotypes and 16 (35%) did not respond to any serotype. Sixteen patients received a second dose and eight (50%) of the 16 responded to all serotypes. In a study including only adults, the responses to the different serogroups varied between 51.7% and 76.9%. Meningococcal vaccination is recommended to older children and teenagers after allogeneic HSCT ^, but can be considered in other age groups in countries where vaccination for the general population is recommended. Two doses seem to be needed to optimize the immune response.

There are also vaccines for HSCT patients living in certain areas of the world or travelling to these areas where certain infections are endemic. These include vaccine against TBE, ^, and vaccine against Japanese encephalitis. The response to hepatitis A vaccine was shown to be poor in both seronegative and seropositive HSCT patients.

Varicella Vaccine

Primary VZV infections can be very severe after HSCT. The existing vaccine is live and attenuated and should not be used early in the posttransplantation period. A seronegative patient should, if possible, be immunized before transplantation, providing that enough time can elapse from the vaccination to the transplantation procedure. No data exist regarding the interval needed between vaccination and start of conditioning but rash after vaccination has been noted up to 60 days after vaccination in patients with cancer undergoing chemotherapy and in children with acute leukemia in remission. ^, Children with acute leukemia who have been immunized with the varicella vaccine have subsequently undergone allogeneic HSCT. The care of varicella-seronegative HSCT recipients is frequently problematic; exposure to varicella-infected individuals is not uncommon and either prophylactic zoster immunoglobulin or antiviral prophylaxis is needed. Vaccination of seronegative family members of allogeneic HSCT recipients is recommended. A few uncontrolled studies have been performed and reported that varicella vaccination is safe and can result in seroconversion if performed more than 2 years after HSCT in patients without chronic GVHD and without ongoing immunosuppression. ^,

A high proportion of HSCT patients develop herpes zoster that occasionally becomes severe. Redman et al. used heat-inactivated varicella vaccine and showed that immunization conferred no reduction in risk but was associated with a reduced severity of the herpes zoster. Inactivated zoster vaccines have been studied in allogeneic HSCT recipients but not in a controlled trial. Camargo et al. showed that two doses of RZV was less immunogenic in allogeneic HSCT recipients compared to autologous recipients and that VZV reactivations occurred. Baumrin et al. showed that a two-dose RZV regimen was safe and tolerable without increasing the rates of GVHD, but also that VZV reactivations were seen after vaccination. Additional studies are therefore needed. In a phase II study with a heat-treated vaccine the immune responses were poor. Issa et al. gave one dose of live, attenuated zoster vaccine to 58 allogeneic HSCT recipients and did not note any significant side effects. Due to the proven efficacy and safety of acyclovir prophylaxis, vaccination with the live zoster vaccine is not recommended during at least the first years after HSCT. Further studies are needed with RZV before its place after allogeneic HSCT can be determined.

Measles, Mumps, and Rubella Vaccine

With the return of measles in many countries, protection against this infection is important because a majority of allogeneic HSCT patients will become seronegative to measles during extended follow-up. ^{, ,} The loss of immunity is more rapid in patients previously vaccinated against measles compared to those having experienced natural infection. There are documented cases of fatal measles in HSCT recipients. ^, Immunization can only be considered in a patient without chronic GVHD or without ongoing immunosuppression. Existing data indicate that measles vaccine can be given safely at 2 years after HSCT. ^{, ,} In an outbreak in Brazil, one of eight HSCT patients with measles developed interstitial pneumonia but all survived. During the outbreak in Brazil, patients were vaccinated at 1 year after HSCT without serious side effects. The reported effect of vaccination varies between different studies with a seemingly higher response rate in adults than in children. ^{, , ,}

Rubella vaccine is indicated in female patients who have retained the potential for becoming pregnant. Existing data indicate that rubella vaccine can be given without severe side effects at 2 years after HSCT in patients without chronic GVHD or without ongoing immunosuppression. The effectiveness of the vaccine is high. ^{, ,} The risk for severe infections with mumps virus in HSCT recipients is likely to be very low, although a case report of a fatal infection in a HSCT recipient has been published. Furthermore, the efficacy of mumps vaccination to induce long-lasting serological immunity is rather poor, even in immunocompetent individuals. ^, Vaccination with MMR is recommended in children and seronegative adults. ^{, ,} A second dose of MMR is recommended in children younger than 9 years old. ^,