ChAdOx1 nCoV-19 (AZD1222) vaccine-induced Fc receptor binding tracks with differential susceptibility to COVID-19.

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.

Potential for Maternally Administered Vaccine for Infant Group B Streptococcus.

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.).

Single-dose administration and the influence of the timing of the booster dose on immunogenicity and efficacy of ChAdOx1 nCoV-19 (AZD1222) vaccine: a pooled analysis of four randomised trials.

BACKGROUND: The ChAdOx1 nCoV-19 (AZD1222) vaccine has been approved for emergency use by the UK regulatory authority, Medicines and Healthcare products Regulatory Agency, with a regimen of two standard doses given with an interval of 4-12 weeks. The planned roll-out in the UK will involve vaccinating people in high-risk categories with their first dose immediately, and delivering the second dose 12 weeks later. Here, we provide both a further prespecified pooled analysis of trials of ChAdOx1 nCoV-19 and exploratory analyses of the impact on immunogenicity and efficacy of extending the interval between priming and booster doses. In addition, we show the immunogenicity and protection afforded by the first dose, before a booster dose has been offered. METHODS: We present data from three single-blind randomised controlled trials-one phase 1/2 study in the UK (COV001), one phase 2/3 study in the UK (COV002), and a phase 3 study in Brazil (COV003)-and one double-blind phase 1/2 study in South Africa (COV005). As previously described, individuals 18 years and older were randomly assigned 1:1 to receive two standard doses of ChAdOx1 nCoV-19 (5 × 1010 viral particles) or a control vaccine or saline placebo. In the UK trial, a subset of participants received a lower dose (2·2 × 1010 viral particles) of the ChAdOx1 nCoV-19 for the first dose. The primary outcome was virologically confirmed symptomatic COVID-19 disease, defined as a nucleic acid amplification test (NAAT)-positive swab combined with at least one qualifying symptom (fever ≥37·8°C, cough, shortness of breath, or anosmia or ageusia) more than 14 days after the second dose. Secondary efficacy analyses included cases occuring at least 22 days after the first dose. Antibody responses measured by immunoassay and by pseudovirus neutralisation were exploratory outcomes. All cases of COVID-19 with a NAAT-positive swab were adjudicated for inclusion in the analysis by a masked independent endpoint review committee. The primary analysis included all participants who were SARS-CoV-2 N protein seronegative at baseline, had had at least 14 days of follow-up after the second dose, and had no evidence of previous SARS-CoV-2 infection from NAAT swabs. Safety was assessed in all participants who received at least one dose. The four trials are registered at ISRCTN89951424 (COV003) and ClinicalTrials.gov, NCT04324606 (COV001), NCT04400838 (COV002), and NCT04444674 (COV005). FINDINGS: Between April 23 and Dec 6, 2020, 24 422 participants were recruited and vaccinated across the four studies, of whom 17 178 were included in the primary analysis (8597 receiving ChAdOx1 nCoV-19 and 8581 receiving control vaccine). The data cutoff for these analyses was Dec 7, 2020. 332 NAAT-positive infections met the primary endpoint of symptomatic infection more than 14 days after the second dose. Overall vaccine efficacy more than 14 days after the second dose was 66·7% (95% CI 57·4-74·0), with 84 (1·0%) cases in the 8597 participants in the ChAdOx1 nCoV-19 group and 248 (2·9%) in the 8581 participants in the control group. There were no hospital admissions for COVID-19 in the ChAdOx1 nCoV-19 group after the initial 21-day exclusion period, and 15 in the control group. 108 (0·9%) of 12 282 participants in the ChAdOx1 nCoV-19 group and 127 (1·1%) of 11 962 participants in the control group had serious adverse events. There were seven deaths considered unrelated to vaccination (two in the ChAdOx1 nCov-19 group and five in the control group), including one COVID-19-related death in one participant in the control group. Exploratory analyses showed that vaccine efficacy after a single standard dose of vaccine from day 22 to day 90 after vaccination was 76·0% (59·3-85·9). Our modelling analysis indicated that protection did not wane during this initial 3-month period. Similarly, antibody levels were maintained during this period with minimal waning by day 90 (geometric mean ratio [GMR] 0·66 [95% CI 0·59-0·74]). In the participants who received two standard doses, after the second dose, efficacy was higher in those with a longer prime-boost interval (vaccine efficacy 81·3% [95% CI 60·3-91·2] at ≥12 weeks) than in those with a short interval (vaccine efficacy 55·1% [33·0-69·9] at <6 weeks). These observations are supported by immunogenicity data that showed binding antibody responses more than two-fold higher after an interval of 12 or more weeks compared with an interval of less than 6 weeks in those who were aged 18-55 years (GMR 2·32 [2·01-2·68]). INTERPRETATION: The results of this primary analysis of two doses of ChAdOx1 nCoV-19 were consistent with those seen in the interim analysis of the trials and confirm that the vaccine is efficacious, with results varying by dose interval in exploratory analyses. A 3-month dose interval might have advantages over a programme with a short dose interval for roll-out of a pandemic vaccine to protect the largest number of individuals in the population as early as possible when supplies are scarce, while also improving protection after receiving a second dose. FUNDING: UK Research and Innovation, National Institutes of Health Research (NIHR), The Coalition for Epidemic Preparedness Innovations, the Bill & Melinda Gates Foundation, the Lemann Foundation, Rede D'Or, the Brava and Telles Foundation, NIHR Oxford Biomedical Research Centre, Thames Valley and South Midland's NIHR Clinical Research Network, and AstraZeneca.

Safety and efficacy of the ChAdOx1 nCoV-19 vaccine (AZD1222) against SARS-CoV-2: an interim analysis of four randomised controlled trials in Brazil, South Africa, and the UK.

BACKGROUND: A safe and efficacious vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), if deployed with high coverage, could contribute to the control of the COVID-19 pandemic. We evaluated the safety and efficacy of the ChAdOx1 nCoV-19 vaccine in a pooled interim analysis of four trials. METHODS: This analysis includes data from four ongoing blinded, randomised, controlled trials done across the UK, Brazil, and South Africa. Participants aged 18 years and older were randomly assigned (1:1) to ChAdOx1 nCoV-19 vaccine or control (meningococcal group A, C, W, and Y conjugate vaccine or saline). Participants in the ChAdOx1 nCoV-19 group received two doses containing 5 × 1010 viral particles (standard dose; SD/SD cohort); a subset in the UK trial received a half dose as their first dose (low dose) and a standard dose as their second dose (LD/SD cohort). The primary efficacy analysis included symptomatic COVID-19 in seronegative participants with a nucleic acid amplification test-positive swab more than 14 days after a second dose of vaccine. Participants were analysed according to treatment received, with data cutoff on Nov 4, 2020. Vaccine efficacy was calculated as 1 - relative risk derived from a robust Poisson regression model adjusted for age. Studies are registered at ISRCTN89951424 and ClinicalTrials.gov, NCT04324606, NCT04400838, and NCT04444674. FINDINGS: Between April 23 and Nov 4, 2020, 23 848 participants were enrolled and 11 636 participants (7548 in the UK, 4088 in Brazil) were included in the interim primary efficacy analysis. In participants who received two standard doses, vaccine efficacy was 62·1% (95% CI 41·0-75·7; 27 [0·6%] of 4440 in the ChAdOx1 nCoV-19 group vs71 [1·6%] of 4455 in the control group) and in participants who received a low dose followed by a standard dose, efficacy was 90·0% (67·4-97·0; three [0·2%] of 1367 vs 30 [2·2%] of 1374; pinteraction=0·010). Overall vaccine efficacy across both groups was 70·4% (95·8% CI 54·8-80·6; 30 [0·5%] of 5807 vs 101 [1·7%] of 5829). From 21 days after the first dose, there were ten cases hospitalised for COVID-19, all in the control arm; two were classified as severe COVID-19, including one death. There were 74 341 person-months of safety follow-up (median 3·4 months, IQR 1·3-4·8): 175 severe adverse events occurred in 168 participants, 84 events in the ChAdOx1 nCoV-19 group and 91 in the control group. Three events were classified as possibly related to a vaccine: one in the ChAdOx1 nCoV-19 group, one in the control group, and one in a participant who remains masked to group allocation. INTERPRETATION: ChAdOx1 nCoV-19 has an acceptable safety profile and has been found to be efficacious against symptomatic COVID-19 in this interim analysis of ongoing clinical trials. FUNDING: UK Research and Innovation, National Institutes for Health Research (NIHR), Coalition for Epidemic Preparedness Innovations, Bill & Melinda Gates Foundation, Lemann Foundation, Rede D'Or, Brava and Telles Foundation, NIHR Oxford Biomedical Research Centre, Thames Valley and South Midland's NIHR Clinical Research Network, and AstraZeneca.

Estimation of invasive Group B Streptococcus disease risk in young infants from case-control serological studies.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Association of Group B Streptococcus (GBS) Serum Serotype-Specific Anticapsular Immunoglobulin G Concentration and Risk Reduction for Invasive GBS Disease in South African Infants: An Observational Birth-Cohort, Matched Case-Control Study.

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.

Hemagglutinin Stalk Antibody Responses Following Trivalent Inactivated Influenza Vaccine Immunization of Pregnant Women and Association With Protection From Influenza Virus Illness.

BACKGROUND: The conserved, immuno-subdominant influenza virus hemagglutinin (HA) stalk region is a potential universal group-specific influenza virus vaccine epitope. We analyzed antibody responses to H1 hemagglutinin stalk domain (H1/stalk) following trivalent influenza inactivated vaccine (IIV3) immunization in pregnant women, and association with protection against influenza virus illness. METHODS: One hundred forty-five human immunodeficiency virus (HIV)-uninfected pregnant women (68 IIV3 and 77 placebo recipients) and 140 pregnant women with HIV infection (72 IIV3 and 68 placebo recipients) were independently randomized in placebo-controlled efficacy trials of IIV3. Plasma samples were tested for H1/stalk immunoglobulin G (IgG) and hemagglutination inhibition (HAI) antibodies prevaccination and 1 month postvaccination. Women had weekly surveillance for influenza illness, confirmed by polymerase chain reaction. RESULTS: Increases in H1/stalk IgG (and HAI) antibody levels were elicited post-IIV3, with responses being higher in HIV-uninfected women than in women living with HIV. Among HIV-uninfected vaccinees, there was no correlation (postvaccination) between H1/stalk and HAI antibody responses, whereas a strong correlation was observed in vaccinees with HIV. The H1/stalk IgG concentration was lower among women developing A/H1N1 illness (85.3 arbitrary units [AU]/mL) than those without A/H1N1 illness (219.6 AU/mL; P = .001). H1/stalk IgG concentration ≥215 AU/mL was associated with 90% lower odds (odds ratio, 0.09; P = .005) of A/H1N1 illness. Also, H1/stalk IgG was significantly lower among women with influenza B illness (93.9 AU/mL) than among their counterparts (215.5 AU/mL) (P = .04); however, no association was observed after adjusting for HAI titers. CONCLUSIONS: H1/stalk IgG concentration was associated with lower odds for A/H1N1 influenza virus illness, indicating its potential as an epitope for a universal vaccine against group 1 influenza virus.

The Association Between Breast Milk Group B Streptococcal Capsular Antibody Levels and Late-onset Disease in Young Infants.

BACKGROUND: Animal-model studies have demonstrated less group B streptococcal (GBS) invasive disease and gastrointestinal colonization after enteral administration of serotype-specific capsular antibodies. There is, however, a paucity of information on the association of breast milk GBS serotype-specific capsular antibodies and risks for invasive disease in infants. The aim of this study was to explore the association between natural secretory immunoglobulin A (sIgA) capsular antibodies in breast milk and the occurrence of late-onset disease (LOD) in young infants. METHODS: A matched case-control study was undertaken in infants <3 months of age in Johannesburg, South Africa. Breast milk samples were collected on cases and controls matched for gestational age, maternal age, and human immunodeficiency virus status at time of enrollment. Capsular serotype Ia, Ib, III, and V sIgA antibody concentrations were measured using the fluorescence-based micro-bead immunosorbent assay. RESULTS: Breast milk samples were available for 31 LOD cases (8 serotype Ia and 23 serotype III), 21 recto-vaginally colonized matched controls (10 serotype Ia and 11 serotype III), and 84 serotype Ia and 105 serotype III noncolonized matched controls. Using a Bayesian model to estimate the probability of disease, there were 90% reductions in the risks of developing serotypes Ia and III LOD with sIgA concentrations ≥0.14 µg/mL and ≥2.52 µg/mL, respectively. CONCLUSIONS: Breast milk sIgA capsular antibodies were associated with lower risks for LOD in young infants. The ability of GBS polysaccharide-protein conjugate vaccines currently under development to induce sIgA responses warrant investigation as potential mediators of protection against LOD.

Unraveling Specific Causes of Neonatal Mortality Using Minimally Invasive Tissue Sampling: An Observational Study.

BACKGROUND: Postmortem minimally invasive tissue sampling (MITS) is a potential alternative to the gold standard complete diagnostic autopsy for identifying specific causes of childhood deaths. We investigated the utility of MITS, interpreted with available clinical data, for attributing underlying and immediate causes of neonatal deaths. METHODS: This prospective, observational pilot study enrolled neonatal deaths at Chris Hani Baragwanath Academic Hospital in Soweto, South Africa. The MITS included needle core-biopsy sampling for histopathology of brain, lung, and liver tissue. Microbiological culture and/or molecular tests were performed on lung, liver, blood, cerebrospinal fluid, and stool samples. The "underlying" and "immediate" causes of death (CoD) were determined for each case by an international panel of 12-15 medical specialists. RESULTS: We enrolled 153 neonatal deaths, 106 aged 3-28 days. Leading underlying CoD included "complications of prematurity" (52.9%), "complications of intrapartum events" (15.0%), "congenital malformations" (13.1%), and "infection related" (9.8%). Overall, infections were the immediate or underlying CoD in 57.5% (n = 88) of all neonatal deaths, including the immediate CoD in 70.4% (58/81) of neonates with "complications of prematurity" as the underlying cause. Overall, 74.4% of 90 infection-related deaths were hospital acquired, mainly due to multidrug-resistant Acinetobacter baumannii (52.2%), Klebsiella pneumoniae (22.4%), and Staphylococcus aureus (20.9%). Streptococcus agalactiae was the most common pathogen (5/15 [33.3%]) among deaths with "infections" as the underlying cause. CONCLUSIONS: MITS has potential to address the knowledge gap on specific causes of neonatal mortality. In our setting, this included the hitherto underrecognized dominant role of hospital-acquired multidrug-resistant bacterial infections as the leading immediate cause of neonatal deaths.

Potential of Minimally Invasive Tissue Sampling for Attributing Specific Causes of Childhood Deaths in South Africa: A Pilot, Epidemiological Study.

BACKGROUND: Current estimates for causes of childhood deaths are mainly premised on modeling of vital registration and limited verbal autopsy data and generally only characterize the underlying cause of death (CoD). We investigated the potential of minimally invasive tissue sampling (MITS) for ascertaining the underlying and immediate CoD in children 1 month to 14 years of age. METHODS: MITS included postmortem tissue biopsies of brain, liver, and lung for histopathology examination; microbial culture of blood, cerebrospinal fluid (CSF), liver, and lung samples; and molecular microbial testing on blood, CSF, lung, and rectal swabs. Each case was individually adjudicated for underlying, antecedent, and immediate CoD by an international multidisciplinary team of medical experts and coded using the International Classification of Diseases, Tenth Revision (ICD-10). RESULTS: An underlying CoD was determined for 99% of 127 cases, leading causes being congenital malformations (18.9%), complications of prematurity (14.2%), human immunodeficiency virus/AIDS (12.6%), diarrheal disease (8.7%), acute respiratory infections (7.9%), injuries (7.9%), and malignancies (7.1%). The main immediate CoD was pneumonia, sepsis, and diarrhea in 33.9%, 19.7%, and 10.2% of cases, respectively. Infection-related deaths were either an underlying or immediate CoD in 78.0% of cases. Community-acquired pneumonia deaths (n = 32) were attributed to respiratory syncytial virus (21.9%), Pneumocystis jirovecii (18.8%), cytomegalovirus (15.6%), Klebsiella pneumoniae (15.6%), and Streptococcus pneumoniae (12.5%). Seventy-one percent of 24 sepsis deaths were hospital-acquired, mainly due to Acinetobacter baumannii (47.1%) and K. pneumoniae (35.3%). Sixty-two percent of cases were malnourished. CONCLUSIONS: MITS, coupled with antemortem clinical information, provides detailed insight into causes of childhood deaths that could be informative for prioritization of strategies aimed at reducing under-5 mortality.

An Observational Pilot Study Evaluating the Utility of Minimally Invasive Tissue Sampling to Determine the Cause of Stillbirths in South African Women.

BACKGROUND: 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. METHODS: 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. RESULTS: 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%). CONCLUSIONS: 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.

Pneumococcal conjugate vaccines and hospitalization of children for pneumonia: a time-series analysis, South Africa, 2006-2014.

OBJECTIVE: To assess the impact of immunization with pneumococcal conjugate vaccines on all-cause pneumonia hospitalizations among children in Soweto, South Africa. METHODS: We used data collected at the Chris Hani Baragwanath Hospital in Soweto between 2006 and 2014 - i.e. before and after April 2009, when a pneumococcal conjugate vaccine was first included in South Africa's routine immunization programme. Using a Bayesian generalized seasonal autoregressive moving-average model and the data collected in 2006-2008, we estimated the numbers of children that would have been hospitalized for pneumonia between 2010 and 2014 if no pneumococcal conjugate vaccines had been used. These estimates were then compared with the corresponding numbers of hospitalizations observed. FINDINGS: Between 2006 and 2014, 26 778 children younger than five years - including 3388 known to be infected with human immunodeficiency virus (HIV) - were admitted to the study hospital for pneumonia. We estimated that, for the children known to be infected with HIV and for the other children, pneumococcal conjugate vaccines reduced the numbers of hospitalizations for pneumonia in 2014 by 33% (50% credible interval, CrI: 6 to 52) and 39% (50% CrI: 24 to 50), respectively. In the study hospital in 2012-2014, as a result of immunizations with these vaccines, there were an estimated 3100 fewer pneumonia hospitalizations of children younger than five years. CONCLUSION: In our study hospital, following the introduction of pneumococcal conjugate vaccines into the national immunization programme, there were significant reductions in pneumonia hospitalizations among children.

Serotype-Specific Cell-Mediated Immunity Associated With Clearance of Homotypic Group B Streptococcus Rectovaginal Colonization in Pregnant Women.

We investigated the association between group B Streptococcus (GBS) serotype-specific capsular polysaccharide cellular immunity, measured with enzyme-linked immunospot (ELISPOT) interferon γ release assay at 20 weeks gestation in pregnant women, and its effect on rectovaginal serotype-specific GBS colonization up to 37 weeks gestation. Among women colonized by serotype III at enrollment, interferon γ ELISPOT positivity was more common in those in whom colonization was cleared (44.4%) than in those in whom colonization persisted (7.4%; P = .008), with a similar trend observed for serotype Ia. Presence of serotype-specific capsular polysaccharide cell-mediated immunity contributes to the clearance of GBS rectovaginal colonization.

Temporal Association of Rotavirus Vaccine Introduction and Reduction in All-Cause Childhood Diarrheal Hospitalizations in South Africa.

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 byInternational Classification of Diseases, Tenth Revisioncodes 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.

HIV-1 Is Associated With Lower Group B Streptococcus Capsular and Surface-Protein IgG Antibody Levels and Reduced Transplacental Antibody Transfer in Pregnant Women.

BACKGROUND: Human immunodeficiency virus (HIV)-exposed infants are at increased risk of invasive Group B Streptococcus (GBS) disease; however, the reason for this increased susceptibility has not been characterized. METHODS: We compared GBS capsular and surface-protein maternal immunoglobin G antibody concentrations and cord-maternal ratios between HIV-infected and HIV-uninfected mother-newborn dyads. RESULTS: Median capsular antibody concentrations (µg/mL) were lower in HIV-infected than HIV-uninfected women for serotypes Ib (P = .033) and V (P = .040); and for pilus island (PI)-1 (P = .016), PI-2a (P = .015), PI-2b (P = .015), and fibrinogen-binding protein A (P < .001). For serotypes Ia and III, cord-maternal ratios were 37.4% (P < .001) and 32.5% (P = .027) lower in HIV-infected compared to HIV-uninfected mother-newborn dyads. The adjusted odds of having capsular antibody concentration ≥2 µg/mL when comparing HIV-infected to -uninfected women were 0.33 (95% confidence interval [CI], .15-.75) and 0.34 (95% CI, .12-1.00) for serotypes Ia and III, respectively. Antibody levels and cord-maternal ratios were independent of CD4(+) lymphocyte counts or HIV-1 viral load. CONCLUSIONS: The lower GBS antibody concentrations and reduced transplacental antibody transfer in HIV-infected women, which likely contribute to their infants being at heightened susceptibility for invasive GBS disease, could possibly be mitigated by vaccination with a GBS conjugate vaccine currently under clinical development.

Kinetics of Hemagglutination-Inhibiting Antibodies Following Maternal Influenza Vaccination Among Mothers With and Those Without HIV Infection and Their Infants.

BACKGROUND: We evaluated the immunogenicity of trivalent inactivated influenza vaccine (IIV3) in pregnant women with and those without human immunodeficiency virus (HIV) infection and the persistence of hemagglutination-inhibiting antibodies in mothers and infants. METHODS: Antibodies were measured before vaccination, 1 month after vaccination, at delivery, and at postpartum week 24 in mothers and within 1 week of birth and at 8, 16, and 24 weeks of age in infants. RESULTS: We enrolled 98 HIV-uninfected and 100 HIV-infected pregnant women, including 93% with a CD4(+) T-cell count of ≥ 200 cells/µL. Compared with HIV-uninfected women, HIV-infected women had lower seroconversion rates (ranging from 63%-92% vs 36%-40%), lower antibody titers through postpartum week 24, and overlapping antibody half-lives (ranging from 106-121 vs 87-153 days). Infant titers were lower than the maternal titers within 1 week of delivery, regardless of vaccine strain and HIV exposure status. Compared with HIV-unexposed infants, HIV-exposed infants had a similar transplacental influenza virus antibody transfer ratio, lower titers, and a lower frequency of titers ≥ 1:40 (ranging from 82%-95% vs 43%-79%) at birth and higher antibody half-lives (ranging from 43-45 vs 56-65 days). CONCLUSIONS: Compared with HIV-uninfected pregnant women, HIV-infected pregnant women had lower antibody responses and persistence. Compared with HIV-unexposed infants, HIV-exposed infants had lower antibody levels at birth but similar antibody levels after 8 weeks of life. Early IIV3 administration during pregnancy did not decrease antibody titers among infants at birth.

Bayesian estimation of mixture models with prespecified elements to compare drug resistance in treatment-naïve and experienced tuberculosis cases.

We propose a Bayesian approach for estimating branching tree mixture models to compare drug-resistance pathways (i.e. patterns of sequential acquisition of resistance to individual antibiotics) that are observed among Mycobacterium tuberculosis isolates collected from treatment-naïve and treatment-experienced patients. Resistant pathogens collected from treatment-naïve patients are strains for which fitness costs of resistance were not sufficient to prevent transmission, whereas those collected from treatment-experienced patients reflect both transmitted and acquired resistance, the latter of which may or may not be associated with lower transmissibility. The comparison of the resistance pathways constructed from these two groups of drug-resistant strains provides insight into which pathways preferentially lead to the development of multiple drug resistant strains that are transmissible. We apply the proposed statistical methods to data from worldwide surveillance of drug-resistant tuberculosis collected by the World Health Organization over 13 years.

Bacterial nasopharyngeal colonisation in children in South Africa before and during the COVID-19 pandemic: an observational study.

BACKGROUND: Deployment of non-pharmaceutical interventions such as face masking and physical distancing during the COVID-19 pandemic could have altered the transmission dynamics and carriage of respiratory organisms. We evaluated colonisation with Streptococcus pneumoniae and other upper respiratory tract bacterial colonisers before and during the COVID-19 pandemic. METHODS: We did two cross-sectional surveys in Soweto, South Africa from July 3 to Dec 13, 2018 (pre-COVID-19 period) and from Aug 4, 2021, to March 31, 2022 (COVID-19 period) in healthy children (aged ≤60 months) who had recorded HIV status and had not received antibiotics in the 21 days before enrolment. At enrolment, we collected nasopharyngeal swab samples from child participants. Following nucleic acid extraction, nanofluidic quantitative PCR was used to screen all samples for 92 S pneumoniae serotypes and 14 other bacteria. The primary objective was to compare the prevalence and density of pneumococcal nasopharyngeal colonisation, overall and stratified by 13-valent pneumococcal conjugate vaccine (PCV13) serotypes and non-vaccine serotypes. Secondary study objectives included a comparison of serotype-specific pneumococcal colonisation and density, as well as colonisation by the 14 other bacteria in the COVID-19 versus pre-COVID-19 period. We used an adjusted multiple logistic and linear regression model to compare the colonisation prevalence and density between study periods. FINDINGS: We analysed nasopharyngeal swabs from 1107 children (n=571 in the pre-COVID-19 period; n=536 in the COVID-19 period). We observed no change in overall pneumococcal colonisation between periods (274 [51%] of 536 in the COVID-19 period vs 282 [49%] of 571 in the pre-COVID-19 period; adjusted odds ratio [aOR] 1·03 [95% CI 0·95-1·12]). The prevalence of PCV13 serotypes was lower in the COVID-19 than in the pre-COVID-19 period (72 [13%] vs 106 [19%]; 0·87 [0·78-0·97]), whereas the prevalence of non-typeable S pneumoniae was higher (34 [6%] vs 63 [12%]; 1·30 [1·12-1·50]). The mean log10 density for overall pneumococcal colonisation was lower in the COVID-19 period than in the pre-COVID-19 period (3·96 [95% CI 3·85-4·07] vs 4·72 [4·63-4·80] log10 genome equivalents per mL; p<0·0001). A lower density of non-vaccine serotypes (3·63 [3·51-3·74] vs 4·08 [3·95-4·22] log10 genome equivalents per mL; p<0·0001) and non-typeable S pneumoniae (3·11 [2·94-3·29] vs 4·41 [4·06-4·75] log10 genome equivalents per mL; p<0·00001) was also observed in the COVID-19 period. There was no difference in the density of PCV13 serotypes between the periods. The prevalence of colonisation during the COVID-19 versus pre-COVID-19 period was lower for non-typeable Haemophilus influenzae (280 [49%] vs 165 [31%]; aOR 0·77 [95% CI 0·71-0·84]), Moraxella catarrhalis (328 [57%] vs 242 [45%]; 0·85 [0·79-0·92]), and Neisseria lactamica (51 [9%] vs 13 [2%]; 0·64 [0·52-0·78]), but higher for Acinetobacter baumannii (34 [6%] vs 102 [19%]; 1·55 [1·35-1·77]) and Staphylococcus aureus (29 [5%] vs 52 [10%]; 1·28 [1·10-1·50]). INTERPRETATION: There were variable effects on the colonisation prevalence and density of bacterial organisms during the COVID-19 compared with the pre-COVID-19 period. The lower prevalence of PCV13 serotype together with other respiratory organisms including non-typeable H influenzae and M catarrhalis could have in part contributed to a decrease in all-cause lower respiratory tract infections observed in South Africa during the initial stage of the COVID-19 pandemic. The pathophysiological mechanism for the increase in A baumannii and S aureus colonisation warrants further investigation, as does the clinical relevance of these findings. FUNDING: The Bill & Melinda Gates Foundation.

Immunogenicity and seroefficacy of pneumococcal conjugate vaccines: a systematic review and network meta-analysis.

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.

Pneumococcal disease is a serious illness caused by a bacterial infection that can result in death. Children in the United Kingdom receive a vaccine to prevent this disease that protects against 13 different types of pneumococcal diseases. It is very effective, but other vaccines are also available, such as one that contains 10 types of pneumococcal diseases. Vaccines in the United Kingdom are bought by the government and the choice of which vaccine to provide is based on the cost of the vaccine as well as the benefits to our health. However, there is very little information comparing different vaccines and it is often assumed they are the same. We did a large analysis combining all studies of the two main licensed pneumococcal vaccines to determine which vaccine provides better protection against infection and how this affects costs. We used information from studies published in medical journals, and also data from studies done by the companies that own the vaccines. Our results showed that pneumococcal conjugate vaccine-13 vaccine provided better protection than pneumococcal conjugate vaccine-10 for 5 of the 10 serotypes that are contained in both vaccines. When we used these results to model what might have happened had either of these vaccines been introduced into the United Kingdom vaccination programme in 2006, we found that both vaccines caused a rapid decrease in the amount of disease, but that the decrease in disease was faster with pneumococcal conjugate vaccine-13 than pneumococcal conjugate vaccine-10. This resulted in 2808 cases of diseases prevented over a 25-year time frame with pneumococcal conjugate vaccine-13 compared with pneumococcal conjugate vaccine-10. Our methods can be used to compare other vaccines and we recommend this type of study be done in future when making decisions on vaccine product choice.