Group B Streptococcus (GBS) infections are a major cause of invasive disease (IGbsD) in young infants and cause miscarriage and stillbirths. Immunization of pregnant women against GBS in addition to ...intrapartum antibiotic prophylaxis could prevent disease. Establishing accurate serological markers of protection against IGbsD could enable use of efficient clinical trial designs for vaccine development and licensure, without needing to undertake efficacy trials in prohibitively large number of mother-infant dyads. The association of maternal naturally acquired serotype-specific anti-capsular antibodies (IgG) against serotype-specific IGbsD in their infants has been studied in case-control studies. The statistical models used so far to estimate IGbsD risk from these case-control studies assumed that the antibody concentrations measured sharing the same disease status are sampled from the same population, not allowing for differences between mothers colonised by GBS and mothers also potentially infected (e.g urinary tract infection or chorioamnionitis) by GBS during pregnancy. This distinction is relevant as infants born from infected mothers with occult medical illness may be exposed to GBS prior to the mother developing antibodies measured in maternal or infant sera.
Unsupervised mixture model averaging (MMA) is proposed and applied here to accurately estimate infant IGbsD risk from case-control study data in presence or absence of antibody concentration subgroups potentially associated to maternal GBS carriage or infection. MMA estimators are compared to non-parametric disease risk estimators in simulation studies and by analysis of two published GBS case-control studies.
MMA provides more accurate relative risk estimates under a broad range of data simulation scenarios and more accurate absolute disease risk estimates when the proportion of IGbsD cases with high antibody levels is not ignorable. MMA estimates of the relative and absolute disease risk curves are more amenable to clinical interpretation compared to non-parametric estimates with no detectable overfitting of the data. Antibody concentration thresholds predictive of protection from infant IGbsD estimated by MMA from maternal and infant sera are consistent with non-parametric estimates.
MMA is a flexible and robust method for design, accurate analysis and clinical interpretation of case-control studies estimating relative and absolute IGbsD risk from antibody concentrations measured at or after birth.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Summary Background South Africa has the highest incidence of tuberculosis in the world, largely resulting from a high population prevalence of HIV infection. We investigated the incidence of ...microbiologically confirmed pulmonary tuberculosis, and new cases of pulmonary tuberculosis registered for treatment, nationally and provincially in South Africa from 2004 to 2012, during which time there were changes in antiretroviral therapy (ART) coverage among individuals with HIV infection. Methods We identified cases of microbiologically confirmed pulmonary tuberculosis from 2004 to 2012 from the National Health Laboratory Service Corporate Data Warehouse. New cases registered for treatment were identified from National Department of Health electronic registries. A time series analysis, using autoregressive models, was undertaken on incidence of microbiologically confirmed pulmonary disease nationally and provincially; this trend was also examined relative to ART coverage of adults with HIV infection. Findings During the 9-year period, 3 523 371 cases of microbiologically confirmed pulmonary tuberculosis were recorded nationally. Annual incidence (per 100 000 population) increased from 650 (95% CI 648–652) in 2004 to 848 (845–850) in 2008, declining to 774 (771–776) by 2012 (9% decrease from 2008 to 2012). Incidence varied by age-group, sex, and province. There was an inverse association between incidence of microbiologically confirmed disease and ART coverage among HIV-infected individuals nationally and provincially. Trends in incidence of tuberculosis cases registered for treatment mirrored those of microbiologically confirmed cases nationally and provincially; however, incidence of microbiologically confirmed cases was consistently higher than cases registered for treatment nationally and in seven of nine provinces. Interpretation Since its peak in 2008, the incidence of microbiologically confirmed pulmonary tuberculosis in South Africa had declined by 2012; this decline is associated with an increase in ART coverage. Future integration of registries for microbiologically confirmed cases and new cases registered for treatment would improve the assessment of the burden of pulmonary tuberculosis in South Africa. Funding National Institute for Communicable Diseases: Division of the National Health Laboratory Service, South Africa.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Abstract SARS-CoV-2 cell-mediated immunity remains understudied during pregnancy in unvaccinated Black African women living with HIV (WLWH) from low- and middle-income countries. We investigated ...SARS-CoV-2-specific T-cell responses 1 month following infection in 24 HIV-uninfected women and 15 WLWH at any stage during pregnancy or postpartum. The full-length spike (FLS) glycoprotein and nucleocapsid (N) protein of wild-type (WT) SARS-CoV-2, as well as mutated spike protein regions found in the Omicron variant (B.1.1.529) were targeted by flow cytometry. WT-specific CD4 + and CD8 + T cells elicited similar FLS- and N-specific responses in HIV-uninfected women and WLWH. SARS-CoV-2-specific T-lymphocytes were predominantly TNF-α monofunctional in pregnant and postpartum women living with and without HIV, with fever cells producing either IFN-γ or IL-2. Furthermore, T-cell responses were unaffected by Omicron-specific spike mutations as similar responses between Omicron and the ancestral virus were detected for CD4 + and CD8 + T cells. Our results collectively demonstrate comparable T-cell responses between WLWH on antiretroviral therapy and HIV-uninfected pregnant and postpartum women who were naïve to Covid-19 vaccination. Additionally, we show that T cells from women infected with the ancestral virus, Beta variant (B.1.351), or Delta variant (B.1.617.2) can cross-recognize Omicron, suggesting an overall preservation of T-cell immunity.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Background. The public health impact of rotavirus vaccination in African settings with a high human immunodeficiency virus (HIV) infection prevalence is yet to be established. We evaluated trends in ...all-cause diarrheal hospitalizations in Soweto, Johannesburg, before and after the introduction of rotavirus vaccine into South Africa's national immunization program in August 2009. Methods. Hospitalizations in children <5 years of age with a diagnosis of diarrhea, defined by International Classification of Diseases, Tenth Revision codes A00–A05, A06.0–A06.3, A06.9, A07.0–A07.2, A07.9, and A08–A09, were identified at the Chris Hani Baragwanath Academic Hospital from 1 January 2006 to 31 December 2014. The median annual prevaccine (2006–2008) hospitalization incidence was compared to that of the vaccine era (2010–2014), and stratified by age group and HIV infection status. Results. Incidence reductions (per 1000 population) were greatest in children aged <12 months: 54.4 in the prevaccine era vs 30.0, 23.6, 20.0, 18.8, and 18.9 in the postvaccine years 2010–2014, respectively (a 44.9%–65.4% reduction). Lower incidence reductions (39.8%–49.4%) were observed among children aged 12–24 months from the second year post–vaccine introduction onward. Reductions were observed in both HIV-infected and HIV-uninfected children. There was a change in the seasonal pattern of diarrheal hospitalizations post–vaccine introduction, with flattening of the autumn–winter peaks seen in the prevaccine years. Conclusions. An accelerated and sustained decline in all-cause diarrheal hospitalizations, temporally associated with rotavirus vaccine introduction, was observed in children <2 years of age. However, the impact of other interventions such as improved sanitation and changes in HIV management cannot be discounted.
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BFBNIB, NUK, PNG, UL, UM, UPUK
Background Vaccination of infants with pneumococcal conjugate vaccines is recommended by the World Health Organization. Evidence is mixed regarding the differences in immunogenicity and efficacy of ...the different pneumococcal vaccines. Objectives The primary objective was to compare the immunogenicity of pneumococcal conjugate vaccine-10 versus pneumococcal conjugate vaccine-13. The main secondary objective was to compare the seroefficacy of pneumococcal conjugate vaccine-10 versus pneumococcal conjugate vaccine-13. Methods We searched the Cochrane Library, EMBASE, Global Health, MEDLINE, ClinicalTrials.gov and trialsearch.who.int up to July 2022. Studies were eligible if they directly compared either pneumococcal conjugate vaccine-7, pneumococcal conjugate vaccine-10 or pneumococcal conjugate vaccine-13 in randomised trials of children under 2 years of age, and provided immunogenicity data for at least one time point. Individual participant data were requested and aggregate data used otherwise. Outcomes included the geometric mean ratio of serotype-specific immunoglobulin G and the relative risk of seroinfection. Seroinfection was defined for each individual as a rise in antibody between the post-primary vaccination series time point and the booster dose, evidence of presumed subclinical infection. Each trial was analysed to obtain the log of the ratio of geometric means and its standard error. The relative risk of seroinfection (‘seroefficacy’) was estimated by comparing the proportion of participants with seroinfection between vaccine groups. The log-geometric mean ratios, log-relative risks and their standard errors constituted the input data for evidence synthesis. For serotypes contained in all three vaccines, evidence could be synthesised using a network meta-analysis. For other serotypes, meta-analysis was used. Results from seroefficacy analyses were incorporated into a mathematical model of pneumococcal transmission dynamics to compare the differential impact of pneumococcal conjugate vaccine-10 and pneumococcal conjugate vaccine-13 introduction on invasive pneumococcal disease cases. The model estimated the impact of vaccine introduction over a 25-year time period and an economic evaluation was conducted. Results In total, 47 studies were eligible from 38 countries. Twenty-eight and 12 studies with data available were included in immunogenicity and seroefficacy analyses, respectively. Geometric mean ratios comparing pneumococcal conjugate vaccine-13 versus pneumococcal conjugate vaccine-10 favoured pneumococcal conjugate vaccine-13 for serotypes 4, 9V and 23F at 1 month after primary vaccination series, with 1.14- to 1.54-fold significantly higher immunoglobulin G responses with pneumococcal conjugate vaccine-13. Risk of seroinfection prior to the time of booster dose was lower for pneumococcal conjugate vaccine-13 for serotype 4, 6B, 9V, 18C and 23F than for pneumococcal conjugate vaccine-10. Significant heterogeneity and inconsistency were present for most serotypes and for both outcomes. Twofold higher antibody after primary vaccination was associated with a 54% decrease in risk of seroinfection (relative risk 0.46, 95% confidence interval 0.23 to 0.96). In modelled scenarios, pneumococcal conjugate vaccine-13 or pneumococcal conjugate vaccine-10 introduction in 2006 resulted in a reduction in cases that was less rapid for pneumococcal conjugate vaccine-10 than for pneumococcal conjugate vaccine-13. The pneumococcal conjugate vaccine-13 programme was predicted to avoid an additional 2808 (95% confidence interval 2690 to 2925) cases of invasive pneumococcal disease compared with pneumococcal conjugate vaccine-10 introduction between 2006 and 2030. Limitations Analyses used data from infant vaccine studies with blood samples taken prior to a booster dose. The impact of extrapolating pre-booster efficacy to post-booster time points is unknown. Network meta-analysis models contained significant heterogeneity which may lead to bias. Conclusions Serotype-specific differences were found in immunogenicity and seroefficacy between pneumococcal conjugate vaccine-13 and pneumococcal conjugate vaccine-10. Higher antibody response after vaccination was associated with a lower risk of subsequent infection. These methods can be used to compare the pneumococcal conjugate vaccines and optimise vaccination strategies. For future work, seroefficacy estimates can be determined for other pneumococcal vaccines, which could contribute to licensing or policy decisions for new pneumococcal vaccines. Study registration This study is registered as PROSPERO CRD42019124580. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 17/148/03) and is published in full in Health Technology Assessment; Vol. 28, No. 34. See the NIHR Funding and Awards website for further award information.
Despite approximately 2.6 million stillbirths occurring annually, there is a paucity of systematic biological investigation and consequently knowledge on the causes of these deaths in low- and ...middle-income countries (LMICs). We investigated the utility of minimally invasive tissue sampling (MITS), placental examination, and clinical history, in attributing the causes of stillbirth in a South African LMIC setting.
This prospective, observational pilot study undertook sampling of brain, lung, and liver tissue using core biopsy needles, blood and cerebrospinal fluid collection, and placental examination. Testing included microbial culture and/or molecular testing and tissue histological examination. The cause of death was determined for each case by an international panel of medical specialists and categorized using the World Health Organization's International Classification of Diseases, Tenth Revision application to perinatal deaths.
A cause of stillbirth was identifiable for 117 of 129 (90.7%) stillbirths, including an underlying maternal cause in 63.4% (n = 83) and an immediate fetal cause in 79.1% (n = 102) of cases. The leading underlying causes of stillbirth were maternal hypertensive disorders (16.3%), placental separation and hemorrhage (14.0%), and chorioamnionitis (10.9%). The leading immediate causes of fetal death were antepartum hypoxia (35.7%) and fetal infection (37.2%), including due to Escherichia coli (16.3%), Enterococcus species (3.9%), and group B Streptococcus (3.1%).
In this pilot, proof-of-concept study, focused investigation of stillbirth provided granular detail on the causes thereof in an LMIC setting, including provisionally highlighting the largely underrecognized role of fetal sepsis as a dominant cause.
We evaluated the association between early-onset sepsis and neonatal encephalopathy in a low-middle-income setting.
We undertook a retrospective study in newborns with gestational age ≥35 weeks ...and/or birth weight ≥2500 grams, diagnosed with neonatal encephalopathy. Early-onset sepsis was defined as culture-confirmed sepsis or probable sepsis.
Of 10,182 hospitalised newborns, 1027 (10.1%) were diagnosed with neonatal encephalopathy, of whom 52 (5.1%) had culture-confirmed and 129 (12.5%) probable sepsis. The case fatality rate for culture-confirmed sepsis associated neonatal encephalopathy was threefold higher compared to neonatal encephalopathy without sepsis (30.8% vs. 10.5%, p < 0.001). Predictors of mortality for culture-confirmed sepsis associated neonatal encephalopathy included severe neonatal encephalopathy (aOR 6.51, 95%CI: 1.03-41.44) and seizures (aOR 10.64, 95%CI: 1.05-107.39).
In this setting, 5% of neonatal encephalopathy cases was associated with culture-confirmed sepsis and a high case fatality rate.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
About 2·6 million third-trimester stillbirths occur annually worldwide, mostly in low-income and middle-income countries, where the causes of these deaths are rarely investigated.
We did a ...prospective, hospital-based, observational study in Soweto, South Africa, to investigate the causes of stillbirths in fetuses of at least 22 weeks' gestational age or with a birthweight of at least 500 g. Maternal clinical information was abstracted from medical records. Investigations included placental macroscopic and histopathological examination and fetal blood culture (including screening for pathogenic bacteria associated with stillbirth). Cases missing one or more of these investigations were considered to have incomplete samples and were excluded from the analysis of cause of stillbirth. Causes of stillbirths were assessed by individual case reviews by at least two obstetricians, and classified with a modified Stillbirth Collaborative Research Network classification system.
Between Oct 9, 2014, and Nov 8, 2015, we enrolled 354 stillbirths (born to 350 women). Among the women with available data, 133 (38%) of 350 had hypertension, median age was 27 years (IQR 23–33), 51 (18%) of 291 were obese, six (2%) of 344 had syphilis, and 94 (27%) of 350 had HIV. 63 (18%) of 341 fetuses showed intrauterine growth restriction. Of 298 cases (born to 294 mothers) with complete samples, the most common causes of stillbirth were maternal medical conditions (64 21% cases; among them 56 19% with hypertensive disorders and six 2% with diabetes), placental or fetal infections (58 19%; 47 16% with fetal invasive bacterial infection), pathological placental conditions (57 19%; among them 27 9% with fetal membrane and placental inflammation and 26 9% with circulatory abnormalities), and clinical obstetric complications (54 18%; 45 15% with placental abruption). Six (2%) stillbirths were attributed to fetal, genetic, or structural abnormalities. In 55 (18%) cases, no cause of death was identified. The most common bacteria to which stillbirths due to fetal invasive infections were attributed were group B streptococcus (15 5% cases), E coli (12 4%), E faecalis (six 2%), and S aureus (five 2%).
Targeted investigation of stillbirths (even without fetal autopsy) can ascertain a cause of stillbirth in most cases. Further studies using such investigations are needed to inform the prioritisation of interventions to reduce stillbirths globally.
Novartis and GlaxoSmithKline.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
There is a paucity of longitudinal data on the serotype-specific burden of invasive group B Streptococcus (GBS) disease from low-middle income countries, which could inform selection of vaccine ...epitopes.
From 2005 to 2014, infants less than 90 days of age with invasive GBS disease were identified through sentinel laboratory and hospital admission surveillance at Chris Hani Baragwanath Academic Hospital in Soweto, South Africa.
We identified 820 cases of invasive GBS disease, including 55% among newborns <7 days age (i.e. early-onset disease; EOD). The overall incidence (per 1,000 live births) of invasive GBS disease was 2.59 (95% CI: 2.42-2.77), including 1.41 (95% CI: 1.28-1.55) for EOD and 1.18 (95% CI: 1.06-1.30) in infants 7-89 days age (late-onset disease). Year-on-year, from 2005 to 2014, we observed a 9.4% increase in incidence of serotype Ia invasive disease (RR: 1.09; 95% CI: 1.04-1.15; p<0.001), and a 7.4% decline in serotype III invasive disease (RR: 0.93; 95% CI: 0.90-0.96; p<0.001). Overall, serotypes Ia (28.2%), III (55.4%) and V (7.9%) were the commonest disease causing serotypes.
The incidence of invasive GBS disease has remained persistently high in our setting, with some changes in serotype distribution, albeit mainly involving the same group of dominant serotypes.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
We conducted an epidemiologic survey to determine the seroprevalence of SARS-CoV-2 anti-nucleocapsid (anti-N) and anti-spike (anti-S) protein IgG from 1 March to 11 April 2022 after the BA.1-dominant ...wave had subsided in South Africa and prior to another wave dominated by the BA.4 and BA.5 (BA.4/BA.5) sub-lineages. We also analysed epidemiologic trends in Gauteng Province for cases, hospitalizations, recorded deaths, and excess deaths were evaluated from the inception of the pandemic through 17 November 2022. Despite only 26.7% (1995/7470) of individuals having received a COVID-19 vaccine, the overall seropositivity for SARS-CoV-2 was 90.9% (95% confidence interval (CI), 90.2 to 91.5) at the end of the BA.1 wave, and 64% (95% CI, 61.8 to 65.9) of individuals were infected during the BA.1-dominant wave. The SARS-CoV-2 infection fatality risk was 16.5-22.3 times lower in the BA.1-dominant wave compared with the pre-BA.1 waves for recorded deaths (0.02% vs. 0.33%) and estimated excess mortality (0.03% vs. 0.67%). Although there are ongoing cases of COVID-19 infections, hospitalization and death, there has not been any meaningful resurgence of COVID-19 since the BA.1-dominant wave despite only 37.8% coverage by at least a single dose of COVID-19 vaccine in Gauteng, South Africa.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
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