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
]. 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
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
Pneumococcal serogroup 6 currently includes four structurally-related serotypes: 6A, 6B, 6C and 6D [13
]. 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
]. 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
]. 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.