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.
A double-blind randomized trial in South Africa documented poor efficacy of two doses of the ChAdOx1 nCoV-19 vaccine against the B.1.351 variant of SARS-CoV-2 that emerged in South Africa. Infections ...occurred in 3.2% of placebo recipients and in 2.5% of vaccine recipients. Thirty-nine of the 42 virus isolates were the B.1.351 variant. None of the cases led to hospitalization or death.
There are an estimated 2.6 million stillbirths each year, many of which are due to infections, especially in low- and middle-income contexts. This paper, the eighth in a series on the burden of group ...B streptococcal (GBS) disease, aims to estimate the percentage of stillbirths associated with GBS disease.
We conducted systematic literature reviews (PubMed/Medline, Embase, Literatura Latino-Americana e do Caribe em Ciências da Saúde, World Health Organization Library Information System, and Scopus) and sought unpublished data from investigator groups. Studies were included if they reported original data on stillbirths (predominantly ≥28 weeks' gestation or ≥1000 g, with GBS isolated from a sterile site) as a percentage of total stillbirths. We did meta-analyses to derive pooled estimates of the percentage of GBS-associated stillbirths, regionally and worldwide for recent datasets.
We included 14 studies from any period, 5 with recent data (after 2000). There were no data from Asia. We estimated that 1% (95% confidence interval CI, 0-2%) of all stillbirths in developed countries and 4% (95% CI, 2%-6%) in Africa were associated with GBS.
GBS is likely an important cause of stillbirth, especially in Africa. However, data are limited in terms of geographic spread, with no data from Asia, and cases worldwide are probably underestimated due to incomplete case ascertainment. More data, using standardized, systematic methods, are critical, particularly from low- and middle-income contexts where the highest burden of stillbirths occurs. These data are essential to inform interventions, such as maternal GBS vaccination.
Abstract
Background
Licensure of a group B Streptococcus (GBS) polysaccharide-protein conjugate vaccine for protecting infants against invasive GBS disease (IGbsD) will likely need to be based on ...demonstrating vaccine safety in pregnant women, and benchmarking immunogenicity against a serological threshold associated with risk reduction of IGbsD. We investigated the association between naturally derived GBS serotype Ia and III IgG and risk reduction of IGbsD in infants ≤90 days of age.
Methods
In a matched case-control study, IGbsD cases were identified from a cohort of 38 233 mother-newborn dyads. Mothers colonized vaginally with serotype Ia or III at birth and their healthy infants were eligible as matched controls. GBS serotype-specific anticapsular immunoglobulin G (IgG) was measured on maternal and cord blood/infant sera by multiplex Luminex assay, and the IgG threshold associated with 90% risk reduction of IGbsD was derived by estimating absolute disease risk.
Results
In infants born at ≥34 weeks’ gestational age, cord-blood IgG geometric mean concentrations (GMCs) were lower in cases than controls for serotypes Ia (0.05 vs 0.50 µg/mL; P = .004) and III (0.20 vs 0.38 µg/mL; P = .078). Cord-blood IgG concentrations ≥1.04 and ≥1.53 µg/mL were associated with 90% risk reduction of serotype Ia and III IGbsD, respectively. The maternal sera IgG threshold associated with 90% risk reduction was ≥2.31 µg/mL and ≥3.41 µg/mL for serotypes Ia and III, respectively.
Conclusions
The threshold associated with a reduced risk for serotype Ia and III IGbsD identified on infant sera supports the case for licensure of a GBS polysaccharide-protein conjugate vaccine based on an immunogenicity evaluation benchmarked against the defined thresholds.
Clinical Trials Registration
NCT02215226.
Infant serotype-specific anticapsular IgG concentrations ≥1.04 and ≥1.53 µg/mL were associated with 90% risk reduction of serotype Ia and III invasive group B Streptococcus (GBS) disease, respectively. These findings could assist in the licensure of a GBS polysaccharide-protein conjugate vaccine based on immunogenicity and safety.
People living with HIV are at an increased risk of fatal outcome when admitted to hospital for severe COVID-19 compared with HIV-negative individuals. We aimed to assess safety and immunogenicity of ...the ChAdOx1 nCoV-19 (AZD1222) vaccine in people with HIV and HIV-negative individuals in South Africa.
In this ongoing, double-blind, placebo-controlled, phase 1B/2A trial (COV005), people with HIV and HIV-negative participants aged 18–65 years were enrolled at seven South African locations and were randomly allocated (1:1) with full allocation concealment to receive a prime-boost regimen of ChAdOx1 nCoV-19, with two doses given 28 days apart. Eligibility criteria for people with HIV included being on antiretroviral therapy for at least 3 months, with a plasma HIV viral load of less than 1000 copies per mL. In this interim analysis, safety and reactogenicity was assessed in all individuals who received at least one dose of ChAdOx1 nCov 19 between enrolment and Jan 15, 2021. Primary immunogenicity analyses included participants who received two doses of trial intervention and were SARS-CoV-2 seronegative at baseline. This trial is registered with ClinicalTrials.gov, NCT04444674, and the Pan African Clinicals Trials Registry, PACTR202006922165132.
Between June 24 and Nov 12, 2020, 104 people with HIV and 70 HIV-negative individuals were enrolled. 102 people with HIV (52 vaccine; 50 placebo) and 56 HIV-negative participants (28 vaccine; 28 placebo) received the priming dose, 100 people with HIV (51 vaccine; 49 placebo) and 46 HIV-negative participants (24 vaccine; 22 placebo) received two doses (priming and booster). In participants seronegative for SARS-CoV-2 at baseline, there were 164 adverse events in those with HIV (86 vaccine; 78 placebo) and 237 in HIV-negative participants (95 vaccine; 142 placebo). Of seven serious adverse events, one severe fever in a HIV-negative participant was definitely related to trial intervention and one severely elevated alanine aminotranferase in a participant with HIV was unlikely related; five others were deemed unrelated. One HIV-negative participant died (unlikely related). People with HIV and HIV-negative participants showed vaccine-induced serum IgG responses against wild-type Wuhan-1 Asp614Gly (also known as D614G). For participants seronegative for SARS-CoV-2 antigens at baseline, full-length spike geometric mean concentration (GMC) at day 28 was 163·7 binding antibody units (BAU)/mL (95% CI 89·9–298·1) for people with HIV (n=36) and 112·3 BAU/mL (61·7–204·4) for HIV-negative participants (n=23), with a rising day 42 GMC booster response in both groups. Baseline SARS-CoV-2 seropositive people with HIV demonstrated higher antibody responses after each vaccine dose than did people with HIV who were seronegative at baseline. High-level binding antibody cross-reactivity for the full-length spike and receptor-binding domain of the beta variant (B.1.351) was seen regardless of HIV status. In people with HIV who developed high titre responses, predominantly those who were receptor-binding domain seropositive at enrolment, neutralising activity against beta was retained.
ChAdOx1 nCoV-19 was well tolerated, showing favourable safety and immunogenicity in people with HIV, including heightened immunogenicity in SARS-CoV-2 baseline-seropositive participants. People with HIV showed cross-reactive binding antibodies to the beta variant and Asp614Gly wild-type, and high responders retained neutralisation against beta.
The Bill & Melinda Gates Foundation, South African Medical Research Council, UK Research and Innovation, UK National Institute for Health Research, and the South African Medical Research Council.
COVID-19 vaccine rollout is lagging in Africa, where there has been a high rate of SARS-CoV-2 infection. We aimed to evaluate the effect of SARS-CoV-2 infection before vaccination with the ...ChAdOx-nCoV19 (AZD1222) vaccine on antibody responses through to 180 days.
We did an unmasked post-hoc immunogenicity analysis after the first and second doses of AZD1222 in a randomised, placebo-controlled, phase 1b–2a study done in seven locations in South Africa. AZD1222 recipients who were HIV-uninfected, were stratified into baseline seropositive or seronegative groups using the serum anti-nucleocapsid (anti-N) immunoglobulin G (IgG) electroluminescence immunoassay to establish SARS-CoV-2 infection before the first dose of AZD1222. Binding IgG to spike (anti-S) and receptor binding domain (anti-RBD) were measured before the first dose (day 0), second dose (day 28), day 42, and day 180. Neutralising antibody (NAb) against SARS-CoV-2 variants D614G, beta, delta, gamma, and A.VOI.V2, and omicron BA1 and BA.4 variants, were measured by pseudovirus assay (day 28, day 42, and day 180). This trial is registered with ClinicalTrials.gov, NCT04444674, and the Pan African Clinicals Trials Registry, PACTR202006922165132.
Of 185 individuals who were randomly assigned to AZD1222, we included 91 individuals who were baseline seropositive and 58 who were baseline seronegative, in the final analysis. In the seropositive group, there was little change of anti-S IgG (and anti-RBD IgG) or neutralising antibody (NAb) titres at day 42 compared with at day 28. Anti-S (and anti-RBD) IgG geometric mean concentrations (GMCs) were higher throughout in the seropositive compared with the seronegative group, including at day 180 (GMCs 517·8 95% CI 411·3–651·9 vs 82·1 55·2–122·3 BAU/mL). Also D614G NAb geometric mean titres (GMTs) were higher in the seropositive group than the seronegative group, as was the percentage with titres of at least 185 (80% putative risk reduction threshold PRRT against wild-type–alpha COVID-19), including at day 180 (92·0% 74·0–99·0 vs 18·2% 2·3–51·8). Similar findings were observed for beta, A.VOI.V2, and gamma. For delta, BA.1, and BA.4, NAb GMTs and the proportion with titres above the PRRT were substantially higher in the seropositive compared with seronegative group at day 28 and day 42, but no longer differed between the groups by day 180.
A single dose of AZD1222 in the general African population, where COVID-19 vaccine coverage is low and SARS-CoV-2 seropositivity is 90%, could enhance the magnitude and quality of antibody responses to SARS-CoV-2.
The Bill & Melinda Gates Foundation, the South African Medical Research Council, the UK Research and Innovation, the UK National Institute for Health Research, and the South African Medical Research Council.
For the Zulu translation of the abstract see Supplementary Materials section.
Despite the success of COVID-19 vaccines, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern have emerged that can cause breakthrough infections. Although protection ...against severe disease has been largely preserved, the immunological mediators of protection in humans remain undefined. We performed a substudy on the ChAdOx1 nCoV-19 (AZD1222) vaccinees enrolled in a South African clinical trial. At peak immunogenicity, before infection, no differences were observed in immunoglobulin (Ig)G1-binding antibody titers; however, the vaccine induced different Fc-receptor-binding antibodies across groups. Vaccinees who resisted COVID-19 exclusively mounted FcγR3B-binding antibodies. In contrast, enhanced IgA and IgG3, linked to enriched FcγR2B binding, was observed in individuals who experienced breakthrough. Antibodies unable to bind to FcγR3B led to immune complex clearance and resulted in inflammatory cascades. Differential antibody binding to FcγR3B was linked to Fc-glycosylation differences in SARS-CoV-2-specific antibodies. These data potentially point to specific FcγR3B-mediated antibody functional profiles as critical markers of immunity against COVID-19.
•COVID-19 vaccine efficacy (VE) varies against SARS-CoV-2 variants of concern.•We present a final VE analysis from a phase 1b/2 AZD1222 trial in South Africa.•VE was 90% for WT, 6.7% for Beta and ...77.1% for Delta ≥ 9 months post-vaccination.•Safety was consistent with the interim analysis and no new concerns were reported.•AZD1222 offers durable protection, potentially due to anamnestic immune responses.
COVID-19 vaccine efficacy (VE) has been observed to vary against antigenically distinct SARS-CoV-2 variants of concern (VoC). Here we report the final analysis of VE and safety from COV005: a phase 1b/2, multicenter, double-blind, randomized, placebo-controlled study of primary series AZD1222 (ChAdOx1 nCoV-19) vaccination in South African adults aged 18–65 years. South Africa’s first, second, and third waves of SARS-CoV-2 infections were respectively driven by the ancestral SARS-CoV-2 virus (wild type, WT), and SARS-CoV-2 Beta and Delta VoCs. VE against asymptomatic and symptomatic infection was 90.6% for WT, 6.7% for Beta and 77.1% for Delta. No cases of severe COVID-19 were documented ahead of unblinding. Safety was consistent with the interim analysis, with no new safety concerns identified. Notably, South Africa’s Delta wave occurred ≥ 9 months after primary series vaccination, suggesting that primary series AZD1222 vaccination offers a good durability of protection, potentially due to an anamnestic response.
Clinical trial identifier: CT.gov NCT04444674.
Licensure of a Group B streptococcus (GBS) polysaccharide-protein conjugate vaccine for protecting infants against invasive GBS disease (IGbsD) will likely need to be based on demonstrating vaccine ...safety in pregnant women, and benchmarking immunogenicity against a serological threshold associated with risk reduction of IGbsD. We investigated the association between naturally-derived GBS serotype-Ia and III IgG and risk reduction of IGbsD in infants' ≤90 days of age.
In a matched case-control study (ClinicalTrials.gov NCT02215226), IGbsD cases were identified from a cohort of 38,233 mother-newborn dyads. Mothers colonized vaginally with serotype-Ia or III at birth, and their healthy infants were eligible as matched controls. GBS serotype-specific anti-capsular IgG was measured on maternal and cord blood/infant sera by multiplex Luminex assay; and the IgG threshold associated with 90% risk reduction of IGbsD derived by estimating absolute disease risk.
In infants born ≥34 weeks gestational age, cord-blood IgG geometric mean concentrations (GMC) were lower in cases than controls for serotype-Ia (0.05 vs. 0.50µg/ml; p=0.004) and III (0.20 vs. 0.38µg/ml; p=0.078). Cord-blood IgG concentration ≥1.04 and ≥1.53µg/ml were associated with 90% risk reduction of serotype-Ia and III IGbsD, respectively. The maternal sera IgG threshold associated with 90% risk reduction was ≥2.31 and ≥3.41µg/ml for serotype-Ia and III, respectively.
The threshold associated with a reduced risk for serotype-Ia and III IGbsD identified on infant sera supports the case for licensure of a GBS polysaccharide-protein conjugate vaccine based on immunogenicity evaluation benchmarked against the defined thresholds.
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