Vaccine-preventable infections (VPIs) have reemerged as the rate of vaccine coverage has decreased in the United States and around the world. The United States is currently experiencing the largest measles outbreak since the disease was declared eliminated in 2000, according the Centers for Disease Control and Prevention (CDC), and outbreaks of pertussis and meningococcal disease have also been increasingly reported . Immunocompromised children include a heterogeneous population of patients with oncologic conditions, primary immunodeficiencies, those who have undergone solid organ transplantation (SOT) or hematopoietic stem-cell transplantation (HSCT), and individuals receiving biologic immunomodulatory or immunosuppressive medications for treatment of a wide range of rheumatologic, neurologic, and gastrointestinal conditions such as inflammatory bowel disease (IBD). Immunocompromising conditions among children have become more prevalent as a broader range of medical conditions are treated with SOT, HSCT, and immunomodulatory therapies. Potential exposures to VPIs are of particular concern since immunocompromised pediatric patients are at greater risk for developing more severe disease from VPIs. This heightened risk is multifactorial, and driven by overall immune status, reason for immunosuppression – whether due to exogenous immunosuppressive therapies or innate immune defects, age of initiation of immunosuppression which may occur prior to completion of the routine childhood vaccination schedule, and the potential for suboptimal vaccine responses after initiation of immunosuppressive therapies. It is imperative that care providers recognize the urgent need to optimize vaccination for immunocompromised pediatric patients, as these vaccines will offer disease protection throughout their lifetime. Pediatric patients have the benefit of routine childhood visits in addition to their specialty care visits, increasing the number of opportunities for vaccine administration with multidisciplinary collaboration. In this review, we summarize important findings from the literature published within the last 12 months regarding vaccination recommendations in immunocompromised hosts.
INCIDENCE OF VACCINE PREVENTABLE-INFECTIONS IN THE IMMUNOCOMPROMISED PATIENT POPULATION
Pediatric SOT recipients require immunosuppressive medications to prevent rejection of their transplanted organ, and are therefore at risk of developing infections, including VPIs. Feldman et al.[2▪▪] describes the incidence of hospitalization for VPIs in pediatric SOT recipients. The investigators examined a cohort of nearly 7,000 SOT recipients in the Pediatric Health Information System database from 2004 to 2011, to analyze the associated morbidity, mortality, and costs of infection in this patient population. More than 15% of SOT recipients experienced a VPI in the first 5 years post-SOT, a rate that is 87 times higher than the general population. Influenza, rotavirus, varicella, and pneumococcal infection were the most common VPIs resulting in hospitalization. The study found that children 2 years of age and under at the time of transplant and those who had received intestinal, multiorgan, heart, or lung transplant were at greatest risk for developing VPIs. Children with VPIs had higher rates of morbidity and mortality due to the infection and were more likely to have a prolonged hospital stay.
Patients with IBD receiving biologic therapies to control their disease represent a growing population of pediatric immunocompromised individuals. Available data are largely from adult studies, but the findings can be broadly applied for providers who care for pediatric patients. Vinsard et al. examines the most frequent infections for which adult IBD patients are hospitalized, and the impact vaccination may have had on preventing these hospitalizations. VPIs that were evaluated included pneumococcal pneumonia, herpes zoster virus (referring to varicella reactivation), primary varicella zoster virus (VZV) infection, meningococcal meningitis, influenza, tetanus, diphtheria, pertussis, hepatitis A, hepatitis B, and human papillomavirus. Of these, herpes zoster infection, hepatitis B, influenza, and pneumococcal pneumonia were the most common VPIs identified. This study reported that patients with IBD had two times the risk of hospitalization with herpes zoster than their peers. Unlike the previous study of VPIs in pediatric SOT recipients, this study of adult IBD patients did not find a higher incidence of invasive pneumococcal or influenza infections. Although this study did not specifically evaluate VPIs in pediatric IBD patients, it is notable that the infections most commonly identified are often preventable through completion of childhood and adolescent vaccination series. Therefore, ensuring that adolescents are up to date on vaccines as they move into adult care settings may have implications for preventing VPIs. More research is needed to quantify the need for vaccine coverage in pediatric patients receiving biologic therapies.
NEW APPROACHES TO LIVE VACCINATION IN THE IMMUNOCOMPROMISED PATIENT
Optimization of live vaccines in immunocompromised pediatric populations is a significant challenge. Current CDC childhood vaccination guidelines recommend initiation of live vaccines (VZV and Measles-Mumps-Rubella [MMR]) at 1 year, with a booster dose given between 4 and 6 years of age for immunocompetent children. According to these guidelines, however, live vaccines are typically contraindicated in immunocompromised patients. Accelerated vaccine administration schedules from CDCs Advisory Committee on Immunization Practices (ACIP) are in place for children who are behind on vaccines and need to be caught up. These same schedules can be applied for children in whom immunosuppression can be anticipated in advance, to optimize the number of doses of live vaccine received prior to initiation of immunosuppressive therapies. The accelerated vaccine schedules currently endorse MMR to be given as early as 6 months of age, with second dose of VZV and MMR vaccine 4 weeks following the first in an effort to complete the series preimmunosuppression .
Patients requiring life-long immunosuppression, such as SOT recipients, are a challenging population, as compared with oncology or HSCT recipients who will be eligible for live vaccines upon discontinuation of immunosuppressive therapies. Current guidelines do not include routine administration of live vaccines after SOT due to concerns regarding safety in the setting of immunosuppression and adequacy of immune response [5▪▪]. While efforts should be made to fully immunize pediatric SOT candidates prior to transplant, including live vaccines, this is often not possible. Children may be too young to receive live vaccines due to age at time of SOT, their clinical condition, or potential lack of time between pre-SOT evaluation or listing and time to actual transplantation, as a 28 day waiting period is recommended between live vaccines and proceeding with transplantation [6▪▪].
With recent large outbreaks throughout the United States and in Europe, incomplete MMR vaccination rates among pediatric SOT patients has highlighted the vulnerability of children within many transplant centers. The potential for atypical presentation of measles in immunocompromised populations, and significant communicability of the virus creates additional concern. Previous literature has demonstrated that only 40% of patients older than 12 months were up to date on MMR vaccination at their pre-SOT visit emphasizing the need for considering innovative approaches to live vaccination in these groups [5▪▪].
Recent studies have evaluated safety, tolerability, and immunogenicity of live vaccines in pediatric SOT recipients and have supported the use of live attenuated VZV vaccine in pediatric liver transplant recipients [5▪▪]. Pittet et al.[5▪▪] conducted a prospective interventional national cohort study that evaluated 44 pediatric liver transplant recipients who received MMR vaccine. Patients were required to meet specific eligibility criteria (>1-year posttransplant, low doses of steroids and/or tacrolimus, and absolute lymphocyte count ≥7.5 G/l). Sero-response after a two-dose series schedule was 98%. At 1-year follow-up seropositivity remained in 62% of the patients who had responded to vaccination initially. Among those who became seronegative within the follow-up time period, there was a sero-protection rate of 100% after booster vaccine administration. During the study period, the vaccinations were well tolerated, and there were no serious vaccine-related adverse events identified. Based on this work, MMR vaccine is now able to be considered for liver transplant recipients who meet the eligibility criteria.
A similar recent study by Kamei et al.[6▪▪] evaluated the safety and immunogenicity of live vaccines in 60 pediatric patients who were receiving immunosuppressive therapies for nephrotic syndrome. Children were eligible to receive MMR, VZV, or mumps vaccines if their disease process was stable and cellular and humoral immunological parameters including CD4+ T-cell count, phytohemagglutinin stimulation index, and serum IgG levels were within normal limits. Following vaccination, seroconversion rates were high for both measles at 95.7% and rubella at 100%. Seroconversion for VZV and mumps was 61.9 and 40.0%, respectively. There were no serious adverse events associated with the administration of these vaccines, including symptomatic infection with a vaccine strain. It was also noted that immunity waned for both VZV and mumps over the course of 1 year, suggesting that booster vaccination may be required in this patient population. For children who require immunosuppressive therapy to manage their nephrotic syndrome, live vaccines can be considered if the disease process is stable.
Overall, these recent studies demonstrate that live vaccines can be safe and immunogenic when administered during ongoing immunosuppressive therapy, to SOT patients who meet specific criteria. While the 2019 American Society of Transplantation (AST) guidelines for administration of live vaccines have not changed, and continue to recommend these be given at least 28 days prior to planned immunosuppression, they do acknowledge that live vaccines could be considered for certain liver and kidney transplant patients in the posttransplant period based on increasing availability of safety and immunogenicity data [7▪]. In addition a newly published consensus statement, developed through a consortium meeting of experts in the field of transplant infectious diseases, provides more explicit guidance for consideration of live vaccines in SOT recipients, including specific minimum standards which providers can use to determine which patients may be able to receive these vaccines. The consensus statement acknowledges that these recommendations are based on studies in liver and kidney SOT patients alone, and emphasizes the need for further study with heart, lung, and multivisceral transplant patients [8▪▪].
Live-attenuated herpes zoster vaccine is recommended for immunocompetent adults, and while herpes zoster is considered somewhat rare in the healthy pediatric population, there is increased risk of reactivation in immunocompromised patients, especially children with malignancies . The live-attenuated herpes zoster vaccine is contraindicated for immunocompromised patients; however, an adjuvant recombinant zoster vaccine has recently been introduced. Work by Bastidas et al.[10▪] highlights the use of this recombinant zoster vaccine in adult HSCT recipients, which led to significantly decreased incidence of herpes zoster compared with a placebo group. Pediatric data are needed to assess the utility this vaccine to decrease the incidence of herpes zoster in pediatric immunocompromised populations.
NEW CONSIDERATIONS TO CURRENT VACCINATION RECOMMENDATIONS
Meningococcal B (MenB) vaccine has gained much attention since its introduction to the U.S. in 2015. A Morbidity and Mortality Weekly Report in 2017 reported the significantly increased risk of invasive meningococcal infection for those patients who require eculizumab therapy, a mAb complement component inhibitor . To optimize protection against meningococcal infection, administration of both the quadrivalent (A, C, Y, W-135) meningococcal conjugate vaccine as well as MenB vaccine is recommended for persons age 10 or older who are at increased risk for meningococcal disease, defined as patients with persistent complement component deficiencies, those who are receiving eculizumab, and those with anatomic or functional asplenia . Changes to the MenB vaccination schedule for persons at increased risk were made in 2016 by ACIP . These included a change to the dosing recommendations for MenB-FHbp formulation requiring administration as a three dose series for those at increased risk (0, 1–2, and 6 months). Healthy adolescents not considered high-risk, could continue with the two dose series of MenB-FHbp at 0 and 6 months. Dosing recommendations for MenB-4C formulation did not change, and a two-dose series continues to be recommended. Potential updates to MenB guidelines have been discussed by ACIP, including addition of vaccine booster doses for individuals who remain with ongoing risk of invasive disease .
The utility of high-dose influenza vaccine is another consideration in immunocompromised children. Several influenza vaccine dosing formulations are available including standard dose, high-dose, MF59-adjuvanted and live-attenuated. While the live-attenuated vaccine is not currently recommend in the immunosuppressed population, there have been no updates to the current ACIP guidelines regarding the use of the standard-dose vaccination vs. the high-dose concentration of this vaccine. Notably, no influenza efficacy studies have been completed in many immunocompromised populations. In the post-SOT setting, however, there have been randomized trials that have demonstrated that high-dose influenza dosing induced a significantly greater seroconversion rate and antibody titers when compared with the standard dose in both adult and pediatric SOT recipients [7▪]. Given the support from this data, the 2019 AST vaccination guidelines do note that the high-dose influenza vaccine may be preferred over the standard dosing.
VACCINATION RATES IN THE IMMUNOCOMPROMISED PATIENT POPULATION
Low rates of vaccination among SOT and HSCT recipients were reported in a study from 2017 . Olarte et al. found an overall higher incidence of invasive pneumococcal infection (IPI) in these patient populations, despite the introduction of the pneumococcal conjugate vaccine in 2000. In another study, rates of IPI in the immunocompromised patient population were 20 to nearly 50 times higher than in the general population . In 2012, ACIP created guidelines to bring high-risk patients up to date with available pneumococcal vaccines . Vietri et al. reported the uptake of the pneumococcal 13-valent conjugate vaccine (PCV13) among United States adults aged 19–64 years with immunocompromising conditions, and found that less than 15% of adults had received the appropriate PCV13 vaccine as recommended by ACIP. This study emphasizes the importance of providers’ knowledge and adherence to the most recent vaccination guidelines.
A study by Temtem et al. evaluated the use of pneumococcal vaccines specifically in children with IBD. Within a cohort of 106 patients, the investigators found that while all patients had received PCV13 the majority had not received pneumococcal polysaccharide vaccine (PPSV23), which is recommended in addition to PCV13 for administration to patients receiving high-level immunosuppression. IPI was fortunately not a significant burden in this group, with only one patient having a documented IPI. Appropriate use of the PCV13 and PPSV23 starting in childhood, even before the onset of a chronic illness, will offer immunocompromised hosts the benefits of protection from IPI throughout their lifetime.
Another recent study reviewed vaccination status against influenza and pneumococcus in adult patients with autoimmune disorders on biological therapies . The study investigators found vaccination rates of only 28% for influenza and 48% for pneumococcal vaccines. This study also reported that vaccination status was inadequately assessed during specialty clinical visits and vaccine information was insufficiently delivered by caregivers to patients. Patients therefore had an overall lack of awareness of vaccine importance, resulting in continued risk of infection.
A survey of adults with autoimmune diseases patients and caregivers regarding their knowledge of vaccine status and importance found that the overall knowledge of vaccines was low [18▪]. This study identified several factors that affected a patient's overall vaccine status including: a lack of awareness of vaccination, misperception about the safety of vaccines, fear of side effects, and confusion regarding the role that specialty care providers vs. primary care providers play in a patient's overall care. The importance of reviewing vaccine history at the time of diagnosis and planning vaccine administration early was also emphasized. Many patients will not require immunosuppressive therapy until later in their disease process, giving providers an opportunity to discuss and optimize vaccination prior to immunosuppression.
Despite known risk for VPIs among all of the immunocompromised patient populations, suboptimal vaccination rates require exploration of the barriers to vaccination for this vulnerable group. A recent review evaluated the challenges to optimizing vaccination in IBD patients and emphasized prior literature which demonstrated close provider counseling as a strong predictor for patients receiving all of their vaccinations . As reported in other studies, common patient-identified barriers to vaccination included lack of awareness due to inadequate education from providers, unclear indications for certain vaccine recommendations, and fear of side effects. Physician uncertainty regarding which vaccinations were indicated or acceptable to administer in patients with IBD, and lack of comfort in providing vaccination recommendations among care providers were also cited as barriers.
STRATEGIES TO PROMOTE VACCINES IN IMMUNOCOMPROMISED PATIENT POPULATIONS
Updated guidelines published in 2019 by the American Society of Transplantation Infectious Diseases Community of Practice discuss the importance of vaccination status to be reviewed at the time of first pretransplant visit among SOT candidates [7▪]. The guidelines recommend development of a vaccination strategy to be implemented at the time of transplant evaluation, and reviewed at the time of listing, as well as implementation of a plan for monitoring serological response. For the patients who are incompletely vaccinated prior to transplant, evaluation by an infectious disease specialist is also recommended.
Discussions continue at individual transplant centers regarding the decision of whether to offer a nonemergent transplant to a child who is under immunized. In a recent review article published by Feldman et al. a survey including medical and surgical directors and transplant coordinators from 138 pediatric heart, kidney and liver transplant programs in the United States, 39% of respondents reported their programs had encountered listing decisions involving a case with vaccine refusal of parents prior to transplant. Only 4% reported a written policy in place regarding these situations. This review raises the question of whether a national policy requiring completed vaccination for nonemergent transplant candidates should be instituted by the United Network of Organ Sharing to optimize these vaccination rates and remove these decisions from individual centers .
The current review also highlights that in addition to stricter vaccine policies as a strategy to optimize vaccine status in our immunocompromised patient population, a multidisciplinary approach must be taken for these patients who are cared for jointly by both primary care providers and subspecialists. Further education is needed regarding the accelerated vaccination schedules that could be utilized in patients being evaluated for transplant, or other patients who are likely to need immunosuppressive biologic therapies in the future. Feldman et al. conveys the need for use of health information technology to facilitate patient–provider and provider–provider communication. Standardized communication portals between provider teams regarding a patient's vaccination status and plan for future medical therapies should be implemented. These communication portals must have easily accessible vaccine records and automated vaccine reminders which could include alerts and education about vaccines. Vaccine reminders could also be automatically sent to patients and families with the assistance of digital health tools such as mobile applications which would empower patients and families to be involved in their own care, as well as reduce possible missed vaccine opportunities .
Although immunocompromised children are at higher risk of invasive infection from VPIs, this patient population remains largely under-vaccinated. Recent studies show a lack of awareness on the part of physicians and patients regarding vaccination status and guidelines. Systematic approaches to optimizing vaccine coverage should be implemented and shared amongst the team of specialty and primary care providers for each patient. Inactived vaccines have been shown to be safe and continue to offer benefit for children even after immunosuppression, and emerging data show that live vaccines may also be safe and immunogenic in certain populations of immunocompromised children. Pediatric primary care and specialty providers have a unique opportunity to optimize vaccination and ensure that patients are up to date on the most recent recommendations.
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Conflicts of interest
There are no conflicts of interest.
REFERENCES AND RECOMMENDED READING
Papers of particular interest, published within the annual period of review, have been highlighted as:
- ▪ of special interest
- ▪▪ of outstanding interest
1. Centers for Disease Control and Prevention. Measles Cases 2019. Retrieved from https://www.cdc.gov/measles/cases-outbreaks.html
2▪▪. Feldman AG, Beaty BL, Curtis D, et al. Incidence of hospitalization for vaccine-preventable infections in children following solid organ transplant and associated morbidity, mortality, and costs. J Am Med Assoc Pediatr 2019; 173:260–268.
This is the first study that quantifies vaccine-preventable infections in the solid organ transplant (SOT) population.
3. Vinsard DG, Wakefield D, Vaziri H, Karagozian R. Vaccine-preventable diseases in hospitalized patients with inflammatory bowel disease: a nationwide cohort analysis. Inflamm Bowel Dis 2019; [Epub ahead of print].
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There is emerging data that live vaccines may be safe for certain SOT recipients.
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Live vaccines were found to be safe and effective in nephrotic syndrome patients receiving immunosuppressive therapy.
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The article is an update to the previous 2013 guidelines for immunizing SOT candidates and recipients.
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Consensus statement that provides guidance on use of live vaccines after SOT with guidance on minimum standards for baseline immune evaluations that was developed through a consortium meeting of experts in the field of transplant infectious diseases.
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The article demonstrates the efficacy of the recombinant zoster vaccine in immunocompromised autologous hematopoietic stem-cell transplant recipients.
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