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

Thesis (M Med.(Obstetrics & Gynecology))--University of Limpopo,2009. / OBJECTIVE: The objectives of the study were: 1) To determine the pattern of toxicity/side-effects among women using Highly Active Antiretroviral Therapy (HAART) in the perinatal period in comparison with women who were treated with intra- partum prophylaxis of nevirapine at the time of delivery. 2) To evaluate the effects of either approach of therapy on maternal and fetal outcomes. METHODOLOGY: STUDY DESIGN The department of Obstetrics and Gynaecology has begun to administer HAART to pregnant women identified for ARV programme. These women were counseled and recruited prospectively for the study. The study involved comparison of pregnancy outcomes between women identified for HAART and those who were HIV infected but who only required intra-partum prophylaxis in labour to prevent mother-to-child transmission of HIV with nevirapine.

Thesis (Ph.D.)--Kent State University, 2009. / Title from PDF t.p. (viewed Jan. 22, 2010). Advisor: Cynthia Symons. Keywords: Medical students'; pregnant; alcohol use; alcohol screening; alcohol counseling Includes bibliographical references (p. 183-206).

Thesis (Ed. S.)--Marshall University, 2002. / Title from document title page. Document formatted into pages; contains 34 p. Includes bibliographical references (p. 20-22).

Thesis (Ph. D.)--University of Texas at Austin, 2002. / Vita. Includes bibliographical references. Available also from UMI Company.

Thesis (Ph. D.)--University of Toronto, 2004. / Adviser: Ardra Cole.

Thesis (Ph. D.)--University of New South Wales, 1999. / Bibliographical references: leaves 283-320. Also available online.

Thesis (Ph.D.)--University of Melbourne, Faculty of Medicine,Dentistry and Health Sciences, 2005. / Typescript. Includes bibliographical references (leaves 292-320).

Thesis (M.D.S.)--University of Sydney, 1964. / Includes tables. Title from title screen (viewed 17 April 2009). Includes bibliographical references. Also available in print form.

Thesis (M.P.A.)--University of Hong Kong, 2008. / Includes bibliographical references (p. 145-150).