News & Views: Manipulating the Immune System — When Vaccination and Treatment Therapies Collide

Scenario 1: It’s been a long day, and you are thinking about what you’ll have for dinner when you walk into the exam room where your last patient for the day is waiting for you. As you review the 52-year-old patient’s chart, you realize they are due for a couple of vaccines, specifically, hepatitis B and shingles vaccines. However, as you review their current medications, you see that they are also taking Humira^® to treat rheumatoid arthritis. So, now you are wondering if they can get the vaccines they need.

Scenario 2: As you talk about today’s vaccinations with the parents of your 2-month-old patient, they inquire about whether the baby should get the rotavirus vaccine. Mom tells you that she took Remicade^® for her Crohn’s disease during pregnancy and that her doctor said because of this the baby should not get the rotavirus vaccine.

With the increasing availability and use of biologic agents (medications that impact one or more components of the immune system), situations such as those described above are becoming more common. As a result, healthcare providers often find themselves trying to determine whether to vaccinate and if the vaccine will be effective. As such, we thought it might be useful to provide an overview and resources related to these issues.

The big picture

Patients can be immune compromised for a variety of reasons. Primary immune deficiencies are those that are inherited or congenital in nature. Secondary immune deficiencies are acquired and can result from disease, malnutrition, asplenia due to accident or illness, or treatment of other conditions. While primary immune deficiencies are often lifelong, secondary types may be long- or short-lived depending on the cause.

Medications can be a cause of secondary immune compromise. While people often think about medications as treating diseases, in many cases medications are prescribed to address the symptoms caused by our immune response to an infection or disease. As described in Janeway’s Immunobiology (Murphy & Weaver, 2017), we have developed a variety of ways to address “unwanted immune responses.” Vaccines and medications can both be categorized this way:

• Vaccines prevent “unwanted immune responses” that result from infections by controlling the timing and dose of exposure. Because the vaccine introduces the smallest dose necessary and is typically given at a time when the individual is healthy, the immune response necessary to overcome the exposure is also limited. In contrast, pathogens often take hold at moments when an individual is already immune compromised. As a result, the immune response required to overcome the infection can itself cause significant damage.
• Medications can act generally (e.g., fever reducers) or be more targeted in which aspect of the immune response is affected (e.g., biologics). In the case of chronic diseases involving some aspect of the immune system (e.g., autoimmune-based diseases), biologics offer a way to focus treatment on the part of the immune response that is causing disease. However, given that some aspect of the immune system is limited by treatment, the individual is at some level immune compromised. Whether the level of compromise requires special consideration in any situation depends on a variety of factors, such as the dose, length of use, mechanism of action, and overall patient health and medical history.

Because vaccines and medications both involve the immune system, consideration of whether they will interfere with each other is an important step in the treatment process.

Biologics

While some medications have global effects, biologics are a newer class of therapies that target specific aspects of the immune response. Biologics aimed at controlling “unwanted immune responses” can act in one of several ways:

• Deplete or block cells at inflammatory sites
• Block particular cell-cell interactions or pathways
• Target the products of immune mechanisms, such as specific cytokines

Regardless of which mechanism is employed, while a patient is taking these medications, they experience some level of immune compromise.

Many biologics are monoclonal antibody preparations. Monoclonal antibodies are made from the progeny of a single B cell, so they are identical in their shape and specificity. They offer important advantages over heterogeneous antibody mixtures isolated from people (like intravenous immunoglobulin or IVIG), such as standardization of the resulting product, less potential for cross-reactivity, and a more reliable supply chain. Because the starting material for monoclonal antibody preparations can be made in one of several ways, a naming system has been developed to distinguish between products:

• Any preparation with a name ending in -omab was produced using a gene from a mouse-derived antibody.
• Any preparation with a name ending in -umab was produced using a gene from a human-derived antibody.
• Preparations with names ending in either -ximab or -zumab are chimeric in nature, meaning the gene was part mouse and part human. Which suffix is used depends on the portion of mouse gene used, with the former employing the entire variable region of the mouse antibody and the latter only using the so-called “hypervariable regions” of the mouse gene, which are the areas most directly related to antibody binding.

Vaccines and biologics

Because of the variety of biologics and the different conditions they are used to treat, the data related to vaccination of people using them is somewhat limited. For an overview based on the literature, check out the Vaccine Education Center’s Q&A for patients, “Vaccines and Biologics: What You Should Know.” The Q&A can be photocopied for easy sharing.

For a more detailed dive into the literature, two review articles published in 2019, and an update of the second in 2020, will be helpful:

• Papp KA, Haraoui B, Kumar D, et al. Vaccination Guidelines for Patients with Immune-Mediated Disorders on Immunosuppressive Therapies. J Cutan Med Surg. 2019 Jan/Feb;23(1):50-74.
• Rondaan C, Furer V, Heijstek MW, et al. Efficacy, Immunogenicity and Safety of Vaccination in Adult Patients with Autoimmune Inflammatory Rheumatic Diseases: A Systematic Literature Review for the 2019 Update of EULAR Recommendations. RMD Open. 2019 Sep 9;5(2):e001035.
• Furer V, Rondaan C, Heijstek MW, et al. 2019 Update of EULAR Recommendations for Vaccination in Adult Patients with Autoimmune Inflammatory Rheumatic Diseases. Ann Rheum Dis. 2020 Jan;79(1):39-52.

Additionally, the following resources offer information about vaccine recommendations:

• CDC’s General Best Practices Guidelines, particularly the section related to “Altered Immunocompetence.”
• AAP’s Red Book: 2021–2024 Report of the Committee on Infectious Diseases (32nd Edition), particularly pages 72-86 on “Immunization and Other Considerations in Immunocompromised Children.”
• The Vaccine Handbook: A Practical Guide for Clinicians (8^th Edition), written by Gary S. Marshall, MD, particularly the section related to “Disease-Modifying Antirheumatic Drugs and Biologic Response Modifiers.” The book is also available for free as part of “The Vaccine Handbook” app.

Wondering about those scenarios?

Scenario 1: Precluding any contraindications or precautions based on other health factors or medical history, this patient could receive both vaccines in different anatomical locations. Because of their immune suppression resulting from treatment of a rheumatologic condition, the patient should have a blood sample taken prior to vaccination to test for hepatitis B infection. Two additional concepts are important to note related to this scenario:

1. Because the patient is taking an immunosuppressant that inhibits TNF-alpha, their antibody response to the hepatitis B vaccine may be lower than expected. Post-vaccination testing for this situation is not recommended, but it is recommended for some other groups of immune-compromised individuals. Find out more in the hepatitis B recommendations.
2. In January 2022, the CDC expanded its recommendations for shingles vaccine to include immunocompromised persons 19 years of age and older. If possible, the doses should be administered before the patient starts the immune-suppressing treatment, but even if that is not possible, the patient should be vaccinated at a time when interference would be least likely. The dosing interval can also be shortened to accommodate the second dose one to two months after the first to assist with ensuring protection prior to immune suppression. Find out more in the shingles recommendations.

Scenario 2: Your 2-month-old patient can receive the rotavirus vaccine. Some biologics cross the placenta, so a baby may have the medication in their system in the months after birth, but in this case, the medication mom was taking does not preclude receipt of the rotavirus vaccine. An important note about this scenario is that CDC and AAP recommendations diverge when it comes to an infant’s exposure to mom’s biologics during pregnancy:

• The CDC recommendations do not list any contraindications or precautions related to mom’s use of biologics during pregnancy.
• The AAP recommendations suggest that due to low risk of life-threatening disease in the U.S. and lack of data on many biologics, infants exposed to them in utero should not be given the rotavirus vaccine. The exceptions are if mom took certolizumab (e.g., Cimzia^®) or infliximab (e.g., Remicade^®) for which the data show them not to be an issue.
• Additionally important to consider is that some of these products are directed against cytokines that are not important in developing rotavirus-specific immune responses.