A Vaccine Against Group B Streptococcus: Recent Advances

Group B streptococcus (GBS) causes a high burden of neonatal and infant disease globally. Implementing a vaccine for pregnant women is a promising strategy to prevent neonatal and infant GBS disease and has been identified as a priority by the World Health Organisation (WHO). GBS serotype-specific polysaccharide – protein conjugate vaccines are at advanced stages of development, but a large number of participants would be required to undertake Phase III clinical efficacy trials. Efforts are therefore currently focused on establishing serocorrelates of protection in natural immunity studies as an alternative pathway for licensure of a GBS vaccine, followed by Phase IV studies to evaluate safety and effectiveness. Protein vaccines are in earlier stages of development but are highly promising as they might confer protection irrespective of serotype. Further epidemiological, immunological and health economic studies are required to enable the vaccine to reach its target population as soon as possible

Developing a serocorrelate of protection against invasive group B streptococcus disease in pregnant women: a feasibility study.

BACKGROUND: Group B streptococcus is the leading cause of infection in infants. Currently, intrapartum antibiotic prophylaxis is the major strategy to prevent invasive group B streptococcus disease. However, intrapartum antibiotic prophylaxis does not prevent maternal sepsis, premature births, stillbirths or late-onset disease. Maternal vaccination may offer an alternative strategy. Multivalent polysaccharide protein conjugate vaccine development is under way and a serocorrelate of protection is needed to expedite vaccine licensure. OBJECTIVES: The ultimate aim of this work is to determine the correlate of protection against the major group B streptococcus disease-causing serotypes in infants in the UK. The aim of this feasibility study is to test key operational aspects of the study design. DESIGN: Prospective cohort study of pregnant women and their infants in a 6-month period (1 July to 31 December 2018). SETTING: Five secondary and tertiary hospitals from London and South England. National iGBS disease surveillance was conducted in all trusts in England and Wales. PARTICIPANTS: Pregnant women aged ≥ 18 years who were delivering at one of the selected hospitals and who provided consent during the study period. There were no exclusion criteria. INTERVENTIONS: No interventions were performed. MAIN OUTCOME MEASURES: (1) To test the feasibility of collecting serum at delivery from a large cohort of pregnant women. (2) To test the key operational aspects for a proposed large serocorrelates study. (3) To test the feasibility of collecting samples from those with invasive group B streptococcus. RESULTS: A total of 1823 women were recruited during the study period. Overall, 85% of serum samples were collected at three sites collecting only cord blood. At the two sites collecting maternal, cord and infant blood samples, the collection rate was 60%. A total of 614 women were screened for group B streptococcus with a colonisation rate of 22% (serotype distribution: 30% III, 25% Ia, 16% II, 14% Ib, 14% V and 1% IV). A blood sample was collected from 34 infants who were born to colonised women. Maternal and infant blood and the bacterial isolates for 15 newborns who developed invasive group B streptococcal disease during the study period were collected (serotype distribution: 29% III, 29% II, 21% Ia, 7% Ib, 7% IV and 7% V). LIMITATIONS: Recruitment and sample collection were dependent on the presence of research midwives rather than the whole clinical team. In addition, individualised consent limited the number of women who could be approached each day, and site set-up for the national surveillance study and the limited time period of this feasibility study limited recruitment of all eligible participants. CONCLUSIONS: We have verified the feasibility of collecting and processing rectovaginal swabs and blood samples in pregnant women, as well as samples from those with invasive group B streptococcal disease. We have made recommendations for the recruitment of cases within the proposed GBS3 study and for controls both within GBS3 and as an extension of this feasibility study. FUTURE WORK: A large case-control study comparing specific immunoglobulin G levels in mothers whose infants develop invasive group B streptococcal disease with those in colonised mothers whose infants do not develop invasive group B streptococcal disease is recommended. TRIAL REGISTRATION: Current Controlled Trials ISRCTN49326091; IRAS project identification number 246149/REC reference number 18/WM/0147. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 23, No. 67. See the NIHR Journals Library website for further project information

Enabling access to pharmacy law teaching during COVID-19 : student perceptions of MyDispense and assessment outcomes

During the COVID-19 pandemic, it was not always possible to teach pharmacy practice and practical dispensing skills in person. Second-year pharmacy students (n = 147) were given access to a virtual simulation tool, MyDispense, to supplement their learning. This software enabled students to work remotely and access exercises in a ‘safe’ community pharmacy setting. This study evaluated second-year pharmacy students’ perceptions of MyDispense, and the impact on assessment performance in the pharmacy law and ethics module. Students were able to access 22 MyDispense activities throughout the academic year (2020/2021). Exercise completion rates and assessment marks were analysed, along with findings from a cross-sectional survey about user experience. MyDispense data were available for all students (n = 147), and 76.1% (n = 115) completed the survey. The mean number of MyDispense exercises completed was nine. Higher levels of MyDispense exercise completion were associated with higher pass rates and mean scores (no exercises completed versus 1–10 activities completed: mean score 77.1 versus 83.1, respectively) and a statistically significant association between exercise usage and in-class assessed prescription scores. Overall, 46.1% (n = 53/115), 33.0% (n = 38/115) and 33.9% (n = 39/115) of students felt that MyDispense had helped them to prepare for their assessed prescriptions, mid-module test, and final exam, respectively. MyDispense has provided an accessible alternative to in-person teaching for students during the COVID-19 pandemic, and results showed a positive association with assessment performance in pharmacy law and ethics

What is the result of vaginal cleansing with chlorhexidine during labour on maternal and neonatal infections? A systematic review of randomised trials with meta-analysis

Abstract Background Infection with vaginal microorganisms during labour can lead to maternal and neonatal mortality and morbidity. The objective of this systematic review is to review the effectiveness of intrapartum vaginal chlorhexidine in the reduction of maternal and neonatal colonisation and infectious morbidity. Methods Search strategy – Eight databases were searched for articles published in any language from inception to October 2016. Selection criteria – Randomised controlled trials were included. Data Collection and analysis - Publications were assessed for inclusion. Data were extracted and assessed for risk of bias. Relative risks from individual studies were pooled using a random effects model and the heterogeneity of treatment was evaluated using Chi2 and I 2 tests. Results Eleven randomised controlled trials (n = 20,101) evaluated intrapartum vaginal chlorhexidine interventions. Meta-analysis found no significant differences between the intervention and control groups for any of the four outcomes: maternal or neonatal colonization or infection. The preferred method for chlorhexidine administration was vaginal irrigation. Conclusions Meta-analysis did not demonstrate improved maternal or neonatal outcomes with intrapartum vaginal chlorhexidine cleansing, however this may be due to the limitations of the available studies. A larger, multicentre randomised controlled trial, powered to accurately evaluate the effect of intrapartum vaginal chlorhexidine cleansing on neonatal outcomes may still be informative; the technique of douching may be the most promising

CD36 coordinates NLRP3 inflammasome activation by facilitating the intracellular nucleation from soluble to particulate ligands in sterile inflammation

Particulate ligands including cholesterol crystals and amyloid fibrils induce NLRP3-dependent production of interleukin-1β (IL-1β) in atherosclerosis, Alzheimer's disease and diabetes. Soluble endogenous ligands including oxidized-LDL, amyloid-β and amylin peptides accumulate in these diseases. Here we identify a CD36-mediated endocytic pathway that coordinates the intracellular conversion of these soluble ligands to crystals or fibrils, resulting in lysosomal disruption and NLRP3-inflammasome activation. Consequently, macrophages lacking CD36 failed to elicit IL-1β production in response to these ligands and targeting CD36 in atherosclerotic mice reduced serum IL-1β and plaque cholesterol crystal accumulation. Collectively, these findings highlight the importance of CD36 in the accrual and nucleation of NLRP3 ligands from within the macrophage and position CD36 as a central regulator of inflammasome activation in sterile inflammation

Reliability of dried blood spot (DBS) cards in antibody measurement: A systematic review

Background Increasingly, vaccine efficacy studies are being recommended in low-and-middle-income countries (LMIC), yet often facilities are unavailable to take and store infant blood samples correctly. Dried blood spots (DBS), are useful for collecting blood from infants for diagnostic purposes, especially in low-income settings, as the amount of blood required is miniscule and no refrigeration is required. Little is known about their utility for antibody studies in children. This systematic review aims to investigate the correlation of antibody concentrations against infectious diseases in DBS in comparison to serum or plasma samples that might inform their use in vaccine clinical trials. Methods and findings We searched MEDLINE, Embase and the Cochrane library for relevant studies between January 1990 to October 2020 with no language restriction, using PRISMA guidelines, investigating the correlation between antibody concentrations in DBS and serum or plasma samples, and the effect of storage temperature on DBS diagnostic performance. We included 40 studies in this systematic review. The antibody concentration in DBS and serum/plasma samples reported a good pooled correlation, (r2 = 0.86 (ranged 0.43 to 1.00)). Ten studies described a decline of antibody after 28 days at room temperature compared to optimal storage at -20°C, where antibodies were stable for up to 200 days. There were only five studies of anti-bacterial antibodies. Conclusions There is a good correlation between antibody concentrations in DBS and serum/plasma samples, supporting the wider use of DBS in vaccine and sero-epidemiological studies, but there is limited data on anti-bacterial antibodies. The correct storage of DBS is critical and may be a consideration for longer term storage

Antibody kinetics between birth and three months of life in healthy infants with natural exposure to Group B streptococcus: A UK cohort study

Introduction Capsular polysaccharide (CPS) serotype-specific Immunoglobulin G (IgG) in cord blood has been proposed as a correlate of protection against invasive Group B Streptococcus (iGBS) disease. Although protective levels are required in infants throughout the window of vulnerability up to 3 months of age, little is known regarding the kinetics of GBS-specific IgG over this period. Methods We enrolled 33 healthy infants born to mothers colonized with GBS. We collected cord blood and infant blood samples either at one (21–35 days), two (49–63 days), or three months of age (77–91 days). We measured GBS serotype-specific CPS IgG concentrations and calculated the decay rate using a mixed-effects model. We further explored whether the antibody kinetics were affected by common maternal and infant factors and estimated the correlation between IgG concentration at birth and one, two, and three months of age. Results The half-life estimate of IgG concentration for homologous and non-homologous GBS serotypes in paired samples with detectable IgG levels at both time points was 27.4 (95 % CI: 23.5–32.9) days. The decay rate did not vary by maternal age (p = 0.7), ethnicity (p = 0.1), gravida (p = 0.1), gestation (p = 0.7), and infant sex (p = 0.1). Predicted IgG titres above the assay lower limit of quantification on day 30 strongly correlated with titres at birth (Spearman correlation coefficient 0.71 [95 % CI: 0.60–0.80]). Conclusion Our results provide a basis for future investigations into the use of antibody kinetics in defining a serocorrelate of protection against late-onset iGBS disease

Using Dried Blood Spots for a Sero-Surveillance Study of Maternally Derived Antibody against Group B Streptococcus.

Vaccination during pregnancy could protect women and their infants from invasive Group B Streptococcus (GBS) disease. To understand if neonatal dried blood spots (DBS) can be used to determine the amount of maternally derived antibody that protects infants against invasive GBS disease, a retrospective case-control study was conducted in England between 1 April 2014 and 30 April 2015. The DBS of cases with invasive GBS disease (n = 61) were matched with healthy controls (n = 125). The haematocrit, DBS storage temperature, freeze-thaw cycle, and paired serum/DBS studies were set up to optimise the antibody assessment. The samples were analysed using a multiplex immunoassay, and the results were assessed using parametric and nonparametric tests. Antibody concentrations were stable at haematocrits of up to 50% but declined at 75%. DBS storage at room temperature was stable for three months compared with storage from collection at -20 °C and rapidly degraded thereafter. Total IgG levels measured in DBS and paired serum showed a good correlation (r2 = 0.99). However, due to suboptimal storage conditions, no difference was found in the GBS IgG levels between DBS samples from cases and controls. We have demonstrated a proof of concept that assays utilising DBS for assessing GBS serotype-specific antibodies in infants is viable. This method could be used to facilitate future large sero-correlate studies, but DBS samples must be stored at -20 °C for long term preservation of antibody

Loss of SOCS3 expression in T cells reveals a regulatory role for interleukin-17 in atherosclerosis

Atherosclerosis is an inflammatory vascular disease responsible for the first cause of mortality worldwide. Recent studies have clearly highlighted the critical role of the immunoinflammatory balance in the modulation of disease development and progression. However, the immunoregulatory pathways that control atherosclerosis remain largely unknown. We show that loss of suppressor of cytokine signaling (SOCS) 3 in T cells increases both interleukin (IL)-17 and IL-10 production, induces an antiinflammatory macrophage phenotype, and leads to unexpected IL-17–dependent reduction in lesion development and vascular inflammation. In vivo administration of IL-17 reduces endothelial vascular cell adhesion molecule–1 expression and vascular T cell infiltration, and significantly limits atherosclerotic lesion development. In contrast, overexpression of SOCS3 in T cells reduces IL-17 and accelerates atherosclerosis. We also show that in human lesions, increased levels of signal transducer and activator of transcription (STAT) 3 phosphorylation and IL-17 are associated with a stable plaque phenotype. These results identify novel SOCS3-controlled IL-17 regulatory pathways in atherosclerosis and may have important implications for the understanding of the increased susceptibility to vascular inflammation in patients with dominant-negative STAT3 mutations and defective Th17 cell differentiation