Association between functional antibody against Group B Streptococcus and maternal and infant colonization in a Gambian cohort

Kirsty Le Doare, Amadou Faal, Mustapha Jaiteh, Francess Sarfo, Stephen Taylor, Fiona Warburton, Holly Humphries, Jessica Birt, Sheikh Jarju, Saffiatou Darboe, Edward Clarke, Martin Antonio, Ebenezer Foster-Nyarko, Paul T Heath, Andrew Gorringe, Beate Kampmann, Kirsty Le Doare, Amadou Faal, Mustapha Jaiteh, Francess Sarfo, Stephen Taylor, Fiona Warburton, Holly Humphries, Jessica Birt, Sheikh Jarju, Saffiatou Darboe, Edward Clarke, Martin Antonio, Ebenezer Foster-Nyarko, Paul T Heath, Andrew Gorringe, Beate Kampmann

Abstract

Background: Vertical transmission of Group B Streptococcus (GBS) is a prerequisite for early-onset disease and a consequence of maternal GBS colonization. Disease protection is associated with maternally-derived anti-GBS antibody. Using a novel antibody-mediated C3b/iC3b deposition flow cytometry assay which correlates with opsonic killing we developed a model to assess the impact of maternally-derived functional anti-GBS antibody on infant GBS colonization from birth to day 60-89 of life.

Methods: Rectovaginal swabs and cord blood (birth) and infant nasopharyngeal/rectal swabs (birth, day 6 and day 60-89) were obtained from 750 mother/infant pairs. Antibody-mediated C3b/iC3b deposition with cord and infant sera was measured by flow cytometry.

Results: We established that as maternally-derived anti-GBS functional antibody increases, infant colonization decreases at birth and up to three months of life, the critical time window for the development of GBS disease. Further, we observed a serotype (ST)-dependent threshold above which no infant was colonized at birth. Functional antibody above the upper 95th confidence interval for the geometric mean concentration was associated with absence of infant GBS colonization at birth for STII (p<0.001), STIII (p=0.01) and STV (p<0.001). Increased functional antibody was also associated with clearance of GBS between birth and day 60-89.

Conclusions: Higher concentrations of maternally-derived antibody-mediated complement deposition are associated with a decreased risk of GBS colonization in infants up to day 60-89 of life. Our findings are of relevance to establish thresholds for protection following vaccination of pregnant women with future GBS vaccines.

Keywords: Group B Streptococcus; Meningitis; Neonatal; Vaccines.

Copyright © 2017 The Author(s). Published by Elsevier Ltd.. All rights reserved.

Figures

Fig. 1
Fig. 1
Correlation between antibody-mediated complement deposition (FI-C′) and opsonophagocytosis killing (OPkA) for serotypes Ia (A), II (B) and V (C). Panel (D) – Correlation between antibody-mediated complement deposition (FI-C′) performed with formaldehyde-fixed and live serotype III GBS. r = Pearson product-moment correlation coefficient.
Fig. 2
Fig. 2
GM antibody-mediated C3b/iC3b deposition (95% CI) in cord blood onto GBS ST Ia, II, III and V. Dot plot demonstrating GM antibody-mediated C3b/iC3b deposition against GBS STIa, II, III and V in cord blood (n = 525). GM FI-C′ [95% CI] compared between mothers colonized with homologous serotype (colored shapes), non-colonized mothers (gray shapes) and mothers colonized with other serotypes (blue squares). ANOVA was calculated to compare groups *p 

Fig. 3

Antibody-mediated C3b/iC3b deposition comparing mother…

Fig. 3

Antibody-mediated C3b/iC3b deposition comparing mother and infant colonization groups. Dot plots representing the…

Fig. 3
Antibody-mediated C3b/iC3b deposition comparing mother and infant colonization groups. Dot plots representing the mean and 95% confidence intervals of log10 FI-C′ values of antibody-mediated C3b/iC3b deposition onto the surface of whole GBS STs Ia, II, III and V bacteria (n = 525). FI-C′ – fluorescence intensity minus complement control; M−I− – neither mother nor infant colonized; M+I+(Ia/II/III/V) – both mother and infant colonized with the homologous GBS ST; M+I− – mother colonized with homologous ST, infant non-colonized with any ST; M+I+O – mother and infant colonized with different GBS ST; M−I+ – infant colonized with homologous ST, mother non-colonized with any ST. M−I− = neither mother nor infant colonized; M+I+ mother and infant colonized; M+I− = mother only colonized; M−I+ infant only colonized; ST = serotype. ANOVA was used to compare groups; *p < 0.05; ***P < 0.01; ****p < 0.001. STIb not shown.

Fig. 4

Infant GBS colonization, functional antibody…

Fig. 4

Infant GBS colonization, functional antibody threshold observed and associated Deming regression with calculated…

Fig. 4
Infant GBS colonization, functional antibody threshold observed and associated Deming regression with calculated threshold. Scatter plots of log10GBS CFU/mL from infant swabs and log10 FI-C′: for GBS STII, III and V. Horizontal line represents threshold above which there was no bacterial colonization observed. STII n = 21 STIII n = 10; STV n = 62.CFU/mL – colony-forming units per milliliter; FI-C′ fluorescence intensity minus C3b/iC3b only control; ST – serotype. Deming regression of log10 FI-C′ against log10 bacterial concentration for GBS ST II, III and V comparing cord serum with CFU/mL from infant swabs at birth. Log10 bacterial concentration on the x-axis (CFU/mL), log10 FI-C′ on the y-axis.

Fig. 5

Median and standard deviation of…

Fig. 5

Median and standard deviation of antibody-mediated C3b/iC3b deposition in cord blood comparing non-colonized,…

Fig. 5
Median and standard deviation of antibody-mediated C3b/iC3b deposition in cord blood comparing non-colonized, intermittently and persistently colonized infants. Box and whisker plot with Tukey correction demonstrating median antibody-mediated C3b/iC3b deposition in non-colonized infants, intermittently colonized infants (one occasion), infants colonized on two occasions and persistently colonized infants with GBS STIa, II, III and V. FI-C′ = fluorescence intensity minus complement control, n = 525. ANOVA was calculated to determine differences between the four groups, *p 
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References
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Fig. 3
Fig. 3
Antibody-mediated C3b/iC3b deposition comparing mother and infant colonization groups. Dot plots representing the mean and 95% confidence intervals of log10 FI-C′ values of antibody-mediated C3b/iC3b deposition onto the surface of whole GBS STs Ia, II, III and V bacteria (n = 525). FI-C′ – fluorescence intensity minus complement control; M−I− – neither mother nor infant colonized; M+I+(Ia/II/III/V) – both mother and infant colonized with the homologous GBS ST; M+I− – mother colonized with homologous ST, infant non-colonized with any ST; M+I+O – mother and infant colonized with different GBS ST; M−I+ – infant colonized with homologous ST, mother non-colonized with any ST. M−I− = neither mother nor infant colonized; M+I+ mother and infant colonized; M+I− = mother only colonized; M−I+ infant only colonized; ST = serotype. ANOVA was used to compare groups; *p < 0.05; ***P < 0.01; ****p < 0.001. STIb not shown.
Fig. 4
Fig. 4
Infant GBS colonization, functional antibody threshold observed and associated Deming regression with calculated threshold. Scatter plots of log10GBS CFU/mL from infant swabs and log10 FI-C′: for GBS STII, III and V. Horizontal line represents threshold above which there was no bacterial colonization observed. STII n = 21 STIII n = 10; STV n = 62.CFU/mL – colony-forming units per milliliter; FI-C′ fluorescence intensity minus C3b/iC3b only control; ST – serotype. Deming regression of log10 FI-C′ against log10 bacterial concentration for GBS ST II, III and V comparing cord serum with CFU/mL from infant swabs at birth. Log10 bacterial concentration on the x-axis (CFU/mL), log10 FI-C′ on the y-axis.
Fig. 5
Fig. 5
Median and standard deviation of antibody-mediated C3b/iC3b deposition in cord blood comparing non-colonized, intermittently and persistently colonized infants. Box and whisker plot with Tukey correction demonstrating median antibody-mediated C3b/iC3b deposition in non-colonized infants, intermittently colonized infants (one occasion), infants colonized on two occasions and persistently colonized infants with GBS STIa, II, III and V. FI-C′ = fluorescence intensity minus complement control, n = 525. ANOVA was calculated to determine differences between the four groups, *p 

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