The impact of pneumococcal conjugate vaccines on carriage of and disease caused by Streptococcus pneumoniae serotypes 6C and 6D in southern Israel

Highlights

• A prospective surveillance was conducted in children <5 years in southern Israel.

• We assessed the impact of PCV7/PCV13 sequential introduction on the dynamics of serotypes 6C/6D.

• PCV introduction resulted in decreased carriage rates and conjunctivitis caused by 6C/6D.

• Incidences of 6C/6D decreased in otitis media and dropped to zero in IPD in the PCV13 era.

• We conclude that 6C/6D do not act as replacement serotypes for 6A/6B following PCV13 vaccination.

Abstract

The introduction of the 7-valent pneumococcal conjugate vaccine (PCV7) followed by PCV13 resulted in a dramatic reduction in carriage and disease rates of Streptococcus pneumoniae (Sp) serotype 6B (Sp6B) and Sp6A. The structural modifications of the capsule of Sp6A and Sp6B to become Sp6C and Sp6D, respectively, raised a concern that eradication of Sp6A/Sp6B by PCV could be accompanied by an increase in Sp6C/Sp6D. This study examines the dynamics and clonal distribution of Sp6C/Sp6D relative to Sp6A/Sp6B during 1999–2014, pre- and post-PCV implementation. Sp were cultured from Blood/CSF and MEF of children <2 years, and from conjunctiva and nasopharynx of children <5 years. PCR was applied for Sp6C and Sp6D identification. Clonality was determined by PFGE and MLST. PCV introduction resulted in decreased carriage rates and conjunctivitis caused by serogroup 6 serotypes. Incidence of Sp6A, Sp6B and Sp6D in otitis media dropped gradually along with PCV7/13 introduction, whereas Sp6C rates increased in the PCV7 period and then decreased following PCV13 implementation. In invasive pneumococcal disease, complete elimination of serogroup 6 was found in the PCV era. Similar clonal composition was found for Sp6C and Sp6D pre- and post-PCV. We conclude that Sp6C and Sp6D do not act as replacement serotypes for Sp6A and Sp6B following vaccination with PCV13. The major Sp6C and Sp6D clones present pre-PCV persisted also post-PCV implementation, suggesting that these clones possess an advantage retained post-vaccination.

Introduction

Streptococcus pneumoniae (Sp) is one of the most important pathogens worldwide, especially among children and elderly people. The polysaccharide capsule is an important virulence factor. Over 90 polysaccharide pneumococcal serotypes have been described, differing in their invasive potential [1]. Traditionally, pneumococcal serogroup 6 was classified into two serotypes: 6A (Sp6A) and 6B (Sp6B). Two additional members of serogroup 6, Sp6C and Sp6D, have been identified in the last decade [2], [3], [4]. Sp6C consists of a polysaccharide similar to that of Sp6A in which the wciN_α gene is replaced by the wciN_β gene [5]. The same change was detected in the polysaccharide of Sp6B to be transformed into Sp6D [3], [4]. Recent publications show that the majority of Sp6B could be genetically classified as Sp6E [6], [7], [8], [9], and that serotype 6E declined after the introduction of the 7-valent pneumococcal conjugate vaccine (PCV7) [9]. However, classification of 6E as a serotype, in the absence of phenotypic data to support this, is premature and needs further investigation. In addition, new hybrid capsule types, namely 6F, 6G and 6H have been identified in vitro, that may differ in their interaction with the immune system of the host [10].

The polysaccharide antigen of Sp6B is included in PCV7, which can also elicit some level of antibodies, cross-reacting with Sp6A, Sp6C and Sp6D [11], [12], [13]. However, PCV7 was shown to be partially protective against Sp6A, but not against Sp6C [14]. The expansion of PCV7 to the 13-valent PCV (PCV13), which includes, among others, the 6A polysaccharide antigen, resulted in higher IgG and opsonophagocytic activity against Sp6A [15]. Because serotype 6A has extensive structural and immunological similarity with serotype 6C, the inclusion of serotype 6A in PCV13 resulted in higher concentrations of anti-6C antibodies than those obtained by PCV7 [16].

Before PCV introduction, serogroup 6 was frequently found among carriage and disease isolates [17], [18], [19]. The incidence of invasive pneumococcal disease (IPD) and otitis media (OM) caused by Sp6B decreased rapidly following PCV7 implementation and this trend continued in the PCV13 period [18], [19], [20], [21]. However, the impact of PCV7 on Sp6A was not homogenous. While the direct protection against IPD was impressive with higher efficacy against IPD caused by this serotype, reduction of OM and especially carriage by Sp6A were less evident, and thus mucosal Sp6A disease and carriage were reduced more successfully after introduction of PCV13 [18], [19]. This suggests that for mucosal infections, the cross reacting antibodies to Sp6A elicited by Sp6B may not be sufficiently protective. On the other hand, IPD incidence due to Sp6C increased significantly following PCV7 implementation [22], [23] before declining after PCV13 [21], [24], [25], suggesting no cross-protection from 6B in PCV7 recipients, but at least some protection against Sp6C elicited by the 6A antigen in PCV13. Sp6D has been relatively rare, both pre- and post-PCV implementation [20], [26], [27], [28], [29]. However, Sp6D was a common cause of IPD in Asia [30]. The impact of PCV implementation on Sp6D has not yet been fully established [13].

This study aimed to examine the dynamics and clonal distribution of Sp6D and Sp6C, relative to Sp6B and Sp6A, pre- and post-PCV7/PCV13 implementation. We had the unique opportunity for such a study since we have a large database of serogroup 6 isolates from carriage, mucosal diseases (OM and conjunctivitis (CJ)) and IPD, collected during a 15-year period from children <5 years old in southern Israel.