Vaccine Immunity in Children After Hematologic Cancer Treatment: A Retrospective Single-center Study

Abstract

Background:

Children lose their vaccine-induced protection and are particularly vulnerable to vaccine-preventable diseases after chemotherapy. However, revaccination guidelines are heterogeneous, and there is often a lack of revaccination post-treatment.

Aims:

We conducted a retrospective study of children with hematologic cancer to evaluate vaccine immunity before and after the end of treatment and to determine whether the current institutional revaccination program based on vaccine serology results was followed and effective.

Materials and Methods:

Data of all children treated by chemotherapy between April 2015 and July 2021 were extracted from hospital medical records for analysis. Serum antibody levels and time of vaccination were evaluated for diphtheria, tetanus, Streptococcus pneumoniae, Haemophilus influenzae type b (Hib), measles, varicella, and hepatitis B.

Results:

We included 31 patients (median age, 9 years). At cancer diagnosis, 90% of children were protected against tetanus, diphtheria, and measles; 65% to 67% were protected against pneumococcus and varicella; and 25% against hepatitis B. At the end of chemotherapy, 67% to 71% of patients were protected against tetanus, varicella, and measles; 40% remained protected against hepatitis B; and 27% to 33% against pneumococcus and diphtheria. Patients were revaccinated at various times after the end of treatment but not systematically. During the first-year post-treatment, 20% to 25% of children remained unprotected against pneumococcus, measles, and hepatitis B, one third against diphtheria, but all were protected against tetanus and varicella.

Conclusions:

An effective individualized vaccination program post-cancer based on serology results should be accompanied by an appropriate serology tracking method and follow-up to assess if booster doses are necessary. Our study supports vaccinating all children with a dose of the 13-valent pneumococcal conjugate at cancer diagnosis and at 3 months post-treatment with the combined diphtheria-tetanus-acellular pertussis/poliomyelitis vaccine/hepatitis B virus plus or minus Hib and 13-valent pneumococcal conjugate and meningococcal vaccine, including measles/mumps/rubella-varicella zoster virus vaccine if good immune reconstitution is present.

Malignant diseases are among the principal causes of death in children worldwide.¹ Each year, 141 cases per million children 0 to 14 years old and 185 cases per million children 15 to 19 years old develop cancer around the world.² The most common cancers among those 0 to 14 years of age are leukemia, central nervous system tumors, and lymphomas.² For children 15 to 19 years old, the most common are lymphoma, epithelial tumors, and melanoma.² In Switzerland, ~400 children between 0 and 19 years of age are diagnosed with cancer each year.³

Children with cancer have their immune capacity altered due to the disease itself and the treatment received. Immunodeficiency is mostly caused by T-cell depletion (CD4 more than CD8), as well as B-cell depletion, causing a humoral immune defect.^4,5 Notably, immunodeficiency is more important in children treated for acute lymphoblastic leukemia (ALL) compared with solid tumor, acute myeloid lymphoma (AML), and Hodgkin lymphoma.^5–10 An important distinction is that children with AML will have more impairment in innate immunity, while those with ALL will have impairment in adaptive immunity. Severe infections occur mostly during the induction phase of chemotherapy for patients with ALL, especially bacterial infections. After treatment, patients are at high risk of vaccine-preventable diseases (VPD) due to their immunosuppressive state, such as pneumococcal infections, measles, varicella zoster virus (VZV), and influenza infections.^5,6,10–13 The long-term serological protection of VPD depends on the immunologic memory, which allows a faster response after re-exposure to the antigen. The aim of vaccines is to induce this long-term protection. At the end of cancer treatment, the immunologic memory seems to be partly preserved as a sufficient serological response to revaccination is observed rapidly for certain vaccines.^6,12 For this reason, it is very important to start vaccinating children as soon as possible after the end of oncologic treatment.¹⁴

The immune system usually already recovers after the first 3 months after the end of the cancer treatment. However, immune recovery can take longer, depending on the patient’s age, the type of cancer and the treatment received (dose and duration).^4–6,15,16 While nonlive vaccines are known to be safe in immunosuppressed patients,¹⁷ it is important to choose the right moment to revaccinate children post-treatment so as to induce an appropriate immune response.^4,12,14 Nevertheless, previous studies have shown a good antibody response already at 3 months’ postoncologic treatment, although some centers start vaccination later.^6,14,16–19 However, there is a lack of universal evidence-based guidelines for the revaccination of children after chemotherapy. For example, current USA guidelines recommend to revaccinate 3 months after chemotherapy,¹¹ while revaccination in the United Kingdom is recommended 6 months after chemotherapy.¹⁷

According to Ruggiero et al, there are various approaches when revaccinating children after cancer treatment: (1) restarting a new complete vaccination schedule and immunizing every child against all VPD, without taking into consideration any possible residual immunity for a vaccine antigen; (2) assessing first the residual vaccine immunity by measuring the vaccine serology against each vaccine antigen and then administering booster doses according to serology results; and (3) continuing the regular vaccination schedule according to the standard vaccine plan for healthy children.¹⁹

The aim of this study was to evaluate the vaccination status of pediatric patients with hematologic cancer and to determine whether the current institutional program of revaccination post-cancer therapy was followed and effective.

MATERIALS AND METHODS

Study Design

This retrospective study reviewed all children 0 to 19 years of age at diagnosis with hematologic cancer treated by chemotherapy at Geneva University Hospitals from April 2015 to July 2021 (Table 1). The following patient characteristics were assessed: diagnosis, type of oncologic treatment received, duration of treatment, vaccine serology at diagnosis, and vaccine serology for various VPD at different time points after the end of treatment, depending on data availability. Serologic testing for the following vaccine antigens was assessed at cancer diagnosis and at several time points post-treatment (end of treatment [T0], 3, 6, and 12 mo): Haemophilus influenzae type b (Hib) for children below 5 years, and pneumococci, tetanus, diphtheria, varicella, measles, hepatitis A and B for all ages. Data were collected from the hospital’s electronic medical records. This study was approved by the Geneva Cantonal Research Ethics Committee (CCER 2020-01537).

TABLE 1.

Individualized Vaccination Program After Cancer at the Children’s Hospital of the Geneva University Hospitals

Time following end of treatment	At diagnosis	End of treatment	3 mo*	6 mo*	9 mo*	12 mo*	Once per year*
Tetanus (DTPa-X)†	—	—	X‡	X‡	—	X‡	X‡
Diphtheria (DTPa-X)†	—	—	X‡	X‡	—	X‡	X‡
Pneumococci (PCV13)	—	—	X‡	X‡	—	X‡	X‡
Varicella (VZV)	—	—	X§	X§	—	X‡	—
Measles (MMR)	—	—	—	—	X§	X‡	X‡
Hepatitis B (HBV)	—	—	—	—	—	X‡	X‡
Papilloma virus (HPV)	—	—	—	—	—	X∥	—
Seasonal influenza	X (October to March)	X (October to March)	—	—	—	—	X (October to March)

^*Time following the end of treatment.

^†DTPa-IPV±Hib± HBV (Hib if <5 years old).

^‡In case of negative serology, it is recommended to give a vaccine booster dose and to assess the vaccine response 1 month later.

^§In case of negative serology, it is possible to vaccinate if CD4 cells are above the normal ranges for age.

^∥For children between 11 and 16 years, it is recommended to give 2 doses of Engerix B20/HPV at a 6 month interval. For older children, it is recommended to give 3 doses at 0, 1, and 6 months.

Between diagnosis and 12 months post-end of cancer treatment, the following immunology and vaccinology workup is performed: serology for diphtheria, tetanus, pneumococci, varicella, measles, hepatitis B, and Hib for children below 5 years: at diagnosis, at the end of the treatment, at 3, 6, 9, and 12 months’ post-treatment and then, once a year until complete immune recovery; dosage of IgG, A and M as well as lymphocyte immunophenotyping; if CD4 cells are below the normal ranges for age, lymphocyte immunophenotyping is repeated every 3 months.

Catch-up vaccination schedule of family members according to age.

DTPa indicates diphtheria, tetanus, acellular pertussis; Hib, haemophilus influenzae type b; MMR, measles-mumps-rubella; PCV13, 13-valent pneumococcal conjugate.

Population

Patients were excluded if they had undergone hematopoietic stem cell transplant or if their treatment was not completed. Treatment intensity was categorized according to the Intensity of Treatment Rating scale, which depends on various criteria such as the type and stage of cancer, being part of a risk group for relapse, and the type of treatment (surgery, chemotherapy, radiation, or transplant).²⁰ Immunization records of the selected population were collected through a systematic review of the hospital’s electronic medical records system, especially the summary of vaccinations performed at the hospital and the patient’s personal vaccine card.

Antibody Measurement and Definition of Vaccine Seroprotection

Vaccine antibody concentrations were determined by enzyme-linked immunosorbent assay for tetanus, diphtheria, Hib, pneumococcus, varicella, measles, and hepatitis A and B at the Laboratory of Vaccinology and Virology of Geneva University Hospitals according to a method previously described.²¹ The following antibody titers were considered protective: anti-tetanus toxoid IgG levels≥100 IU/L; anti-diphtheria toxin IgG levels ≥100 IU/L; anti-Hib IgG levels ≥0.15 mg/L;²² anti-VZV IgG levels ≥150 IU/L; anti-measles IgG levels ≥150 IU/L; anti-hepatitis A IgG level ≥20 IU/L; and anti-hepatitis B virus (HBV) surface antigen (anti-HBs) IgG levels ≥10 IU/L (26). For pneumococci, the IgG concentration for 3 or 7 serotypes contained in the 13-valent pneumococcal protein conjugate vaccine (PCV13; Prevenar13®) (4, 6B, .9V, 14, 18C, 19F, 23F) was measured depending on the time of the serology test. Indeed, before 2019, only 3 serotypes were tested by enzyme-linked immunosorbent assay, and after 2019, 7 pneumococcal serotypes were tested by Multiplex.²³ Seroprotection was defined as serotype-specific IgG levels ≥0.3 mg/L and overall protection when it was achieved for >2/3 or >4/7 serotypes.^24–28

Lymphocyte Immunophenotyping

The following immunologic parameters were also collected at 3 to 4 months post-treatment to assess immune reconstitution: total CD45+ lymphocyte count; total CD19+ B-cell count; total CD3+ T-cell counts; CD4+ T-cell count; and CD8+ T-cell count.^29,30

Statistical Analysis

Clinical characteristics were reported by descriptive statistics. The percentage of patients with vaccine immunity at various time points after the end of oncologic treatment was reported. Given the small sample size and the number of patients with available serology at each time point, no statistical tests could be performed to compare the percentage of children with seroprotective antibody levels at different time points after cancer treatment.

RESULTS

Patient Characteristics

In total, 42 children between 0 and 19 years were treated between 2015 and 2021 for a hematologic malignancy with chemotherapy only or chemotherapy associated with radiotherapy. Among these, 11 patients were excluded as they had received a hematopoietic stem cell transplant because treatment was still ongoing or the patient was deceased (Fig. 1). Among the 31 patients fulfilling the inclusion criteria, 26 patients were treated only with chemotherapy, and 5 patients with chemotherapy associated with radiotherapy. Patient characteristics are reported in Table 2. The median duration of treatment was 2 years ±4 months. Patients had a median age of 9 years; 4/31 (13%) patients were below 5 years at the end of cancer treatment. Intensity of treatment was classified according to the Intensity of Treatment Rating scale classification.

FIGURE 1.

Study population flowchart.

TABLE 2.

Characteristics of the Study Population

Characteristics	Patients, n (%)
Total no. patients	31
Age at diagnosis
Median age (y)	9
<5 y	9 (29)
5≤×<10 y	6 (19)
10≤×<15 y	13 (42)
≥15 y	3 (10)
Sex
Male	19 (61)
Female	12 (39)
Diagnosis
B ALL	16 (52)
AML	3 (10)
Burkitt lymphoma	4 (13)
Hodgkin lymphoma	7 (23)
Diffuse large B-cell lymphoma	1 (3)
ITR classification
Class 2	27 (87)
Class 3	1 (3)
Class 4	3 (10)
Treatment duration
3 mo	5 (16)
6 mo ±2 mo	10 (32)
2 y ±4 mo	9 (29)
3 y	7 (23)

AML indicates acute myeloid lymphoma; B ALL, B-cell acute lymphoblastic leukemia; ITR, Intensity of Treatment Rating.

Serologic Immunity for Various Vaccine Antigens at Several Time Points

Not all patients had serologies taken at each time point, thus explaining the different denominators.

Tetanus

Before chemotherapy, 10/11 (91%) had protective antibody levels. After the end of treatment (T0), 21/30 (70%) children had protective tetanus antibody levels, while at 3 months, 19/28 (68%) patients had protective tetanus antibody levels. However, all children were protected against tetanus at 6 months and 12 months (Fig. 2 and Table 3). Among the 9 patients not protected after treatment, 8/9 were revaccinated at 3 months and 1/9 at 6 months. All children responded well to vaccination and reached a protective level of antibody specific for tetanus after vaccination.

FIGURE 2.

Vaccine immunity at cancer diagnosis and at various times following the end of treatment. #End of treatment (T0), 3, 6, and 12 months post-treatment for different vaccine antigens. *Patients <5 years. There were not enough serologies at 6 months post-treatment for varicella, measles, hepatitis A, and B.

TABLE 3.

Vaccine Immunity at Cancer Diagnosis and at Various Times^*

	At diagnosis	T0	3 mo	6 mo	12 mo
Tetanus	11/11 (100)	21/30 (70)	19/28 (68)	8/8 (100)	13/13 (100)
Diphtheria	9/10 (90)	10/30 (33)	13/28 (46)	9/12 (75)	6/10 (60)
Varicella	8/12 (67)	23/31 (74)	20/26 (77)	0/0 (0)	4/4 (100)
Measles	9/10 (90)	20/30 (67)	17/23 (74)	1/1 (100)	5/6 (83)
Hib†	0	2/2 (100)	2/2 (100)	0/0 (0)	1/1 (100)
Pneumococcus	6/9 (67)	8/30 (27)	15/26 (58)	11/13 (85)	9/11 (82)
Hepatitis A	9/21 (43)	0/3 (0)	0/1 (0)	0	0
Hepatitis B	6/24 (25)	2/5 (40)	0/1 (0)	0	3/4 (75)

^*After the end of treatment (T0), 3, 6, and 12 months’ post-treatment.

^†Patients below 5 years.

Hib indicates Haemophilus influenzae type b.

Overall, 23 children were revaccinated with the combined diphtheria, tetanus, acellular pertussis, and poliomyelitis vaccine (DTPa-IPV) in the first year after the end of treatment, with 13/23 (57%) patients revaccinated at 3 months, 6/23 (26%) at 6 months, 3/23 (13%) at 12 months, and 1/23 after 12 months (Fig. 3).

FIGURE 3.

Times of first vaccine administration for each vaccine. *Haemophilus influenzae type b.

Diphtheria

Before chemotherapy, 9/10 (90%) had protective antibody levels against diphtheria. At the end of chemotherapy (T0), 10/30 (33%) children were seroprotected against diphtheria at 3 months post-treatment, 13/28 (46%) had protective antibody levels at 6 months, 9/12 (75%) were protected, and 6/10 (60%) at 12 months (Fig. 2 and Table 3). Among the 20 children with an unprotected antibody level at the end of treatment, 18/20 were revaccinated: 10/18 (55%) at 3 months, 5/18 (28%) at 6 months, and 3/18 (17%) at 12 months. Most children responded well to vaccination with 17/18 (94%) reaching a protective level after vaccination.

Hib

Among the 9 children below 5 years in the cohort, none had a Hib-specific serology assessed at diagnosis, and very few had a Hib-specific serology assessed at the end of treatment. However, among the 2 children with a serology assessed, both were seroprotected.

S. pneumoniae

At diagnosis, 9/31 (29%) patients had a measured serology for pneumococci and 6/9 (67%) had protective antibody levels against pneumococcus. After the end of treatment (T0), only 8/30 (27%) children remained protected against pneumococcus, while 15/26 (58%) patients were protected at 3 months, 11/13 (85%) at 6 months, and 9/11 (82%) at 12 months (Fig. 2 and Table 3). Among the children unprotected against pneumococci at the end of treatment, 15/20 (75%) were revaccinated with Prevenar13 at 3 months, 3/20 (15%) at 6 months, and 2/20 (10%) after 12 months. Most responded well to the PCV13 (16/20 [80%]) (Fig. 3).

Varicella

Before chemotherapy, 12/31 (39%) patients had a VZV serology assessed. Among these, 8/12 (67%) had protective antibody levels against varicella due to a past infection, and 8/8 (100%) had a residual protective antibody level at the end of the treatment. Overall, 23/31 (74%) were protected against varicella at the end of treatment (T0) and 20/26 (77%) at 3 months post-treatment, while 4/4 (100%) were seroprotected at 12 months (Fig. 2 and Table 3). There was no serology done 6 months after the end of treatment.

Among the patients unprotected at T0, only 4/8 (50%) were vaccinated against varicella during the study follow-up, with 2/4 (50%) children vaccinated at 12 months post-treatment and 2/4 (50%) at a later date. Only 2/4 (50%) children had a serology assessed after vaccination, but none reached a protective level after 1 dose of VZV vaccine.

Measles

Before chemotherapy, 10/31 (32%) patients had a measles serology. Among these, 9/10 (90%) had protective antibody levels against measles, with 5/9 (56%) showing a residual protective antibody level at the end of chemotherapy. Overall, 20/30 (67%) children were protected against measles at the end of treatment (T0) and 17/23 (74%) at 3 months, while 1/1 (100%) was seroprotected at 6 months and 5/6 (83%) at 12 months (Fig. 2 and Table 3).

Among patients unprotected against measles at T0, only 6/10 (60%) were vaccinated during the study follow-up, with 4/6 (67%) children vaccinated at 12 months post-treatment and 2/6 (33%) at a later date. A total of 4/6 (67%) children had a serology assessed after vaccination. Among these, 3/4 (75%) reached a protective level after 1 dose (1/3) or after 2 doses of measles vaccine (2/3).

Hepatitis A

Before chemotherapy, 21/31 (68%) patients had a hepatitis A serology assessed. Among these, 9/21 (43%) had protective antibody levels against hepatitis A. However, only 1 patient had a hepatitis A serology at 3 months postchemotherapy and 2 at 12 months. The 3 patients with a post-treatment hepatitis A serology were not protected, and none has been vaccinated post-treatment (Figs. 2 and 3 and Table 3).

Hepatitis B

Before chemotherapy, 24/31 (77%) children had a hepatitis B serology assessed. Among these, 6/24 (25%) had protective antibody levels against hepatitis B. However, most children did not have a hepatitis B serology postchemotherapy. Among patients who had a serology, 2/5 (40%) children remained protected against hepatitis B at the end of treatment. Only 3 patients were vaccinated against hepatitis B during study follow-up: 1/3 at 3 months, 1/3 at 12 months, and 1/3 at a later date (Fig. 3). Children who had a hepatitis B serology assessed postvaccination showed a good response to vaccination (3/4 [75%]) (Fig. 2 and Table 3).

Immune Recovery

Immunophenotyping of lymphocytes performed at 3 to 4 months post-treatment showed normal numbers of all T, B, and natural killer cells in most children (Fig. 4).

FIGURE 4.

Different lymphocyte subpopulations 3 to 4 months after treatment completion. Concentrations of cells per microliter with 95% CIs. Normal ranges represented in green.^29,30

DISCUSSION

Our study demonstrates that protection against VPD is not sufficient at the time of cancer diagnosis and during the first year after the end of oncologic treatment, despite a good immune reconstitution already observed between 3 and 4 months after the end of treatment in most children.

At cancer diagnosis, it is expected that most children have been vaccinated according to the standard vaccination program for their age. In Switzerland, hepatitis A vaccination is a complementary vaccine and is only recommended in the case of exposure risk factors or hepatic disease,³¹ while hepatitis B is recommended for adolescents at 11 years of age and in infants as a combined hexavalent vaccine since 2005.³² This explains why only 43% and 25% of children were protected against hepatitis A and B, respectively, at cancer diagnosis. In contrast, more than 80% of children were protected against tetanus, diphtheria, and measles while two thirds were protected against varicella and pneumococci. Data on Hib (serology and vaccination) is not significant in this study and is therefore not discussed.

We observed a general loss of immunity for VPD after cancer treatment, especially against pneumococcus. Similarly, Patel et al³³ assessed pneumococcal antibody concentrations in children treated for ALL and AML 6 months or more after chemotherapy using the same cutoff for seroprotection (≥0.35 μg/mL) and reported that <30% if children remained protected for each specific pneumococcal serotype at the end of chemotherapy. At present, it remains unknown whether all patients treated with any kind of chemotherapy lose their vaccine immunity and need to undergo revaccination. Indeed, there may be a difference between children undergoing intense chemotherapy and those receiving weekly vinblastine for a fixed amount of time. However, our study was not designed to respond to this question.

It has also been reported that children undergoing therapy for an ALL have a relative risk of 11.4 times of developing an invasive pneumococcal disease (IPD) during the first 2 years post-cancer diagnosis compared with healthy children.³⁴ Pneumococcal vaccination also reduces the number of hospitalizations due to IPD in patients with comorbidities, such as cancer.³⁵ Moreover, a study in adults showed that influenza and pneumococcal vaccinations were immunogenic when administered early in the course of disease, ideally 4 to 6 weeks (at least 2 weeks) before starting the chemotherapy and, if not possible, 3 months after the end of chemotherapy.³⁶ Several other studies suggest that vaccination with PCV13 directly after completion of chemotherapy is safe and highly effective to prevent IPD without age restriction.^37–39

However, there is a lack of international consensus regarding pneumococcal vaccination for children with cancer. In Switzerland, vaccination against pneumococcus with the PCV13 is given to children below 5 years old and is only recommended after this age for children at risk of IPD, such as children with a malignancy.^40–42 In the United States, the approach aligns with guidance provided by the Infectious Diseases Society of America, emphasizing routine immunization without supplementary vaccines for oncologic children, that is, PCV13 vaccine until 5 years for everyone and after 5 years following associated immune system deficiencies.⁴³ By contrast, in Europe and Australia, booster doses of pneumococcal vaccines are recommended in leukemia patients 3 to 6 months after chemotherapy, according to the age and the country’s own recommendations.⁴⁴ In Canada, there is a lack of established immunization protocols for children receiving treatment for malignancies and the approach is medical center dependent. In 45% of facilities, it is recommended to revaccinate children of any age with DTaP-IPV-Hib, PCV13, and the 23-valent pneumococcal polysaccharide vaccine 3 to 6 months after chemotherapy.^37,45

Concerning varicella, one third of children in our study were not protected at the time of cancer diagnosis. It is known that children with leukemia or lymphoma have a higher risk of varicella and related morbidity (pneumonitis) during and after chemotherapy compared with other cancer types.^46,47 This underlines the importance of surveillance and prophylactic procedures during treatment in the case of varicella exposure.^48,49 Varicella vaccination also lowers the risk of zoster infection for children with leukemia.⁵⁰ In Switzerland, vaccination with the recombinant inactivated vaccine against zona is recommended at cancer diagnosis for adults, while the live attenuated varicella vaccine is contraindicated.⁴¹ Indeed, live vaccines such as varicella and measles-mumps-rubella (MMR) are contraindicated at cancer diagnosis.⁴³ VZV vaccine has been introduced since January 2023 in the infant vaccination schedule in Switzerland as a combined vaccine with MMR vaccine.⁵¹ We hope that this change will increase varicella immunity in the general pediatric population and therefore decrease the risk of transmission to nonimmune children. This will also make it less likely that children diagnosed with a cancer are nonimmune to varicella at diagnosis.

Although most children responded well to revaccination after the end of treatment, our study was not designed to assess vaccine responses or potential factors that could influence the vaccine response post-cancer treatment. Predictors of a lower vaccine response post-cancer have been reported previously, such as a higher intensity of chemotherapy administered, a younger age, and sex (being a female increased the vaccine response to tetanus).^9,37,52 Of note, a previous study with a cohort of 59 ALL pediatric patients observed that 29% of patients were not protected at least 1 month after the varicella booster dose given 12 months post-end of treatment.⁹Another study of ALL pediatric patients observed that 1 year after the first varicella vaccination given at 12 months after the end of treatment, 40% of patients remained protected when they received only 1 dose, whereas 75% of those who received 2 doses remained protected.⁵³

We observed that the individualized vaccination program after cancer treatment was not well followed at our institution despite regular serology tests. This can be explained by the fact that most vaccine serology results arrive several days after the child has already left the hospital. Vaccine recommendations are then transmitted to the pediatrician or planned for the next hospital visit. Therefore, it is difficult to check for each child that the recommended vaccines are given shortly after the vaccine serology results according to national guidelines. An Australian study assessed the compliance of revaccination of pediatric cancer survivors’ postchemotherapy with local recommendations. Findings acknowledged poor compliance of health care workers as 39% of children were not revaccinated for a median time of 3 years post-cancer.⁵⁴ In addition, the fact that vaccination is non-mandatory (parental decision) in Switzerland can be an obstacle to the prevention of VPD. Indeed, health care workers have a major role in the vaccination of children with cancer, but they may feel stressed about vaccinating this population.

Overall, most children in our study received a dose of DTPa-IPV plus or minus Hib, plus or minus HBV, and PCV13 at 3 months post-treatment. By contrast, most doses of varicella and MMR vaccines were given at 12 months post-treatment or after, even though the lymphocyte immunophenotyping showed already normal T-cell and B-cell numbers at 3 to 4 months post-treatment for most children, thus allowing vaccination with live vaccines. Recommending vaccination at a fixed time after cancer has probably some advantages as it may be more cost-effective and time-effective than vaccinating children, according to vaccine serology results. However, it is probable that some children will receive unnecessary doses of vaccines, and others may need more doses of vaccines than others.

According to our results, we recommend vaccinating children with PCV13 at cancer diagnosis and at 3 months after the end of treatment, together with the combined DTPa-IPV/HBV plus or minus Hib, and against meningococci. We also recommend vaccinating children with 2 doses of the MMR and varicella vaccines at a 1-month interval, from 3 months’ post-end of cancer treatment in the case of good immune reconstitution (ie, CD4 T lymphocytes >200/μL [0.2 g/L] [>5 years]; >500/μL [0.5 g/L] [between 1 and 5 years]; >750/μL [0.75 g/L] [<1 y]), in line with the new Swiss recommendations (Table 4).⁴¹ This systematic vaccination should be followed by a serology check when possible to ascertain if booster doses of vaccines are necessary.

TABLE 4.

Swiss 2022 Vaccination Recommendations After Conventional Cytotoxic Chemotherapy/Radiotherapy for Children and Adolescents Diagnosed With a Malignant Neoplasia⁴¹

Vaccine	Age (years old)	Time of vaccination (mo) post-treatment
DTPa-IPV	<1	3 – 4 - 11
	≥1	3 – 5 – 11
HBV*	—	3 – 4 – 9
Hib	<1	3 – 4 – 11
	1≤×< 5	3 – 5
PCV	<1	3 – 4 – 11
	1≤×< 5	3 – 5
MMR	≥6 mo	6† – 7
Varicella	≥9 mo‡	6† – 7
HPV	11-14	3 – 9
	15-26	3 – 5 – 9
Meningococcal ACWY	2-5 and 11-19	3

If the child has been vaccinated before treatment (>1 vaccine shot), only the first booster vaccine shot is recommended. If the child has received none or 1 vaccine shot before treatment, the complete vaccination scheme post-treatment is recommended.

^*In the case of absence of HBV vaccination records and in children <15 years, a complete vaccination is recommended after chemotherapy or at adolescence (11 to 15 y).

^†Vaccination already possible between 3 and 6 months’ post-CT/RT if CD4 T lymphocytes >200/μL (0.2 g/L) (>5 y), >500/μL (0.5 g/L) (between 1 and 5 y), >750/μL (0.75 g/L) (<1 y).

^‡In the case of VZV serology between 0 and 150 IU/L at diagnosis and absence of a history of varicella.

ACWY indicates MenACWY vaccine; CT chemotherapy; DTPa-IPV, diphtheria, tetanus, acellular pertussis, and poliomyelitis vaccine; HBV, hepatitis B virus; Hib, Haemophilus influenzae type b; HPV, human Papilloma virus; MMR, measles, mumps, rubella; PCV, 13-valent pneumococcal conjugate; RT, radiotherapy.

Although our study gives valuable insight into vaccine seroprotection and vaccine responses postvaccination in pediatric oncologic patients, larger studies are necessary to define the best timing to start vaccination after cancer and to define the factors influencing the vaccine responses and the loss of vaccine seroprotection after treatment, such as the vaccine seroprotection status at diagnosis, the patient’s age and the intensity of the treatment.

Overall, we have observed that children were not sufficiently protected against VPD due to the lack of vaccination rather than the lack of immune response. An effective individualized vaccination program based on serology results with an effective serology tracking method is crucial to vaccinate appropriate patients who need it. We suggest vaccinating all children with a dose of PCV13 at cancer diagnosis and then at 3 months post-treatment with the combined DTPa-IPV-HBV plus or minus Hib and PCV13 and meningococcal vaccine, including the MMR-VZV vaccine in the case of good immune reconstitution. This should be followed by a vaccine serology check at 4 months post-treatment to determine whether additional doses of vaccines remain necessary.