Previously published abstract:
Humoral Immune Status and Response to Re-Vaccination in Pediatric Cancer Survivors Following Standard of Care Therapy. Podium Presentation presented at: Association of Pediatric Hematology/Oncology Nurses (APHON) Annual Conference; September 11, 2024; Salt Lake City, Utah.
Introduction:
Survivors of childhood cancer exhibit variable humoral immunity to vaccine preventable diseases (VPDs) following cancer treatment. An increasing number of children are surviving a cancer diagnosis, making it imperative to document the extent to which survivors are at risk for VPDs and their response to vaccinations.
Methods:
This Phase II prospective study included 65 pediatric patients diagnosed with and treated with intensive chemotherapy without transplantation. Serum vaccine antibody concentrations were determined for twelve VPDs: tetanus, diphtheria, pertussis, polio, haemophilus influenzae, pneumococcus, hepatitis B, meningococcus A, measles, mumps, rubella, and varicella following completion of cancer treatment and after vaccination.
Results:
Many patients lacked protective antibody levels to VPDs at the end of treatment. After vaccination 87–100% of patients had protective antibody titers against inactivated vaccines. The percentage of patients protected against the live attenuated vaccines was lower; measles (79%), mumps (83%), rubella (85%) and varicella (82%). Differences in response rates to vaccinations were not statistically significant for age (<7 years versus ≥7 years of age), diagnosis (hematologic disease versus solid tumor), time between end of treatment and vaccination (3–6 months versus >6 months for inactivated vaccines), or between absolute lymphocyte count or CD4+ T cell count at baseline.
Conclusion:
For pediatric cancer survivors a single dose of inactivated vaccines given three months following end of treatment protects against these VPDs without need for assessment of serostatus after inoculation. For live attenuated vaccines, patients require two inoculations for protection, and we recommend assessment of serostatus to inform patients and providers of their risk for acquiring one of these communicable VPDs.
Keywords: Child, Cancer Survivor, Vaccination, Humoral Immunity
Introduction
Improved treatments for childhood cancers have raised the 5-year survival rate for many childhood cancers from less than 10% in the 1960s to more than 80% in recent years1. While much literature has expounded on late effects of cancer treatment on organ systems, there is a paucity of studies directed at the possible late effects of treatment on immune reconstitution in pediatric cancer survivors2. Most published works addressing immune reconstitution and a patient’s ability to respond to vaccine preventable diseases (VPDs) in pediatric cancer survivors have focused on recipients of hematopoietic stem cell transplantation (HSCT). Fewer studies have explored the immune status and response to VPDs of pediatric cancer survivors who received standard chemotherapy treatments. Although reported rates of protection from VPDs following treatment vary within the literature, there is strong evidence that children surviving pediatric cancers are inadequately protected, leaving this patient population susceptible to these communicable diseases2–15. We conducted a prospective study in pediatric cancer survivors to measure baseline immunity and immunogenicity of childhood vaccines following treatment.
Material and Methods
Study Design
Patients were recruited to this Institutional Review Board (IRB) approved Phase II prospective trial of vaccine responses in childhood cancer survivors at MSK Kids (NCT00505063), Memorial Sloan Kettering Cancer Center between January 2008 and October 2011. Analysis and publication of results were delayed by the unexpected death of the principal investigator (Dr. Trudy N. Small).
Inclusion and Exclusion Criteria
The research sample included children who were ≤ 18 years at date of cancer diagnosis and 3–24 months post completion of chemotherapy. Exclusion criteria included: 1) Karnofsky score <70%; 2) prior receipt of an autologous or allogeneic HSCT; 3) a history of an allergic reaction to vaccine components or latex; 4) receipt of any immunosuppressive drugs at the time of enrollment; 5) prior receipt of rituximab; or 6) asplenia or prior abdominal radiation (spleen). Patients or guardians provided consent in all cases.
Pre- treatment Evaluation:
Prior to vaccination the following immunologic parameters were assayed to assess immune reconstitution: total IgG serum level, absolute lymphocyte count (ALC) from routine complete blood count (CBC), absolute CD45+ lymphocyte count, absolute CD3+ T cell count, absolute CD4+ T cell count, absolute CD19+ B cell count, as well as T cell proliferation response to the mitogen, phytohemagglutinin (PHA.) To proceed with vaccination, patients were required to have an absolute CD4+ T cell count ≥ 200 cell/mcL and a total IgG level >500 mg/dl (≥ 6 weeks after last dose of IVIG). With IRB approval, 12 patients not meeting these thresholds proceeded to vaccination. Seven patients had an absolute CD4+ T-cell count < 200 cells/mcL (median = 183 cells/mcL range 77–198 cells/mcL); all seven patients had normal responses to PHA indicating the presence of functional CD4+ T cells. There was a technical error in assessing absolute CD4+ T cell count for two patients; these two patients also had normal responses to PHA. Three patients had a total IgG level < 500 mg/dl; all 3 patients had an absolute CD19+ B cell count greater than 400 cells/mcL. All patients enrolled in study were considered to have immune reconstituted sufficiently to proceed to vaccination without delay.
Serum antibody concentrations were assessed pre- and post-vaccination by enzyme-linked immunosorbent assay for tetanus, diphtheria, pertussis, polio, haemophilus influenzae (H. Flu), pneumococcus, hepatitis B (HepB), measles, mumps, rubella (MMR), varicella and meningococcus ACWY (MenACWY). Protective antibody concentrations for each vaccine were defined as in Table 1.
Table 1:
Serum Antibody Evaluations and Vaccine Characteristics
| Vaccine | Considered Immune | Vaccine Used |
|---|---|---|
| Tetanus | tetanus antitoxin IgG level >0.15 international units (IU)/ml |
Pediarix (GlaxoSmithKline): 0.5ml intramuscularly for children <7 years of age. BOOSTRIX (GlaxoSmithKline): 0.5ml intramuscularly for those >7 years of age |
| Diphtheria | anti-diphtheria IgG level ≥ 0.01 IU/ml |
Pediarix (GlaxoSmithKline): 0.5ml intramuscularly for children <7 years of age.. BOOSTRIX (GlaxoSmithKline): 0.5ml intramuscularly for those >7 years of age |
| Pertussis | anti-pertussis toxin (PT) IgG level > 5 IU/mL |
Pediarix (GlaxoSmithKline): 0.5ml intramuscularly for children <7 years of age. BOOSTRIX (GlaxoSmithKline): 0.5ml intramuscularly for those >7 years of age |
| Polio | anti-poliovirus Types I-III IgG levels >1:8 |
Pediarix (GlaxoSmithKline): 0.5ml intramuscularly for children <7 years of age. IPOL®:0.5ml intramuscularly for children >7 years |
| Haemophilus Influenzae (Hib) | anti-haemophilus influenzae IgG level ≥ 1 mg/dl |
PedVax HIB (PRP-OMP) (Merck): 0.5 ml) |
| Pneumococcus | 0.35mg IgG/ml in serotypes 14, 19F, 23F | Prevnar13 (Wyeth): 0.5 ml intramuscularly |
| Hepatitis B (HepB) | Presence of anti-hepatitis B surface antibody (reported as positive or negative) |
Pediarix (GlaxoSmithKline): 0.5ml intramuscularly for children <7 years of age. Engerix-B (GlaxoSmithKline): 0.5 ml intramuscularly. |
| Measles | anti-measles IgG level ≥ 0.70 (>120 IU/ml) | MMR (Merck): 0.5 mL subcutaneously |
| Mumps | anti-mumps IgG level ≥ 0.50 | MMR (Merck): 0.5 mL subcutaneously |
| Rubella | anti-rubella IgG level ≥ 1.10 | MMR (Merck): 0.5 mL subcutaneously |
| Varicella | >0.9 immunologic status ratio (ISR) | Varivax (Merck): 0.5ml subcutaneously |
| Meningococcus | A, C, Y, and W-135 was defined as a specific IgG level of >4, 5, 4, and 3 μg/mL, respectively | Menactra II (Merck): 0.5ml intramuscularly. |
Pediarix (GlaxoSmithKline): Diphtheria and Tetanus Toxoids and Acellular Pertussis Adsorbed, Hepatitis B (recombinant) and inactivated poliovirus Vaccine Combined. 0.5ml intramuscularly for children <7 years of age.
BOOSTRIX (GlaxoSmithKline): Tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis vaccine adsorbed. 0.5ml intramuscularly for those >7 years of age.
IPOL®: inactivated polio virus, IPV Injection, suspension: Type 1 poliovirus 40 D antigen units/0.5 mL, Type 2 poliovirus 8 D antigen units/0.5 mL, and Type 3 poliovirus 32 D antigen units/0.5 mL (5 mL multidose vial) [may contain calf serum protein, neomycin, streptomycin, and polymyxin B]. 0.5ml intramuscularly.
PedVax HIB (PRP-OMP) (Merck): Haemophilus influenza b conjugate vaccine 0.5 ml intramuscularly.
Engerix-B (GlaxoSmithKline): Recombinant Hepatitis B. For those 0–18 years: 10 mcg/0.5 ml, 0.5 ml intramuscularly. For those >18 years: 20 mcg/ml, 1 ml intramuscularly.
Prevnar (Wyeth): Diphtheria CRM197 Protein; PCV7; Pneumococcal 13-Valent Conjugate Vaccine. Injection, suspension: 2 mcg of each saccharide for serotypes 1,3,5, 6A, 7F, 19A, 4, 9V, 14, 18C, 19F, and 23F, and 4 mcg of serotype 6B per 0.5 mL (0.5 mL) [contains 16 mcg total saccharide; also contains CRM197 carrier protein. 20 mcg/0.5 mL and aluminum 0.125 mg/0.5 mL (as aluminum phosphate adjuvant)]. 0.5 ml intramuscularly.
Menactra II (Merck): Protein conjugated meningococcal vaccine, solution: 4 mcg each of polysaccharide antigen groups A, C, Y and W-135 per 0.5 mL [conjugated to 48 mcg diphtheria toxoid protein; adjuvant and preservative free. 0.5ml intramuscularly.
MMR (Merck): Injection, powder for reconstitution: Measles virus 1000 TCID50, rubella virus 1000 TCID50, and mumps virus 20,000 TCID50 [may contain neomycin 25 mcg, gelatin, human albumin, and bovine serum; produced in chick embryo cell culture]: 0.5 mL subcutaneously.
Varivax (Merck): Live, attenuated varicella vaccine, Injection, powder for reconstitution [single-dose vial]: 1350 plaque- forming units (PFU) [may contain gelatin and trace amounts of neomycin]. For those 12 months to 12 years: 0.5ml subcutaneously, for those 13 years-adults: 0.5 ml subcutaneously.
Vaccination
Inactivated vaccines included tetanus, diphtheria, pertussis, H. Flu, polio, pneumococcus, Hep B and MenACWY (Table 1). Regardless of immune status at baseline, patients received all inactivated vaccines. Only patients ≥ 11 years of age received MenACWY vaccine. Patients with immunity to ≥ 3 inactivated vaccines were eligible to proceed to receipt of the live attenuated vaccines, MMR and varicella. Permitted by protocol, patients whose baseline titers were protective against measles and/or varicella were not required to be revaccinated with these vaccines. Patients who remained seronegative to measles and/or varicella after the first vaccine were eligible to receive a second vaccine. Vaccines were administered on schedules shown in Table 2.
Table 2:
Vaccination Schedule
| Age <7 years | Month 0 | Month 1 | Month 2 | Month 3 | Month 4 | Month 6–8 |
|---|---|---|---|---|---|---|
| Prevnar 13 | X (1/2) | X (2/2) | ||||
| Hib | X (1/2) | X (2/2) | ||||
| Pediarix | X (1/2) | X (2/2) | ||||
| MMR | X (1/1) | |||||
| Varicella | X (1/1) | |||||
| Age ≥ 7 years | ||||||
| Prevnar | X (1/2) | X (2/2) | ||||
| Hib | X (1/2) | X (2/2) | ||||
| Boostrix | X (1/2) | X (2/2) | ||||
| Hep B | X (1/2) | X (2/2) | ||||
| IPV | X (<11 years, 1/1) | X (≥11 years, 1/1) | ||||
| Menactra | X (≥11 years, 1/1) | |||||
| MMR | X (1/1) | |||||
| Varicella | X (1/1) | |||||
Hib, Haemophilus influenzae type b; MMR, measles, mumps, rubella; Hep B, hepatitis B; IPV, inactivated polio virus.
Statistical Analysis
Patients were assessed for age at cancer diagnosis, age at time of initiating vaccine schedule, disease, time between end of treatment (EOT) and vaccine administration, and response to vaccination.
Immune status and vaccination response were assessed for patients <7 years of age versus ≥ 7 years of age. Age group delineation was based on recommended ages for Pediarix versus Boostrix administration (Table 2). Appropriate schedule was selected based on patient age at vaccination. As a result of the small sample size for patients with solid tumors, disease specific comparisons were made only between the hematological malignancy group and the brain tumor group.
Chi square tests were performed to compare proportions (age groups: <7 vs ≥7 years, and disease groups: hematological malignancies vs brain tumors). Mann Whitney U tests were performed to test for statistically significant differences in mean values of ALC and CD4+ T cell counts between age and disease groups. Statistical analysis was run using Stata software, version 18.5 16.
Data sharing statement:
The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.
Results
Patient Characteristics
Seventy-five patients were enrolled in the study. Ten patients were removed during study; four due to insufficient data, two due to noncompliance or delayed follow up, and four due to early disease relapse. The demographics of the remaining 65 patients including treatment intensity are shown in Table 3. The median time between EOT and first vaccines was 7.2 months (range 3.5 – 20.3 months). Twenty-eight (43%) patients were < 6 months from EOT; eight patients started vaccination between 3- and 4-months post treatment; 10 patients started between 4- and 5-months post treatment and 10 patients started between 5- and 6-months post treatment. The median and ranges were: ALC 1500 cells/mcL (range 500–6300); CD4+ 556 cells/mcL (range 201–2880); CD8+ 479 cells /mcL (101–1909).
Table 3:
Patient Demographics and Timing of Vaccines
| Characteristics | Overall, n = 65 |
|---|---|
|
| |
| Median Age at Diagnosis (years, range) | 8.8 (0.3–17.71) |
| - <7 years | - 28 (43%) |
| - ≥7 years | - 37 (57%) |
|
| |
| Sex (male, female) | 30 (46%); 35 (54%) |
|
| |
| Diagnosis | |
| - Brain Tumor | 18 (28%) |
| - Hematologic Malignancy | 43 (66%) |
| - Leukemia/B cell NHL | - 29 (45%) |
| - Hodgkin Lymphoma | - 14 (21%) |
| - Solid Tumor (ovary [n= 2], rhabdomyosarcoma [n =1], Wilms [n=1]) | 4 (6%) |
|
| |
| Intensity of Treatment Rating17 | |
| - Level 2 | 24 (37%) |
| - Level 3 | 38 (58%) |
| - Level 4 | 3 (5%) |
|
| |
| Median Age at first vaccination (years, range) | 10.64 (0.9–19.16) |
| - <7 years | - 21 (32%) |
| - ≥7 years | - 44 (68%) |
|
| |
| Median time between end of treatment and first vaccine (months, range) | 7.2 (3.5 – 20.3) |
| - < 6 months | - 28 (43%) |
| - ≥ 6 months | - 37 (57%) |
|
| |
| Median time between end of treatment and MMR vaccine (months, range) | 14.2 (7.8 – 31.56) |
n (%) number and percent of patients; median (range); MMR – measles, mumps, and rubella; NHL: Non-Hodgkin lymphoma
Inactivated Vaccines
After EOT, residual immunity to these VPDs ranged from 7% to 95% (Table 4, Figures 1A and 1B). After inactivated vaccine inoculations, 94–100% of patients had protective antibody titers to tetanus, diphtheria, H. Flu, Polio, HepB and MenACWY while 87% had protective antibodies to pneumococcus regardless of age (<7 years or ≥ 7 years), primary cancer diagnosis (hematologic malignancy or brain tumor) or time between EOT and vaccination (< 6 months or ≥ 6 months). Of note, all 28 patients who were seronegative at baseline with an absolute CD4+ ≥ 200 cells/mcl and total IgG level of > 500 mg/dl vaccinated between 3 and 6 months from EOT seroconverted to tetanus (10 patients), diphtheria (2 patients), H. Flu (18 patients), pneumococcus (27 patients), and polio (2 patients).
Table 4:
Positive Antibody Titers Pre and Post Vaccine (s): total patients and by age
| Vaccine | Positive Titer Pre/Post | <7 yrs. | ≥7 yrs. | Total |
|---|---|---|---|---|
| Tetanus | Evaluable (n) | 21 | 44 | 65 |
| Tetanus | Pre vaccine | 12 (57%) | 36 (86%) | 48 (74%) |
| Tetanus | Post 2 vaccines | 21 (100%) | 44 (100%) | 65 (100%) |
| Diphtheria | Evaluable (n) | 21 | 44 | 65 |
| Diphtheria | Pre vaccine | 19 (90%) | 43 (98%) | 62 (95%) |
| Diphtheria | Post 2 vaccines | 21 (100%) | 44 (100% | 65 (100%) |
| H. Influenza | Evaluable (n) | 21 | 44 | 65 |
| H. Influenza | Pre vaccine | 4 (19%) | 19 (43%) | 23 (35%) |
| H. Influenza | Post 2 vaccines | 21 (100%) | 44 (100%) | 65 (100%) |
| Polio | Evaluable (n) | 21 | 42 | 63 |
| Polio | Pre vaccine | 19 (90%) | 41 (98%) | 60 (95%) |
| Polio | Post 2 vaccines | 21 (100%) | 42 (100%) | 63 (100%) |
| Hepatitis B | Evaluable (n) | 21 | 43 | 64 |
| Hepatitis B | Pre vaccine | 8 (38%) | 17 (40%) | 25 (39%) |
| Hepatitis B | Post2 vaccines | 21 (100%) | 41 (93%) | 62 (97%) |
| Pneumococcus | Evaluable (n) | 20 | 44 | 64 |
| Pneumococcus | Pre vaccine | 3 (15%) | 6 (13%) | 9 (14%) |
| Pneumococcus | Post 2 vaccines | 20 (100%) | 36 (82%) | 56 (87%) |
| Meningococcus A | Evaluable (n) | 31 | 31 | |
| Meningococcus A | Pre | 3 (10%) | 3 (10%) | |
| Meningococcus A | Post | 29 (94%) | 29 (94%) | |
| Pertussis | Evaluable (n) | 21 | 40 | 61 |
| Pertussis | Pre vaccine | 0 (0%) | 5 (13%) | 5 (7%) |
| Pertussis | Post 2 vaccines | 10 (48%) | 10 (25%) | 20 (33%) |
| Measles | Evaluable | 17 | 39 | 56 |
| Measles | Pre vaccine | 8 (47%) | 24 (36%) | 32 (57%) |
| Measles | Post 1 vaccine | 12 (71%) | 26 (67%) | 38 (68%) |
| Measles | Post 2 vaccines | 15 (88%) | 29 (76%) | 44 (79%) |
| Mumps | Evaluable (n) | 17 | 36 | 53 |
| Mumps | Pre | 6 (35%) | 25 (69%) | 31(58%) |
| Mumps | Post 1 vaccine | 13 (76%) | 28 (78%) | 41(77%) |
| Mumps | Post 2 vaccines | 14 (82%) | 30 (83%) | 44 (83%) |
| Rubella | Evaluable (n) | 17 | 37 | 53 |
| Rubella | pre | 9 (53%) | 28 (76%) | 37 (67%) |
| Rubella | Post 1 vaccine | 15 (88%) | 32 (86% | 47 (85%) |
| Rubella | Post 2 vaccines | 15 (88%) | 32 (86%) | 47 (85%) |
| Varicella | Evaluable (n) | 14 | 37 | 51 |
| Varicella | Pre | 3 (21%) | 20 (54%) | 23 (38%) |
| Varicella | Post 1 vaccine | 8 (57%) | 28 (76% | 36 (71%) |
| Varicella | Post 2 vaccines | 10 (71%) | 32 (86%) | 42 (82%) |
n: number of patients (%)
Figure 1.
Response to vaccines: (A) inactivated vaccines; (B) pertussis and live attenuated vaccines; (C) response to pertussis and live attenuated vaccines by age; (D) response to pertussis and live attenuated vaccines by disease.
Response to pertussis was suboptimal: after vaccination only 33% of patients had a protective antibody for pertussis (Table 4, Figure 1B). There was no difference in post vaccine immunity to pertussis by age (p = 0.073, Figure 1C) or diagnosis (p=0.676, Figure 1D).
Live Attenuated Vaccines
Measles:
Fifty-six of 65 (86%) patients were evaluable for immunity to measles. Six patients who were seropositive for measles did not receive a vaccine. Prior to vaccination 32 (57%) patients were seropositive and after one vaccine 38 (68%) of patients were seropositive. Six of ten patients who did not respond to the first vaccine responded to a second vaccination, such that 44 (79%) patients were seropositive to measles after completing the vaccination schedule (Table 4, Figure 1B). There was no difference in post vaccine immunity by age (p = 0.244, Table 4, Figure 1C), primary cancer diagnosis (p=0.144, Figure 1D), or time between EOT and vaccination (vaccination < 6 months and versus vaccination >6 months after EOT (p=0.228)). Seroconversion to measles was not significantly different in those vaccinated >1 year post treatment as compared to those vaccinated <1 year post treatment (p=0.940). Examining patients whose serostatus was non-protective at baseline (n = 24), neither the ALC nor the absolute CD4+ T cell count was significantly different between patients who seroconverted and those who did not (p = 0.74 and p=0.94, respectively)
Mumps:
Fifty-three of 65 (82%) patients were evaluable for immunity to mumps. Prior to vaccination 31 (58%) patients were seropositive for mumps and after one vaccine 41 (77%) patients were seropositive. Three of 11 patients who did not respond to the first vaccine responded to a second vaccination, such that 44 (83%) patients were seropositive to mumps after completing the vaccination schedule (Table 4, Figure 1B). There was no difference in post vaccine immunity by age, (p = 0.929, Table 4, Figure 1C), primary cancer diagnosis (p=0.145, Figure 1D), or time between EOT and vaccination.
Rubella:
Fifty-three of 65 (85%) patients were evaluable for immunity to rubella. Prior to vaccination 37 (67%) patients were seropositive for rubella and after one vaccine 47 (85%) patients were seropositive (Table 4, Figure 1B). Only one of seven patients who was seronegative after one vaccine received a second vaccine and this patient did not seroconvert. There was no difference in post vaccine immunity to rubella by age (p=0.858, Table 4, Figure 1C). However, patients with brain tumors were more likely to convert to seropositive status to rubella than those with hematologic malignancy (p = 0.004, Figure 1D).
Varicella:
Fifty-one patients of 65 (78%) were evaluable for immunity to varicella. Twelve of 23 (38%) patients who were seropositive at EOT were not vaccinated. After one vaccine 36 (71%) patients were seropositive. Six of nine patients who were seronegative after one vaccine and received a second vaccine seroconverted, such that 42 (82%) patients were seropositive to varicella after completing the vaccination schedule (Table 4, Figure 1B). There was no difference in immunity after vaccination for varicella by age (p=0.208, Table 4, Figure 1C) or primary cancer diagnosis (p=0.130, Figure 1D).
Examining patients whose serostatus was non-protective at baseline (n = 28), neither the ALC nor the absolute CD4+ T cell count was significantly different between patients who seroconverted and those who did not (p = 0.77 and p=0.75, respectively)
Discussion
In this prospective Phase II study, the protective antibody titers for 12 VPDs were evaluated before and after immunization in 65 survivors of childhood cancer. The study is notable for completeness of data; all 65 (100%) patients were evaluated for serostatus before and after receipt of inactivated vaccines, while 78% - 86% of patients were evaluated before and after receipt of live attenuated vaccines.
The literature surrounding seroconversion and immunogenicity of various vaccines following standard of care cancer chemotherapy treatment in the pediatric population focuses mostly on survivors of acute lymphocytic leukemia (ALL) who received a limited number of vaccines (Table S1)3,4,6–15. In contrast, 66% of our patients had a hematologic malignancy, 28% had brain tumors, 6% had solid tumors and we assessed responses to a total of 12 vaccines.
In our series, all patients regardless of serostatus were vaccinated, whereas, in other studies only patients who were seronegative at baseline received vaccination(s) 3,4,12–15,17. Our patients were selected for having a CD4+ T cell count ≥ 200 cells/ml and an IgG level > 500mg/dl prior to vaccination, while no other reported series required patients to have achieved these immune recovery milestones. Notably, all patients were found to have sufficient immune recovery to proceed with vaccination.
Our analysis indicates that pediatric survivors of hematologic malignancies and solid tumors treated with conventional chemotherapy show a consistently high response to tetanus, diphtheria, polio, and H. Flu following two vaccines starting at 3 months from EOT. Several other studies show a single booster given at 3-, 6- or 12-months following EOT is sufficient (Table S1)3,6–10,12–14,17. We identified fewer studies that examined the immunogenicity of Prevnar13 (pneumococcus)3,10 or Hep B12,13,17and no study that examined immune response to MenACWY (Table S1). Hung et al performed a prospective study looking at response to all pneumococcal serotypes; post vaccination ≥ 70% of patients had protective antibody titers for 11 serotypes10. In Cetin et al’s retrospective study the percentage of patients who were protected against pneumococcus increased from 58% prior to vaccination to 80% after vaccination3. In three of four studies that examined response to Hep B, ≥ 90% of patients were protected after either a booster or two vaccines12,13. We did not study response to Hepatitis A vaccine (HAV); however, Anafy et al, reported 25 of 26 (96%) of patients with ALL responded to HAV17. In our series of 31 recipients ≥ 11 years of age, only 10% were seropositive to meningococcus serotype A at baseline, while following one vaccine, 90% of patient were seropositive. In our study, we did not measure serostatus between the first and second doses of inactivated vaccines. However, other studies demonstrate a high percentage of patients with protective immunity following a single booster of an inactivated vaccine even in patients seronegative at baseline and vaccinated at 3 months after EOT (Table S1)3,4,6–15,17.
We identified two studies other than our own that reported serostatus after vaccination for pertussis. Like our finding, Koochakzadeh et al and Anafy et al reported low response to pertussis, with only 20% and 36% of patients responding to vaccination, respectively 9,17. Whether it is of value to monitor response to pertussis after vaccination is unclear, as there is no evidence that additional vaccines would improve patient response.
Although many studies show inactivated vaccines being given as early as three months following EOT (Table S1)3,6,8, in general, live attenuated vaccines have been held until at least six months following chemotherapy (Table S1)3,4,6,7,9,11,12,14,15,17. Response rates to measles vaccine are variable across these studies and may reflect differing patient populations or baseline status3,4,6,9,11,12,14,15,17. In the studies where MMR was given to all patients regardless of serostatus at baseline, 60%–94% of patients were protected against measles following one or two vaccines6–9,11. Among those studies that vaccinated only seronegative patients, 57%–83% of patients had protective titers against measles following vaccination(s)3,4,12,14,15,17. In Speckhart’s and our study, a few patients converted following a second vaccine which suggests patients could benefit from receiving two MMR vaccines11. We identified four additional studies that examined responses to mumps vaccination(s); again, response rates varied from 42% to 88% regardless of serostatus at baseline6,9,11,14. We identified five studies in addition to ours in which patients were monitored for response to rubella; a high response (65%–100%) was observed in all studies4,6,9,12,14. Our study is the only one to explore response to two MMR vaccine doses after completion of cancer-directed therapy; results indicate that even if given two vaccines, a significant number of patients will remain seronegative to one or more of these VPDs. Surprisingly few studies have examined pediatric cancer survivor response to varicella vaccines. In both Cakir et al’s study and our study patients benefited from receiving two varicella vaccines with 75%–82% of patients showing immunity following two vaccines15. Still, a significant number of pediatric cancer survivors in our cohort remained seronegative to varicella after vaccination.
Consistent with published studies, responses to vaccines in our study did not differ across age groups (< 7 years versus ≥ 7 years of age) or primary diagnoses (hematologic vs solid tumor)10–13, 17 Van Tilburg et al demonstrated that following chemotherapy patients with ALL/NHL recovered functional T cells between 3- and 6- months post treatment with no difference in recovery based on age (n = 31, median age = 8.6 yrs (range 3.7 – 16.3)18. Cetin et al demonstrated that following chemotherapy pediatric patients with hematologic malignancy recovered CD45+ (lymphocyte gate on flow cytometry, ≥1000 cells/mcL), CD3+ (>800 cells/mcL), CD4+ (>400 cells/mcL), and CD8+ T lymphocytes (>200 cells/mcL), as well as CD 19+ B lymphocytes (≥ 200 cells/mcL) and CD56+ Natural Killer cells 3–4 months after treatment completion3. Although an absolute CD4+ count > 200 cells/mcL and IgG level >500 g/dl were required for initiation of vaccination in our study, we do not advocate utilizing these criteria in the clinical setting. Neither ALC nor absolute CD4+ T cell count correlated with response to measles or varicella vaccine. Our data suggests that recovery of ALC ≥ 500 cells/mcL computed on a routine complete blood count (CBC) is an indication of sufficient T and B cell functional recovery. Should a patient have received prior B cell directed cellular therapy, recovery of CD19+ B cells should be demonstrated. In our cohort, 13 patients had an ALC between ≥ 500 and <1000 cells/mcL at the initiation of vaccine administration. All patients who were seronegative prior to vaccination responded to inactivated vaccines save two of ten patients who did not respond to pneumococcal vaccine. Two of three patients responded to measles vaccine and seven of seven patients responded to varicella vaccine.
A recent Children’s Oncology Group (COG) review performed by the COG Hematopoietic Cell Transplant/Immune/Dermatology Late Effects Taskforce (Taskforce) of immune function in childhood cancer survivors emphasizes the paucity of data on immune reconstitution and the lack of data supporting revaccination or boosters in survivors after conventional cancer therapy without HSCT2. The Taskforce recommends that survivors of childhood cancer who received standard non-HSCT therapy and missed scheduled vaccinations during their cancer therapy be given all vaccinations that were missed beginning at six months after completion of treatment. Although 54 (83%) of our patients were over two years of age at diagnosis and should have received full series of most vaccines, a significant number of these patients lacked protective immunity to VPDs after intensive treatment for childhood cancer, which is consistent with what is reported in the literature 3–12,14,15. Based on our results and those included in Table S1, we believe all childhood cancer survivors should receive at least a single booster of inactivated vaccines regardless of their prior vaccine history and that vaccination can begin at three months from EOT without confirmation of recovered CD4+ T cell count or IgG level. This is consistent with the European Conferenced on Infections in Leukemia, which recommends a single booster of inactivated vaccines18.
Of note, The Centers for Disease Control “catch-up” schedule recommends up to 3–4 doses of some vaccines, which based on the above results do not seem warranted. The COG Taskforce did not address evaluating post vaccine titers; based on our results and those in Table S1 we would not recommend testing serostatus after vaccination with inactivated vaccines as a high percentage of patients seroconverted to all vaccines except pertussis and thus, assume patients are susceptible to pertussis infection if there is a community outbreak.
Both the COG Taskforce and the European Conference on Infections in Leukemia recommend giving a single booster vaccine for MMR and varicella after six months post EOT 2,19. However, we and others 11, 15 demonstrated the value of giving two vaccines to increase the percentage of patients who seroconvert to measles and mumps. Furthermore, Speckhart et al demonstrated that following one vaccine only 21% of patients were seropositive nine years after a single vaccine, while 100% of patients remained seropositive eight years after two vaccines11. We and Cakir et al also demonstrated the value of giving two vaccines to increase the percentage of patients who seroconvert to varicella15.
Serostatus measures only humoral (B cell) immunity and not T cell immunity. T-cell populations may recover faster and it is reasonable to assume survivors may possess a certain degree of T-cell immunity to VPDs if adequately re-vaccinated2,20,21. None of our patients had received prior anti-B cell directed therapies such as rituximab or CD19+ directed CAR T therapy or splenic radiation, however it should be noted that all were heavily treated (intensity scores 2 – 4)22. Patients might mount a T cell response to the live attenuated vaccine series, but administration of a live vaccine to a patient without CD19+ B cell recovery may not be prudent.
It should be acknowledged that a full vaccination history was not taken from patients prior to study activities. However, others have found that complete vaccination prior to cancer directed therapy was not predictive for positive antibody titers at the completion of treatment or higher response rates to re-vaccination3–12,14,15. In our cohort, 11 patients (17%) were under the age of two years at the time of diagnosis and may not have completed all recommended childhood vaccinations prior to cancer treatment. Baseline serostatus and response to vaccination in these patients was consistent with those assumed to have been fully vaccinated prior to cancer treatment. We therefore do not believe complete vaccine history to be particularly salient to the results. Additionally, our cohort lacked diversity of solid tumors; brain tumors (n=18) and other solid tumors (n=4). However, all 22 patients received either level 2 or level 3 treatment intensity similar to treatment that patients with other solid tumors would receive17.
In summary, many pediatric cancer survivors treated with conventional non-HSCT chemotherapy and/or radiation lack immunity to VPDs at completion of therapy. Following treatment most survivors respond to inactivated vaccines, except for pertussis. Fewer patients respond to attenuated live vaccines, with a substantial number of patients not demonstrating a humoral response to measles (~30%), rubella (~20%) or varicella (~25%). Risk for community acquired infection with VPDs has increased markedly in the past decade 23,24 possibly due to decreasing vaccination rates in school aged children and adolescents25,26. This increased risk mandates a full understanding of pediatric cancer survivors’ humoral immune status relative to VPDs to effectively protect this at-risk population20,21. Selective antibody titers such as those to measles, rubella and varicella should be considered for evaluation in patients followed long-term to better inform provider and patient awareness of an individual’s serostatus in the event of exposure to community outbreaks or when contemplating pregnancy.
Supplementary Material
Acknowledgments:
Dr. Trudy N. Small as the original Principal Investigator on this study, Dr. Danielle Friedman for her careful review of the manuscript, Margaret Barton-Burke and the MSK Nursing Research Fellowship for their support of this work, and the Joseph Olechnowicz for his editorial contributions.
Funding:
This research was funded in part through the NIH/NCI Cancer Center Support Grant P30 CA008748, the Society of Memorial Sloan Kettering, the Alexander Reza Pediatric Leukemia Fund, and the Mike Ockrent Leukemia Fund. Additional funds for dissemination and presentation provided by the MSK Geri and ME Fund.
Abbreviations:
- ALL
Acute Lymphoblastic Leukemia
- COG
Children’s Oncology Group
- EOT
End of Treatment
- H. Flu
Haemophilus influenzae
- HepB
Hepatitis B
- HSCT
Hematopoietic Stem Cell Transplantation
- IRB
Institutional Review Board
- MenACWY
Meningococcus ACWY
- MMR
Measles, Mumps, Rubella
- PHA
Phytohemagglutinin
- VPD
Vaccine Preventable Diseases
Footnotes
Conflict of Interest: IJD reports membership in the Astra Zeneca Pediatric Oncology Steering Committee and consultancy for IO Biotech; NAK reports equity shares in Merck, Amgen and Johnson and Johnson; PGS, TT, YK, NS, JR, NZ, SJ report no conflicts of interest.
References
- 1.Bhakta N, Force LM, Allemani C, et al. Childhood cancer burden: a review of global estimates. Lancet Oncol. 2019;20(1):e42–e53. doi: 10.1016/S1470-2045(18)30761-7 [DOI] [PubMed] [Google Scholar]
- 2.Guilcher GMT, Rivard L, Huang JT, et al. Immune function in childhood cancer survivors: a Children’s Oncology Group review. Lancet Child Adolesc Health. 2021;5(4):284–294. doi: 10.1016/S2352-4642(20)30312-6 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Cetin M, Gumy-Pause F, Gualtieri R, Posfay-Barbe KM, Blanchard-Rohner G. Vaccine Immunity in Children After Hematologic Cancer Treatment: A Retrospective Single-center Study. J Pediatr Hematol Oncol. 2024;46(1):e51–e59. doi: 10.1097/MPH.0000000000002774 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Nilsson A, De Milito A, Engström P, et al. Current Chemotherapy Protocols for Childhood Acute Lymphoblastic Leukemia Induce Loss of Humoral Immunity to Viral Vaccination Antigens. Pediatrics. 2002;109(6):e91–e91. doi: 10.1542/peds.109.6.e91 [DOI] [PubMed] [Google Scholar]
- 5.Junak SC. Lack of Consensus on Humoral Immune Status Among Survivors of Pediatric Hematological Malignancies: An Integrative Review. J Pediatr Oncol Nurs. 2021;38(1):51–60. doi: 10.1177/1043454220958675 [DOI] [PubMed] [Google Scholar]
- 6.De La Fuente Garcia I, Coïc L, Leclerc JM, et al. Protection against vaccine preventable diseases in children treated for acute lymphoblastic leukemia: de la Fuente Garcia et al. Pediatr Blood Cancer. 2017;64(2):315–320. doi: 10.1002/pbc.26187 [DOI] [PubMed] [Google Scholar]
- 7.Patel SR, Ortin M, Cohen BJ, et al. Revaccination of Children after Completion of Standard Chemotherapy for Acute Leukemia. Clin Infect Dis. 2007;44(5):635–642. doi: 10.1086/511636 [DOI] [PubMed] [Google Scholar]
- 8.Zengin E, Sarper N. Humoral immunity to diphtheria, tetanus, measles, and hemophilus influenzae type b in children with acute lymphoblastic leukemia and response to re-vaccination. Pediatr Blood Cancer. 2009;53(6):967–972. doi: 10.1002/pbc.22135 [DOI] [PubMed] [Google Scholar]
- 9.Koochakzadeh L, Khosravi MH, Pourakbari B, Hosseinverdi S, Aghamohammadi A, Rezaei N. Assessment of Immune Response following Immunization with DTP/Td and MMR Vaccines in Children Treated for Acute Lymphoblastic Leukemia. Pediatr Hematol Oncol. 2014;31(7):656–663. doi: 10.3109/08880018.2013.877111 [DOI] [PubMed] [Google Scholar]
- 10.Hung T, Kotecha RS, Blyth CC, et al. Immunogenicity and safety of single-dose, 13-valent pneumococcal conjugate vaccine in pediatric and adolescent oncology patients. Cancer. 2017;123(21):4215–4223. doi: 10.1002/cncr.30764 [DOI] [PubMed] [Google Scholar]
- 11.Speckhart SA. MMR vaccination timing and long-term immunity among childhood cancer survivors. Pediatr Blood Cancer. 2023;70(4):e30133. doi: 10.1002/pbc.30133 [DOI] [PubMed] [Google Scholar]
- 12.Zignol M, Peracchi M, Tridello G, et al. Assessment of humoral immunity to poliomyelitis, tetanus, hepatitis B, measles, rubella, and mumps in children after chemotherapy. Cancer. 2004;101(3):635–641. doi: 10.1002/cncr.20384 [DOI] [PubMed] [Google Scholar]
- 13.Fayea NY, Kandil SM, Boujettif K, Fouda AE. Assessment of hepatitis B virus antibody titers in childhood cancer survivors. Eur J Pediatr. 2017;176(9):1269–1273. doi: 10.1007/s00431-017-2970-4 [DOI] [PubMed] [Google Scholar]
- 14.Fouda AE, Kandil SM, Boujettif F, Salama YS, Fayea NY. Humoral immune response of childhood acute lymphoblastic leukemia survivors against the measles, mumps, and rubella vaccination. Hematology. 2018;23(9):590–595. doi: 10.1080/10245332.2018.1460035 [DOI] [PubMed] [Google Scholar]
- 15.Cakir FB, Timur C, Yoruk A, Cakir E, Ayhan AC. Seroconversion Status After Single Dose and Double Doses of Varicella Vaccination in Children With Leukemia. Pediatr Hematol Oncol. 2012;29(2):191–194. doi: 10.3109/08880018.2011.593093 [DOI] [PubMed] [Google Scholar]
- 16.StataCorp. StataNow 18.5 SE-Standard Edition. [Google Scholar]
- 17.Anafy A, Gilad G, Michaan N, et al. Revaccination of children with acute lymphoblastic leukemia following completion of chemotherapy. Pediatr Blood Cancer. 2023;70(6):e30321. doi: 10.1002/pbc.30321 [DOI] [PubMed] [Google Scholar]
- 18.Van Tilburg CM, Sanders EAM, Rovers MM, Wolfs TFW, Bierings MB. Loss of antibodies and response to (re-)vaccination in children after treatment for acute lymphocytic leukemia: a systematic review. Leukemia. 2006;20(10):1717–1722. doi: 10.1038/sj.leu.2404326 [DOI] [PubMed] [Google Scholar]
- 19.Mikulska M, Cesaro S, De Lavallade H, et al. Vaccination of patients with haematological malignancies who did not have transplantations: guidelines from the 2017 European Conference on Infections in Leukaemia (ECIL 7). Lancet Infect Dis. 2019;19(6):e188–e199. doi: 10.1016/S1473-3099(18)30601-7 [DOI] [PubMed] [Google Scholar]
- 20.Koskenvuo M, Ekman I, Saha E, et al. Immunological Reconstitution in Children After Completing Conventional Chemotherapy of Acute Lymphoblastic Leukemia is Marked by Impaired B-cell Compartment. Pediatr Blood Cancer. 2016;63(9):1653–1656. doi: 10.1002/pbc.26047 [DOI] [PubMed] [Google Scholar]
- 21.Wiegering V, Frank J, Freudenberg S, et al. Impaired B-cell reconstitution in children after chemotherapy for standard or medium risk acute precursor B-lymphoblastic leukemia. Leuk Lymphoma. 2014;55(4):870–875. doi: 10.3109/10428194.2013.816423 [DOI] [PubMed] [Google Scholar]
- 22.Kazak AE, Hocking MC, Ittenbach RF, et al. A revision of the intensity of treatment rating scale: Classifying the intensity of pediatric cancer treatment. Pediatr Blood Cancer. 2012;59(1):96–99. doi: 10.1002/pbc.23320 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23.Centers for Disease Control and Prevention. The Epidemiology and Prevention of Vaccine-Preventable Diseases. 14th ed. Public Health Foundation; 2021. [Google Scholar]
- 24.Centers for Disease Control and Prevention. Measles Cases and Outbreaks. Published online June 7, 2024. [Google Scholar]
- 25.Centers for Disease Control and Prevention. Vaccination Coverage and Exemptions among Kindergartners. [Google Scholar]
- 26.Centers for Disease Control and Prevention. TeenVaxView. https://www.cdc.gov/teenvaxview/interactive/index.html
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.