Hailey E Steuber, PharmD, BCPPS

As medicine and science advances, pediatric clinicians are seeing ever increasing numbers of approved immunomodulatory therapies approved by the US Food and Drug Administration (FDA). A few examples of drugs approved in recent years include emapalumab (Gamifant) for primary hemophagocytic lymphohistiocytosis and the expanded approval for tocilizumab (Actemra) for cytokine release syndrome due to chimeric antigen receptor T-cell therapy.

Additionally, clinicians may see increased use of older agents such as anakinra (Kineret) for off-label indications such as macrophage activating syndrome and, of course, there are numerous agents once reserved for use in adult populations that are making their way into the world of pediatric medicine.

 Given this increased prevalence and current state of vaccine compliance within the United States, general practice physicians may find themselves wondering how to best protect patients who previously received an immunomodulatory agent from vaccine-preventable diseases.

Whereas many of these therapies are being used in an acute care setting, it is important to remember that immunomodulatory therapies new and old can have ramifications on the immune system for weeks to months after administration. The problem of how to vaccinate children receiving these immunomodulatory agents is being increasingly recognized as evident by the development of guidelines from bodies such as the Infectious Diseases Society of America and the Canadian Paediatric Society.

 Both guidelines stress the importance of obtaining vaccination records and vaccinating if at all possible before starting immunomodulatory therapies.

In the case of patients receiving immunomodulator therapy for a stable, chronic condition, it is likely feasible to postpone therapy while live vaccines are completed. Immunosuppressed patients receiving chemotherapy or after bone marrow transplants will likely be under the care of an oncologist and may need to undergo revaccination according to their practice’s protocol. Unfortunately, not all children will fall neatly into either of these categories.

Currently, published guidelines do not address how to modify or return to a child’s normal immunization schedule after therapy has been completed. In a small but growing population of patients, these therapies are not chronically administered, and patients may have already returned to the routine care of their primary care provider. It is critical that primary care providers are fully informed of when such therapies were administered. This overview aims to highlight established recommendations for selected agents and reveal knowledge gaps where specialty guidance may be warranted.

As the Table shows, most recommendations for altering a patient’s immunization schedule will apply to live vaccines only. However, there are a few exceptions. Also evident in the Table is the fact that not all agents have established recommendations and that recommendations stemming from robust scientific studies are extremely limited. For example, although the manufacturers of anakinra recommend not administering live vaccines during therapy, the prescribing information does state this is due to a lack of evidence as it has not been studied.

 A published case series of patients who received interleukin (IL)-1 or IL-6 blockade (n=17) concluded that live attenuated vaccines are not safe for use during therapy with these agents.

 Interestingly, the authors remarked that many of the patients were inadvertently vaccinated through national vaccination programs.

This begs the question of whether medical professionals need to better educate parents that their children’s vaccination schedule may need to be altered as 13 of the 17 patients were pediatric. Another knowledge gap is whether titers should be pursued to assure physicians and patients that immunizations are effective and antibody formation has taken place. As noted in the American Academy of Pediatrics (AAP) 

, many immunization titers are available and may be helpful, but there is currently no formal guidance as to when they should be used.

When examining some of the more specific recommendations available such as the AAP 

 recommendations for immune globulin products, one should note that these recommendations are specific to the dose received.

 It may be difficult to discern how to proceed if thorough communication does not take place concerning the patient’s actual dose. This also applies to patients who received blood products. Physicians should also be aware of existing literature for agents such as infliximab or adalimumab but note the role of certain disease states such as inflammatory bowel diseases or rheumatologic indications. In this literature, it can be assumed that the therapies are chronic, and that alteration of the immune system is ongoing due to both the inflammatory condition and the immunomodulating agent itself, and so it may not apply to patients treated off label.

As pediatric providers begin utilizing new agents previously reserved to the adult population and explore the off-label use of other immunomodulating agents, it is becoming increasingly likely that general practice providers will encounter patients who may have had exposure to immunomodulation. In the era of an infectious outbreak exceeding levels seen in previous decades, it is more important than ever that clinicians do all they can to advocate for patients to receive timely vaccination.

Reviewing established vaccine recommendations after immunomodulatory therapies can help pediatric patients stay on an appropriate schedule and, given the current gaps in knowledge, may help guide practitioners toward the consultation of a specialist when necessary.

1. Rajasekaran S, Kruse K, Kovey K, et al. Therapeutic role of anakinra, an interleukin-1 receptor antagonist, in the management of secondary hemophagocytic lymphohistiocytosis/sepsis/multiple organ dysfunction/macrophage activating syndrome in critically ill children. 

2. Rubin LG, Levine MJ, Ljungman P, et al; Infectious Diseases Society of America. 2013 IDSA clinical practice guideline for vaccination of the immunocompromised host. 

3. Le Saux N; Canadian Paediatric Society, Infectious Diseases and Immunization Committee. Biologic response modifiers to decrease inflammation: focus on infection risks [article in English, French]. 

4. American Academy of Pediatrics. Immunization in special clinical circumstances. In: Kimberlin DW, Long SS, Brady MT, Jackson MA, eds. Red Book: 2018-2021 Report of the Committee on Infectious Diseases. 31st ed. Itasca, IL: American Academy of Pediatrics; 2018:67.

5. Humira [package insert]. Abbott Laboratories; North Chicago, IL: 2011.

6. Kineret [package insert]. Swedish Orphan Biovitrum AB; Stockholm, Sweden: 2012.

7. Gamifant [package insert]. Novimmune SA; Geneva, Switzerland: 2018.

8. Remicade [package insert]. Janssen Biotech; Horsham, PA: 2013.

9. Actemra [package insert]. Genentech; South San Francisco, CA: 2013.

10. Rituxan [package insert]. Genentech; South San Francisco, CA: 2010.

11. Nazi I, Kelton JG, LarchÃ© M, et al. The effect of rituximab on vaccine responses in patients with immune thrombocytopenia. 

12. Jeyaratnam J, Ter Haar NM, Lachmann HJ, et al. The safety of live-attenuated vaccines in patients using IL-1 or IL-6 blockade: an international survey. 

13. Croce E, Hatz C, Jonker EF, Visser LG, Jaeger VK, BÃ¼hler S. Safety of live vaccinations on immunosuppressive therapy in patients with immune-mediated inflammatory diseases, solid organ transplantation or after bone-marrow transplantation-a systematic review of randomized trials, observational studies and case reports. 

14. Reich J, Wasan S, Farraye FA. Vaccinating patients with inflammatory bowel disease. 

Articles

Clinicians must advocate for pediatric patients receiving immunomodulation therapies to also receive timely vaccinations for vaccine-preventable diseases.

Author | Hailey E Steuber, PharmD, BCPPS

Articles

Immunizations after immunomodulation: Clinical data and recommendations