Background
Invasive pneumococcal disease (IPD) causes significant morbidity and mortality in children [
1]. Primarily children with known risk factors experience recurrent IPD (rIPD). Between 40—92% of children with rIPD have comorbidities such as leukemia, cerebrospinal fluid leak or primary immune deficiency [
2‐
8]. Some children with rIPD respond insufficiently to pneumococcal vaccination [
9]. Little is known about how to handle these children and if they benefit from additional vaccination.
The polysaccharide vaccines (PPV14 and later the PPV23) have been available since the late 1970s. They are T-cell independent vaccines and therefore not immunogenic in children under the age of 2 years, who suffer the highest burden of disease. Vaccination with the pneumococcal conjugate vaccines (PCVs) has been possible since 2000. The conjugation of polysaccharides to a carrier protein results in a T-cell dependent immune response and induction of memory cells and thereby the possibility for a booster response upon subsequent antigen exposure [
10‐
12].
The introduction of conjugate vaccines in childhood vaccination programmes has had a significant impact on the morbidity caused by
Streptococcus pneumoniae, including in Denmark [
13,
14]. However, IPD does still occur and it is important to protect children at risk of IPD. Schedules combining PCVs with PPV23 have been proposed and studied in order to expand disease protection against serotypes not included in the PCVs [
11,
15,
16], but little is known on vaccination response in children with rIPD.
In this paper we present results from a 33-year retrospective nationwide study of an unselected population of children with rIPD. We present data on vaccination response in 26 children experiencing rIPD. The specific aim was to quantify the serotype specific vaccination response to PPV23 and PCV in children experiencing rIPD and to discuss the clinical management of these children.
Discussion
In this nationwide study of pediatric rIPD, we found that, two children failed to respond acceptably to the PCV7. Moreover, more than half of the children vaccinated with PPV23 had a reduced vaccination response. The group was heterogenous and no clear differences were observed regarding background disease between PPV23 responders and PPV23 non responders.
Our results illustrate the importance of evaluating pneumococcal antibody response on an individual level in children at high risk of experiencing IPD. The identification of vaccine non-responders is important and may allow optimization of vaccination status and consideration of other prophylactic measures, such as treatment with replacement immunoglobulin, prophylactic antibiotics and information to the parents and the child about how to handle signs of infection.
Most PPV23 non- responders had a known background disease, however three of the non-responders occurred in apparently healthy children. Antibody response to polysaccharide antigens is impaired in young children less than two years of age. If this non-responsiveness to polysaccharides persist over the year of two it becomes an abnormality. In our cohort three apparently normal children over the age of two failed to respond to PPV23, fulfilling the criteria of Specific Antibody Deficiency (SAD). Nonresponsiveness to pneumococcal polysaccharides may be the only detectable immune abnormality or it may be associated with IgG2 subclass deficiency or other B-cell disturbances [
26,
27]. The prevalence of this selective immunodeficiency is not known, but the condition is a common finding in some groups of children [
25‐
27]. SAD can be associated with repetitive upper respiratory tract infections [
25], which may lead to invasive disease. Susceptibility to infections in these children may decrease over time, although in some children the condition progresses to Common Variable Immunodeficiency (CVID) [
30,
31], which is the reason that these children may require long-term follow-up.
We documented two children with a subnormal PCV response. Hyporesponsiveness to a single or two PCV antigens in children has previously been described [
32‐
35]. It has been suggested that serotype-specific hyporesponsiveness in apparently healthy children may be a result of nasopharyngeal carriage of that particular pneumococcal serotype at the time of vaccination [
33]. Moreover it is wellrecognized that not all serotypes in the PCVs are equally immunogenic. [
12,
34,
36] and that the immune response can vary according to the number of doses administered [
36]. A way to handle children lacking an antibody response to all PCV serotypes is to revaccinate with an extra PCV dose, which may lead to a sufficient response [
37]. A child with a subnormal response for several PCV serotypes, like in our two patients, is an unusual clinical situation and suggests severe B-cell defect and/or underlying T-cell dysfunction. [
37]. The compromised vaccination response of the child with TLR deficiency is in accordance with observations from others [
38,
39]. Interestingly, one of our patients who responded subnormally to PCV experienced two episodes with IPD due to serotype 6B episodes but was putatively protected against 6B according to the serology. This illustrates the complexity of serological testing and is a reminder that serology is just a correlate of protection. It can be considered that this child’s antibodies might be of poor quality however this is just speculative because we did not have the opportunity to examine the antibody quality in a functional assay.
The PPV23 respondergroup was heterogenous regarding background disease and included, among others, three complement C2 deficient children, two children with congential asplenia, one child with leukemia (vaccinated with the PPV23 during sustainment therapy) and one child who had undergone stem cell transplantation.
In the PCV era it has been a matter of debate if a supplemental booster PPV23 vaccine is beneficial in the interest of broadening the serotype coverage in children with a high at risk of IPD or if it makes more sense to include repeat PCV13 doses. Our results show that at least in some high risk children PPV23 provides a good response, however the response is individual and somewhat inpredictable.
Further, it must be kept in mind that serotype-specific correlates of protection are not necessarily adequate to predict the level of clinical protection in individuals. We do, nevertheless, on the basis of our findings and others [
40‐
43] find it beneficial to recommend PPV23 vaccination as a supplement to primary PCV vaccination.
Children experiencing rIPD are a heterogenous group and may respond insufficiently to PPV23 vaccination, therefore each child should probably be assessed individually with measurement of PNA pre- and post immunization to tailor the best programme.
A limitation of our study is the retrospective design. A prospective study adressing pneumococccal vaccine response in children with recurrent IPD could in more detail adress the specific response after and before vaccination and compare different strategies concerning revaccination. Moreover, due to the long time span of the study, the children in our cohort were exposed to different pneumococcal vaccine regimes for high risk children, which makes it difficult to compare the children and extrapolate the results directy to high risk children in 2016. Also we did not have the possibility to measure the opsonophagocytic activity of the antibodies which could have further illucidate the functional vaccine response.
We do, however, find the results important. This Danish cohort of children with rIPD is populationbased and one of the largest known cohorts to date. To our knowledge, a study of vaccination response of an unselected cohort of children with rIPD has not previously been carried out.
Acknowledgements
We gratefully acknowledge the helpful and highly skilled laboratory staff at the department of serology, Statens Serum Institut for performing the pneumococcal antibody ELISA determination.