Cough is the most common symptom reported for new presentations to primary health care services internationally, [1
] and in Australia accounts for 6.8% of family medical practitioner consultations [2
]. Chronic cough (>4 weeks duration) [3
] in children is associated with increased morbidity and often an unrecognised social and economic burden upon the family and hidden costs for the health care system [4
]. There are many causes of chronic cough, but amongst children with a persistent wet cough indicating the presence of excessive airway mucus, there is a subset that has a spectrum of chronic pulmonary diseases. These particular children, if left untreated may develop irreversible airway injury, an event that was well recognised in the pre-antibiotic era [5
]. These disorders, protracted bacterial bronchitis (PBB), chronic suppurative lung disease (CSLD) and bronchiectasis, have in common impaired mucociliary clearance, bacterial infection and lower airway inflammation, features consistent with the ‘vicious circle hypothesis’ for the pathogenesis of bronchiectasis [6
]. PBB is the most common of these entities, occurring predominantly in preschool children [7
]. It is characterised by an isolated chronic wet cough without an alternative cause, such as cystic fibrosis (CF) or immunodeficiency being present, which resolves promptly with a two to four-week course of antibiotics [9
] In contrast, bronchiectasis is defined as abnormal, irreversible bronchial dilatation and is usually diagnosed by chest high-resolution computed tomography (cHRCT) scans [10
]. Children with bronchiectasis have a chronic wet cough that responds slowly or incompletely to antibiotic therapy. They also have recurrent lower respiratory infections and can develop additional respiratory symptoms and signs [12
]. Bronchiectasis is either idiopathic or results from underlying systemic or local pulmonary diseases predisposing to chronic endobronchial infection. Between these two extremes are children with CLSD who have the clinical features of bronchiectasis, but lack the supporting cHRCT evidence [10
]. Recurrent (at least four) episodes of PBB may occur [1
], and if these no longer respond promptly to antibiotics, underlying CSLD or bronchiectasis should be considered.
There is a direct relationship between lower airway bacterial load and systemic and lower airway inflammation, risk of acute respiratory exacerbations and quality of life measures in adults with bronchiectasis [13
]. Haemophilus influenzae
(usually unencapsulated or non-typeable (NTHi) strains) is consistently the predominant pathogen found in the sputum of adults with bronchiectasis [14
] and chronic obstructive pulmonary disease (COPD) [15
]. It is also the most common bacterial pathogen isolated from the lower airways of children with PBB, CSLD or bronchiectasis, followed less often by Streptococcus pneumoniae (pneumococcus)
and Moraxella catarrhalis
]. Furthermore, acquiring new H. influenzae
strains can lead to exacerbations in adults with COPD [15
]. Acute exacerbations are also important in bronchiectasis as they are associated with lower quality of life (QoL) scores [22
] and poorer long-term outcomes. In adults with bronchiectasis, the frequency of exacerbations, increased systemic inflammatory markers and Pseudomonas aeruginosa
infection are each determinants of an accelerated pulmonary decline [24
]. Amongst other factors, an increased mortality risk is associated with the degree of lung function impairment [25
]. In children with bronchiectasis, no prospective study exists, but the only significant predictor of pulmonary decline found in one retrospective study was the frequency of hospitalised exacerbations [26
While pneumococcal polysaccharide and protein conjugate vaccines seem to have had little impact on the incidence of these chronic pulmonary diseases [8
], interventions targeting H. influenzae
may be more successful in reducing exacerbations and leading to improved clinical outcomes. Indeed, adult studies provide “proof of concept” that a H. influenzae
vaccine may be beneficial. A systematic review of six randomised controlled trials (RCT; 440 patients) reported oral monobacterial whole-cell, killed H. influenzae
vaccine reduced the incidence of “bronchitis” episodes at three months (rate ratio 0.69; 95% confidence interval (CI) 0.41, 1.14) and six months after vaccination (rate ratio 0.82; 95% CI 0.62, 1.09) [28
Current oral H. influenzae
vaccines are not licensed and to date have not been tested in children. Although very different to a whole cell oral vaccine whole cell, oral vaccine, the only vaccine available for children at present that may impact upon H. influenzae
infection is the parenteral 10-valent pneumococcal-H. influenzae
protein D conjugate vaccine (PHiD-CV; Synflorix®, GlaxoSmithKline Biologicals, Rixensart, Belgium). The protein D (PD) component is an outer membrane lipoprotein, which is antigenically conserved, surface located and present in most H. influenzae
(encapsulated and NTHi) strains [29
]. It is one of three H. influenzae
proteins (PD, P6 and OMP26) that have been the focus of potential vaccine antigens for both adults and children in recent years [30
], with PD and P6 showing the most promise. Vaccine-induced anti-PD antibodies have been associated with protective efficacy against H. influenzae
infection in middle ear and pulmonary clearance in rat disease models [32
]. A RCT of an 11-valent prototype for PHiD-CV (Pneumococcal Otitis Efficacy Trial (POET)) where children had tympanocentesis during their first episode of acute otitis media (AOM) found that the vaccine reduced the overall incidence of AOM by 34%, including a 35% reduction in H. influenzae
-related cases [33
However, since our trial commenced, data have been published from a trial of PHiD-CV in 780 Dutch children [34
], and GlaxoSmithKline has made aggregate data from a large trial of the vaccine in Latin American infants (COMPAS) publicly available [35
]. In the Dutch study [34
], infants received the vaccine at 2, 3, 4 and 11 to 13 months of age. Although the study found a lack of vaccine efficacy (VE) against H. influenzae
(principally NTHi) nasopharyngeal colonisation (VE: 0.5%, 95% CI, -21.8%, 18.4%) and acquisition (VE: 10.9%, 95% CI, -31.3%, 38.9%) no disease endpoints were reported. In COMPAS, vaccine was administered at 2, 4, 6 and 12 to 15 months of age and, despite inducing high serum anti-PD antibody levels, no reduction in H. influenzae
nasopharyngeal carriage was observed at each three-monthly time point following the third dose of vaccine up until the study ceased when children reached two years of age [35
]. There was a marginal effect on any clinically confirmed AOM (VE 16.1%, 95% CI −1.1, 30.4), but none observed for H. influenzae
confirmed AOM (VE 15%, 95% CI −83.8, 60.7).
The data from COMPAS are difficult to interpret given a surprisingly low prevalence of H. influenzae
nasopharyngeal carriage in all children at each time point (approximately 5%), and that carriage data were only obtained in a subset of children from a single participating centre (n = 2,000). Furthermore, of all clinically confirmed AOM episodes (n = 243), H. influenzae
was only detected in 26 (10.7%), of which all were confirmed as NTHi. Hence, there is a clear lack of study power to address the clinical efficacy of the vaccine. The implications of these findings [34
] and those of the Dutch study for older children, particularly those with chronic respiratory disease, need to be established and more studies are required in different populations with differing H. influenzae
epidemiology to confirm vaccine efficacy.
Thus, our trial aims to determine whether respiratory exacerbations in children with recurrent PBB, CSLD and bronchiectasis can be reduced by PHiD-CV vaccination.
Objectives of the study
Our primary objective is to determine the clinical efficacy of PHiD-CV in reducing respiratory exacerbations in children aged 18 months to 14 years with recurrent PBB, CSLD or bronchiectasis.
Our secondary objectives are:
1. To evaluate the impact of a PHiD-CV vaccine on nasopharyngeal carriage and bacterial load of H. influenzae and pneumococcal vaccine-type and vaccine-related serotypes at 2 months post-vaccine dose 1 and then at 1, 6 and 12 months following the second vaccine dose in children with recurrent PBB, CSLD or bronchiectasis.
2. To evaluate the systemic and mucosal immune responses to PD and non-vaccine type H. influenzae proteins (P4, P6) and PHiD-CV pneumococcal vaccine and vaccine-related serotypes at 2 months post-dose 1, and then at 1, 6 and 12 months following the second vaccine dose in children with recurrent PBB, CSLD or bronchiectasis.
3. To determine the effect of PHiD-CV vaccine on lung function in children with recurrent PBB, CSLD and bronchiectasis.
4. To evaluate the safety of PHiD-CV vaccine and meningococcal (ACYW135) conjugate vaccine in children with recurrent PBB, CSLD or bronchiectasis.
Our study tests the primary hypothesis that amongst children aged 18 months to 14 years with PBB, CSLD or bronchiectasis, vaccination with PHiD-CV reduces the incidence of respiratory exacerbations in the 12 months following two doses of vaccine compared to children who received the control (meningococcal ACYW135 Sanofi Pasteur, Lyon, France) conjugate vaccine.