The Who, What, and When of Immunizations

As the world scrambles to find a vaccine for the newest coronavirus, appropriate use of existing vaccines remains vital for immunosuppressed patients. Current vaccination guidelines, however, are open to interpretation.

Many patients with either malignant or nonmalignant hematologic disorders will experience secondary immunodeficiency as a result of their disease or its treatment. The incidence and severity of some vaccine-preventable diseases is greater among certain patients in this group, making appropriate vaccination a crucial element of treatment. However, practical questions of who, when, and against what to vaccinate are often difficult to answer.

“Many hematologists in the U.S. recognize that we need to vaccinate certain patients, but one of the big issues is that immunization schedules change annually and each new recommendation has to be addressed separately in our patients,” Luis Malpica Castillo, MD, a fellow in the division of hematology and oncology at University of North Carolina School of Medicine, told ASH Clinical News. “We need to be better at [appropriately vaccinating], but keeping up with these updates can be difficult for clinicians.”

Recently, Dr. Castillo and colleagues conducted a single-center retrospective study of adherence to immunization guidelines, which illustrated the scope of this challenge: Of 269 adult patients with nonmalignant immune-mediated hematologic disorders, only 6% received all the recommended immunizations and at the recommended times for the type of treatment they received.1 The investigators also reflected that there are few studies examining trends in vaccination among patients with hematologic disorders.

“We do not know how many people are being appropriately vaccinated,” said Monika Shah, MD, an infectious disease specialist at Memorial Sloan Kettering Cancer Center. “We don’t have much data, but I am sure that we could all be doing a better job, regardless of our treatment center.”

ASH Clinical News spoke with Drs. Castillo, Shah, and other hematologists and infectious disease specialists about the risks of infection in immunosuppressed patients and the debate over whom to vaccinate – and with what.

Who Is at Risk?

When patients receive a treatment that suppresses a component of the immune system, the risk for certain infections is heightened. Depending on the specific type of therapy, that increased risk can persist after therapy is discontinued, explained Dr. Shah.

The risk also varies according to the type of disease. For patients with nonmalignant hematologic disorders, the main risk factors for infections are usually the length and dose of treatment, according to Dr. Castillo. In contrast, among patients with malignant hematologic disorders, immunosuppression commonly occurs as a result of the disease itself.

“Patients who have acute leukemias do not have normal white blood cell counts [or normal granulocyte function] and are at serious risk for severe opportunistic infections that would not otherwise happen in someone with a normal immune system,” Dr. Shah said. “Increasingly, though, patients with lymphoma are [also] at risk, depending on the type of disease and the increasingly effective but aggressive therapies we are able to offer them.”

Common Treatments, Common Risks

Corticosteroids are a mainstay of treatment for autoimmune hemolytic anemia (AIHA), idiopathic thrombocytopenic purpura (ITP), and lymphoid malignancies – among other hematologic conditions – as well as the treatment of graft-versus-host disease (GVHD). They also are among the most commonly used therapies that put patients at increased risk for infection. Opportunistic infections associated with corticosteroid use include bacterial pneumonia, herpes zoster reactivation, tuberculosis and other mycobacterial infections, and fungal infections such as aspergillosis. While the risk is dose-dependent, a study of patients with rheumatoid arthritis showed that use of systemic corticosteroids even at low doses (7.5-10 mg/day) almost doubled the risk for herpes zoster compared with no steroid use.2

Rituximab is another treatment associated with immunosuppression. Although commonly used in hematologic malignancies, rituximab also is used off-label in nonmalignant diseases such as AIHA, ITP, and thrombotic thrombocytopenia purpura (TTP).

“Rituximab can produce long-lasting immunosuppression, lasting months even after treatment is stopped,” Dr. Castillo said. That long-lasting effect puts rituximab-treated patients at increased risk for hepatitis B and hepatitis C reactivation, with research suggesting that as many as 20 to 50% of hepatitis B virus carriers experience reactivation while undergoing immunosuppressive treatment with a rituximab-containing regimen or chemotherapy.3,4

In the nonmalignant hematology realm, other recently approved targeted therapies are also associated with immunosuppression. “Complement inhibitors, such as eculizumab or ravulizumab, put patients at increased risk for meningococcal infections,” said Spero R. Cataland, MD, a hematologist specializing in thrombotic disorders at The Ohio State University Wexner Medical Center and James Cancer Hospital. The risk may remain elevated even if patients receive appropriate vaccination.

Eculizumab is approved for the treatment of paroxysmal nocturnal hemoglobinuria (PNH), atypical hemolytic uremic syndrome (aHUS), and myasthenia gravis. Ravulizumab is approved for PNH and aHUS in adults and aHUS in children. Patients treated with eculizumab are at a 1,000- to 2,000-fold increased risk for meningococcal disease. Because of its similar mechanism of action, it is believed that this increased risk will also apply to ravulizumab.5

There are additional immunosuppressive drugs and drug combinations, such as cyclophosphamide and azathioprine, used to treat nonmalignant immune-mediated hematologic disorders that also raise one’s risk of infection. The specific risks of these agents are often poorly understood, and new agents may have unexpected adverse effects. For example, post-marketing trials of Janus kinase inhibitors, which are used for treatment of myeloproliferative neoplasms, found modest increases in herpes zoster and hepatitis virus reactivation risk.

Who Sets the Schedule?

As Dr. Castillo mentioned, keeping current with recommended immunization schedules is made more difficult by the frequency with which the schedules change. Each year, the Centers for Disease Control and Prevention (CDC) publishes general guidelines about vaccination schedules based on recommendations developed by its Advisory Committee on Immunization Practices (ACIP).6 The organization also has developed “general best practice guidelines” for specific groups of immunocompromised patients.7,8

For adults, the CDC breaks down immunizations by age group (19-26, 27-49, 50-64, and ≥65 years), medical condition, and other indications (such as pregnancy, chronic liver disease, diabetes, or altered immunocompetence). This information is available at and the CDC Vaccine Schedules app.

The CDC schedule currently recommends the following in immunocompromised adults (excluding those with HIV):

  • annual inactivated or recombinant influenza vaccine
  • 1 dose of Tdap (for tetanus, diphtheria, and pertussis), then Td or Tdap booster every 10 years
  • 3 doses of human papillomavirus through age 26
  • 1 dose of pneumococcal conjugate (PCV13)
  • 1, 2, or 3 doses of pneumococcal polysaccharide (PPSV23), depending on age
  • 3 doses of Haemophilus influenzae type b (Hib) in immunocompromised adults undergoing hematopoietic stem cell transplant only

Some patients will also require hepatitis A, hepatitis B, or meningococcus vaccines. Vaccines that are not recommended in immunocompromised adults include the live, attenuated influenza vaccine; the measles, mumps, and rubella (MMR) vaccine; the varicella or chickenpox vaccine; and the live zoster vaccine.

“There is no specific concern regarding the safety of inactivated vaccines,” Dr. Shah explained. “However, live attenuated vaccines, which contain a weakened form of the virus or bacteria, are not safe to give in people who have an immunosuppressive condition.” These patients can safely receive effective inactivated forms of the influenza and zoster vaccines. The inactivated zoster vaccine, which was approved in 2017, is the CDC’s recommended vaccine for preventing shingles.8

In 2013, the Infectious Diseases Society of America (IDSA) issued its own guidelines for vaccinations in immunocompromised patients, noting that “some [of these] recommendations have not been addressed by the ACIP to the CDC or they deviate from [CDC] recommendations.”9 IDSA’s recommendations include guidance on the timing of vaccinations in immunocompetent patients who are planned to start immunosuppressive medications, such as administering live vaccines at least 4 weeks prior to treatment start and administering inactivated vaccines at least 2 weeks prior to immunosuppression.

However, Dr. Shah said, “An individual with an acute hematologic malignancy often has to be started on treatment right away, and we don’t have time to wait weeks after vaccination,” so it is not always possible to adhere to IDSA’s recommended timing guidelines. Among patients with a hematologic malignancy, she added, the most important vaccinations are against influenza, pneumococcus, and shingles. Influenza, which has an inactivated version, can be given in the middle of therapy.

“We don’t know how effective it is in severely immunocompromised patients, but our general mantra is that it is better to give it if it’s safe. Even partial response is better than nothing,” Dr. Shah said. “If it is not urgent, though, we will wait 3 months or longer after immune restoration to catch up on other more routine vaccinations.”

Searching for Guidance

While the CDC and other organizations have established recommendations on immunization schedules for the general population and those with certain special conditions, there is much less guidance available on the administration of vaccines in patients with nonmalignant hematologic disorders, according to Dr. Castillo. A hematologist who searches for immunization guidance in patients with nonhematologic disorders will struggle to find a succinct summary of recommendations.

“The reason there are fewer standard protocols is that many therapies are given off-label and the CDC and other entities have not established recommendations,” Dr. Castillo said, other than general considerations for immunosuppressed patients, which may not apply to each situation.

Dr. Castillo recently published a paper discussing the prevention of infectious complications in nonmalignant immune-mediated hematologic disorders, where he and colleagues attempted to summarize available immunization recommendations.10

“One of the only [vaccination] recommendations found easily for ITP is related to patients who plan to undergo splenectomy,” he said, adding that his recommendations would go beyond that indication, including for cases where immunosuppressive therapies are being used.

“If first-line prednisone fails and we’re going to head into rituximab as second-line treatment – with the knowledge that patients may eventually need a splenectomy if their disease fails to respond to rituximab and other treatments – I would recommend vaccinations for influenza and streptococcal and meningococcal disease, prior to rituximab,” Dr. Castillo said.

Pediatric Patients

In the CDC’s guideline for vaccinations in children aged 18 or younger, practitioners are referred to a specific table addressing immunization schedules in children with compromised immune systems.8 The table addresses several primary and secondary immunodeficiencies (such as complement factor B deficiency, chronic renal disease, malignant neoplasm, planned transplantation, and immunosuppressive or radiation therapy), and lists contraindicated and recommended vaccines.

For children with hematologic malignancies undergoing chemotherapy, immunization will often be deferred until the body can mount an appropriate immune response, according to Cindy Neunert, MD, Associate Professor of Pediatrics at Columbia University Medical Center. Like adult patients, children who are on immunosuppressive treatments should not be exposed to any live, attenuated vaccines. Vaccination of household members should also be discussed.

“If someone gets a live vaccine, they could technically be shedding that virus,” Dr. Neunert said. “In very high-risk populations, certain vaccines should be avoided in family members, such as the oral polio vaccine.” Since this decision requires consideration of the reason for the immunosuppressed state and the various vaccines, physicians should consult the CDC guidelines, she noted.

Dr. Neunert stressed, though, that in any situation where vaccines are delayed, they are later given as soon as it is safe.

“We support vaccinations,” she said. “Deferral should be a decision of medical necessity made by the provider. We try as much as possible to keep kids on schedule but recognize that is not always achievable.”

The Perils of Procedures

Organizations also outline special considerations for vaccination in patients undergoing splenectomy or stem cell transplant, regardless of age.

Certain patients with a malignant or nonmalignant hematologic disorder may have to undergo splenectomy, as is the case in ITP outlined above, as well as leukemias and lymphomas. In situations where this procedure is elective, appropriate vaccinations can be administered ahead of time.

“We know that the spleen is important for not only clearing certain types of organisms, but also for enhancing the effectiveness of certain types of vaccines,” Dr. Shah explained. “So, if you can vaccinate, it is important to do it before the spleen is removed.” In cases of elective splenectomy, the CDC recommends that pneumococcal, meningococcal, and Hib vaccinations be given at least 4 to 6 weeks prior to the procedure, if possible. If this is not feasible, patients should receive vaccines at least 2 weeks before an elective splenectomy or at least 2 weeks after the surgical intervention in emergency cases.7

In their review, Dr. Castillo and colleagues stressed the importance of administering postoperative vaccinations as soon as the patient is stable, noting that “overwhelming postsplenectomy infection, a rapidly developing and often fatal syndrome, can progress from a mild flulike illness to fulminant sepsis in a matter of hours.”10

Hematopoietic cell transplantation presents another challenge for adhering to standard immunization schedules. The procedure results in an immunocompromised state because of the ablative therapy given prior to transplant and the drugs used to prevent GVHD. Transplant recipients are susceptible to certain vaccine-preventable diseases caused by bacteria such as pneumococcus, meningococcus, and Hib. The effectiveness of prior vaccines decreases for years after transplant, so recipients require revaccinations.

“In general, most centers are not going to start vaccinating their patients immediately after transplant because they typically are not going to mount an immune response until 3 to 6 months post-transplant,” Dr. Shah said. “Although there are some early immunization protocols for inactivated vaccines, the timing relates more to when we think the immune system is going to be sufficiently recovered.” Clinicians tend to wait at least 2 years posttransplantation to administer live or activated vaccines, she added.

A Uniquely Vulnerable Population: Sickle Cell Disease

Children born with sickle cell disease (SCD) require a different approach to immunization. “Instead of deferring vaccination, we are giving additional vaccinations to protect patients with SCD,” Dr. Neunert explained.

Splenic damage from vaso-occlusion and infarction can make children with SCD more susceptible to encapsulated bacterial organisms such as Hib and pneumococcus. “These are both encapsulated organisms that can be lethal for babies with SCD,” explained Russell Ware, MD, PhD, the Marjory J. Johnson Endowed Chair of Hematology Translational Research and Director of the Division of Hematology at Cincinnati Children’s Hospital Medical Center.

In the U.S., the CDC recommends that every newborn be immunized against Hib and with PCV13. Babies with SCD are given prophylactic antibiotics, ideally starting in the first few months of life or immediately after diagnosis. The agency also advises that children with SCD receive all age-appropriate recommended vaccinations, as they are considered at high risk for infections generally, as well as specifically for encapsulated organisms. In addition to these routine vaccinations, anyone with SCD aged 2 or older should receive 2 doses of PPSV23 separated by 5 years, starting 8 or more weeks after completing all recommended doses of PCV13.

While these recommendations are now widely followed in the U.S., most babies born with SCD are born in sub-Saharan Africa. “In the Caribbean, Africa, or other low-resource settings, there is no newborn screening and often people don’t know the child has SCD until they present with a problem, which may be a fatal bacterial infection,” Dr. Ware said.

ASH is now part of a two-pronged approach to lessen the risk of serious infection and death among babies born with SCD in these regions.

First, in 2018, ASH launched the Sickle Cell Disease Coalition to amplify the voice of the SCD stakeholder community, promote awareness, and improve outcomes for individuals with SCD. The coalition now includes more than 65 public health, research, and provider organizations; patient groups; federal agencies; industry representatives; and foundations interested in SCD.11

ASH also is working with partners in sub-Saharan Africa to build newborn screening capacity and clinical follow-up networks for SCD. The African Newborn Screening and Early Intervention Consortium has introduced standard-of-care practices for screening and early intervention therapies (such as the vaccinations referenced above) at participating institutions, with the goal of screening 10,000 to 20,000 babies per year in each country and evaluating the effectiveness of early identification and clinical interventions for newborns with SCD.

“The initiative in Africa is a bold step forward by ASH to actually assist countries in establishing newborn screening programs,” Dr. Ware said. The Consortium establishes minimum requirements for participation related to laboratory and clinical infrastructure based on local resources and, in some cases, ASH has worked with these countries and other stakeholders to help them satisfy the requirements. The member countries are poised to launch their screening networks sometime in 2020.

Second, there is increasing effort to improve global vaccination rates. Gavi, The Vaccine Alliance (formerly the Global Alliance for Vaccines and Immunisation) is an international organization with the goal of creating equal access to new and underused vaccines for children, including those in Africa.

“Gavi has done a fabulous job, and immunization rates are up quite a bit for routine things,” Dr. Ware said. However, there is still a big gap, specifically in providing cold-chain vaccines such as PCV13.

These increasing efforts seem to have gotten the attention of other organizations like the World Health Organization and UNICEF, which are getting on board. Hopefully, Dr. Ware added, as has happened in the U.S., the tide is beginning to turn. —By Leah Lawrence


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