BACKGROUND:Natural history studies have correlated serotype-specific anti-capsular polysaccharide (CPS) IgG in newborns with a reduced risk of group B streptococcal disease. A hexavalent CPS-cross-reactive material 197 glycoconjugate vaccine (GBS6) is being developed as a maternal vaccine to prevent invasive group B streptococcus in young infants. METHODS:In an ongoing phase 2, placebo-controlled trial involving pregnant women, we assessed the safety and immunogenicity of a single dose of various GBS6 formulations and analyzed maternally transferred anti-CPS antibodies. In a parallel seroepidemiologic study that was conducted in the same population, we assessed serotype-specific anti-CPS IgG concentrations that were associated with a reduced risk of invasive disease among newborns through 89 days of age to define putative protective thresholds. RESULTS:Naturally acquired anti-CPS IgG concentrations were associated with a reduced risk of disease among infants in the seroepidemiologic study. IgG thresholds that were determined to be associated with 75 to 95% reductions in the risk of disease were 0.184 to 0.827 μg per milliliter. No GBS6-associated safety signals were observed among the mothers or infants. The incidence of adverse events and of serious adverse events were similar across the trial groups for both mothers and infants; more local reactions were observed in the groups that received GBS6 containing aluminum phosphate. Among the infants, the most common serious adverse events were minor congenital anomalies (umbilical hernia and congenital dermal melanocytosis). GBS6 induced maternal antibody responses to all serotypes, with maternal-to-infant antibody ratios of approximately 0.4 to 1.3, depending on the dose. The percentage of infants with anti-CPS IgG concentrations above 0.184 μg per milliliter varied according to serotype and formulation, with 57 to 97% of the infants having a seroresponse to the most immunogenic formulation. CONCLUSIONS:GBS6 elicited anti-CPS antibodies against group B streptococcus in pregnant women that were transferred to infants at levels associated with a reduced risk of invasive group B streptococcal disease. (Funded by Pfizer and the Bill and Melinda Gates Foundation; C1091002 ClinicalTrials.gov number, NCT03765073.).

Background. In children, hypernatraemia occurs most commonly in infants (younger than 1 year). Although hypernatraemia is associated with high mortality and morbidity rates, it is variably defined in the paediatric literature as either serum sodium ≥150 mmol/L or serum sodium >145 mmol/L. In hospitalised adults, a serum sodium level >145 mmol/L but <150 mmol/L (called borderline hypernatraemia) has recently been identified as an independent risk factor for mortality. There are limited data about a potential association between borderline hypernatraemia and mortality in infants. Objectives. To determine whether borderline hypernatraemia is associated with increased mortality in hospitalised infants. Methods. We conducted a single-centre, retrospective observational study of 8 343 infants admitted to a tertiary-level academic hospital in Johannesburg, South Africa, of whom 254 had borderline hypernatraemia, 376 had hypernatraemia (serum sodium ≥150 mmol/L), and 7 713 did not have hypernatraemia. Mortality rates were reported as odds ratios (ORs) with 95% confidence intervals (CIs). Results. In 254 infants with borderline hypernatraemia, 115 (45.3%) were neonates (≤28 days old) and 140 (55.1%) were male. In 139 infants >28 days old with borderline hypernatraemia, the mortality rate (n=9/139; 6.5%) was significantly higher than the mortality rate observed in infants without hypernatraemia (n=194/5 857; 3.3%) (OR 2.02; 95% CI 1.03 - 3.98). Conclusion. Borderline hypernatraemia may be a risk factor associated with higher mortality in hospitalised infants. Prospective studies are required to determine whether borderline hypernatraemia contributes independently to mortality risk in hospitalised infants.

BACKGROUND:Assessment of the safety and efficacy of vaccines against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in different populations is essential, as is investigation of the efficacy of the vaccines against emerging SARS-CoV-2 variants of concern, including the B.1.351 (501Y.V2) variant first identified in South Africa. METHODS:We conducted a multicenter, double-blind, randomized, controlled trial to assess the safety and efficacy of the ChAdOx1 nCoV-19 vaccine (AZD1222) in people not infected with the human immunodeficiency virus (HIV) in South Africa. Participants 18 to less than 65 years of age were assigned in a 1:1 ratio to receive two doses of vaccine containing 5×1010 viral particles or placebo (0.9% sodium chloride solution) 21 to 35 days apart. Serum samples obtained from 25 participants after the second dose were tested by pseudovirus and live-virus neutralization assays against the original D614G virus and the B.1.351 variant. The primary end points were safety and efficacy of the vaccine against laboratory-confirmed symptomatic coronavirus 2019 illness (Covid-19) more than 14 days after the second dose. RESULTS:Between June 24 and November 9, 2020, we enrolled 2026 HIV-negative adults (median age, 30 years); 1010 and 1011 participants received at least one dose of placebo or vaccine, respectively. Both the pseudovirus and the live-virus neutralization assays showed greater resistance to the B.1.351 variant in serum samples obtained from vaccine recipients than in samples from placebo recipients. In the primary end-point analysis, mild-to-moderate Covid-19 developed in 23 of 717 placebo recipients (3.2%) and in 19 of 750 vaccine recipients (2.5%), for an efficacy of 21.9% (95% confidence interval [CI], -49.9 to 59.8). Among the 42 participants with Covid-19, 39 cases (95.1% of 41 with sequencing data) were caused by the B.1.351 variant; vaccine efficacy against this variant, analyzed as a secondary end point, was 10.4% (95% CI, -76.8 to 54.8). The incidence of serious adverse events was balanced between the vaccine and placebo groups. CONCLUSIONS:A two-dose regimen of the ChAdOx1 nCoV-19 vaccine did not show protection against mild-to-moderate Covid-19 due to the B.1.351 variant. (Funded by the Bill and Melinda Gates Foundation and others; ClinicalTrials.gov number, NCT04444674; Pan African Clinical Trials Registry number, PACTR202006922165132).

Background. There is a paucity of data on the aetiology of neonatal sepsis in sub-Saharan Africa. Objectives. To investigate the incidence, aetiology and outcomes of physician-diagnosed sepsis in hospitalised neonates who had previously been discharged home after delivery in Soweto, South Africa. Methods. A retrospective review using data abstracted from clinical and laboratory databases identified physician-diagnosed sepsis cases in neonates admitted to the general paediatric wards at Chris Hani Baragwanath Academic Hospital from January 2015 to September 2016. Neonates with physician-diagnosed sepsis were categorised into two groups based on putative pathogens recovered from blood and/or cerebrospinal fluid specimens: (i) culture-confirmed sepsis; and (ii) culture-negative sepsis. Results. Of 1 826 neonatal admissions, 1 025 (56.2%) had physician-diagnosed sepsis: 166 (16.2%) with culture-confirmed sepsis and 859 (83.8%) with culture-negative neonatal sepsis. The commonest pathogens causing culture-confirmed neonatal sepsis were Streptococcus viridans (n=53; 26.5%), S. agalactiae (n=38; 19.0%), and Staphylococcus aureus (n=25; 12.5%). The case fatality rates for culture-confirmed sepsis and culture-negative sepsis were 10.8% (18/166) and 2.6% (22/859), respectively. The odds of death occurring during hospitalisation was 10-fold (95% confidence interval 3.7 - 26.9) higher in neonates with culture-confirmed sepsis compared with culture-negative sepsis. Conclusions. In our setting, physician-diagnosed sepsis represents a huge disease burden in previously healthy neonates hospitalised from home. Most sepsis cases were attributed to S. viridans, S. agalactiae and S. aureus.

Abstract Background Children with cancer are immunocompromised, with increased susceptibility to infections including infections with Mycobacterium tuberculosis. Method This prospective study, enrolled children one-19 years old hospitalized for cancer treatment. Screening for M. tuberculosis infection was undertaken by tuberculin skin testing (Mantoux method), and ELISPOT (T-SPOT®.TB) (T-spot) on whole blood. Sputum/gastric-washings were investigated for microscopy and culture; and the diagnosis of probable TB was based on existing guidelines. We evaluated the burden of TB in South African children in a setting of high TB-HIV prevalence. Results We enrolled 169 children, 82 (42.5%) with hematological malignancy (HM) and 87 (51.5%) with solid tumors (ST), median age 68.5 months, 10.7% HIV-infected. The majority had severe malnutrition, 78.3% using mid-upper arm circumference and 57.8% using arm muscle anthropometry. Five (2.9%) children with a reactive TST at enrollment, were empirically treated for TB, and were excluded from further analyses. The T-Spot yielded indeterminate/negative results in the first 100 children (including 2.9% who had a reactive TST), and further IGRA testing was terminated. Thirty-four (20.7%) children were diagnosed with TB, (70.6% with HM and 29.4% with ST). At the screening, 14 had indeterminate and 7 negative T-Spot results. Twelve (35.3%) of the 34 TB cases were culture-confirmed. The mean time from initiation of cancer treatment to TB diagnosis was 5.5 months and the time to TB diagnosis from presentation of malignant disease was 6.6 and 4.9 months for culture-confirmed and probable TB, respectively. The spectrum of cancer was acute lymphoblastic leukemia (ALL) (n = 12/32, 37.5%), followed by non-Hodgkin Lymphoma (n = 8/19, 42.1%; seven with HIV infection). The overall incidence (per 100 child-years) of TB was 7.6 (95% CI: 5.3–10.7), 11.3 (95% CI: 7.2–16.8) with HM and 4.3 (95% CI: 2.1–7.9) with ST. HIV-infected children had a higher rate of TB (19.3; 95% CI: 8.3–38) than those not (6.4; 95% CI: 4.2–9.4). Cancer type, HIV-status nor nutritional status was independently associated with risk of TB. Children who developed TB had a higher exposure period to high-dose corticosteroid courses (350 per 100 child-years) than those who did not (29.4 per 100 child-years; P < 0.001). Children with TB compared with those who remained TB-free were more likely to have been treated for septic episodes (SE) associated with profound neutropenia (322.2 vs. 31.3; P < 0.001), profound lymphopenia (288.9 vs. 27.2; P < 0.001) and profound monocytopenia (416.7 vs. 43.0; P < 0.001) prior to the diagnosis of TB. There were 26 deaths (76.5%) in the 34 children with TB and 39/83 (50.0%; P = 0.004) in those who did not develop TB. Eleven had ALL, eight NHL (seven living with HIV), 3 had acute myeloid leukemia, and one each had HIV-related Kaposi Sarcoma, Nephroblastoma, osteosarcoma, and adrenocortical-carcinoma. At the time of death, multiple pathogens were isolated (multi-drug-resistant bacteria, fungi, and respiratory viruses). Conclusion Screening of children undergoing cancer treatment for MTB infection in a setting of high HIV and TB prevalence, was of limited value. The high rate of TB, and poor outcomes, emphasize the need for a high index of suspicion to diagnose TB and consideration for routine prophylaxis.

Globally, a decline in diarrhoeal disease has been observed over the last two decades. This may he attributable to several interventions, including rotavirus vaccination since 2009 in South Africa. From January 2002 to December 2016, we conducted a retrospective trend analysis of diarrhoeal hospitalisations with mild or moderate dehydration to a short-stay ward (SSW) in children <11 years of age. We found that diarrhoeal hospitalisation to the SSW accounted for 29.3% of the 53 717 children who presented with diarrhoea to the emergency department. A significant decline in disease incidence was noted after 2009/2010, coinciding with rotavirus vaccine implementation into the Expanded Programme on Immunisation. The yearly incidence (per 100 000) declined from 307 (95% confidence interval (CI) 277 - 337) over the 2002/2008 period to 141(95% CI 120 - 161) from 2011/2016; p<0.001. In conclusion, rotavirus vaccination was associated with a decline of diarrhoea' disease hospitalisations to the SSW at this hospital.

Background. Vitamin D deficiency (VDD) in pregnant women has been associated with adverse pregnancy and neonatal outcomes. 25-hydroxyvitamin D (25(OH)D) levels are affected by numerous factors, including vitamin D intake, skin pigmentation, latitude and season of the year; they therefore vary by race and country. Vitamin D status in pregnant women and their offspring in South Africa (SA) is not well established. Objectives. To assess vitamin D status by measuring serum 25(OH)D in pregnant black SA women and their offspring in Johannesburg (latitude 26 degrees S) and to assess whether vitamin D status is affected by maternal HIV infection. Methods. We prospectively enrolled pregnant women and their healthy neonates, and measured 25(OH)D in maternal and cord blood at delivery. Pregnant women were stratified by their HIV status. Predictors of maternal and neonatal VDD (levels <30 nmol/L) were assessed using multiple logistic regression analysis. Results. A total of 291 pregnant women and their healthy neonates were enrolled over a 21-month period. Mean (standard deviation) maternal and cord blood 25(OH)D levels were 57.0 (29.7) and 41.9 (21.0) nmol/L and the prevalence of VDD was 15.9% and 32.8%, respectively. On average, concentrations of 25(OH)D in cord blood were similar to 80% of those in the mother. There was no association between cord 25(OH)D and gestational age, but levels were associated with birth weight (p<0.001). There were no differences in maternal or cord blood 25(OH)D levels between those HIV-infected or uninfected. The predictor of VDD in mothers was giving birth in winter (odds ratio (OR) 2.87, 95% confidence interval (CI) 1.47 - 5.61), and in neonates the predictors were maternal age (OR 16.5, 95% CI 1.82 - 149), being born in winter (OR 3.68, 95% CI 2.05 - 6.61), being born by caesarean section (OR 4.92, 95% CI 1.56 - 15.57) and being of low birth weight (OR 1.99, 95% CI 1.13 - 3.50). Conclusions. Among black SA women delivering in Johannesburg, about one in six mothers and one in three neonates have 25(OH)D levels indicative of VDD. Maternal HIV status appears not to affect levels of 25(OH)D in either the mother or her neonate. Research on the effects of VDD on the outcomes of pregnancy and the best methods to combat the high prevalence of VDD in women of childbearing age in the SA context is required.

Background. There is a paucity of information on empyema in children from low-and middle-income countries since the introduction of the pneumococcal conjugate vaccine. Objectives. To describe the aetiology and management of empyema in a setting of high HIV and tuberculosis (TB) prevalence. Methods. A retrospective descriptive study was undertaken between January 2012 and December 2016 in children aged <14 years at a large secondary-tertiary referral hospital in Soweto, South Africa. Cases of empyema were identified through administrative databases. Clinical, laboratory and radiological data were extracted from patient records. Results. We identified 65 cases of protocol-defined empyema, including 22 (33.8%) referred from surrounding hospitals. The median age at presentation was 53.2 months (interquartile range (IQR) 19.5 - 103.6). Thirteen patients (20.0%) were HIV-infected and 6 (9.2%) were HIV-exposed but uninfected. A bacterial pathogen was identified in 36 cases (55.3%). The commonest causative organisms were Staphylococcus aureus (14/65, 21.5%) and Streptococcus pneumoniae (5/65, 7.7%). Treatment for TB, initiated in 28 children (43.1%), was more frequent in HIV-infected children (10/13, 76.9%) (p=0.011); however, microbiological evidence of TB was present in only 5 cases (7.7%). Forty-three children (66.2%) had an intercostal drain (ICD) inserted and 16 (24.6%) a pigtail percutaneous catheter, while a fibrinolytic was only used in 6 (10.2%). Eight children (12.3%) had a thoracotomy and 7 (10.7%) had video-assisted thorascopic drainage, all of whom had a prior ICD inserted, a median of 20 days (IQR 10 - 33) before surgery. Overall, 7 children (10.8%) were mechanically ventilated and 1 (1.5%) died. Conclusions. Our study showed a dominance of S. aureus as a cause of empyema. A high proportion of HIV-infected children with empyema were initiated on TB treatment, highlighting challenges in managing TB-HIV co-infection. Although fibrinolytics or early surgery are recommended, neither practice was common in this setting.

SETTING:This study was undertaken at a tertiary hospital in Soweto, a peri-urban low-middle income setting. Mycobacterium tuberculosis meningitis (TBM) is a severe manifestation of extra-pulmonary tuberculosis.OBJECTIVE:To describe the incidence, mortality and clinical features of TBM in human immunodeficiency virus (HIV) infected and non-infected children in South Africa from 2006 to 2011.DESIGN:A retrospective, cross-sectional descriptive study.METHODS:Electronic databases and individual patient records of all children with a discharge diagnosis of TBM were reviewed to yield incidence rate ratios (IRR) in HIV-infected and non-infected children. Clinical, laboratory and radiological characteristics were compared between HIV-infected and non-infected children with TBM.RESULTS:Overall TBM incidence per 100 000 population in 2006 was 6.9 (95%CI 4.4-10.3) and 9.8 (95%CI 6.9-13.6) in 2009, but had subsequently declined to 3.1 (95%CI 1.6-5.5) by 2011. There was a significant reduction in the IRR of TBM among HIV-infected children (IRR 0.916, P = 0.036). The overall case fatality ratio was 6.7%. Clinical features, cerebrospinal fluid and computed tomography brain findings were similar in HIV-infected and non-infected children.CONCLUSION:TBM incidence decreased over the study period from 2006 to 2011, and was temporally associated with an increase in the uptake of antiretroviral treatment in HIV-infected individuals.