Considerations for a phase-III trial to evaluate a group B Streptococcus polysaccharide-protein conjugate vaccine in pregnant women for the prevention of early- and late-onset invasive disease in young-infants

Group B streptococcus (GBS) is a leading cause of serious neonatal infections. Maternal GBS colonization is associated with early- and late-onset neonatal disease (EOD/LOD). In Greece, a screening-based strategy is recommended, in which concurrent vaginal-rectal cultures should be obtained between 36 0/7 and 37 6/7 weeks’ gestation. We sought to examine the level of adherence to the GBS screening guidelines and estimate the prevalence of GBS colonization among pregnant women. Although in Greece the screening-based strategy is followed, we also examined known EOD risk factors and linked them to GBS colonization. A cross-sectional study of 604 women postpartum in three hospitals and maternity clinics was conducted. Following written informed consent, data were collected via a short self-completed questionnaire and review of patients’ records. In 34.6% of the enrolled pregnant women, no culture had been taken. Of the remaining, 12.8% had proper vaginal-rectal sample collections. The overall maternal colonization rate was 9.6%. At least one risk factor for EOD was identified in 12.6% of participants. The presence of risk factors was associated with positive cultures (p = 0.014). The rate of culture collection did not differ between women with or without an EOD risk factor. Adherence to a universal screening of pregnant women with vaginal-rectal cultures was poor. Despite probable underestimation of GBS carrier status, almost 1 in 10 participants were GBS positive during pregnancy. Screening of women with risk factors for EOD should, at least, be prioritized to achieve prevention and prompt intervention of EOD.

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Genomic and phenotypic characterisation of invasive neonatal and colonising group B Streptococcus isolates from Slovenia, 2001–2018

BMC Infectious Diseases ◽

10.1186/s12879-020-05599-y ◽

2020 ◽

Vol 20 (1) ◽

Author(s):

Tina Perme ◽

Daniel Golparian ◽

Maja Bombek Ihan ◽

Andrej Rojnik ◽

Miha Lučovnik ◽

...

Keyword(s):

Pregnant Women ◽

Virulence Factors ◽

Late Onset ◽

Group B Streptococcus ◽

Genomic Diversity ◽

Neonatal Disease ◽

Phenotypic Characterisation ◽

High Prevalence ◽

Group B ◽

The Impact

Abstract Background Group B Streptococcus (GBS) is the leading cause of invasive neonatal disease in the industrialized world. We aimed to genomically and phenotypically characterise invasive GBS isolates in Slovenia from 2001 to 2018 and contemporary colonising GBS isolates from screening cultures in 2018. Methods GBS isolates from 101 patients (invasive isolates) and 70 pregnant women (colonising isolates) were analysed. Basic clinical characteristics of the patients were collected from medical records. Antimicrobial susceptibility and phenotypic capsular serotype were determined. Whole-genome sequencing was performed to assign multilocus sequence types (STs), clonal complexes (CCs), pathogenicity/virulence factors, including capsular genotypes, and genome-based phylogeny. Results Among invasive neonatal disease patients, 42.6% (n = 43) were females, 41.5% (n = 39/94) were from preterm deliveries (< 37 weeks gestation), and 41.6% (n = 42) had early-onset disease (EOD). All isolates were susceptible to benzylpenicillin with low minimum inhibitory concentrations (MICs; ≤0.125 mg/L). Overall, 7 serotypes were identified (Ia, Ib, II-V and VIII); serotype III being the most prevalent (59.6%). Twenty-eight MLST STs were detected that clustered into 6 CCs. CC-17 was the most common CC overall (53.2%), as well as among invasive (67.3%) and non-invasive (32.9%) isolates (p < 0.001). CC-17 was more common among patients with late-onset disease (LOD) (81.4%) compared to EOD (47.6%) (p < 0.001). The prevalence of other CCs was 12.9% (CC-23), 11.1% (CC-12), 10.5% (CC-1), 8.2% (CC-19), and 1.8% (CC-498). Of all isolates, 2.3% were singletons. Conclusions A high prevalence of hypervirulent CC-17 isolates, with low genomic diversity and characteristic profile of pathogenicity/virulence factors, was detected among invasive neonatal and colonising GBS isolates from pregnant women in Slovenia. This is the first genomic characterisation of GBS isolates in Slovenia and provides valuable microbiological and genomic baseline data regarding the invasive and colonising GBS population nationally. Continuous genomic surveillance of GBS infections is crucial to analyse the impact of IND prevention strategies on the population structure of GBS locally, nationally, and internationally.

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Group B Streptococcus (Streptococcus agalactiae)

10.1093/med/9780190604813.003.0019 ◽

2018 ◽

Author(s):

Kirsty Le Doare ◽

Christine E. Jones ◽

Paul T. Heath

Keyword(s):

Early Onset ◽

Late Onset ◽

Group B Streptococcus ◽

Significant Risk ◽

Neonatal Infection ◽

Significant Risk Factor ◽

Invasive Disease ◽

Neurodevelopmental Outcomes ◽

Intrapartum Antibiotic ◽

Group B

Group B Streptococcus (GBS) is a leading cause of early neonatal infection and neonatal mortality, with long-term adverse neurodevelopmental outcomes in up to 50% of survivors of GBS meningitis. GBS has a likely underappreciated role in causing preterm birth and stillbirth. GBS colonizes the vagina and gastrointestinal tract of the pregnant woman, and transmission to the infant occurs during or just before delivery. Although the majority of these infants do not develop invasive disease, maternal colonization is a prerequisite for early onset disease (0–6 days of life, most commonly associated with sepsis and respiratory distress) and a significant risk factor for late onset disease (7–89 days of life, most commonly associated with sepsis and meningitis). The introduction of intrapartum antibiotic prophylaxis has resulted in significant declines in the incidence of early onset disease but provides no protection against late onset disease.

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An empirical Bayes method for serotype case-carrier ratios, with an application to Group B streptococcus

10.1101/421412 ◽

2018 ◽

Author(s):

Joseph A. Lewnard ◽

Lauren A. Cowley

Keyword(s):

Empirical Bayes ◽

Ad Hoc ◽

Late Onset ◽

Group B Streptococcus ◽

Invasive Disease ◽

Random Effects Model ◽

Bayes Method ◽

Disease States ◽

Invasive Infections ◽

Group B

ABSTRACTBackgroundCase-carrier ratios quantifying the relative pathogenicity of serotypes can inform vaccine formulations for antigenically-diverse pathogens. However, sparse serotype-specific counts in epidemiologic datasets may undermine such analyses, most notably for rare serotypes that pose emergence risks in vaccinated populations. This challenge is well-illustrated in Group B streptococcus (GBS), where serotype III dominates in both carriage and disease.MethodsWe develop an empirical Bayes random-effects model based on conjugate Dirichlet-multinomial distributions of serotype frequencies in carriage and disease states. We validate the model using simulated datasets, and apply it to data from 15 paired sets of GBS isolates from intrapartum rectovaginal colonization (n=3403) and neonatal invasive disease (NID; n=1088), 16 from blood (n=2352) and cerebrospinal fluid (n=780) neonatal specimens, and 3 from fatal (n=173) and non-fatal (n=1684) neonatal invasive infections.ResultsOur method accurately recovers parameters in simulated datasets. Using this approach, we confirm that GBS serotype III exhibits the greatest invasiveness, followed by serotype Ia with a 75.3% (95%CrI: 43.7-93.8%) lower estimate. Enhanced invasiveness of serotypes III and Ia is most evident in late-onset disease. Non–hexavalent-vaccine serotypes, which are rare in carriage and disease, generally show lower invasiveness; serotype IX/non-typeable GBS, the most prevalent cause of non–vaccine-preventable disease, is 98.7% (81.7-99.9%) and 94.2% (13.9-99.6%) less invasive than serotypes III and Ia, respectively.ConclusionsWe present a strategy for measuring associations of serotype with carrier and disease states in the presence of sparse counts, avoiding biases that exist in common ad-hoc approaches.

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Enhanced identification of Group B streptococcus in infants with suspected meningitis in Ethiopia

PLoS ONE ◽

10.1371/journal.pone.0242628 ◽

2020 ◽

Vol 15 (11) ◽

pp. e0242628

Author(s):

Alene Geteneh ◽

Tesfaye Kassa ◽

Yared Alemu ◽

Derbie Alemu ◽

Mulugeta Kiros ◽

...

Keyword(s):

Detection Rate ◽

Causes Of Death ◽

Late Onset ◽

Group B Streptococcus ◽

Young Infants ◽

Specialized Hospital ◽

Tikur Anbessa Specialized Hospital ◽

One Year ◽

Group B ◽

Culture Negative

Meningitis is one of the top ten causes of death among Ethiopian infants. Group B streptococcus (GBS) has emerged as a leading cause of meningitis in neonates and young infants, resulting in high mortality. Despite this, there is no report on GBS associated meningitis in Ethiopia where infant meningitis is common. Hence, the aim of this study was to determine the proportion of GBS associated meningitis among Ethiopian infants. PCR was prospectively used to detect GBS in culture-negative cerebrospinal fluid (CSF) samples, which were collected from infants suspected for meningitis, at Tikur Anbessa specialized hospital, Ethiopia, over a one-year period. GBS was detected by PCR in 63.9% of culture-negative CSF samples. Out of the 46 GBS positive infants, 10.9% (n = 5) of them died. The late onset of GBS (LOGBS) disease was noted to have a poor outcome with 3 LOGBS out of 5 GBS positive samples collected from patients with the final outcome of death. PCR was advantageous in the identification of GBS in culture-negative CSF samples. GBS was detected in 64% of the CSF samples from infants with meningitis compared with zero-detection rate by culture.

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OC 8465 THE DEVELOPMENT OF A CONJUGATE VACCINE AGAINST GROUP B STREPTOCOCCUS: AN AFRICAN PERSPECTIVE

BMJ Global Health ◽

10.1136/bmjgh-2019-edc.18 ◽

2019 ◽

Vol 4 (Suppl 3) ◽

pp. A8.1-A8

Author(s):

Seanette Wilson ◽

Patrick Tippoo

Keyword(s):

South Africa ◽

Clinical Trial ◽

Conjugate Vaccine ◽

Capsular Polysaccharide ◽

Disease Risk ◽

Group B Streptococcus ◽

International Health ◽

Infant Deaths ◽

Young Infants ◽

Group B

BackgroundStreptococcus agalactiae, or group B streptococcus (GBS), is a gram-positive streptococcal bacterium that is well-recognised as one of the leading causes of infant death, particularly in the early neonatal period (the first week of life). An estimated one in five pregnant women around the world carries GBS bacteria in their gastrointestinal or genitourinary tracts and vertical transmission from colonised mothers can lead to invasive disease in their offspring. A recent study conservatively estimated that out of 410,000 GBS cases globally every year, there are at least 1 47 000 stillbirths and infant deaths. Despite being home to only 13% of the world’s population, Africa has the highest GBS disease burden, with 54% of estimated cases and 65% of stillbirths and infant deaths.An effective GBS vaccine, given during pregnancy, is a promising strategy to protect against GBS disease. Currently, no licensed vaccine exists to prevent it, but scientific evaluation of feasibility is favourable. The leading vaccine candidates are capsular polysaccharide-protein conjugate vaccines. Evidence suggests maternal immunisation with a safe and effective GBS vaccine may reduce the disease risk in neonates and young infants.The Biovac Institute was established as a private-public partnership and is the only Southern African vaccine manufacturer. Located in Cape Town, South Africa, Biovac’s mission is to become a leading vaccine developer and producer in South Africa to increase capacity in Africa which only has four other vaccine manufacturers.In collaboration with PATH, an international health organisation, and other partners, Biovac is developing a multivalent conjugate vaccine against GBS. The first stage of the project involves the development of biopharmaceutical manufacturing processes and analytical tests, the preparation of clinical trial product, and execution of a first-in-human clinical trial.This presentation will provide an overview of the project, progress to date, and the path to commercialisation.

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

Clinical Infectious Diseases ◽

10.1093/cid/ciz360 ◽

2019 ◽

Cited By ~ 1

Author(s):

Ziyaad Dangor ◽

Mahtaab Khan ◽

Gaurav Kwatra ◽

Alane Izu ◽

Firdose Nakwa ◽

...

Keyword(s):

Breast Milk ◽

Late Onset ◽

Immunoglobulin A ◽

Invasive Disease ◽

Human Immunodeficiency Virus Status ◽

Model Studies ◽

Milk Samples ◽

Young Infants ◽

Group B ◽

Gastrointestinal Colonization

Abstract 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.

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Immunogenicity in animals of a polysaccharide-protein conjugate vaccine against type III group B Streptococcus.

Journal of Clinical Investigation ◽

10.1172/jci114858 ◽

1990 ◽

Vol 86 (5) ◽

pp. 1428-1433 ◽

Cited By ~ 119

Author(s):

M R Wessels ◽

L C Paoletti ◽

D L Kasper ◽

J L DiFabio ◽

F Michon ◽

...

Keyword(s):

Conjugate Vaccine ◽

Group B Streptococcus ◽

Type Iii ◽

Protein Conjugate ◽

Group B

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Guidelines for Prevention of Group B Streptococcal (GBS) Infection by Chemoprophylaxis

PEDIATRICS ◽

10.1542/peds.90.5.775 ◽

1992 ◽

Vol 90 (5) ◽

pp. 775-778 ◽

Cited By ~ 8

Author(s):

Keyword(s):

Pregnant Women ◽

Early Onset ◽

Late Onset ◽

The United States ◽

Geographic Region ◽

Culture Methods ◽

Term Infants ◽

Mortality And Morbidity ◽

Young Infants ◽

Group B

BACKGROUND For two decades streptococci classified serologically as Lancefield group B Streptococcus agalactiae (GBS) have been a leading cause of perinatal infections. In neonates and young infants these infections include congenital pneumonia, sepsis, or meningitis; in pregnant women they include urinary tract infection, chorioamnionitis, early postpartum endometritis, postcesarean section febrile morbidity, and—less frequently—pelvic thrombophlebitis or endocarditis. Although the incidence varies somewhat by geographic region, 12 000 infants and 50 000 pregnant women in the United States are estimated to develop GBS-associated morbidity or mortality annually.1 Overall mortality for early-onset (less than 7 days of age) and late-onset (7 days to 3 months of age) infant disease is approximately 15% and 10%, respectively.2-4 Gestational age significantly correlates with mortality among early-onset cases and is approximately 25% to 30% in preterm infants and 2% to 8% in term infants. Thus, every year approximately 1 600 infants die and an equal number have permanent neurologic sequelae following meningitis.1 This substantial GBS-associated perinatal mortality and morbidity make prevention strategies imperative. Among proposed strategies, including chemoprophylaxis and immunoprophylaxis, only intrapartum maternal chemoprophylaxis has been evaluated for safety and efficacy. EPIDEMIOLOGY GBS are frequently harbored in the genitourinary and lower gastrointestinal tracts of adults. When sensitive culture methods are used for their detection (ie, antibiotic-containing or selective broth media) and both lower vaginal and anorectal sites are sampled, GBS are found in 15% to 40% of pregnant women.5-8 Direct plating of swabs from body surfaces onto solid media or sampling of the cervix as a single genital tract site fails to identify as many as 50% of women who are culture-positive for GBS.4

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Prevalence, Risk Factors, and Serotype Distribution of Group B Streptococcus Colonization in HIV-Infected Pregnant Women Living in Belgium: A Prospective Cohort Study

Open Forum Infectious Diseases ◽

10.1093/ofid/ofy320 ◽

2018 ◽

Vol 5 (12) ◽

Cited By ~ 2

Author(s):

Nicolas Dauby ◽

Catherine Adler ◽

Veronique Y Miendje Deyi ◽

Rosalie Sacheli ◽

Laurent Busson ◽

...

Keyword(s):

Risk Factors ◽

Pregnant Women ◽

Late Onset ◽

Group B Streptococcus ◽

Neonatal Infection ◽

Colonization Rate ◽

Vaccine Serotypes ◽

Related Data ◽

Significant Difference ◽

Group B

Abstract Background Group B streptococcus (GBS) infection is a leading cause of severe neonatal infection. Maternal GBS carriage during pregnancy is the main risk factor for both early-onset and late-onset GBS disease. High incidence of GBS infection has been reported in HIV-exposed but -uninfected infants (HEU). We aimed to determine the prevalence, characteristics, and risk factors for GBS colonization in HIV-infected and HIV-uninfected pregnant women living in Belgium. Methods Between January 1, 2011, and December 31, 2013, HIV-infected (n = 125) and -uninfected (n = 120) pregnant women had recto-vaginal swabs at 35–37 weeks of gestation and at delivery for GBS detection. Demographic, obstetrical, and HIV infection–related data were prospectively collected. GBS capsular serotyping was performed on a limited number of samples (33 from HIV-infected and 16 from HIV-uninfected pregnant women). Results There was no significant difference in the GBS colonization rate between HIV-infected and -uninfected pregnant women (29.6% vs 24.2%, respectively). HIV-infected women were more frequently colonized by serotype III (36.4% vs 12.5%), and the majority of serotype III strains belonged to the hypervirulent clone ST-17. Exclusively trivalent vaccine serotypes (Ia, Ib, and III) were found in 57.6% and 75% of HIV-infected and -uninfected women, respectively, whereas the hexavalent vaccine serotypes (Ia, Ib, II, III, IV, and V) were found in 97% and 100%, respectively. Conclusions HIV-infected and -uninfected pregnant women living in Belgium have a similar GBS colonization rate. A trend to a higher colonization rate with serotype III was found in HIV-infected women, and those serotype III strains belong predominantly to the hypervirulent clone ST17.

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