Natural antibodies against several pneumococcal virulence proteins in children during the pre-pneumococcal-vaccine era: the generation R study

Abstract

The currently available pneumococcal vaccines do not protect against all serotypes of Streptococcus pneumoniae. A shift toward nonvaccine serotypes causing colonization and invasive disease has occurred, and studies on protein-based vaccines have been undertaken. We assessed the association between specific antibodies against pneumococcal virulence proteins and colonization and respiratory tract infections (RTIs). Additionally, we assessed the extent to which colonization induces a humoral immune response. Nasopharyngeal swabs collected from children at 1.5, 6, 14, and 24 months of age were cultured for pneumococcus. Serum samples were obtained at birth and at 6, 14, and 24 months (n = 57 children providing 177 serum samples). Data were collected prior to the pneumococcal vaccine era. IgG, IgA, and IgM levels against 17 pneumococcal protein vaccine candidates were measured using a bead-based flow cytometry technique (xMAP; Luminex Corporation). Information regarding RTIs was questionnaire derived. Levels of IgG against all proteins were high in cord blood, decreased in the first 6 months and increased again thereafter, in contrast to the course of IgA and IgM levels. Specific antibodies were induced upon colonization. Increased levels of IgG against BVH-3, NanA, and SP1003 at 6 months, NanA, PpmA, PsaA, SlrA, SP0189, and SP1003 at 14 months, and SlrA at 24 months were associated with a decreased number of RTIs in the third year of life but not with colonization. Maternal antipneumococcal antibodies did not protect against pneumococcal colonization and infection. Certain antibodies against pneumococcal virulence proteins, some of which are induced by colonization, are associated with a decreased number of RTIs in children. This should be taken into account in future pneumococcal vaccine studies.

FIG. 1.

Dynamics of IgG, IgM, and IgA levels in the first 2 years of life. Median MFI values, averaged for all children (n = 57), are presented by age (1.5, 6, 14, and 24 months). High levels of placentally transferred IgG are observed at 1.5 months and decrease in the first 6 months of life. After 6 months, an increase in the IgG levels is observed. Low levels of IgM and IgA in serum were observed after birth, but these clearly increased during the first year of life.

FIG. 2.

Association between specific antipneumococcal IgG levels and RTIs in the third year of life. IgG levels at 6, 14, and 24 months are compared with the numbers of doctor visits for RTIs in the 3rd year of life. Higher levels of IgG against certain pneumococcal proteins were correlated with a lack of doctor visits for RTIs (first box in every box plot). The median level of IgG against certain pneumococcal proteins was lower in children with at least 3 doctor visits for RTIs (third box in every box plot). This was statistically significant for all pneumococcal proteins presented in these box plots, except for PpmA and SP1003 at 24 months (P = 0.065 and 0.075, respectively). The analyses were conducted for the group of children with at least three doctor visits versus children with a lack of doctor visits. Results for children with one or two doctor visits were included in this figure but not analyzed. P values are presented in Table 4. Values are median MFI levels, with an interquartile (25 to 27%) box, a 5 to 95% range, outliers (○), and extreme outliers (*). Numbers represent child identification numbers.