Introduction: Childhood cancer may be immunocompromised as a result of the primary disease itself and the use of intensive chemotherapy (CT) with or without radiotherapy (RT). The damage to the immune system varies with the age of the patient, the type of cancer, and the type of CT used to treat it. Children with cancer need to be immunized against the common vaccine-preventable diseases after completion or during ongoing treatment of cancer. However, the immunization schedule for these children needs to be developed in our country. There are many guidelines from around the world to address this issue, however, there is no such comprehensive guideline from Bangladesh for the needs of our children with cancer.

The aims of this paper will be to address the rationale, methodology, relevant literature review, and process of development of updated guidelines for the vaccination of pediatric cancer patients. This document will help the pediatric oncologist and vaccine experts to prepare a contemporary revaccination guideline for the children of Bangladesh, which will help pediatricians to choose the best immunization program against vaccine-preventable diseases in children with cancer.

Objective:To review the current evidence on the revaccination of children and advice the best guidelines which are used in foreign countries for immunization of children with cancer. To inform the policy of immunization practices for contracts.

Methodology: Reviewing the available literature, especially those pieces of literature and guidelines from developing nations, a proposal has been drafted for Bangladeshi children. This proposal has mentioned guidelines used in developed and developing countries, which will help to generate a nationally relevant guideline for immunization of children with cancer. This proposal does not mention an immunization plan for children treated with targeted therapy, immunotherapy, or Bone Marrow Transplantation (BMT).

Proposal: Most of the available guidelines mentioned live vaccines are contraindicated during and up to 6 months after the chemotherapy. Non-live vaccines are also best given after 6 months. Annual inactivated influenza vaccine is recommended during chemotherapy whereas hepatitis B vaccine is recommended only for previously unimmunized children. Post-treatment re-immunization or catch-up schedule largely depends on the pre-chemotherapy immunization status. Sibling immunization should continue uninterrupted except for the oral polio vaccine which needs to be substituted by the injectable vaccine. Inactivated influenza vaccine is recommended and varicella vaccine is encouraged for all contacts including siblings.

Pediatric cancer treatment Children have advanced faster in both poor and rich nations in the last two decades and in advanced countries, 85% of children with cancer now survive 5 years or more.¹ On the other hand, developing countries are also steadily improving outcomes of childhood cancer.² It is a new challenge for medical science to the prevention of infectious diseases in children who received chemotherapy or who are in follow-up. Bangladesh is far behind to address this proficiency and technology.

In Bangladesh, there are 13 to 15 lakh cancer patients with about 2 lakh newly diagnosed cases every year.³ And expected near 13000 new pediatric cancer/year in Bangladesh .⁴ All of those children did not have a chance to immunize during infancy due to the early start of cancer symptoms. A hospital-based study by Ghosh et al showed that fully immunized under five (U­5) children with cancer were only 27.5%, whereas partially immunized and unimmunized U­5 were 65% and 7.5% respectively.⁵ This means the immunization percentage of children with cancer is much less than national coverage and survivors of those children have no chance of immunization/ re-immunization as we have no national policy and guidelines.

During CT and after CT+RT, infectious diseases are the main contributor to mortality and morbidity of children with cancer. So, immunization for vaccine-preventable diseases is very important in children with cancer as it can lessen infection-related mortality/ morbidity and bestow benefits to the comprehensive outcome of child health. Many developed countries have formulated guidelines for immunizing children with cancer^6,7 throughout chemotherapy as well as at the end of CT/RT, together with their national immunization schedules. But immunization of cancer-affected people is neglected in Low and Middle-Income countries (LMICs) due to the enormous caseload, the scarcity of trained personnel and funds as well as lack of awareness among treating oncologists and parents.⁸ However, such recommendations from developing countries are scarce and hardly any guidance on childhood immunization strategies have come from Low and Middle-Income Countries.⁹ In Bangladesh, any national body has not addressed the need for such immunization schedules. In the absence of any assigned recommendation in Bangladesh, the children who received chemotherapy are not getting reimmunization.

The present document will address the rationale for revaccination, the methodology of this proposal, relevant literature review in favor of revaccination, and the process of developing updated guidelines for the vaccination of pediatric cancer patients. This proposal will help the pediatric oncologist and vaccine experts of Bangladesh to prepare a contemporary vaccine guideline for children, which will help pediatricians of Bangladesh to select the best immunization program in case of infectious diseases of children who were treated for cancer and their siblings and parents/caregivers. 

Objectives:

1. To review the current evidence on the revaccination of children.
2. To find out the internationally used best recommendations for vaccination of children receiving Chemotherapy and or Radiotherapy.
3. To inform the vaccination experts and Pediatric Oncologists of Bangladesh about the best Immunization program for children with cancer, their parents, siblings and caregivers.

Methodology

A Google and PubMed search has taken up to procure all recent publications on childhood immunization and the important publications on the revaccination of children with cancer were reviewed, including the immunization schedule of Bangladesh. A proposal has been generated based on the practice and evidence-based recommendations which have been published in journals in Bangladesh and foreign countries. This proposal has addressed the need for future research regarding the issue.

The proposed guidelines did not mention the needs of children treated with targeted therapy, BMT and immunotherapy. Other modalities of immunotherapy presently being augmented in the management of childhood cancers were not included in the proposal.

Process of development of guideline

This proposal will be circulated to departments of Pediatric Hematology and Oncology (PHO), respected pediatricians, immunization experts, and government bodies of Bangladesh. They will review the available literature again, especially those studied in developing nations, and by conducting essential research which is possible in our country, a guideline will be drafted. The draft guideline will be circulated among pediatric oncologists of Bangladesh and vaccine specialists of the Bangladesh Pediatric Association (BPA). After a discussion about the draft in a meeting subsequently, finalize the recommendation as a guideline.

Immune suppression is a major problem for cancer patients. Due to the involvement of the T-cell/natural killer (NK) cells and B-lymphocytes both cellular and humoral immunity is affected.¹⁰ The immune system develops compromise mostly because of cancer itself and because of treatment (CT /RT).^11,12 This immunosuppression may range from the slightest involvement of the immune system with localized solid tumors to huge immune suppression like acute leukemia. Some hematological cancers show specific immune defects e.g., Hodgkin lymphoma and Burkitt’s lymphoma are related to lack of lymphocytic response to numerous antigens¹³ and several levels of lymphocyte depletion, respectively.¹⁴ In spite of these changes, the pediatric population rarely shows clinically significant immune deficiency prior to the start of chemotherapeutic agents.¹⁵ The available statistics indicate that the damage to the immune system is related to the patient’s age, the type of malignancy and the intensity of anticancer agents used to treat it.¹⁶ Compared to the B-cells, the time to recovery seems to be longer in the case of T-cells^10,17 and some of the immune defects may persist even long after the end of chemotherapy.¹⁸ Therefore, immunization during chemotherapy and for some time after the therapy may be unpredictable. Childhood acquired immunity through previous infections or vaccination also declines due to the cytotoxic therapy for cancer and needs boosting on recovery of immunity following the end of chemotherapy.¹⁹

Till now it is a critical question whether there is any real need for reimmunization after chemotherapy when the primary immunization has been completed previously in childhood? It is difficult to answer the question appropriately because the accessible data are conflicting and controversial. Though there is a lack of consensus, most scientists recommend immunization at the age of 6 months from the end of chemotherapy with the presumption that adequate immunity is gained around that time.^20–26 However, till now revaccination in children receiving cancer chemotherapy remains a conscious area for research to understand the need for it.

Optimal timing for vaccination following chemotherapy

Though children treated with CT and RT suffer from immunosuppression, booster doses of vaccines after the end of treatment can yield protective reactions in most cases. Among them some antigens (e.g., tetanus) seem to be more immunogenic than others antigens (e.g., measles, HBV, S.pneumoniae, H.influenzae type b).^24,27–30 Even cases of no sensitization to booster antigens have been described against measles.¹⁷ General rules have been outlined as follows: live attenuated vaccines (poliovirus, yellow fever, typhus, measles, rubella, mumps and tuberculosis) should be avoided in immunosuppressive conditions, that is, when patients are receiving chemotherapy or within six months after the end of treatment. On the other hand, killed vaccines are also best given after 6 months from the termination of treatment. If any inactivated vaccine is given during anticancer therapy or before completion of 6 months following therapy, should not be taken into account as an effective dose. But an allocated annual inactivated influenza vaccine is recommended during chemotherapy. Vaccine for Hepatitis B virus is given for previously unvaccinated children as per the national schedule. Children with newly diagnosed cancer are to have pneumococcal vaccines (PCV23 and PCV13); if they fail to be administered earlier. Siblings of cancer patients should avoid the oral polio vaccine, while other immunization schedules can proceed without change. Contacts, including siblings, should be encouraged for varicella and annual influenza vaccination.^31–33

Strategy for vaccination

Re-immunization strategies for the pediatric population with cancer after CT/RT differ among research groups.³⁴ But mainly three feasible strategies have been described²⁹ i.e (a) A child associated with low protective antibody titers, she/he can get a booster shot (b) re-immunization without evaluating the remaining immunity, or (c) resume the meticulous national immunization schedule. Zignol, et al.²⁹ advocated the first plan. These researchers evaluated the serum antibodies titers of 192 pediatric cancer patients with solid tumors or leukemia and found low antibodies titers in 52% of patients, mostly Hepatitis B Virus (46%), followed by rubella virus, mumps virus, and measles. Evaluating the cost/effectiveness ratio and financial burden first strategy is not applicable in Bangladesh. Rather the second strategy is more suitable for Bangladesh.

Immunity and type of infection differ from country to country and the pattern of cancer and patient management is different in underdeveloped and developed nations. So, guidelines from the high-income countries (HICs) on immunization of children with cancer,^23–24,26 rarely reflect the problems of Low and Middle-Income Countries (LMICs) where most (90%) of the childhood cancers in the world are diagnosed. It is not wise to follow the guidelines of HICs in toto for the children of Bangladesh due to various reasons, including the cancer epidemiology, different national vaccination schedules, vaccine availability, price of vaccines, and national health infrastructure. Very few countries of LMICs like India developed immunization plans for their children with cancer.⁹ We can review all those guidelines for preparing the contemporary vaccine guideline for children of Bangladesh. The present paperwork is a piece of sketch evidence and proposal for revaccination strategies of the developed and developing nations for children with cancer, which also dealt with the immunization of siblings and parents/caregivers. Immunization for children with BMT differs from children getting CT/RT and is far off the scope of this proposal. 

The safe and efficacious use of vaccines has always been a vital challenge in children with immunodeficiency like cancer. These children with cancer are often at high risk of adverse consequences from vaccine-preventable diseases. Primary concerns are the safety of the vaccines used and the capability of the children to first mount and then a continuous protective immune response. Thus, special recommendations are required^35–37 for children under the age of one year with cancer, because the onset of iatrogenic immunosuppression by CT and RT occur before the completion of their primary immunizations.

Table 1 shows an overall synopsis of the various types of vaccines and the nature of the immune responses observed in the host.³⁸ Killed vaccines generally evoke a limited range of immune responses compared with live attenuated vaccines. In addition, long-lasting immunity with killed vaccines usually requires the use of boosters shot periodically.

Life Vaccines for children with cancer

When live vaccines are being considered in cancer patients, two things are taken into consideration i.e. efficacy and safety of vaccination. Most of the studies revealed that live vaccines should not be given within the first three months after the end of chemotherapy. The duration of withheld varies according to the type and duration of the immunosuppressive chemotherapeutic agent. Thus, it is impossible to make an absolute recommendation that encloses all sides. Other researchers considered that in vitro testing of immune function may provide a guide for safe timing in selected patients.³⁹ For most patients, in vitro testing is not a practical solution in many countries like Bangladesh as this test is not available here. Even many developed countries like Australia, Canada, United Kingdom, and USA do not practice in vitro testing. They recommended that live vaccines should be delayed for 6–12 months after immunosuppressive therapy.^39–42 Table 2 shows the recommendation for live vaccines by the Pediatric Hematology-Oncology Chapter, India; and the Indian Academy of Paediatrics.

Inactivated Vaccines for children with cancer

Like all other vaccines, the main aim of these inactivated vaccines is protective and continuous immune responses to pediatric cancer patients. The ability to develop protective immune responses in children with cancer depends on the gap between immunization and the administration of immunosuppressive therapy. After the end of chemotherapy, required immune responses can be yielded between 3 to 12 months after cessation of CT. Total lymphocyte counts exceeding 1×10^-9 /L are required to elicit an adequate immune response by inactivated vaccines.⁴⁰ Re-immunization yields poor immune responses if vaccines are given during or immediately after the intensive phases of chemotherapy. Inactivated vaccination is better to give at the maintenance phase of chemotherapy and booster dose is recommended more than three months after the end of chemotherapy. Table 3 summarizes the immunization schedules recommended for Indian cancer-affected children by the PHO chapter of India.⁹

Some infants with cancer do not complete their primary immunization schedule. Younger children, especially those who had not finished their primary immunization schedule, are less protected against vaccine-preventable infection than the older ones⁴² and these children suffer from several infections frequently. A hospital-based study in Bangladesh by Ghosh et al.⁵ showed that 27.5% of under-five (U₅) children were unimmunized and 67.5% of children were partially immunized. These large numbers of children need different vaccine schedules. Table 4 describes briefly the immunization schedule of these unimmunized younger children.

Family members, health care providers, and caregivers

Immunization of siblings and family members is an important part of the prevention of vaccine-preventable diseases in cancer patients. Pediatric oncologists should be acutely aware of the vaccination of siblings and Health care workers.

Siblings: Siblings should get all non-live vaccines as per the national immunization program like inactivated influenza vaccine. They are recommended live vaccines like MMR, BCG, Rotavirus, Varicella, and Yellow fever vaccine as per schedule. The oral polio vaccine is not allowed for siblings including pulse polio but IPV is recommended for them. They can take the varicella vaccine if siblings are unimmunized and have not suffered from chickenpox before. When a child’s sibling develops varicella vaccine-induced rash, then should not be in the contract of the index child till all lesions crust. Siblings can take rotavirus vaccine but child with cancer should refrain from changing the diapers of the vaccinated infant till 4 weeks from the day of vaccination.²¹

Parents: Varicella vaccine is recommended for parents if they are unimmunized and had not chickenpox before and if the parent develops varicella vaccine-induced rash, then they should stay away from the index child.⁸ Inactivated Influenza vaccine is strongly recommended for them.

Health care workers: For proper care of immunocompromised children, Health care workers should be up to date on their immunizations. They should take all available vaccines but special attention should be given to hepatitis B vaccines, varicella, and influenza.

Re-immunization of cancer patients is not a known treatment option in our country. It is neglected in LMICs like Bangladesh. But it is very important for children with cancer to get protection against vaccine-preventable infection. To address this issue, we need to develop an updated guideline, which will incorporate our nation-specific concerns, integrate our national immunization schedule, and will be instrumental in achieving this important target.

None.

The authors declare that they have no competing interests.

1. The American Cancer Society. January 12, 2022.
2. Craft AW. Childhood cancer – mainly curable so where next? Acta Paediatr. 2000;89(4):386–392.
3. Noronha V, Tsomo U, Jamshed A, et al. A Fresh Look At Oncology Facts On South Central Asia And Saarc Countries. South Asian J Cancer. 2012;1(1):1–4.
4. Magrath I, Steliarova-Foucher E, Epelman S, et al. Paediatric cancer in low-income and middle-income countries. Lancet Oncol. 2013;14(3):104–116.
5. Ghosh AK, Saha S, Yasmin F, et al. Immunization of under five children suffering from cancer: a hospital based study. Bang Onc J. 2019;14:31–37.
6. Immunization in Special Clinical Circumstances. In: Pickering LK, Baker CJ, Kimberlin DW, Long SS, editors. Red book: 2009 report of the committee on infectious diseases. 28th ed. Elk Grove Village, Ill: American Academy of Pediatrics. 2009;72–86.
7. Immunisation of the immunocompromised child. Best practice statement. London: Royal College of Paediatrics and Child Health. 2002.
8. Naqvi A, Fadoo Z, Alvi S. Vaccination guidelines for children with cancer and hematopoietic stem cell transplantation living in resource-poor countries. Pediatr Blood Canc. 2010;54(1):3–7.
9. Moulik NR, Mandal P, Chandra J, et al. Immunization of children with cancer in India treated with chemotherapy -consensus guideline from the pediatric hematology-oncology chapter and the Advisory committee on vaccination and immunization practices of the Indian academy of pediatrics. Indian Pediatr. 2019;56(12):1041–1048.
10. Mackall CL. T-cell immunodeficiency following cytotoxic antineoplastic therapy: A review. Oncologist. 1999;4(5):370–378.
11. Mackall CL. T-cell immunodeficiency following cytotoxic antineoplastic therapy: A review. Stem Cells. 2000;18(1):10–18.
12. Adamson PC, Balis FM, Berg S, et al. General principles of chemotherapy from Pizzo DA and Poplack DG Principles and practice of pediatric oncology, 5th edition. 2006;290–365.
13. Fuks Z, Strober S, Bobrove AM, et al. Long term effects of radiation of T and B lymphocytes in peripheral blood of patients with Hodgkin’s disease. J Clin Invest. 1976;58(4):803–814.
14. Magrath IT, Simon RM. Immunosuppression in Burkitt’s lymphoma. II. Peripheral blood lymphocyte populations related to clinical status. Int J Cancer. 1976;18(4):399–408.
15. Hersh EM, Whitecar JP, McCredie KB, et al. Chemotherapy, immunocompetence, immunosuppression and prognosis in acute leukemia. N Engl J Med. 1971;285(22):1211–1216.
16. van Tilburg CM, Sanders EAM, Rovers MM, et al. 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.
17. 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.
18. Leung W, Neale G, Behm F, et al. Deficient innate immunity, thymopoiesis, and gene expression response to radiation in survivors of childhood acute lymphoblastic leukemia. Cancer Epidemiol. 2010;34(3):303–308.
19. Shetty AK, Winter MA. Immunization of children receiving immunosuppressive therapy for cancer or hematopoietic stem cell transplantation. Ochsner J. 2012;12(3):228–243.
20. Chowdhury P, Vashishtha VM. Immunization in special situations: In: IAP Guidebook on immunization [2013-14] – By Advisory Committee on Vaccines and Immunization Practices [ACVIP], Indian Academy of Pediatrics. National Publishing House, Indian Academy of Pediatrics.Gwalior. 2014;365–384.
21. Rubin LG, Levin MJ, Ljungman P, et al. 2013 IDSA clinical practice guideline for vaccination of the immunocompromised host. Clin Infect Dis. 2014;58(3):309–318.
22. Patel SR, Chisholm JC, Heath PT. Vaccinations in children treated with standard-dose cancer therapy or hematopoietic stem cell transplantation. Pediatr Clin North Am. 2008;55(1):169–186.
23. Patel SR, Ortín M, Cohen BJ, et al. Revaccination of children after completion of standard chemotherapy for acute leukemia. Clin Infect Dis. 2007;44(5):635–642.
24. Cesaro S, Giacchino M, Fioredda F, et al. Guidelines on vaccinations in pediatric hematology and oncology patients. Biomed Res Int. 2014;2014:707691.
25. Allen UD. Immunizations for children with cancer. Pediatr Blood Cancer. 2007;49(7 Suppl):1102–1108.
26. The Australian Immunization handbook. 10th Edn. 2013:148–157.
27. Reinhardt D, Houliara K, Pekrun A, et al. Impact of conventional chemotherapy on levels of antibodies against vaccine preventable diseases in children treated for cancer. Scand J Infect Dis. 2003;35(11-12):851–857.
28. Feldman S, Andrew M, Norris M, et al. Decline in rates of seropositivity for measles, mumps and rubella antibodies among previously immunized children treated for acute leukaemia. Clin Infect Dis. 1998;27(2):388–390.
29. 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.
30. Ljungman P. Vaccination of immune compromised hosts. Plotkin Vaccines. 2018;69:1355–1369.
31. Rubin LG, Levin MJ, Ljungman P, et al. 2013 IDSA clinical practice guideline for vaccination of the immunocompromised host. Clin Infect Dis. 2014;58(3):309–318.
32. General Best Practice Guidelines for Immunization for Altered Immunocompetence Situations by Advisory Committee on Immunization Practices (ACIP). Centers for Disease Control and Prevention.
33. Cecinati V. Vaccinations in Children with Cancer. Onco Pedia. 2019.
34. Verma S, Bansal D. Immunization Guidelines for Children with Cancer in India. Indian Pediatrics. 2019;56:1009–1010.
35. Recommendations of the Advisory Committee on Immunization Practices (ACIP): Use of vaccines and immune globulins in persons with altered immunocompetence. MMWR. 1993;42:1–18.
36. Sung L, Heurter H, Zokvic KM, et al. Practical vaccination guidelines for children with cancer. Pediatr Child Health. 2001;6(6):379–383.
37. Abbas AK, Lichtman AH. Basic immunology: Functions and disorders of the immune system. 2nd ed. Philadelphia: Saunders. 2004. 143–160.
38. Pickering LK, Baker CJ, Long SS, et al. Red book: 2006 report of the committee on infectious diseases, 27th edition. Emerg Infect Dis. 2006;12(12):2003–2004.
39. National Advisory Committee on Immunization, Health Canada. Canadian Immunization Guide. 7th ed. 2006.
40. Somerville H. Immunisation recommendations following treatment of cancer. Aust Fam Physician. 2003;32:33–34.
41. Mahajan A, English MW, Jenney ME, et al. Survey of immunisation practices in the United Kingdom during and follo completion of anti-cancer chemotherapy in children. Med Pediatr Oncol. 2003;40(4):270–271.
42. Haining WN, Neuberg DS, Keczkemethy HL, et al. Antigen-specific T-cell memory is preserved in children treated for acute lymphoblastic leukemia. Blood. 2005;106(5):1749–1754.