Elsevier

Vaccine

Volume 28, Issue 1, 10 December 2009, Pages 71-78
Vaccine

Effect of vaccination with pneumococcal capsular polysaccharides conjugated to Haemophilus influenzae-derived protein D on nasopharyngeal carriage of Streptococcus pneumoniae and H. influenzae in children under 2 years of age

https://doi.org/10.1016/j.vaccine.2009.09.113Get rights and content

Abstract

Following primary and booster vaccination with an 11-valent pneumococcall protein D conjugate vaccine there was a 42.8% (95% CI: −16.7 to 71.9, ns) reduction in the carriage of Streptococcus pneumoniae vaccine serotypes and a 42.6% (95% CI: 1.3–66.6) reduction in the carriage of Haemophilus influenzae identified by standard microbiological techniques. When PCR and immunoblot assays were used to further improve specificity of non-typeable H. influenzae strain identification, carriage of H. influenzae was still reduced with 38.6% (95% CI: −6.3 to 64.6, ns). Reduction of acute otitis media (AOM) episodes preceded the impact on carriage. These data provide further support of the functional role of the protein D immunity.

Introduction

Streptococcus pneumoniae is an important cause of acute otitis media (AOM) and invasive infections among children under 2 years of age. Pneumococcal vaccines containing plain capsular polysaccharides of S. pneumoniae have been widely available since the early 80s [1] but are not immunogenic or effective in this age group. This led to the development of pneumococcal conjugate vaccines (based on capsular polysaccharides conjugated to a carrier protein) known to be immunogenic in infants, to induce immunological memory and to reduce pneumococcal nasopharyngeal carriage. A 7-valent vaccine containing S. pneumoniae polysaccharides conjugated to CRM197 (a non-toxic cross-reacting mutant of diphtheria toxin) was the first to be licensed for use in young children based on demonstration of efficacy against invasive pneumococcal disease (IPD) [2]. This vaccine also showed protective efficacy against pneumococcal AOM caused by serotypes contained in the vaccine [3].

In addition to S. pneumoniae, the other leading cause of AOM is Haemophilus influenzae (mainly the non-encapsulated or “non-typeable” [NTHi] strains) [4]. This has prompted the development of a novel pneumococcal conjugate vaccine containing S. pneumoniae capsular polysaccharides conjugated to a recombinant non-lipidated form of protein D (PD) from H. influenzae. PD is a 42 kD outer membrane lipoprotein which is highly conserved in both encapsulated and non-encapsulated H. influenzae strains [5], [6], [7], [8]. Evidence for the role of PD as a virulence factor in respiratory tract infections comes from experiments with a PD-deficient NTHi mutant in a rat AOM model [9] and a human nasopharyngeal tissue culture model [10]. The role of PD in NTHi virulence appears to be mediated via its glycerophosphodiester phosphodiesterase activity [7], [11]. H. influenzae strains lack a pathway for de novo synthesis of choline, and so must acquire it from an external source like the host. One source is via the hydrolysis of glycerophosphorylcholine, an abundant degradation product of host phospholipids [11]. Incorporation of phosphorylcholine into H. influenzae cell surface lipooligosaccharides appears to be important for the adherence and persistence of bacteria on the mucosal membranes [12], [13].

A protective effect of PD immunization in rats was demonstrated in both middle ear clearance and pulmonary clearance models [14]. Furthermore, in the chinchilla otitis model, which closely mimics human AOM infection, PD was found to induce significant protection both after active immunization with PD and after passive transfer of serum obtained from children immunized with polysaccharide-protein D conjugate vaccines [15], [16]. The protective effect of PD in humans was confirmed during a pneumococcal otitis efficacy trial (POET) in which the pneumococcal PD conjugate vaccine demonstrated significant protective efficacy against AOM caused by both H. influenzae and S. pneumoniae vaccine serotypes [17]. During POET the direct impact of the PD conjugate vaccine on nasopharyngeal carriage of these two major upper respiratory tract bacterial pathogens was also evaluated.

Experience with H. influenzae type b (Hib) has shown that vaccination with Hib conjugate vaccines reduces Hib nasopharyngeal carriage [18], [19]. Similarly, a reduction in the nasopharyngeal carriage of S. pneumoniae vaccine serotypes has been observed in children following pneumococcal conjugate vaccination, although this is often associated with a concomitant increase in the carriage of non-vaccine serotypes [20], [21], [22], [23], [24].

However, the relationship between the direct impact of conjugate vaccination on nasopharyngeal carriage and the indirect (i.e. herd immunity due to reduced transmission of pneumococci) effects on protection against disease is not yet completely understood. Data from the Finnish Otitis Media trial (FinOM) [3], have shown that the reduction in the carriage of S. pneumoniae vaccine serotypes following pneumococcal conjugate vaccination was not apparent until 18 months of age, whereas the protective effect on vaccine serotype AOM was observed from 6.5 months of age [25]. This indicates a direct protective effect of vaccination on AOM in addition to an indirect effect through the reduction of carriage.

In this report we present nasopharyngeal carriage data of both S. pneumoniae and H. influenzae at various time points following PD conjugate vaccination in POET and explore the temporal relationship with the protective efficacy against AOM due to both pathogens.

Section snippets

Study design

POET was a prospective randomized double-blind controlled study conducted in the Czech Republic and Slovakia. It was designed to assess the efficacy of the 11-valent PD conjugate vaccine (containing 1 μg each of capsular polysaccharide of pneumococcal serotypes 1, 3, 4, 5, 6B, 7F, 9V, 14, 18C, 19F and 23F conjugated individually to protein D derived from non-typeable H. influenzae) against AOM in healthy young children. The control group received a non-pneumococcal vaccine (hepatitis A vaccine,

Results

Nasopharyngeal swabs were collected in 381 subjects (191 PD conjugate vaccinees and 190 hepatitis A vaccinees). All except five of these subjects (three who did not receive the full primary vaccination course, one who received medication forbidden by the protocol and one for whom the interval between vaccinations was outside the protocol defined limits) were included in the ATP cohort for efficacy, giving 188 evaluable subjects per group in the carriage subset. The demographic characteristics

Discussion

S. pneumoniae and H. influenzae are both common colonizers of the nasopharynx where they can survive without causing adverse effects to the host [31]. However, nasopharyngeal carriage of S. pneumoniae and H. influenzae is a pre-requisite for the development of disease such as AOM and is also an important source for transmission of these pathogens within the community. In this study, we monitored the effect of a vaccine containing S. pneumoniae capsular polysaccharides conjugated to protein D

Acknowledgments

The authors would like to thank all the infants and their families as well as the study investigational team in the Czech Republic who took part in this carriage study. The authors are grateful to Dr. Miriam Hynes (freelance, UK) for assistance in the preparation of this manuscript, Christine Vanderlinden (GlaxoSmithKline Biologicals) for editorial assistance and manuscript coordination and to Patricia Lommel (GlaxoSmithKline Biologicals) for statistical support. This study was supported by

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