Elsevier

Vaccine

Volume 29, Issue 41, 22 September 2011, Pages 7207-7211
Vaccine

Short communication
The 13-valent pneumococcal conjugate vaccine (PCV13) elicits cross-functional opsonophagocytic killing responses in humans to Streptococcus pneumoniae serotypes 6C and 7A

https://doi.org/10.1016/j.vaccine.2011.06.056Get rights and content

Abstract

The introduction of a 7-valent pneumococcal conjugate vaccine (PCV7) in 2000 dramatically reduced the incidence of invasive pneumococcal disease (IPD) caused by the seven serotypes covered by the vaccine. Following the introduction of PCV7, which contains a serotype 6B conjugate, some decrease in IPD due to serotype 6A was noted suggesting that the serotype 6B conjugate provided some partial cross-protection against serotype 6A. However, no effect on serotype 6C was observed. In 2010, a pneumococcal conjugate vaccine with expanded serotype coverage (PCV13) was introduced that expanded the serotype coverage to 13 serotypes including serotype 6A. To assess whether the 6A conjugate in PCV13 could potentially induce functional anti-6C antibody responses, an opsonophagocytic assay (OPA) for serotype 6C was developed. Randomly chosen subsets of immune sera collected from infants receiving three doses of PCV7 or PCV13 were tested in OPA assays for serotype 6A, 6B and 6C. PCV7 immune sera demonstrated strong OPA responses, defined as percentage of subjects having an OPA titer ≥1:8, to serotype 6B (100% responders), partial responses to serotype 6A (70% responders) but only minimal responses to serotype 6C (22% responders). In contrast, PCV13 immune sera showed strong OPA responses to serotypes 6A (100% responders), 6B (100% responders) and 6C (96% responders). Furthermore, during pre-clinical work it was observed that serotype 7F (included in PCV13) and serotype 7A (not included in PCV13) shared serogroup-specific epitopes. To determine whether such epitopes also may be eliciting cross-functional antibody, PCV13 immune sera were also tested in serotype 7A and 7F OPA assays. All PCV13 immune sera demonstrated OPA responses to both of these serotypes. Taken together these results suggest that immunization with PCV13 has the potential to induce cross-protective responses to related serotypes not directly covered by the vaccine.

Introduction

Streptococcus pneumoniae can persistently colonize the nasopharynx of human infants without causing clinical symptoms or can cause disease ranging from otitis media to more serious and invasive pneumococcal diseases (IPD) including sepsis, meningitis and pneumonia [1]. More than 90 serotypes of S. pneumoniae have been identified, but the vast majority of human disease is caused by fewer than 30 serotypes [2].

In 2000, a 7-valent pneumococcal conjugate vaccine (PCV7, Prevnar®/Prevenar®) was licensed in the United States that contains capsular polysaccharides corresponding to serotypes 4, 6B, 9V, 14, 18C, 19F and 23F conjugated to the carrier protein CRM197, a nontoxic variant of diphtheria toxin, thereby providing coverage for the seven most prevalent serotypes causing IPD in infants and children in the United States at the time [3], [4]. In 2010, a 13-valent pneumococcal conjugate vaccine (PCV13, Prevnar 13™/Prevenar 13™) was licensed in the United States that expanded the serotype coverage to additionally include serotypes 1, 3, 5, 6A, 7F and 19A. PCV13 is expected to provide protection for the 13 most prevalent serotypes causing pneumococcal disease in infants and children globally [5], [6], [7], [8].

The capsular polysaccharides of S. pneumoniae are important determinants of pathogenicity, and protective immune responses to pneumococci in humans are typically directed against the capsular polysaccharides. Pneumococcal serotypes are defined by the chemical structure of the capsular polysaccharides, and pneumococcal serogroups consist of structurally related serotypes that in some cases share some immunological cross-reactivity. However, cross-functional responses, as defined by the opsonophagocytic activity (OPA) assay, and cross-protection provided by immune responses to related serotypes may vary between individual serotypes within serogroups. While strong immunological cross-reactivity by ELISA has been demonstrated in some cases, e.g., serotypes 19A and 19F, little cross-functional activity in OPA assays and no evidence of cross-protection has been observed in human populations for these two related serotypes [9], [10], [11], [12].

Pneumococcal serogroup 6 currently includes four structurally related serotypes: 6A, 6B, 6C and 6D [13], [14]. Due to the similarity in polysaccharide structure between serotypes 6A and 6B, it was expected, also based on immunological cross-reactivity as measured by IgG ELISA, that the serotype 6B conjugate in PCV7 would provide at least partial cross-protection against serotype 6A in human populations. Post marketing IPD effectiveness studies of IPD did indeed report a decline in invasive disease due to serotype 6A, following the introduction of PCV7, but the decline in disease was less extensive than that seen for serotype 6B disease [15], [16]. The interpretation of the effectiveness data for serotype 6A however, was complicated by the increasing prevalence of serotype 6C, which was only recently identified in 2007 [14]. Serotype 6C shares many epitopes with serotype 6A, and had been indistinguishable from serotype 6A using conventional serotyping reagents. Retrospective studies carried out using specific methodologies to distinguish between serotypes 6A and 6C have demonstrated that the prevalence of serotype 6C in IPD and carriage isolates from the US has been steadily increasing [17], [18], [19], [20], [21]. Since serotype 6A has greater structural similarity and immunological cross-reactivity with serotype 6C than does serotype 6B [14], PCV13, which contains a serotype 6A conjugate, may elicit cross-protective responses to serotype 6C. To assess cross-functional responses for serotypes 6A, 6B, and 6C elicited by PCV7 or PCV13 immunization, sera from infants immunized with a 3-dose series of PCV7 or PCV13 were tested in OPA assays with serotype 6A, 6B, or 6C target pneumococcal strains. In addition to the potential for cross-protection for the pneumococcal serogroup 6, pre-clinical studies have also identified monoclonal antibodies (mAbs) that identified cross-reactive epitopes between the related serotypes 7F (present in PCV13) and 7A (not present in PCV13). To address whether these cross-reactive epitopes may induce cross-functional antibodies, sera from PCV13 immunized children were also assessed in OPA assays using serotype 7A and 7F pneumococcal target strains.

Section snippets

Sera

Serum specimens were obtained from children approximately 1 month after the third dose of a 2, 3, and 4 month (infant series) administration schedule of either PCV7 (Prevnar®/Prevenar®, Wyeth) or PCV13 (Prevnar 13™/Prevenar 13™, Pfizer) in a parallel-group, randomized, active-controlled, double-blind, multicenter trial [7]. The trial was conducted in Germany in accordance with the ethical principles that have their origin in the Declaration of Helsinki. The protocol was reviewed and approved by

Serotype 6C OPA responses

Functional antibodies generated to pneumococcal capsular polysaccharide (CPS) following vaccination with polysaccharide conjugate vaccines may specifically recognize the structures of the saccharide repeat units of the CP, linkages between the repeat units, side chains, or other modifications (e.g., O-acetyl groups) of the CPS. Within the pneumococcal serogroup 6, there are four serotypes with related CPS (Fig. 1). The CPS structures of serotypes 6A vs 6B and serotypes 6C vs 6D differ only in

Acknowledgements

The development of the serotype 6C strain used in this study was funded by an NIH grant (AI-31473) awarded to M.H.N. The University of Alabama at Birmingham has applied for a patent on 6C serotype and M.H.N. is an employee of the university. We thank Dr. Peter Paradiso, Pfizer, for critical review of the manuscript and Dr. Roger French, Pfizer, for statistical consult.

References (25)

  • R.R. Reinert et al.

    Advances in pneumococcal vaccines: the 13-valent pneumococcal conjugate vaccine received market authorization in Europe

    Expert Rev Vaccines

    (2010)
  • S.L. Kaplan et al.

    Serotype 19A Is the most common serotype causing invasive pneumococcal infections in children

    Pediatrics

    (2010)
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