Seven-Year Efficacy of RTS,S/AS01 Malaria Vaccine among Young African Children

Background The RTS,S/AS01 malaria vaccine candidate is being evaluated for implementation. Methods We conducted 7 years follow-up of children who were randomized at age 5 to 17 months to receive three doses of either the RTS,S/AS01 vaccine or control vaccine (rabies). The endpoint was clinical malaria (temperature ≥37.5°C and infection with Plasmodium falciparum of ≥2500 parasites per µl). Each child’s malaria exposure was estimated using the prevalence of malaria among residents within a 2km radius of their homestead. Vaccine efficacy was defined as 1 minus the hazard ratio (HR) or incidence rate ratios (IRR) of the RTS,S/AS01 vaccinated versus rabies vaccinated groups. Results We identified 1002 clinical malaria episodes among 223 children randomized to RTS,S/AS01 and 992 clinical malaria episodes among 224 children randomized to control vaccination over seven years follow-up. Intention-to-treat vaccine efficacy (VE) was 4.4% (95%CI: -17 to 21.9, p value=0.67) and per-protocol VE was 7.0% (95%CI -14.5 to 24.6%, p=0.5) by negative binomial regression. VE waned over time (p=0.006 for the interaction between vaccination and time), including negative efficacy during the fifth year among children at higher malaria parasite exposure (-43.5%, 95%CI: -100.3 to -2.8, p value=0.033 by intention-to-treat and -56.8%, 95%CI -118.7 to -12.3, p=0.008 per-protocol). Conclusion A 3-dose vaccination with RTS,S/AS01 is initially protective against clinical malaria, but this is offset by rebound in later years in areas with higher malaria parasite exposure. Further data are needed on longer-term outcomes following four-dose vaccinations. </p

Defining Clinical Malaria: The Specificity and Incidence of Endpoints from Active and Passive Surveillance of Children in Rural Kenya

Febrile malaria is the most common clinical manifestation of P. falciparum infection, and is often the primary endpoint in clinical trials and epidemiological studies. Subjective and objective fevers are both used to define the endpoint, but have not been carefully compared, and the relative incidence of clinical malaria by active and passive case detection is unknown. We analyzed data from cohorts under active and passive surveillance, including 19,462 presentations with fever and 5,551 blood tests for asymptomatic parasitaemia. A logistic regression model was used to calculate Malaria Attributable Fractions (MAFs) for various case definitions. Incidences of febrile malaria by active and passive surveillance were compared in a subset of children matched for age and location. Active surveillance identified three times the incidence of clinical malaria as passive surveillance in a subset of children matched for age and location. Objective fever (temperature≥37.5°C) gave consistently higher MAFs than case definitions based on subjective fever. The endpoints from active and passive surveillance have high specificity, but the incidence of endpoints is lower on passive surveillance. Subjective fever had low specificity and should not be used in primary endpoint. Passive surveillance will reduce the power of clinical trials but may cost-effectively deliver acceptable sensitivity in studies of large populations

Estimating Individual Exposure to Malaria Using Local Prevalence of Malaria Infection in the Field

BACKGROUND: Heterogeneity in malaria exposure complicates survival analyses of vaccine efficacy trials and confounds the association between immune correlates of protection and malaria infection in longitudinal studies. Analysis may be facilitated by taking into account the variability in individual exposure levels, but it is unclear how exposure can be estimated at an individual level. METHOD AND FINDINGS: We studied three cohorts (Chonyi, Junju and Ngerenya) in Kilifi District, Kenya to assess measures of malaria exposure. Prospective data were available on malaria episodes, geospatial coordinates, proximity to infected and uninfected individuals and residence in predefined malaria hotspots for 2,425 individuals. Antibody levels to the malaria antigens AMA1 and MSP1(142) were available for 291 children from Junju. We calculated distance-weighted local prevalence of malaria infection within 1 km radius as a marker of individual's malaria exposure. We used multivariable modified Poisson regression model to assess the discriminatory power of these markers for malaria infection (i.e. asymptomatic parasitaemia or clinical malaria). The area under the receiver operating characteristic (ROC) curve was used to assess the discriminatory power of the models. Local malaria prevalence within 1 km radius and AMA1 and MSP1(142) antibodies levels were independently associated with malaria infection. Weighted local malaria prevalence had an area under ROC curve of 0.72 (95%CI: 0.66-0.73), 0.71 (95%CI: 0.69-0.73) and 0.82 (95%CI: 0.80-0.83) among cohorts in Chonyi, Junju and Ngerenya respectively. In a small subset of children from Junju, a model incorporating weighted local malaria prevalence with AMA1 and MSP1(142) antibody levels provided an AUC of 0.83 (95%CI: 0.79-0.88). CONCLUSION: We have proposed an approach to estimating the intensity of an individual's malaria exposure in the field. The weighted local malaria prevalence can be used as individual marker of malaria exposure in malaria vaccine trials and longitudinal studies of natural immunity to malaria

Iron Deficiency and Acute Seizures: Results from Children Living in Rural Kenya and a Meta-Analysis

There are conflicting reports on whether iron deficiency changes susceptibility to seizures. We examined the hypothesis that iron deficiency is associated with an increased risk of acute seizures in children in a malaria endemic area

Identifying children with excess malaria episodes after adjusting for variation in exposure: identification from a longitudinal study using statistical count models

BACKGROUND: The distribution of Plasmodium falciparum clinical malaria episodes is over-dispersed among children in endemic areas, with more children experiencing multiple clinical episodes than would be expected based on a Poisson distribution. There is consistent evidence for micro-epidemiological variation in exposure to P. falciparum. The aim of the current study was to identify children with excess malaria episodes after controlling for malaria exposure. METHODS: We selected the model that best fit the data out of the models examined and included the following covariates: age, a weighted local prevalence of infection as an index of exposure, and calendar time to predict episodes of malaria on active surveillance malaria data from 2,463 children of under 15 years of age followed for between 5 and 15 years each. Using parameters from the zero-inflated negative binomial model which best fitted our data, we ran 100 simulations of the model based on our population to determine the variation that might be seen due to chance. RESULTS: We identified 212 out of 2,463 children who had a number of clinical episodes above the 95(th) percentile of the simulations run from the model, hereafter referred to as “excess malaria (EM)”. We then identified exposure-matched controls with “average numbers of malaria” episodes, and found that the EM group had higher parasite densities when asymptomatically infected or during clinical malaria, and were less likely to be of haemoglobin AS genotype. CONCLUSIONS: Of the models tested, the negative zero-inflated negative binomial distribution with exposure, calendar year, and age acting as independent predictors, fitted the distribution of clinical malaria the best. Despite accounting for these factors, a group of children suffer excess malaria episodes beyond those predicted by the model. An epidemiological framework for identifying these children will allow us to study factors that may explain excess malaria episodes. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12916-015-0422-4) contains supplementary material, which is available to authorized users

Safety and efficacy of allogeneic umbilical cord red blood cell transfusion for children with severe anaemia in a Kenyan hospital: an open-label single-arm trial

Background In sub-Saharan Africa, children are frequently admitted with severe anaemia needing an urgent blood transfusion, but blood is often unavailable. When conventional blood supplies are inadequate, allogeneic umbilical cord blood could be a feasible alternative. The aim of this study was to assess the safety and efficacy of cord blood transfusion in children with severe anaemia. Methods Between June 26, 2007, and May 20, 2008, 413 children needing an urgent blood transfusion were admitted to Kilifi District Hospital in Kenya. Of these, 87 children were eligible for our study—ie, younger than 12 years, no signs of critical illness, and haemoglobin 100 g/L or lower (if aged 3 months or younger) or 40 g/L or lower (if older than 3 months). Cord blood was donated at Coast Provincial General Hospital, Mombasa, and screened for transfusion-transmitted infections and bacterial contamination. Red blood cells were stored vertically at 2–6°C to enable sedimentation. After transfusion, children were monitored closely for adverse events and followed up for 28 days. The primary outcome measure was the frequency and nature of adverse reactions associated with the transfusion. Secondary outcomes were the changes in haemoglobin concentrations 24 h and 28 days after transfusion, compared with pretransfusion levels. This trial is registered on ISRCTN.com, number ISRCTN66687527. Findings Of the 87 children eligible for the study, cord blood was unavailable for 24, six caregivers declined consent, and two children were withdrawn before transfusion. Therefore, 55 children received umbilical cord red blood cells from 74 donations. Ten (18%) children had ten serious adverse events and 43 (78%) had 94 adverse events; the most frequent adverse events were anaemia (n=14), weight loss (n=12), and vomiting (n=10). An independent expert panel judged none of these adverse events to be probably or certainly caused by the cord blood transfusion (one-sided 97·5% CI 0–6·5). Haemoglobin increased by a median of 26 g/L (IQR 21–31) 24 h after transfusion and by 50 g/L (10–68) a median of 29 days (28–35) after transfusion. Interpretation These preliminary data suggest that cord blood could be an important supplementary source of blood for transfusion in children in sub-Saharan Africa. Further studies are needed to compare the safety and efficacy of cord blood with conventional adult-donated blood for transfusions. Challenges associated with cost, infrastructure, and scale up also need investigating

Four-year efficacy of RTS,S/AS01E and its interaction with malaria exposure.

BACKGROUND: The candidate malaria vaccine RTS,S/AS01E has entered phase 3 trials, but data on long-term outcomes are limited. METHODS: For 4 years, we followed children who had been randomly assigned, at 5 to 17 months of age, to receive three doses of RTS,S/AS01E vaccine (223 children) or rabies vaccine (224 controls). The end point was clinical malaria (temperature of ≥37.5°C and Plasmodium falciparum parasitemia density of &gt;2500 parasites per cubic millimeter). Each child's exposure to malaria was estimated with the use of the distance-weighted local prevalence of malaria. RESULTS: Over a period of 4 years, 118 of 223 children who received the RTS,S/AS01E vaccine and 138 of 224 of the controls had at least 1 episode of clinical malaria. Vaccine efficacies in the intention-to-treat and per-protocol analyses were 29.9% (95% confidence interval [CI], 10.3 to 45.3; P=0.005) and 32.1% (95% CI, 11.6 to 47.8; P=0.004), respectively, calculated by Cox regression. Multiple episodes were common, with 551 and 618 malarial episodes in the RTS,S/AS01E and control groups, respectively; vaccine efficacies in the intention-to-treat and per-protocol analyses were 16.8% (95% CI, -8.6 to 36.3; P=0.18) and 24.3% (95% CI, 1.9 to 41.6; P=0.04), respectively, calculated by the Andersen-Gill extension of the Cox model. For every 100 vaccinated children, 65 cases of clinical malaria were averted. Vaccine efficacy declined over time (P=0.004) and with increasing exposure to malaria (P=0.001) in the per-protocol analysis. Vaccine efficacy was 43.6% (95% CI, 15.5 to 62.3) in the first year but was -0.4% (95% CI, -32.1 to 45.3) in the fourth year. Among children with a malaria-exposure index that was average or lower than average, the vaccine efficacy was 45.1% (95% CI, 11.3 to 66.0), but among children with a malaria-exposure index that was higher than average it was 15.9% (95% CI, -11.0 to 36.4). CONCLUSIONS: The efficacy of RTS,S/AS01E vaccine over the 4-year period was 16.8%. Efficacy declined over time and with increasing malaria exposure. (Funded by the PATH Malaria Vaccine Initiative and Wellcome Trust; ClinicalTrials.gov number, NCT00872963.)