Submitted in fulfilment for the degree of Doctor of Philosophy
Department of Clinical Microbiology and Infectious Diseases
School of Pathology
Faculty of Health Sciences
University of Witwatersrand
2017. / Background Vaccination of pregnant women with conserved group B Streptococcus
(GBS) surface proteins has the potential to confer serotype independent protection
against invasive GBS disease. Susceptibility to early onset (<7 days of age) GBS
disease in infants is associated with maternal recto-vaginal colonisation, low circulating
maternal antibodies and reduced trans-placental transfer of antibodies specific to GBS
capsular polysaccharides (CPS). Additionally, invasive GBS disease beyond infancy has
been reported in individuals with underlying conditions associated with
immunosuppression including HIV infection. In this study we undertook retrospective
analysis of serum IgG titres against select GBS surface proteins in relation to invasive
GBS disease risk factors.
Methods Multiplex Luminex immunoassay was used to measure serum IgG titres
against GBS capsular polysaccharides of serotype Ia, Ib, III and V and surface proteins
Fibrinogen binding surface Antigen (FbsA), GBS Immunogenic Bacterial Adhesin
(BibA), Surface immunogenic protein (Sip), gbs0393, gbs1356, gbs1539, gbs0392; and
lipoproteins gbs0233, gbs2106 and Foldase PsrA. Furthermore, in vitro expression of
Sip, gbs2106, gbs0393 and gbs1356 proteins on the surface of clinical GBS isolates was
assessed by flow cytometry using protein specific polyclonal antibodies generated in
rabbits.
Results Retrospective analyses of serum antibody titres against GBS surface proteins
and CPS were measured in children between 4-7 years of age who were either HIVinfected
(n=68) or HIV-uninfected (n=77). Lower geometric meant titres (GMT, U/mL)
against Sip and gbs2106 were detected in HIV-infected children (77.03 and 53.10)
compared to HIV-uninfected children (196.41 and 139.11, p<0.001) respectively.
Similar results were observed for antibodies against CPS, with HIV-infected children
having lower IgG GMC for serotype Ib (p=0.012) and V (p=0.005).
Protein specific antibody titres were measured in pregnant women at 20-25 and ≥37
weeks of gestation age who were either non-colonised or colonised with GBS in the
rectal and/or vaginal tract. Acquisition of GBS colonisation in the vagina was associated
with higher antibody titres compared to colonisation in the rectum for proteins Sip
(p=0.049), Foldase (p=0.0094), gbs0233 (p=0.0039), gbs0393 (p=0.027), gbs1539
(p=0.0004) and gbs1356 (p=0.039). The likelihood of acquiring GBS colonisation
during pregnancy was lower in women having median IgG titres against gbs0233 ≥200
U/mL (adjusted OR=0.47 [95% CI: 0.25-0.89], p=0.021) and gbs1539 ≥85 U/mL
(adjusted OR=0.44 [95% CI: 0.24-0.82], p=0.01).
The influence of maternal HIV infection on trans-placental transfer of antibodies against
GBS surface proteins was evaluated by comparing IgG titres between 83 HIV-infected
and 81 HIV-uninfected mother-newborn dyads. Maternal HIV infection was associated
with reduced trans-placental transfer of antibodies, demonstrated by the difference in
cord-maternal antibody ratios between HIV-infected and HIV-uninfected mothernewborn
pairs for Sip (25.8%, p<0.001), Foldase (30.4%, p<0.001), gba0392 (36.5%,
p=0.006), gbs0393 (32.9%, p<0.001), gbs1539 (39.2%, p<0.008), gbs2106 (35.7%,
p<0.001) and BibA (19.4%, p=0.004).
A case control study was used to evaluate the association of protein specific IgG titres
and invasive disease in neonates and young infants born to GBS colonised mothers,
including 116 with healthy infants and 66 with invasive GBS disease at <90 days of
age. Lower IgG GMT were detected in neonates who developed early-onset disease
compared to control infants for Sip (65.48 vs 145.43, p<0.001), Foldase (50.45 vs
109.87, p=0.005), gbs0393 (106.42 vs 221.81, p=0.006) and gbs1356 (45.34 vs 94.52,
p=0.01). Similarly, young infants with late-onset disease had significantly lower IgG
GMT (U/mL) compared to healthy controls for Sip (43.72 vs 79.69, p=0.04) and
gbs2106 (30.46 vs 65.35, p=0.003). Infants born to women with Sip specific antibody
titres ≥150 U/mL antibodies titres against Sip were 66% less likely to develop invasive
disease.
Of the 82 GBS isolates collected from mothers who deliverd term babies (39 with
invasive GBS disease and 43 healthy controls) that were assessed for in vitro expression
of specific proteins, Sip, gbs2106 and gbs0393 were expressed in 70.7% 93.9% and
87.8% GBS isolates respectively. The expression of gbs2106 on the surface of GBS was
more frequent in strains of women with infants who developed invasive disease
compared to those with healthy infants (100% vs 88.4%, p=0.028). The distribution of
Sip and gbs0393 expression between GBS isolates from women of infants with invasive
GBS disease and healthy controls was similar, 71.8% vs 69.8% (p=0.84) and 89.7% vs
86.0% (p=0.61) respectively. Among women carrying GBS strains expressing gbs2106,
having antibody titres ≥100 U/mL was associated with 90% lower likelihood for
delivering infants that develop invasive GBS disease (OR=0.11 [95% CI: 0.02-0.54],
p=0.002).
Conclusion Vulnerability to invasive GBS disease in HIV-infected
immunocompromised individuals is possibly due to reduced antibody levels against
CPS, Sip and gbs2106. Also, susceptibility to invasive GBS disease in infants may be
exacerbated by maternal HIV-infection, which was associated with reduced transplacental
transfer of antibody against GBS surface proteins.
Higher maternal antibodies titres against Sip and gbs2106 proteins were associated with reduced odds of their infants developing invasive GBS disease. These data support consideration of Sip and gbs2106 proteins as possible vaccine candidates in pregnant women to protect their infants against invasive GBS disease. Furthermore, reduced GBS colonisation during pregnancy can be achieved by maternal immunisation of gbs0233 and gbs1539, which may subsequently result in lower rates of GBS transmission to newborns and thereby decreasing their risk for invasive GBS disease. / MT2017
| Identifer | oai:union.ndltd.org:netd.ac.za/oai:union.ndltd.org:wits/oai:wiredspace.wits.ac.za:10539/23160 |
| Date | January 2017 |
| Creators | Dzanibe, Sonwabile |
| Source Sets | South African National ETD Portal |
| Language | English |
| Detected Language | English |
| Type | Thesis |
| Format | Online resource (xxiii, 265 leaves), application/pdf |
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