Quality of antibody responses by adults and young children to 13-valent pneumococcal conjugate vaccination and Streptococcus pneumoniae colonisation

Abstract

Childhood pneumococcal conjugate vaccine (PCV) protects against invasive pneumococcal disease caused by vaccine-serotype (VT) Streptococcus pneumoniae by generating opsonophagocytic anti-capsular antibodies, but how vaccination protects against and reduces VT carriage is less well understood. Using serological samples from PCV-vaccinated Malawian individuals and a UK human challenge model, we explored whether antibody quality (IgG subclass, opsonophagocytic killing, and avidity) is associated with protection from carriage. Following experimental challenge of adults with S. pneumoniae serotype 6B, 3/21 PCV13-vaccinees were colonised with pneumococcus compared to 12/24 hepatitis A-vaccinated controls; PCV13-vaccination induced serotype-specific IgG, IgG1, and IgG2, and strong opsonophagocytic responses. However, there was no clear relationship between antibody quality and protection from carriage or carriage intensity after vaccination. Similarly, among PCV13-vaccinated Malawian infants there was no relationship between serotype-specific antibody titre or quality and carriage through exposure to circulating serotypes. Although opsonophagocytic responses were low in infants, antibody titre and avidity to circulating serotypes 19F and 6A were maintained or increased with age. These data suggest a complex relationship between antibody-mediated immunity and pneumococcal carriage, and that PCV13-driven antibody quality may mature with age and exposure.

Keywords: Avidity; Carriage; Colonisation; Opsonophagocytosis; PCV; Pneumococcal conjugate vaccine; Pneumococcus.

Fig. 1

Antibody titres to S. pneumoniae serotype 6B in PCV13-vaccinated adults and HepA-vaccinated controls from EHPC. Bar graphs indicate IgG, IgG1 or IgG2 titres for PCV13-vaccinated (n = 21) (A-C) and HepA-vaccinated (n = 24) (D-F) individuals at three sample collection points. Samples are divided by colonisation outcome after experimental challenge with serotype 6B as part of the EHPC model (uncolonised shown by empty circles, colonised by filled circles). Statistical analysis was performed using Wilcoxon signed rank tests, bars indicate median values. * p <0.05, ** p <0.01, *** p <0.001, **** p <0.0001.

Fig. 2

Opsonophagocytic killing responses to S. pneumoniae serotype 6B in PCV- and HepA-vaccinated adults. OPK by OPA in adult HepA-vaccinated (n = 11) (A) and PCV13-vaccinated (n = 20) (B) individuals. Data are split by colonisation outcome after experimental challenge with serotype 6B as part of the EHPC model. Statistical analysis was performed using Wilcoxon signed rank tests. Opsonic indices (OIs) from PCV13-vaccinated individuals post-vaccination were plotted against IgG (C), IgG1 (D) and IgG2 (E) titres. The R² and p values indicate analysis via linear regression. * p <0.05, ** p <0.01, *** p <0.001, **** p <0.0001.

Fig. 3

Antibody avidity to S. pneumoniae serotype 6B in HepA- and PCV13-vaccinated adults. Antibody avidity measuring IgG avidity by thiocyanate chaotropic disruption is given as avidity index (AI) in molar units of NaSCN. Data are divided by HepA-vaccinated ‘naturally exposed’ individuals (n = 24) (A) and PCV13-vaccinated individuals (n = 21) (B) and split by colonisation outcome after experimental challenge with serotype 6B as part of the EHPC protocol. Box-and-whisker plots indicate medians, IQR and min/max values; statistical comparison of baselines (A) by Mann-Whitney unpaired t test and baseline vs post-vaccination timepoints (B) by Wilcoxon signed rank test. Avidity indices from the post-vaccination samples were plotted against IgG titres (C) and opsonic indices (D) and analysed by linear regression for correlation. R² values are indicated on the plots. ** p <0.01, *** p <0.001, **** p <0.0001.

Fig. 4

Relationship between intensity of colonisation and immunity to S. pneumoniae serotype 6B amongst PCV13-vaccinated and unvaccinated adults. Linear correlations of intensity of colonisation (AUC) against log-transformed IgG1 (A), IgG2 (B), OPK (C) and avidity (D) at the post-vaccination time point (pre-challenge). Grey circles represent unvaccinated individuals (HepA-vaccinated controls). R² and p values shown refer to the linear correlation for unvaccinated controls only, excluding the three PCV13-vaccinated individuals (shown by black circles for reference). All p values are not significant.

Fig. 5

Antibody titres and avidity to S. pneumoniae vaccine serotypes in Malawian children. Box and whisker plots show IgG titres (ug/ml, left y-axis, empty circles) and IgG avidity index (M, right y-axis, filled circles) for children aged 3–9 months (n = 18–20) and >24 months (n = 20–24) for serotypes 19F, 6A and 7F (A-C). Box-and-whisker plots indicate medians, IQR and min/max values. Statistical analysis by unpaired Mann-Whitney t test, * p <0.05, ** p <0.01.

Fig. 6

Opsonophagocytic killing responses in Malawian children to S. pneumoniae serotypes 19F and 6A. OI values are divided by age group (3–9 months (n = 11) or >24 months (n = 20)) for serotypes 19F (A, C) and 6A (B, D). Box-and-whisker plots indicate medians, IQR and min/max values. Scatter plots show OI vs whole IgG titre (ug/ml). R² and p values shown on each plot indicate analysis via linear regression. ** p <0.01.