Vaccination of immune compromised children—an overview for physicians

Immune compromised children are threatened by a higher risk of infections; some of these are preventable by vaccination. Primary care physicians play a fundamental role in optimising vaccination status. In this narrative review, we present the evidence on vaccine safety and immunogenicity in immune compromised children and discuss in which conditions live-attenuated vaccines can possibly be used. Vaccination schedules differ in some of these conditions, including the use of vaccines with higher antigenic contents (e.g. high-dose hepatitis B vaccine), additional vaccine doses (e.g. 2-dose schedule meningococcal vaccine), more frequent booster doses (e.g. life-long pneumococcal vaccine booster), supplementary vaccines (e.g. meningococcal B vaccine) and use of vaccines beyond the age of usual recommendation (e.g. Haemophilus influenza type b vaccine after 5 years of age). Serological monitoring is a useful tool for customizing vaccination schedule in immune compromised children, confirming adequate vaccine response and documenting seroprotection (especially against measles and varicella). Finally, verification of vaccination status of all household members can prevent them being vector of transmission of an infection to the immune compromised children. Conclusion: Intensified information strategies are needed to improve trust, rectify perceived risks and improve vaccine acceptability; primary physicians can play a critical role in the latter. What is Known: • Physician’s awareness is key to success, since it repeatedly correlates with higher vaccination rates What is New: • The vaccination status of immunocompromised children is rarely up-to-date • Knowing the latest vaccine recommendations is challenging, as they differ for each medical condition and change periodically • This review summarises the vaccine recommendations for children with compromised immune systems and highlights how paediatricians play a key role in coordinating their application


Introduction
Protecting immune compromised children against infections is challenging and is a problem of growing importance. Indeed, paediatrician are dealing with more and more patients with deficient immune system, as (i) immunosuppressive therapies are increasingly used in various medical conditions and (ii) the life expectancy of patients with these conditions has substantially raised. The quality of life of these children has also improved over the years: they are able to attend school, travel and be active in their community. This inevitably puts them in contact with others and a variety of infectious pathogens. Moreover, the frequent hospital admission and outpatient visits associated with chronic diseases inevitably increase their risk of nosocomial exposure to pathogens.
Vaccination has repeatedly been recognised as one of the most important and most cost-efficient invention in healthcare [1]. Vaccine-preventable diseases occur more frequently and have a worst outcome in immunocompromised individuals. In a retrospective cohort study of nearly 7000 paediatric solid organ recipients, 15.6% were hospitalised for a vaccinepreventable diseases in the first 5 years following transplantation, an 87-fold higher rate compared with the general population [2]. Worst outcomes are well illustrated by the severity of measles infection, which carries a 40% to 70% fatality rate among immunocompromised patients, despite adequate treatment, up to 35-fold higher compared with immunocompetent hosts [3]. Measles and other vaccine-preventable diseases have recently re-emerged in many regions, mostly due to declining vaccine uptake [4,5]. As herd protection cannot be relied on, prevention of vaccine-preventable diseases in vulnerable population is key.
The aim of this review is to present an overview of the knowledge in the field, provide tables and references that could help primary care physicians when managing immune compromised children. The following questions are addressed: Which fundamental role do primary care physicians play? Who are immune compromised children? Why are their vaccinations status not up-to-date? Are vaccines immunogenic and safe in immune compromised children? Is the vaccination schedule the same than for healthy children? Which additional vaccines are recommended? Why/when should vaccine-preventable diseases serology be monitored? In which situation can live-attenuated vaccine be administrated? Recommendation for passive immunisation are beyond the scope of this review, but details can be find elsewhere [6,7].

Which fundamental role does the primary care physician play
The primary care physician plays a critical role in optimising their patients' protection against vaccine-preventable diseases.
The first step is to identify within all their patients which are the ones who could benefit from an enhanced protection. When a child has a new diagnosis, and the immune system is likely to be affected, a quick review of the patient's vaccination history should be automatic. The ascertainment of the patient's protection status should rely on checking their records or serologies, as trusting oral recall only can lead to undervaccination or overimmunization [44]. Primary care physicians have a key role to play in discussing with families on the importance of vaccination and reassurance on their safety. In collaboration with a specialist team, a customised vaccination schedule could be planed and anticipated, aiming to immunise, for example, early in the disease process, anticipating periods of higher immunosuppression. This schedule should catch up missing vaccination and add the supplementary vaccines when needed. If recommended, vaccine seroresponses should be checked following vaccination and during follow-up visits.
Another fundamental role of the primary care physician is to ensure that all household members have their vaccinations updated. This "cocooning" strategy is a form of indirect protection for non-immune children, or for those who are unable to be vaccinated. Cocooning is, however, usually not sufficient to fully protect these children, especially those with normal lifestyles.
Who are immune compromised children Immunodeficiency can be primary or acquired, secondary to a disease, infection, medication, chronic organ failure or other state (e.g. malnutrition, young age) [8]. Medications can affect the immune system either as an undesirable side effect (e.g. chemotherapy, drug-induced neutropenia) or intentionally in conditions in which the immune response has to be restrained, e.g. management of autoimmune disorders and immunemediated diseases, allergic disorders or solid organ transplant. The most common conditions encountered in daily practice are listed in Table 1.

Why are immune compromised children's vaccination status not up-to-date
Although vaccinations seem particularly indicated in this high-risk population, immune compromised children are often less adequately vaccinated than healthy children [9][10][11]. As vaccines and booster doses are given regularly throughout childhood, most children may not have completed their schedule before the onset of immunosuppression. But the main reasons underlying non-vaccination are summarised in Fig.  1 [11][12][13]. Moreover, as vaccination guidelines change frequently, and differ for each different medical condition, it is IDSA [22] Review [53] The table summarises the vaccine recommendations available for various health conditions. Recommendations can differ between guidelines and between countries. In some countries, the cost of some vaccines may not be reimbursed. Recommendation for serological monitoring is rarely discussed in guidelines and the ones presented in this table summarise  challenging to stay up-to-date with the most recent, specific recommendations [14]. As an example, it was recently reported in patients with inflammatory bowel disease (IBD) that vaccination was the least frequently followed quality of care recommendation [15]. In Italy, vaccination rates in children with HIV, cystic fibrosis, liver transplantation or diabetes were low against pneumococcus (< 25%) and highly variable for influenza (21% to 90%) [11]. Information and better communication appear to be key components for increasing vaccination uptake; primary care physician usually excels in both, being trusted by and close to the patient's family (Fig. 2).

Are vaccines immunogenic in immune compromised children
Concern on vaccine effectiveness is often an obstacle to vaccination in immune compromised children; immune response to vaccination can be suboptimal [16]. Vaccine responses may be reduced in both magnitude and durability, explaining the need for repeated monitoring of antibody levels during follow-up. However, even in highly immunocompromised hosts, vaccination may induce at least some immune response that could be beneficial in case of further encounter with the pathogen. Vaccines should therefore be administered despite possible non-responsiveness; in some medical conditions, monitoring of antibody concentration is recommended (Table 1).

Are vaccines safe in immune compromised children
Whereas immunogenicity is an important aspect, vaccine safety is often the main concern of parents and healthcare practitioners. Live-attenuated vaccines (LAV), in particular, are usually avoided in the immunocompromised hosts as they could theoretically induce vaccine-strain infections; these are discussed in detail in a section below. In contrast, non-live vaccines are incapable of causing infection, since they consist in inactivated toxins (protein), in pathogen that have been killed (inactivated) or in only specific segments of the pathogen (subunit, polysaccharides) that may be conjugated to a protein (conjugate vaccine) to enhance the immunological response ( Table 2). These vaccines can be given to immunocompromised patient without any safety concerns, as demonstrated in many studies in patients with chronic diseases, e.g. in HIV-infected individuals [17], patients with immunemediated diseases [16], chronic kidney diseases [18] and solid organ transplantation recipients [19]. Therefore, information is critical to clearly explain the expected benefit to the patient. Proper communication is particularly important for patients with immune-mediated diseases, inborn error of metabolism or solid organ transplantation, for which questions about the inflammation induced by vaccination could play a role in modulating the auto-immune response or inducing a metabolic crisis. Moreover, since the medical conditions of these children will be lifelong, vaccinations cannot be postponed indefinitely. Therefore, in these children, while it is important as for all children to monitor possible side effects of vaccination, the effect of the vaccine on the underlying condition should also be reported, such as signs of graft rejection or flare in disease activity. However, there is increasing data suggesting that concerns regarding the risk of disease exacerbation are unfounded, with numerous studies showing that immunization did not induce significant worsening of underlying disease [16,[19][20][21].
Is the vaccination schedule the same than for healthy children The vaccination schedules are usually the same; they slightly differ from those of healthy children in that they may include supplementary vaccinations (for example usually not given beyond a certain age), accelerated schedule, extra doses for primary vaccination, extra boosters, as well as specific     Tables 1 and 2, and in the following sections.
Recommendations are somewhat different between immunocompromising conditions: they are determined by the individual risk of infection and the data available. Among the various guidelines available, the Infectious Diseases Society of America provides a good overview of the current evidence available and covers most medical conditions (Table 1) [22]. The different national immunisation schedules can also be found online [23].

Which supplementary non-live vaccines are indicated in which situation
Most immune compromised children benefit from protection against pneumococcus, influenza, meningococcus and human papilloma virus (HPV). These vaccines are included in many national guidelines for healthy children as well, so may not necessarily be considered as "supplementary vaccines".
Invasive pneumococcal diseases carry a high mortality rate (11-30%) [24] and are more frequent in immunocompromised individuals, or those with chronic diseases, such as IBD [25], nephrotic syndrome [26] or a-/hyposplenic conditions [27,28]. The pneumococcal conjugate vaccine (PCV) is usually recommended in healthy children before the age of 5, but also in all medical conditions with immunosuppression, regardless of age. Although some guidelines also recommend to subsequently administer the 23-valent polysaccharide vaccine (PPSV23) to those at high risk [29], many experts disagree, since PPSV23 do not induce memory cells and become less effective after repeated administrations (hyporesponsiveness) [30].
Influenzais probably the most common vaccine-preventable diseases leading to hospitalisation, accounting for 3.4% of all critical care admissions in the USA during the flu season [31]. In a retrospective cohort study in paediatric solid organ transplantation recipient, 40% of the hospitalisation for vaccinepreventable diseases were due to influenza infection [2]. Given the high burden of influenza disease, the vaccine is recommended in virtually all immune compromised children, as of 6 months of age. Moreover, preventing influenza also helps preventing secondary pneumococcal infection. Immune compromised children should always receive the inactivated vaccine and not the live-attenuated influenza vaccine (in Europe, the latter is only available in the UK).
Meningococcal vaccines are recommended to asplenic patients, HIV-infected individuals, those with complement deficiencies or receiving a treatment affecting the complement (such as eculizumab) [32]. .Most guidelines recommend a 2dose schedule of the 4-valent conjugate vaccine (MCV4), and, when available, vaccination against serogroup B as well (Table 1). As the risk of malignancy related to HPV is highly increased (up to 100-fold) in immunocompromised individuals [33], a 3-dose schedule is strongly recommended for all. The 2-doseschedule-used routinely in immunocompetent 11-15-year-old individuals-may not be sufficiently immunogenic, reason why the 3-dose schedule should be preferred [34].
Do immune compromised children need more or higher doses As vaccination may be less immunogenic in immune compromised children and immunity may wane faster, it is sometimes useful to administer vaccines with higher antigenic contents, additional vaccine doses or more frequent booster doses to ensure adequate response (via serological monitoring, as discussed below) and subsequent protection against vaccinepreventable diseases.
High-dose vaccine For vaccination against HBV per example, use of high-dose vaccine is recommended by some experts in HIV-infected adolescents (and adult), haemodialysis adult, and studies involving adults suggest it could be beneficial for oncological patients, or those with immune-mediated diseases [22]. Another example is the high-dose influenza vaccine being currently evaluated in immunocompromised individuals, including oncological patients, solid organ transplantation recipients and haemodialysis patients [35][36][37]. Data in paediatric patients, however, is scarce.
More vaccine doses Regarding schedule, 3-dose(rather than 2-doses) schedule are recommended for HPV in all immunocompromised condition, and a 2-dose (rather than single dose) schedule is recommended for MCV4 [22].
More boosters Regular MCV and PCV booster are recommended in some immunocompromised condition, whereas they are not recommended in healthy children. Diphtheriatetanus booster doses are recommended more often as well, as guided by serological monitoring.

The rationale behind serological monitoring
One of the most useful tools for customization of vaccination schedule in immune compromised children is to regularly monitor their serologies [38]. In children receiving chemotherapy for example, there is strong evidence to suggest that antibody concentrations wane more rapidly during treatment [39]. Cut-off values for seroprotection (i.e. correlates of protection) are available for most vaccine-preventable diseases ( Table 2), but may vary slightly between laboratories. These measures allow to (i) confirm adequate vaccine response, (ii) guide when to administer a booster dose and (iii) document current protection against vaccine-preventable diseases. The latter is of particular importance for varicella and measles viruses, for which the reported mortality rates in infected immunocompromised hosts are up to 25% and 70%, respectively [3,40,41]. For both viruses, absence of seroprotection would require prompt management following contact (intravenous immunoglobulins and/ or antiviral therapy), whereas documentation of highly seroprotective titres could suggest a "wait and see" attitude [42]. Physician can therefore inform individually on the risk of severe disease following contact with varicella or measles and provide guidance on what to do if this situation occurs. Regular monitoring of serologies against vaccine-preventable diseases has been adopted by many as an important part of the regular follow-up of immunocompromised patient. Although this test does not measure the other actors of the immune response, it is the only indirect measure of protection available. There is, however, no clear recommendation on when, in whom and how often should serology be assessed (Tables 1 and 2). Annual monitoring of serologies may be indicated in highly immunocompromised patients, or when the immunosuppressing regimen has recently been increased, whereas less frequent monitoring (i.e. once every 5 years) should probably be enough in well-controlled HIV-infected individuals, for example.

In which situation can live-attenuated vaccines be administered
When vaccinating immunocompromised individuals, the most important safety issue concerns LAV. They consist in live pathogens that have been 'weakened' so that they can still replicate but with difficulty and without having the capacity to cause the disease in an immunocompetent host. Given the fear of a theoretical uncontrolled replication that could lead to severe vaccine-induced disease, LAV are mostly contraindicated in immune compromised children. In patients with severe primary immunodeficiency disease (e.g. severe combined immunodeficiency), LAV carry a significant risk of vaccine-strain infections, which have been reported following the oral rotavirus or poliovirus vaccines, measles-mumpsrubella(MMR) vaccine and bacille Calmette-Guérin vaccine [43,44]. However, there is growing evidence documenting the safety of immunising immunocompromised hosts with different types of LAV in carefully selected settings.
MMR and varicella vaccines are usually well tolerated in case of milder immunosuppression, such as in children with DiGeorge syndrome (if lymphocyte count is > 500 cells/μL) [43], HIV-infected individuals (if CD4 count is > 200 cells/μL) [45,46], liver or kidney transplant recipients (strict conditions [47]), after hematopoietic stem cell transplantation [48,49], or in individuals with immune-mediated diseases on low/no immune suppression [16,22], including children with nephrotic syndrome [50]. MMR and varicella vaccine have indeed the potential to protect patients against threatening pathogen that are endemic or linked with epidemics in many places around the world. However, extra caution should be taken and close safety monitoring is highly recommended following the administration of LAV in any situation when the immune system is affected [22,47]. In the setting of solid organ transplantation, a consensus of worldwide experts has recommended the following surveillance: (i) education on urgency to seek medical attention in case of new onset of rash or fever within 4 weeks following vaccination and (ii) at least one contact with the patient's caregiver in the month following vaccination to identify any adverse event that might have occurred [47].

Concluding discussion
As many questions remain, clinical trials are still needed to refine the study of the immune response induced by each vaccine in all immunocompromising conditions to determine whether, when and for whom there is a need for a specific immunisation schedule. Moreover, additional guidance regarding the serological monitoring of vaccine response and persistence of protection is required.
As new vaccines become available and the epidemiology of vaccine-preventable diseases evolves, it is increasingly important for all those caring for children to be up to date with the recent changes to guidelines, in order to improve the usual low uptake of additional immunisations in high-risk groups [51]; physician's awareness is key, since it repeatedly correlates with higher vaccination rates [11].
Author contribution LFP drafted the initial manuscript. KMPB critically revised the manuscript and both authors approved the final version as submitted.
Funding Open Access funding provided by Université de Genève. LFP is supported by the Swiss National Science Foundation (Early Postdoc.Mobility grant number P2GEP3_178155).
There is no funding source for this review Data availability Not applicable.
Code availability Not applicable.

Declarations
Ethical approval This article does not contain any studies with human participants or animals performed by any of the authors.
Consent to participate Not applicable.
Consent for publication Not applicable.

Conflict of interest
The authors declare that they have no conflict of interest.
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