Blood Stage Malaria Vaccine Eliciting High Antigen-Specific Antibody Concentrations Confers No Protection to Young Children in Western Kenya

The antigen, falciparum malaria protein 1 (FMP1), represents the 42-kDa C-terminal fragment of merozoite surface protein-1 (MSP-1) of the 3D7 clone of P. falciparum. Formulated with AS02 (a proprietary Adjuvant System), it constitutes the FMP1/AS02 candidate malaria vaccine. We evaluated this vaccine's safety, immunogenicity, and efficacy in African children.A randomised, double-blind, Phase IIb, comparator-controlled trial.The trial was conducted in 13 field stations of one mile radii within Kombewa Division, Nyanza Province, Western Kenya, an area of holoendemic transmission of P. falciparum. We enrolled 400 children aged 12-47 months in general good health.Children were randomised in a 1ratio1 fashion to receive either FMP1/AS02 (50 microg) or Rabipur(R) rabies vaccine. Vaccinations were administered on a 0, 1, and 2 month schedule. The primary study endpoint was time to first clinical episode of P. falciparum malaria (temperature >/=37.5 degrees C with asexual parasitaemia of >/=50,000 parasites/microL of blood) occurring between 14 days and six months after a third dose. Case detection was both active and passive. Safety and immunogenicity were evaluated for eight months after first immunisations; vaccine efficacy (VE) was measured over a six-month period following third vaccinations.374 of 400 children received all three doses and completed six months of follow-up. FMP1/AS02 had a good safety profile and was well-tolerated but more reactogenic than the comparator. Geometric mean anti-MSP-1(42) antibody concentrations increased from1.3 microg/mL to 27.3 microg/mL in the FMP1/AS02 recipients, but were unchanged in controls. 97 children in the FMP1/AS02 group and 98 controls had a primary endpoint episode. Overall VE was 5.1% (95% CI: -26% to +28%; p-value = 0.7).FMP1/AS02 is not a promising candidate for further development as a monovalent malaria vaccine. Future MSP-1(42) vaccine development should focus on other formulations and antigen constructs.Clinicaltrials.gov NCT00223990

Long-term impact of giving antibiotics before skin incision versus after cord clamping on children born by caesarean section: protocol for a longitudinal study based on UK electronic health records.

INTRODUCTION In the UK, about a quarter of women give birth by caesarean section (CS) and are offered prophylactic broad-spectrum antibiotics to reduce the risk of maternal postpartum infection. In 2011, national guidance was changed from recommending antibiotics after the umbilical cord was cut to giving antibiotics prior to skin incision based on evidence that earlier administration reduces maternal infectious morbidity. Although antibiotics cross the placenta, there are no known short-term harms to the baby. This study aims to address the research gap on longer term impact of these antibiotics on child health. METHODS AND ANALYSIS A controlled interrupted time series study will use anonymised mother-baby linked routine electronic health records for children born during 2006-2018 recorded in UK primary care (The Health Improvement Network, THIN and Clinical Practice Research Datalink, CPRD) and secondary care (Hospital Episode Statistics, HES) databases. The primary outcomes of interest are asthma and eczema, two common allergy-related diseases in childhood. In-utero exposure to antibiotics immediately prior to CS will be compared with no exposure when given after cord clamping. The risk of outcomes in children delivered by CS will also be compared with a control cohort delivered vaginally to account for time effects. We will use all available data from THIN, CPRD and HES with estimated power of 80% and 90% to detect relative increase in risk of asthma of 16% and 18%, respectively at the 5% significance level. ETHICS AND DISSEMINATION Ethical approval has been obtained from the University of Birmingham Ethical Review Committee with scientific approvals obtained from the independent scientific advisory committees from the Medicines and Healthcare products Regulatory Agency for CPRD and the data provider, IQVIA for THIN. The results will be published in peer-reviewed journals, presented at national and international conferences and disseminated to stakeholders

Long term impact of pre-incision antibiotics on children born by caesarean section : longitudinal study based on UK electronic health records

Aim: To investigate whether the change in the NICE guidance in 2011 from recommending prophylactic antibiotics after cord clamping to pre-incision antibiotics has had any effect on the incidence of allergic and other related health conditions in children born by Caesarean Section (CS). Design: A controlled interrupted time series study using mother-baby linked routine health record data from UK primary (THIN, CPRD) and secondary care (HES) databases. Target population: Children born in the UK during 2006-2018 delivered by CS, compared to a control cohort delivered vaginally. Intervention and comparator: In utero exposure to prophylactic antibiotics immediately prior to CS will be compared to no exposure when given after cord clamping at CS. The exposure to intra-partum antibiotics is not routinely recorded in any available healthcare databases in the UK, but nearly all women undergoing CS receive prophylactic antibiotics. We will use the findings from the national survey of hospitals regarding the change in the timing of antibiotic administration as an indicator of the probability of exposure. We will account for the cumulative increase of hospitals giving pre-incision antibiotics in our analysis. For the analysis of outcomes recorded in secondary care, we will be able to link the survey data regarding the timing of policy change at hospital level for each birth. Primary outcomes: asthma and eczema, the most common allergy related childhood diseases. Secondary outcomes: other allergic and allergy related diseases, autoimmune diseases, infections and inflammation, other immune system related conditions, healthcare utilisation. Maternal postpartum infectious morbidity will allow us to investigate if the effects of pre-incision antibiotics demonstrated in randomised trials can be replicated using routine data. Planned sample size: We will use all available data from THIN, CPRD and HES. We have identified the likely number of deliveries, asthma diagnosis (for primary care) and asthma admissions (for secondary care) across the study time period. For primary care we will compare outcomes in 95,000 CS deliveries receiving pre-incisional antibiotics with 112,000 receiving post-clamping antibiotics, with outcomes from 571,000 vaginal births being used to control for time effects. This will provide 80% and 90% power to detect relative increases in risk of asthma of 16% and 18%, respectively at the 5% significance level. For secondary care we will compare outcomes in 955,000 CS deliveries receiving pre-incisional antibiotics with 1,116,000 receiving post-clamping antibiotics, with outcomes from 5,973,000 vaginal births. This will provide 80% and 90% power to detect relative increases in risk of asthma hospital admission of 10% and 12%, respectively at the 5% significance level. Timetable: Year 1 - Development of the analysis model; exploration of case-mix co-variates; finalisation of the outcome variables including findings from the PPI workshop; HES & CPRD data acquisition; dataset merging and data linkage, dataset cleaning and preparation for the analysis. Year 2 - Analysis and data interpretation; co-production of messages with PPI for dissemination, dissemination of findings

Long term impact of prophylactic antibiotic use before incision versus after cord clamping on children born by caesarean section : longitudinal study of UK electronic health records

Objective To investigate the impact on child health up to age 5 years of a policy to use antibiotic prophylaxis for caesarean section before incision compared with after cord clamping. Design Observational controlled interrupted time series study. Setting UK primary and secondary care. Participants 515 945 children born in 2006-18 with linked maternal records and registered with general practices contributing to two UK primary care databases (The Health Improvement Network and Clinical Practice Research Datalink), and 7 147 884 children with linked maternal records in the Hospital Episode Statistics database covering England, of which 3 945 351 were linked to hospitals that reported the year of policy change to administer prophylactic antibiotics for caesarean section before incision rather than after cord clamping. Intervention Fetal exposure to antibiotics shortly before birth (using pre-incision antibiotic policy as proxy) compared with no exposure. Main outcome measures The primary outcomes were incidence rate ratios of asthma and eczema in children born by caesarean section when pre-incision prophylactic antibiotics were recommended compared with those born when antibiotics were administered post-cord clamping, adjusted for temporal changes in the incidence rates in children born vaginally. Results Prophylactic antibiotics administered before incision for caesarean section compared with after cord clamping were not associated with a significantly higher risk of asthma (incidence rate ratio 0.91, 95% confidence interval 0.78 to 1.05) or eczema (0.98, 0.94 to 1.03), including asthma and eczema resulting in hospital admission (1.05, 0.99 to 1.11 and 0.96, 0.71 to 1.29, respectively), up to age 5 years. Conclusions This study found no evidence of an association between pre-incision prophylactic antibiotic use and risk of asthma and eczema in early childhood in children born by caesarean section

Long term impact of prophylactic antibiotic use before incision versus after cord clamping on children born by caesarean section: longitudinal study of UK electronic health records.

OBJECTIVE To investigate the impact on child health up to age 5 years of a policy to use antibiotic prophylaxis for caesarean section before incision compared with after cord clamping. DESIGN Observational controlled interrupted time series study. SETTING UK primary and secondary care. PARTICIPANTS 515 945 children born in 2006-18 with linked maternal records and registered with general practices contributing to two UK primary care databases (The Health Improvement Network and Clinical Practice Research Datalink), and 7 147 884 children with linked maternal records in the Hospital Episode Statistics database covering England, of which 3 945 351 were linked to hospitals that reported the year of policy change to administer prophylactic antibiotics for caesarean section before incision rather than after cord clamping. INTERVENTION Fetal exposure to antibiotics shortly before birth (using pre-incision antibiotic policy as proxy) compared with no exposure. MAIN OUTCOME MEASURES The primary outcomes were incidence rate ratios of asthma and eczema in children born by caesarean section when pre-incision prophylactic antibiotics were recommended compared with those born when antibiotics were administered post-cord clamping, adjusted for temporal changes in the incidence rates in children born vaginally. RESULTS Prophylactic antibiotics administered before incision for caesarean section compared with after cord clamping were not associated with a significantly higher risk of asthma (incidence rate ratio 0.91, 95% confidence interval 0.78 to 1.05) or eczema (0.98, 0.94 to 1.03), including asthma and eczema resulting in hospital admission (1.05, 0.99 to 1.11 and 0.96, 0.71 to 1.29, respectively), up to age 5 years. CONCLUSIONS This study found no evidence of an association between pre-incision prophylactic antibiotic use and risk of asthma and eczema in early childhood in children born by caesarean section