The clinical, immunological and microbiological impact of the 10-valent pneumococcal-Protein D conjugate vaccine in children with recurrent protracted bacterial bronchitis, chronic suppurative lung disease and bronchiectasis: A multi-centre, double-blind, randomised controlled trial

Abstract

We aimed to determine the efficacy of the 10-valent pneumococcal-Haemophilus influenzae protein D conjugate vaccine (PHiD-CV) in children aged 18-months to <18-years with recurrent protracted bacterial bronchitis (rPBB), chronic suppurative lung disease (CSLD) or bronchiectasis. In a multi-centre, double-blind randomised controlled trial, children received two doses, 2-months apart of the 10vPHiD-CV or quadrivalent meningococcal-ACYW₁₃₅ conjugate vaccine. Active surveillance for acute exacerbations, respiratory symptoms and antibiotic use was undertaken through to 12-months after the second vaccine dose (clinical cohort only). Serum, saliva and nasopharyngeal swabs were collected to measure immunological and microbiological effects (immunology cohort). Between December 2012 and August 2015, 62 children were enrolled onto the clinical protocol (1 excluded from clinical analyses due to unblinding), while 74 contributed to the immunology cohort (overall mean age = 6.8-years (standard deviation = 3.7), 42 (56.8%) male). The absolute risk difference comparing the 10vPHiD-CV group (n = 31 children) to the MenACYW₁₃₅ group (n = 30 children) for acute exacerbations was -0.5 exacerbations/100-weeks at risk (95% confidence interval (CI) -2.0, 0.9). Compared to the MenACYW₁₃₅ group, children who received the 10vPHiD-CV were less likely to have respiratory symptoms in each fortnight of surveillance (incidence density ratio (IDR) 0.82, 95%CI 0.61, 1.10) and required fewer short-course (<14-days duration) antibiotics (IDR 0.81, 95% CI 0.61, 1.09). The vaccine was immunogenic and no serious adverse events related to the vaccine were reported. In conclusion, 10vPHiD-CV might have a future role in managing children with rPBB, CSLD and bronchiectasis, but larger multicentre trials are needed to confirm or refute findings from this preliminary study.

Keywords: H. influenzae; PHID-CV; acute exacerbation; bronchiectasis; children; chronic suppurative lung disease; efficacy; prevention; protracted bacterial bronchitis.

Figure 1.

Consort diagram.

Figure 2.

Saliva anti-protein D IgA and IgG geometric mean antibody units per milligram of protein per millilitre (AU/mgP/mL), with corresponding 95% confidence intervals, by vaccine group and study time-point.

Figure 3.

Serum anti-protein D antibody geometric mean titres (GMTs), with the corresponding 95% confidence intervals, by vaccine group and study time-point.

Figure 4.

Haemophilus influenzae and pneumococcal culture-positive nasopharyngeal swabs, and antibiotic use in 14-days prior to each swab, by vaccine group and study time-point. Hi: H. influenzae, CSpn: capsular pneumococci, 14DayAB: any antibiotics in the 14-days prior to nasopharyngeal swab,14DayAZM: azithromycin in the 14-days prior to nasopharyngeal swab

Figure 5.

Pneumococcal serotypes identified in nasopharyngeal swab cultures (n = 51 positive swabs) by vaccine group. *ON – Omni – negative: negative to pneumococcal omniserum (all pneumococcal serotypes).

Figure 6.

7-day local and general solicited reactions, and 30-day unsolicited symptoms, following each vaccine dose by study group. X: p<0.001.