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Background A recombinant vesicular stomatitis virus vector expressing the Zaire Ebola virus glycoprotein (rVSV Delta G-ZEBOV-GP) vaccine has been reported as safe, immunogenic, and highly protective in a ring vaccination trial. We aimed to identify transcriptomic immune response biomarker signatures induced by vaccination and associated signatures with its immunogenicity and reactogenicity to better understand the potential mechanisms of action of the vaccine.Methods 354 healthy adult volunteers were vaccinated in randomised, double-blind, placebo-controlled trials in Europe (Geneva, Switzerland [November, 2014, to January, 2015]) and North America (USA [Dec 5, 2014, to June 23, 2015]), and dose-escalation trials in Africa (Lambarene, Gabon [November, 2014, to January, 2015], and Kilifi, Kenya [December, 2014, to January, 2015]) using different doses of the recombinant vesicular stomatitis virus vector expressing the Zaire Ebola virus glycoprotein (rVSV Delta G-ZEBOV-GP; 3x 10(5) to 1 x 10(8) plaque-forming units [pfu]). Longitudinal transcriptomic responses (days 0, 1, 2, 3, 7, 14, and 28) were measured in whole blood using a targeted gene expression profiling platform (dual-colour reverse-transcriptase multiplex ligation-dependent probe amplification) focusing on 144 immune-related genes. The effect of time and dose on transcriptomic response was also assessed. Logistic regression with lasso regularisation was applied to identify host signatures with optimal discriminatory capability of vaccination at day 1 or day 7 versus baseline, whereas random-effects models and recursive feature elimination combined with regularised logistic regression were used to associate signatures with immunogenicity and reactogenicity.Findings Our results indicated that perturbation of gene expression peaked on day 1 and returned to baseline levels between day 7 and day 28. The magnitude of the response was dose-dependent, with vaccinees receiving a high dose (>= 9x 10(6) pfu) of rVSV Delta G-ZEBOV-GP exhibiting the largest amplitude. The most differentially expressed genes that were significantly upregulated following vaccination consisted of type I and II interferon-related genes and myeloid cell-associated markers, whereas T cell, natural killer cell, and cytotoxicity-associated genes were downregulated. A gene signature associated with immunogenicity (common to all four cohorts) was identified correlating gene expression profiles with ZEBOV-GP antibody titres and a gene signatures associated with reactogenicity (Geneva cohort) was identified correlating gene expression profiles with an adverse event (ie, arthritis).Interpretation Collectively, our results identify and cross-validate immune-related transcriptomic signatures induced by rVSV Delta G-ZEBOV-GP vaccination in four cohorts of adult participants from different genetic and geographical backgrounds. These signatures will aid in the rational development, testing, and evaluation of novel vaccines and will allow evaluation of the effect of host factors such as age, co-infection, and comorbidity on responses to vaccines. Copyright (C) 2021 The Author(s). Published by Elsevier Ltd.

Background Individuals living in endemic areas acquire immunity to malaria following repeated parasite exposure. We sought to assess the controlled human malaria infection (CHMI) model as a means of studying naturally acquired immunity in Kenyan adults with varying malaria exposure. Methods We analysed data from 142 Kenyan adults from three locations representing distinct areas of malaria endemicity (Ahero, Kilifi North and Kilifi South) enrolled in a CHMI study with Plasmodium falciparum sporozoites NF54 strain (Sanaria® PfSPZ Challenge). To identify the in vivo outcomes that most closely reflected naturally acquired immunity, parameters based on qPCR measurements were compared with anti-schizont antibody levels and residence as proxy markers of naturally acquired immunity. Results Time to endpoint correlated more closely with anti-schizont antibodies and location of residence than other parasite parameters such as growth rate or mean parasite density. Compared to observational field-based studies in children where 0.8% of the variability in malaria outcome was observed to be explained by anti-schizont antibodies, in the CHMI model the dichotomized anti-schizont antibodies explained 17% of the variability. Conclusions The CHMI model is highly effective in studying markers of naturally acquired immunity to malaria. Trial registration Clinicaltrials.gov number NCT02739763. Registered 15 April 2016

Background Naturally acquired immunity to malaria is incompletely understood. We used controlled human malaria infection (CHMI) to study the impact of past exposure to malaria in Kenyan adults in relation to infection with a non-Kenyan parasite strain. Methods We administered 3.2x103 aseptic, purified, cryopreserved Plasmodium falciparum (Pf) sporozoites (SPZ) [Sanaria® PfSPZ Challenge, NF54 West African strain] by direct venous inoculation and undertook clinical monitoring and serial quantitative PCR (qPCR) of the 18S ribosomal RNA gene. The study endpoint was met when either: parasitaemia reached ≥500 parasites/μl blood; clinically significant symptoms were seen; or at 21 days after inoculation. All volunteers received antimalarial drug treatment on meeting the endpoint. Results One hundred and sixty-one (161) volunteers underwent CHMI between Aug 4, 2016, and Feb 14, 2018. CHMI was well tolerated with no severe or serious adverse events. Nineteen volunteers (11.8%) were excluded from the analysis based on detection of antimalarial drugs above the minimal inhibitory concentration or parasites genotyped as non-NF54. Of the 142 volunteers who were eligible for analysis: 26 (18.3%) had febrile symptoms and were treated; 30 (21.1%) reached ≥500 parasites/μl and were treated; 53 (37.3%) had parasitaemia without meeting thresholds for treatment and; 33 (23.2%) remained qPCR negative. Conclusion We find that past exposure to malaria, as evidenced by location of residence, in some Kenyan adults can completely suppress in vivo growth of a parasite strain originating from outside Kenya.TRAIL REGISTRATION. The study was registered on ClinicalTrials.gov (NCT02739763). Funding Wellcome Trust.

Background Human infection studies (HIS) that involve deliberately infecting healthy volunteers with a pathogen raise important ethical issues, including the need to ensure that benefits and burdens are understood and appropriately accounted for. Building on earlier work, we embedded social science research within an ongoing malaria human infection study in coastal Kenya to understand the study benefits and burdens experienced by study stakeholders in this low-resource setting and assess the wider implications for future research planning and policy. Methods Data were collected using qualitative research methods, including in-depth interviews (44), focus group discussions (10) and non-participation observation. Study participants were purposively selected (key informant or maximal diversity sampling), including volunteers in the human infection study, study staff, community representatives and local administrative authorities. Data were collected during and up to 18 months following study residency, from sites in Coastal and Western Kenya. Voice recordings of interviews and discussions were transcribed, translated, and analysed using framework analysis, combining data- and theory-driven perspectives. Findings Physical, psychological, economic and social forms of benefits and burdens were experienced across study stages. Important benefits for volunteers included the study compensation, access to health checks, good residential living conditions, new learning opportunities, developing friendships and satisfaction at contributing towards a new malaria vaccine. Burdens primarily affected study volunteers, including experiences of discomfort and ill health; fear and anxiety around aspects of the trial process, particularly deliberate infection and the implications of prolonged residency; anxieties about early residency exit; and interpersonal conflict. These issues had important implications for volunteers’ families, study staff and the research institution’s reputation more widely. Conclusion Developing ethically and scientifically strong HIS relies on grounded accounts of volunteers, study staff and the wider community, understood in the socioeconomic, political and cultural context where studies are implemented. Recognition of the diverse, and sometimes perverse, nature of potential benefits and burdens in a given context, and who this might implicate, is critical to this process. Prior and ongoing stakeholder engagement is core to developing these insights.

BackgroundYellow fever vaccine stocks have been insufficient to cover exceptional demands for outbreak response. Fractional dosing evidence is limited to the 17DD substrain vaccine. We assessed the immunogenicity and safety of one-fifth fractional dose compared to standard dose of each of the four WHO-prequalified yellow fever vaccines produced from three substrains.MethodsWe conducted a randomized, double-blind, non-inferiority trial in Mbarara, Uganda and Kilifi, Kenya. 960 participants aged 18-59 years without previous yellow fever vaccination or infection were recruited from communities and randomized to receive one of four vaccines and to standard or fractional dosage. Vaccine was administered subcutaneously by unblinded nurse. Other study personnel and participants were blinded to vaccine allocation. Primary immunogenicity outcome, seroconversion, was measured in the per-protocol population; safety outcomes included all vaccinated participants. We defined non-inferiority as no more than 10% decrease in seroconversion in fractional compared to standard dose arms 28 days post-vaccination. Seroconversion was defined as ≥4-fold rise in neutralizing antibody titers measured by 50% plaque reduction neutralization test (PRNT50).ClinicalTrials.gov Identifier: NCT02991495, following participants.FindingsBetween 6th November 2017 and 21st February 2018, 960 participants, total sample goal, were randomized. The primary per-protocol analysis includes 899 participants, with 110 to 117 participants per arm. The absolute difference in seroconversion between fractional and standard doses by vaccine was 1.71% (95%CI: −2.60, 5.28), −0.90% (95%CI: −4.24, 3.13), 1.82% (95%CI: −2.75, 5.39), 0.0% (95%CI: −3.32, 3.29). Fractional doses from all four vaccines met the non-inferiority criterion. There were no safety concerns.InterpretationThese results support fractional dosing of all WHO-prequalified yellow fever vaccines for the general adult population for outbreak response in situations of vaccine shortage.FundingThe study was funded by Médecins Sans Frontières Foundation, Wellcome Trust (grant no. 092654) and the UK Department for International Development. Vaccines were donated in kind.Research in contextEvidence before this studyIn July 2016, following major yellow fever (YF) outbreaks in two countries, WHO published a secretariat information paper including a review of studies assessing the immunogenicity of fractional doses of YF vaccines and recommended consideration of fractional doses to manage a vaccine shortage. Following this, fractional doses of YF vaccine produced by Bio-Manguinhos/Fiocruz (17DD substrain) were given to approximately 7.5 million non-pregnant adults and children ≥ 2 years of age in Kinshasa, Democratic Republic of Congo. The evidence base to support this action was limited to a single vaccine substrain and to a specific context. To broaden and simplify recommendations, WHO called for additional research to be conducted. We designed a trial to assess non-inferiority in seroconversion of fractional (one-fifth dose) versus standard dose for each of the four WHO-prequalified YF vaccines at 28 days post-vaccination in an adult population in Kenya and Uganda. We selected vaccine batches as close as possible to each manufacturer’s minimum release specification.Added value of this studyThis is the first randomized controlled trial assessing all four WHO-prequalified YF vaccines, providing information on the immunogenicity and safety of fractional doses of the different vaccine substrains at 10 days, 28 days and one year post-vaccination. The results show that, at 28 days post-vaccination, most participants had high levels of neutralizing antibodies and that seroconversion rates in the fractional dose arms were non-inferior to standard dose for each of the four vaccines. Seroconversion rates and neutralizing antibodies remained high up to one year post-vaccination for both fractional and standard doses for all vaccines. These results are aligned with previous studies using the 17DD substrain vaccine but extend the evidence to randomized comparisons of all four vaccines and to a sub-Saharan Africa context. To our knowledge, this is the first trial assessing immunogenicity of fractional doses at 10 days post-vaccination.Implications of all the available evidenceOur study supports the use of one-fifth fractional doses of all four WHO-prequalified yellow fever vaccines for the general adult population and fills a critical knowledge gap to support WHO policy on the use of fractional dosing of yellow fever vaccine for outbreak response. The immunogenicity and safety of fractional dosing in children and specific populations, such as those living with HIV, is yet to be determined. Long-term studies are warranted to confirm the duration of protection.

Background Glucose-6-phosphate dehydrogenase (G6PD) deficiency is the most common enzyme deficiency state in humans. The clinical phenotype is variable and includes asymptomatic individuals, episodic hemolysis induced by oxidative stress, and chronic hemolysis. G6PD deficiency is common in malaria-endemic regions, an observation hypothesized to be due to balancing selection at the G6PD locus driven by malaria. G6PD deficiency increases risk of severe malarial anemia, a key determinant of invasive bacterial disease in malaria-endemic settings. The pneumococcus is a leading cause of invasive bacterial infection and death in African children. The effect of G6PD deficiency on risk of pneumococcal disease is undefined. We hypothesized that G6PD deficiency increases pneumococcal disease risk and that this effect is dependent upon malaria. Methods We performed a genetic case-control study of pneumococcal bacteremia in Kenyan children stratified across a period of falling malaria transmission between 1998 and 2010. Results Four hundred twenty-nine Kenyan children with pneumococcal bacteremia and 2677 control children were included in the study. Among control children, G6PD deficiency, secondary to the rs1050828 G>A mutation, was common, with 11.2% (n = 301 of 2677) being hemi- or homozygotes and 33.3% (n = 442 of 1329) of girls being heterozygotes. We found that G6PD deficiency increased the risk of pneumococcal bacteremia, but only during a period of high malaria transmission (P = 0.014; OR 2.33, 95% CI 1.19–4.57). We estimate that the population attributable fraction of G6PD deficiency on risk of pneumococcal bacteremia in areas under high malaria transmission is 0.129. Conclusions Our data demonstrate that G6PD deficiency increases risk of pneumococcal bacteremia in a manner dependent on malaria. At the population level, the impact of G6PD deficiency on invasive pneumococcal disease risk in malaria-endemic regions is substantial. Our study highlights the infection-associated morbidity and mortality conferred by G6PD deficiency in malaria-endemic settings and adds to our understanding of the potential indirect health benefits of improved malaria control.

Background The recent West African Ebola epidemic led to accelerated efforts to test Ebola vaccine candidates. As part of the World Health Organisation-led VSV Ebola Consortium (VEBCON), we performed a phase I clinical trial investigating rVSV-ZEBOV (a recombinant vesicular stomatitis virus-vectored Ebola vaccine), which has recently demonstrated protection from Ebola virus disease (EVD) in phase III clinical trials and is currently in advanced stages of licensing. So far, correlates of immune protection are incompletely understood and the role of cell-mediated immune responses has not been comprehensively investigated to date. Methods: We recruited 30 healthy subjects aged 18–55 into an open-label, dose-escalation phase I trial testing three doses of rVSV-ZEBOV (3 × 105 plaque-forming units (PFU), 3 × 106 PFU, 2 × 107 PFU) (ClinicalTrials.gov; NCT02283099). Main study objectives were safety and immunogenicity, while exploratory objectives included lymphocyte dynamics, cell-mediated immunity and cytokine networks, which were assessed using flow cytometry, ELISpot and LUMINEX assay. Findings: Immunization with rVSV-ZEBOV was well tolerated without serious vaccine-related adverse events. Ebola virus-specific neutralizing antibodies were induced in nearly all individuals. Additionally, vaccinees, particularly within the highest dose cohort, generated Ebola glycoprotein (GP)-specific T cells and initiated a cascade of signaling molecules following stimulation of peripheral blood mononuclear cells with Ebola GP peptides. Interpretation: In addition to a benign safety and robust humoral immunogenicity profile, subjects immunized with 2 × 107 PFU elicited higher cellular immune responses and stronger interlocked cytokine networks compared to lower dose groups. To our knowledge these data represent the first detailed cell-mediated immuneprofile of a clinical trial testing rVSV-ZEBOV, which is of particular interest in light of its potential upcoming licensure as the first Ebola vaccine. VEBCON trial Hamburg, Germany (NCT02283099)., Highlights • A phase I clinical trial was conducted to investigate the live-attenuated Ebola vaccine rVSV-ZEBOV. • Ebola-specific humoral and cell-mediated immune responses show a favorable profile for subjects immunized with 2 × 107 PFU of rVSV-ZEBOV. • The highest dose cohort induced stronger antigen-specific CTL-responses and interlocked cytokine networks compared to lower dose groups. rVSV-ZEBOV is the first Ebola vaccine with human efficacy data, currently undergoing an accelerated licensing process. Nevertheless, to date no human immunological correlate of protection has been identified and mechanisms of immune responses elicited by rVSV-ZEBOV remain incompletely understood. We conducted a phase I trial to test rVSV-ZEBOV in 30 healthy subjects using three dosage levels. We here present a comprehensive evaluation of humoral and cell-mediated responses with an in-depth analysis of signaling molecules following ex vivo stimulation with Ebola GP peptides. Our data suggest a favorable immune response profile for subjects immunized with 2 × 107 PFU. These data address critical knowledge gaps with respect to mechanisms of immuneprotection in the context of Ebola vaccines and may provide additional evidence to support the current dosage used in later stage clinical trials., Graphical Abstract Image 1

Background We assessed the safety and immunogenicity of the RTS,S/AS01 malaria vaccine in a subset of children identified as HIV-infected during a large phase III randomized controlled trial conducted in seven sub-Saharan African countries. Methods Infants 6–12 weeks and children 5–17 months old were randomized to receive 4 RTS,S/AS01 doses (R3R group), 3 RTS,S/AS01 doses plus 1 comparator vaccine dose (R3C group), or 4 comparator vaccine doses (C3C group) at study months 0, 1, 2 and 20. Infants and children with WHO stage III/IV HIV disease were excluded but HIV testing was not routinely performed on all participants; our analyses included children identified as HIV-infected based on medical history or clinical suspicion and confirmed by polymerase chain reaction or antibody testing. Serious adverse events (SAEs) and anti-circumsporozoite (CS) antibodies were assessed. Results Of 15459 children enrolled in the trial, at least 1953 were tested for HIV and 153 were confirmed as HIV-infected (R3R: 51; R3C: 54; C3C: 48). Among these children, SAEs were reported for 92.2% (95% CI: 81.1–97.8) in the R3R, 85.2% (72.9–93.4) in the R3C and 87.5% (74.8–95.3) in the C3C group over a median follow-up of 39.3, 39.4 and 38.3 months, respectively. Fifteen HIV-infected participants in each group (R3R: 29.4%, R3C: 27.8%, C3C: 31.3%) died during the study. No deaths were considered vaccination-related. In a matched case-control analysis, 1 month post dose 3 anti-CS geometric mean antibody concentrations were 193.3 EU/mL in RTS,S/AS01-vaccinated HIV-infected children and 491.5 EU/mL in RTS,S/AS01-vaccinated immunogenicity controls with unknown or negative HIV status (p = 0.0001). Conclusions The safety profile of RTS,S/AS01 in HIV-infected children was comparable to that of the comparator (meningococcal or rabies) vaccines. RTS,S/AS01 was immunogenic in HIV-infected children but antibody concentrations were lower than in children with an unknown or negative HIV status. Clinical trial registration: ClinicalTrials.gov: NCT00866619.

Background Podoconiosis is a disease of the lymphatic vessels of the lower extremities that is caused by chronic exposure to irritant soils. It results in leg swelling, commonly complicated by acute dermatolymphangioadenitis (ADLA), characterised by severe pain, fever and disability. Methods We conducted cost-effectiveness and social outcome analyses of a pragmatic, randomised controlled trial of a hygiene and foot-care intervention for people with podoconiosis in the East Gojjam zone of northern Ethiopia. Participants were allocated to the immediate intervention group or the delayed intervention group (control). The 12-month intervention included training in foot hygiene, skin care, bandaging, exercises, and use of socks and shoes, and was supported by lay community assistants. The cost-effectiveness analysis was conducted using the cost of productivity loss due to acute dermatolymphangioadenitis. Household costs were not included. Health outcomes in the cost-effectiveness analysis were: the incidence of ADLA episodes, health-related quality of life captured using the Dermatology Life Quality Index (DLQI), and disability scores measured using the WHO Disability Assessment Schedule 2.0 (WHODAS 2.0). Results The cost of the foot hygiene and lymphoedema management supplies was 529 ETB (69 I$, international dollars) per person per year. The cost of delivery of the intervention as part of the trial, including transportation, storage, training of lay community assistants and administering the intervention was 1,890 ETB (246 I$) per person. The intervention was effective in reducing the incidence of acute dermatolymphangioadenitis episodes and improving DLQI scores, while there were no significant improvements in the disability scores measured using WHODAS 2.0. In 75% of estimations, the intervention was less costly than the control. This was due to improved work productivity. Subgroup analyses based on income group showed that the intervention was cost-effective (both less costly and more effective) in reducing the number of acute dermatolymphangioadenitis episodes and improving health-related quality of life in families with monthly income, Author summary Podoconiosis is a disease of the lymphatic vessels of the lower extremities that is caused by chronic exposure to irritant soils. The condition has been reported from 32 countries around the world, and is common in low-resource settings in which people do not wear shoes as protection against the soil. It results in leg swelling, commonly complicated by acute dermatolymphangioadenitis (ADLA, or ‘acute attacks’), characterised by severe pain, fever and disability. A low-cost, lay-led treatment package to prevent ADLA and reverse early stages of disease was tested in northern Ethiopia in 2014–2015. The package involves daily foot hygiene, skin care elastic bandaging where necessary, exercises, elevation and regular use of socks and shoes. In this study we report the impact of this package on quality of life and decreasing work productivity losses.

Background Many parts of Africa have witnessed reductions in Plasmodium falciparum transmission over the last 15 years. Since immunity to malaria is acquired more rapidly at higher transmission, the slower acquisition of immunity at lower transmission may partially offset the benefits of reductions in transmission. We examined the clinical spectrum of disease and predictors of mortality after sustained changes in transmission intensity, using data collected from 1989 to 2016. Methods We conducted a temporal observational analysis of 18,000 children, aged 14 days to 14 years old, who were admitted to Kilifi County Hospital, Kenya, from 1989 to 2016 with malaria. We describe the trends over time of the clinical and laboratory criteria for severe malaria and associated risk of mortality. Results During the time periods 1989–2003, 2004–2008, and 2009–2016, Kilifi County Hospital admitted averages of 657, 310, and 174 cases of severe malaria per year including averages of 48, 14, and 12 malaria-associated deaths per year, respectively. The median ages in years of children admitted with cerebral malaria, severe anaemia, and malaria-associated mortality were 3.0 (95% confidence interval (CI) 2.2–3.9), 1.1 (95% CI 0.9–1.4), and 1.1 (95% CI 0.3–2.2) in the year 1989, rising to 4.9 (95% CI 3.9–5.9), 3.8 (95% CI 2.5–7.1), and 5 (95% CI 3.3–6.3) in the year 2016. The ratio of children with cerebral malaria to severe anaemia rose from 1:2 before 2004 to 3:2 after 2009. Hyperparasitaemia was a risk factor for death after 2009 but not in earlier time periods. Conclusion Despite the evidence of slower acquisition of immunity, continued reductions in the numbers of cases of severe malaria resulted in lower overall mortality. Our temporal data are limited to a single site, albeit potentially applicable to a secular trend present in many parts of Africa. Electronic supplementary material The online version of this article (10.1186/s12916-019-1359-9) contains supplementary material, which is available to authorized users.

BACKGROUND: The replication-competent recombinant vesicular stomatitis virus (rVSV)-based vaccine expressing a Zaire ebolavirus (ZEBOV) glycoprotein was selected for rapid safety and immunogenicity testing before its use in West Africa. METHODS: We performed three open-label, dose-escalation phase 1 trials and one randomized, double-blind, controlled phase 1 trial to assess the safety, side-effect profile, and immunogenicity of rVSV-ZEBOV at various doses in 158 healthy adults in Europe and Africa. All participants were injected with doses of vaccine ranging from 300,000 to 50 million plaque-forming units (PFU) or placebo. RESULTS: No serious vaccine-related adverse events were reported. Mild-to-moderate early-onset reactogenicity was frequent but transient (median, 1 day). Fever was observed in up to 30% of vaccinees. Vaccine viremia was detected within 3 days in 123 of the 130 participants (95%) receiving 3 million PFU or more; rVSV was not detected in saliva or urine. In the second week after injection, arthritis affecting one to four joints developed in 11 of 51 participants (22%) in Geneva, with pain lasting a median of 8 days (interquartile range, 4 to 87); 2 self-limited cases occurred in 60 participants (3%) in Hamburg, Germany, and Kilifi, Kenya. The virus was identified in one synovial-fluid aspirate and in skin vesicles of 2 other vaccinees, showing peripheral viral replication in the second week after immunization. ZEBOV-glycoprotein-specific antibody responses were detected in all the participants, with similar glycoprotein-binding antibody titers but significantly higher neutralizing antibody titers at higher doses. Glycoprotein-binding antibody titers were sustained through 180 days in all participants. CONCLUSIONS: In these studies, rVSV-ZEBOV was reactogenic but immunogenic after a single dose and warrants further evaluation for safety and efficacy. (Funded by the Wellcome Trust and others; ClinicalTrials.gov numbers, NCT02283099, NCT02287480, and NCT02296983; Pan African Clinical Trials Registry number, PACTR201411000919191.).

A phase III, double-blind, randomized, controlled trial (NCT00866619) in sub-Saharan Africa showed RTS,S/AS01 vaccine efficacy against malaria. We now present in-depth safety results from this study. 8922 children (enrolled at 5-17\xC2\xA0months) and 6537 infants (enrolled at 6-12\xC2\xA0weeks) were 1:1:1-randomized to receive 4 doses of RTS,S/AS01 (R3R) or non-malaria control vaccine (C3C), or 3 RTS,S/AS01 doses plus control (R3C). Aggregate safety data were reviewed by a multi-functional team. Severe malaria with Blantyre Coma Score \xE2\x89\xA42 (cerebral malaria [CM]) and gender-specific mortality were assessed post-hoc. Serious adverse event (SAE) and fatal SAE incidences throughout the study were 24.2%-28.4% and 1.5%-2.5%, respectively across groups; 0.0%-0.3% of participants reported vaccination-related SAEs. The incidence of febrile convulsions in children was higher during the first 2-3 days post-vaccination with RTS,S/AS01 than with control vaccine, consistent with the time window of post-vaccination febrile reactions in this study (mostly the day after vaccination). A statistically significant numerical imbalance was observed for meningitis cases in children (R3R: 11, R3C: 10, C3C: 1) but not in infants. CM cases were more frequent in RTS,S/AS01-vaccinated children (R3R: 19, R3C: 24, C3C: 10) but not in infants. All-cause mortality was higher in RTS,S/AS01-vaccinated versus control girls (2.4% vs 1.3%, all ages) in our setting with low overall mortality. The observed meningitis and CM signals are considered likely chance findings, that - given their severity - warrant further evaluation in phase IV studies and WHO-led pilot implementation programs to establish the RTS,S/AS01 benefit-risk profile in real-life settings.

We thank Jill Brooks and colleagues for their comments on how their trial was referred to in our article.

Background Infections caused by extended-spectrum β-lactamase–producing Enterobacterales (ESBL-E) among hospitalized neonates in sub-Saharan Africa pose significant clinical challenges. Data on prevalence and acquisition of ESBL-E carriage among hospitalized neonates in the region are few, and risk factors for transmission are not clearly defined. Methods In a cohort study of consecutive neonatal admissions to Kilifi County Hospital from July 2013 through August 2014, we estimated ESBL-E carriage prevalence on admission using rectal swab cultures and identified risk factors using logistic regression. Using twice-weekly follow-up swabs, we estimated the incidence and identified risk factors for ESBL-E acquisition in hospital using Poisson regression. Results The prevalence of ESBL-E carriage at admission was 10% (59/569). Cesarean delivery, older neonatal age, and smaller household size were significant risk factors. Of the 510 infants admitted without ESBL-E carriage, 238 (55%) acquired carriage during their hospital stay. The incidence of acquisition was 21.4% (95% confidence interval, 19.0%–24.0%) per day. The rate was positively associated with the number of known neonatal ESBL-E carriers and with the total number of neonates on the same ward. Conclusions Carriage of ESBL-E was common among neonates on admission, and in-hospital acquisition was rapid. The dissemination and selection of ESBL-E appears to be driven by hospital exposures, operative delivery, and neonatal ward patient density. Further attention to infection control, patient crowding, and carriage surveillance is warranted., We report a prospective hospital-based longitudinal study that estimates the extended-spectrum β-lactamase–producing Enterobacterales (ESBL-E) carriage prevalence among neonates on admission, the incidence of acquisition of ESBL-E carriage in hospital, and the risk factors for neonatal prevalent and incident ESBL-E carriage.

Item does not contain fulltext The International Alliance for Biological Standardization organized the second workshop on human challenge trials (HCT) in Rockville, MD, in September 2017. The objective of this meeting was to examine the use of HCT, in response to the continuing human suffering caused by infectious diseases, preventable by the development of new and improved vaccines. For this, the approach of HCT could be valuable, as HCT can provide key safety, tolerability, immunogenicity, and efficacy data, and can be used to study host-pathogen biology. HCT can generate these data with speed, efficiency and minimal expense, albeit not with the same level of robustness as clinical trials. Incorporated wisely into a clinical development plan, HCT can support optimization or down-selection of new vaccine candidates, assuring that only the worthiest candidates progress to field testing. HCT may also provide pivotal efficacy data in support of licensure, particularly when field efficacy studies are not feasible. Many aspects of HCT were discussed by the participants, including new and existing models, standardization and ethics. A consensus was achieved that HCT, if ethically justified and performed with careful attention to safety and informed consent, should be pursued to promote and accelerate vaccine development. 01 september 2019

Reference intervals for clinical laboratory parameters are important for assessing eligibility, toxicity grading and management of adverse events in clinical trials. Nonetheless, haematological and biochemical parameters used for clinical trials in sub-Saharan Africa are typically derived from industrialized countries, or from WHO references that are not region-specific. We set out to establish community reference values for haematological and biochemical parameters amongst children aged 4 weeks to 17 months in Kilifi, Kenya. We conducted a cross sectional study nested within phase II and III trials of RTS, S malaria vaccine candidate. We analysed 10 haematological and 2 biochemical parameters from 1,070 and 423 community children without illness prior to experimental vaccine administration. Statistical analysis followed Clinical and Laboratory Standards Institute EP28-A3c guidelines. 95% reference ranges and their respective 90% confidence intervals were determined using non-parametric methods. Findings were compared with published ranges from Tanzania, Europe and The United States. We determined the reference ranges within the following age partitions: 4 weeks to

The substrate of the methionine salvage pathway, methylthioadenosine, is a predictor of death in sepsis patients., Sepsis is a deleterious inflammatory response to infection with high mortality. Reliable sepsis biomarkers could improve diagnosis, prognosis, and treatment. Integration of human genetics, patient metabolite and cytokine measurements, and testing in a mouse model demonstrate that the methionine salvage pathway is a regulator of sepsis that can accurately predict prognosis in patients. Pathway-based genome-wide association analysis of nontyphoidal Salmonella bacteremia showed a strong enrichment for single-nucleotide polymorphisms near the components of the methionine salvage pathway. Measurement of the pathway’s substrate, methylthioadenosine (MTA), in two cohorts of sepsis patients demonstrated increased plasma MTA in nonsurvivors. Plasma MTA was correlated with levels of inflammatory cytokines, indicating that elevated MTA marks a subset of patients with excessive inflammation. A machine-learning model combining MTA and other variables yielded approximately 80% accuracy (area under the curve) in predicting death. Furthermore, mice infected with Salmonella had prolonged survival when MTA was administered before infection, suggesting that manipulating MTA levels could regulate the severity of the inflammatory response. Our results demonstrate how combining genetic data, biomolecule measurements, and animal models can shape our understanding of disease and lead to new biomarkers for patient stratification and potential therapeutic targeting.

Internationally, calls for feedback of findings to be made an 'ethical imperative' or mandatory have been met with both strong support and opposition. Challenges include differences in issues by type of study and context, disentangling between aggregate and individual study results, and inadequate empirical evidence on which to draw. In this paper we present data from observations and interviews with key stakeholders involved in feeding back aggregate study findings for two Phase II malaria vaccine trials among children under the age of 5 years old on the Kenyan Coast. In our setting, feeding back of aggregate findings was an appreciated set of activities. The inclusion of individual results was important from the point of view of both participants and researchers, to reassure participants of trial safety, and to ensure that positive results were not over-interpreted and that individual level issues around blinding and control were clarified. Feedback sessions also offered an opportunity to re-evaluate and re-negotiate trial relationships and benefits, with potentially important implications for perceptions of and involvement in follow-up work for the trials and in future research. We found that feedback of findings is a complex but key step in a continuing set of social interactions between community members and research staff (particularly field staff who work at the interface with communities), and among community members themselves; a step which needs careful planning from the outset. We agree with others that individual and aggregate results need to be considered separately, and that for individual results, both the nature and value of the information, and the context, including social relationships, need to be taken into account. Copyright © 2013 Blackwell Publishing Ltd.

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 >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.).

Objectives To evaluate and determine the value of monitoring models developed by the Mahidol Oxford Tropical Research Unit and the East African Consortium for Clinical Research, consider how this can be measured and explore monitors’ and investigators’ experiences of and views about the nature, purpose and practice of monitoring. Research design A case study approach was used within the context of participatory action research because one of the aims was to guide and improve practice. 34 interviews, five focus groups and observations of monitoring practice were conducted. Setting and participants Fieldwork occurred in the places where the monitoring models are coordinated and applied in Thailand, Cambodia, Uganda and Kenya. Participants included those coordinating the monitoring schemes, monitors, senior investigators and research staff. Analysis Transcribed textual data from field notes, interviews and focus groups was imported into a qualitative data software program (NVIVO V. 10) and analysed inductively and thematically by a qualitative researcher. The initial coding framework was reviewed internally and two main categories emerged from the subsequent interrogation of the data. Results The categories that were identified related to the conceptual framing and nature of monitoring, and the practice of monitoring, including relational factors. Particular emphasis was given to the value of a scientific and cooperative style of monitoring as a means of enhancing data quality, trust and transparency. In terms of practice the primary purpose of monitoring was defined as improving the conduct of health research and increasing the capacity of researchers and trial sites. Conclusions The models studied utilise internal and network wide expertise to improve the ethics and quality of clinical research. They demonstrate how monitoring can be a scientific and constructive exercise rather than a threatening process. The value of cooperative relations needs to be given more emphasis in monitoring activities, which seek to ensure that research protects human rights and produces reliable data.

Background Meningitis is notoriously difficult to diagnose in infancy because its clinical features are non-specific. World Health Organization (WHO) guidelines suggest several indicative signs, based on limited data. We aimed to identify indicators of bacterial meningitis in young infants in Kenya, and compared their performance to the WHO guidelines. We also examined the feasibility of developing a scoring system for meningitis. Methods We studied all admissions aged < 60 days to Kilifi District Hospital, 2001 through 2005. We evaluated clinical indicators against microbiological findings using likelihood ratios. We prospectively validated our findings 2006 through 2007. Results We studied 2,411 and 1,512 young infants during the derivation and validation periods respectively. During derivation, 31/1,031 (3.0%) neonates aged < 7 days and 67/1,380 (4.8%) young infants aged 7-59 days (p < 0.001) had meningitis. 90% of cases could be diagnosed macroscopically (turbidity) or by microscopic leukocyte counting. Independent indicators of meningitis were: fever, convulsions, irritability, bulging fontanel and temperature ≥ 39°C. Areas under the receiver operating characteristic curve in the validation period were 0.62 [95%CI: 0.49-0.75] age < 7 days and 0.76 [95%CI: 0.68-0.85] thereafter (P = 0.07), and using the WHO signs, 0.50 [95%CI 0.35-0.65] age < 7 days and 0.82 [95%CI: 0.75-0.89] thereafter (P = 0.0001). The number needed to LP to identify one case was 21 [95%CI: 15-35] for our signs, and 28 [95%CI: 18-61] for WHO signs. With a scoring system, a cut-off of ≥ 1 sign offered the best compromise on sensitivity and specificity. Conclusion Simple clinical signs at admission identify two thirds of meningitis cases in neonates and young infants. Lumbar puncture is essential to diagnosis and avoidance of unnecessary treatment, and is worthwhile without CSF biochemistry or bacterial culture. The signs of Meningitis suggested by the WHO perform poorly in the first week of life. A scoring system for meningitis in this age group is not helpful.

Background An effective malaria vaccine, deployed in conjunction with other malaria interventions, is likely to substantially reduce the malaria burden. Efficacy against severe malaria will be a key driver for decisions on implementation. An initial study of an RTS, S vaccine candidate showed promising efficacy against severe malaria in children in Mozambique. Further evidence of its protective efficacy will be gained in a pivotal, multi-centre, phase III study. This paper describes the case definitions of severe malaria used in this study and the programme for standardized assessment of severe malaria according to the case definition. Methods Case definitions of severe malaria were developed from a literature review and a consensus meeting of expert consultants and the RTS, S Clinical Trial Partnership Committee, in collaboration with the World Health Organization and the Malaria Clinical Trials Alliance. The same groups, with input from an Independent Data Monitoring Committee, developed and implemented a programme for standardized data collection. The case definitions developed reflect the typical presentations of severe malaria in African hospitals. Markers of disease severity were chosen on the basis of their association with poor outcome, occurrence in a significant proportion of cases and on an ability to standardize their measurement across research centres. For the primary case definition, one or more clinical and/or laboratory markers of disease severity have to be present, four major co-morbidities (pneumonia, meningitis, bacteraemia or gastroenteritis with severe dehydration) are excluded, and a Plasmodium falciparum parasite density threshold is introduced, in order to maximize the specificity of the case definition. Secondary case definitions allow inclusion of co-morbidities and/or allow for the presence of parasitaemia at any density. The programmatic implementation of standardized case assessment included a clinical algorithm for evaluating seriously sick children, improvements to care delivery and a robust training and evaluation programme for clinicians. Conclusions The case definition developed for the pivotal phase III RTS, S vaccine study is consistent with WHO recommendations, is locally applicable and appropriately balances sensitivity and specificity in the diagnosis of severe malaria. Processes set up to standardize severe malaria data collection will allow robust assessment of the efficacy of the RTS, S vaccine against severe malaria, strengthen local capacity and benefit patient care for subjects in the trial. Trial registration Clinicaltrials.gov NCT00866619

BACKGROUND An ongoing phase 3 study of the efficacy, safety, and immunogenicity of candidate malaria vaccine RTS,S/AS01 is being conducted in seven African countries. METHODS From March 2009 through January 2011, we enrolled 15,460 children in two age categories--6 to 12 weeks of age and 5 to 17 months of age--for vaccination with either RTS,S/AS01 or a non-malaria comparator vaccine. The primary end point of the analysis was vaccine efficacy against clinical malaria during the 12 months after vaccination in the first 6000 children 5 to 17 months of age at enrollment who received all three doses of vaccine according to protocol. After 250 children had an episode of severe malaria, we evaluated vaccine efficacy against severe malaria in both age categories. RESULTS In the 14 months after the first dose of vaccine, the incidence of first episodes of clinical malaria in the first 6000 children in the older age category was 0.32 episodes per person-year in the RTS,S/AS01 group and 0.55 episodes per person-year in the control group, for an efficacy of 50.4% (95% confidence interval [CI], 45.8 to 54.6) in the intention-to-treat population and 55.8% (97.5% CI, 50.6 to 60.4) in the per-protocol population. Vaccine efficacy against severe malaria was 45.1% (95% CI, 23.8 to 60.5) in the intention-to-treat population and 47.3% (95% CI, 22.4 to 64.2) in the per-protocol population. Vaccine efficacy against severe malaria in the combined age categories was 34.8% (95% CI, 16.2 to 49.2) in the per-protocol population during an average follow-up of 11 months. Serious adverse events occurred with a similar frequency in the two study groups. Among children in the older age category, the rate of generalized convulsive seizures after RTS,S/AS01 vaccination was 1.04 per 1000 doses (95% CI, 0.62 to 1.64). CONCLUSIONS The RTS,S/AS01 vaccine provided protection against both clinical and severe malaria in African children. (Funded by GlaxoSmithKline Biologicals and the PATH Malaria Vaccine Initiative; RTS,S ClinicalTrials.gov number, NCT00866619 .).

Summary Background RTS,S/AS01E is the lead candidate malaria vaccine. We recently showed efficacy against clinical falciparum malaria in 5–17 month old children, during an average of 8 months follow-up. We aimed to assess the efficacy of RTS,S/AS01E during 15 months of follow-up. Methods Between March, 2007, and October, 2008, we enrolled healthy children aged 5–17 months in Kilifi, Kenya, and Korogwe, Tanzania. Computer-generated block randomisation was used to randomly assign participants (1:1) to receive three doses (at month 0, 1, and 2) of either RTS,S/AS01E or human diploid-cell rabies vaccine. The primary endpoint was time to first clinical malaria episode, defined as the presence of fever (temperature ≥37·5°C) and a Plasmodium falciparum density of 2500/μL or more. Follow-up was 12 months for children from Korogwe and 15 months for children from Kilifi. Primary analysis was per protocol. In a post-hoc modelling analysis we characterised the associations between anti-circumsporozoite antibodies and protection against clinical malaria episodes. This study is registered with ClinicalTrials.gov, number NCT00380393. Findings 894 children were assigned, 447 in each treatment group. In the per-protocol analysis, 82 of 415 children in the RTS,S/AS01E group and 125 of 420 in the rabies vaccine group had first or only clinical malaria episode by 12 months, vaccine efficacy 39·2% (95% CI 19·5–54·1, p=0·0005). At 15 months follow-up, 58 of 209 children in the RTS,S/AS01E group and 85 of 206 in the rabies vaccine group had first or only clinical malaria episode, vaccine efficacy 45·8% (24·1–61·3, p=0·0004). At 12 months after the third dose, anti-circumsporozoite antibody titre data were available for 390 children in the RTS,S/AS01E group and 391 in the rabies group. A mean of 15 months (range 12–18 months) data were available for 172 children in the RTS,S/AS01E group and 155 in the rabies group. These titres at 1 month after the third dose were not associated with protection, but titres at 6·5 months were. The level of protection increased abruptly over a narrow range of antibody concentrations. The most common adverse events were pneumonia, febrile convulsion, gastroenteritis, and P falciparum malaria. Interpretation RTS,S/AS01E confers sustained efficacy for at least 15 months and shows promise as a potential public health intervention against childhood malaria in malaria endemic countries. Funding PATH Malaria Vaccine Initiative (MVI), GlaxoSmithKline.

Background Current artesunate (ARS) regimens for severe malaria are complex. Once daily intramuscular (i.m.) injection for 3 d would be simpler and more appropriate for remote health facilities than the current WHO-recommended regimen of five intravenous (i.v.) or i.m. injections over 4 d. We compared both a three-dose i.m. and a three-dose i.v. parenteral ARS regimen with the standard five-dose regimen using a non-inferiority design (with non-inferiority margins of 10%). Methods and Findings This randomized controlled trial included children (0.5–10 y) with severe malaria at seven sites in five African countries to assess whether the efficacy of simplified three-dose regimens is non-inferior to a five-dose regimen. We randomly allocated 1,047 children to receive a total dose of 12 mg/kg ARS as either a control regimen of five i.m. injections of 2.4 mg/kg (at 0, 12, 24, 48, and 72 h) (n = 348) or three injections of 4 mg/kg (at 0, 24, and 48 h) either i.m. (n = 348) or i.v. (n = 351), both of which were the intervention arms. The primary endpoint was the proportion of children with ≥99% reduction in parasitemia at 24 h from admission values, measured by microscopists who were blinded to the group allocations. Primary analysis was performed on the per-protocol population, which was 96% of the intention-to-treat population. Secondary analyses included an analysis of host and parasite genotypes as risks for prolongation of parasite clearance kinetics, measured every 6 h, and a Kaplan–Meier analysis to compare parasite clearance kinetics between treatment groups. A post hoc analysis was performed for delayed anemia, defined as hemoglobin ≤ 7g/dl 7 d or more after admission. The per-protocol population was 1,002 children (five-dose i.m.: n = 331; three-dose i.m.: n = 338; three-dose i.v.: n = 333); 139 participants were lost to follow-up. In the three-dose i.m. arm, 265/338 (78%) children had a ≥99% reduction in parasitemia at 24 h compared to 263/331 (79%) receiving the five-dose i.m. regimen, showing non-inferiority of the simplified three-dose regimen to the conventional five-dose regimen (95% CI −7, 5; p = 0.02). In the three-dose i.v. arm, 246/333 (74%) children had ≥99% reduction in parasitemia at 24 h; hence, non-inferiority of this regimen to the five-dose control regimen was not shown (95% CI −12, 1; p = 0.24). Delayed parasite clearance was associated with the N86YPfmdr1 genotype. In a post hoc analysis, 192/885 (22%) children developed delayed anemia, an adverse event associated with increased leukocyte counts. There was no observed difference in delayed anemia between treatment arms. A potential limitation of the study is its open-label design, although the primary outcome measures were assessed in a blinded manner. Conclusions A simplified three-dose i.m. regimen for severe malaria in African children is non-inferior to the more complex WHO-recommended regimen. Parenteral ARS is associated with a risk of delayed anemia in African children. Trial registration Pan African Clinical Trials Registry PACTR201102000277177, In a randomized trial, Sanjeev Krishna and colleagues test for non-inferiority of a simplified artemisinin regimen as treatment for malaria in a low-resource setting., Editors' Summary Background Globally, about 200 million cases of malaria—a mosquito-borne parasitic disease—occur every year. Malaria infections, which can be caused by several parasites, can be “uncomplicated” or “severe.” Prompt treatment of uncomplicated malaria, which presents with flu-like symptoms, is essential to prevent the development of severe malaria. The World Health Organization (WHO) recommends artemisinin combination therapy (ACT) for the first-line treatment of uncomplicated malaria in countries where the disease is always present. In ACT, artemisinin derivatives (fast-acting antimalarial drugs that are cleared rapidly from the body) are combined with a slower-acting, more slowly eliminated partner drug to prevent the original infection recurring and to reduce the risk of the malaria parasites becoming resistant to either drug. Severe malaria, which is usually caused by Plasmodium falciparum, is characterized by anemia and by damage to the brain and other organs. Severe malaria kills more than 400,000 people (mainly young children living in sub-Saharan Africa) every year. Why Was This Study Done? WHO recommends that severe malaria be treated with intravenous or intramuscular injections of artesunate, a parenteral (injectable) form of artemisinin; patients with severe malaria cannot take pills reliably or safely. Specifically, WHO recommends that patients be given 2.4 mg of artesunate per kilogram of body weight intravenously or intramuscularly at the time of admission (0 hours) and at 12, 24, 48, and 72 hours (followed by ACT to ensure full parasite clearance). But this five-dose regimen is complex. A simpler regimen would be easier to administer in resource-limited settings, where giving the correct doses on time to small, sick children can be challenging. In this open-label, non-inferiority randomized controlled trial (RCT), the researchers investigate the efficacy of a three-dose artesunate regimen for the treatment of severe malaria in African children. RCTs compare outcomes in people randomly chosen to receive different interventions; in an open-label RCT, both the researchers and the participants know which treatment is being given; a non-inferiority trial investigates whether one treatment is not worse than another treatment. What Did the Researchers Do and Find? The researchers randomly allocated 1,047 children aged six months to ten years with severe malaria attending seven clinical centers in five African countries to receive a total dose of 12 mg of artesunate per kilogram of body weight as five intramuscular injections of 2.4 mg/kg given at 0, 12, 24, 48, and 72 hours (the control regimen) or as three intramuscular or intravenous injections of 4 mg/kg given at 0, 12, and 24 hours (three-dose intramuscular and intravenous regimens, respectively). The trial’s primary endpoint was the proportion of children whose parasitemia (parasite count in the blood) at 24 hours was ≤1% of that at admission (in other words, ≥99% parasite clearance). Among the 1,002 children who received the planned drug doses (the per-protocol population), 78% in the three-dose intramuscular group had ≥99% parasite clearance compared to 79% in the five-dose intramuscular group, a result that met a preset criterion for non-inferiority at 24 hours of the three-dose intramuscular regimen to the control regimen. However, because only 74% of the children in the three-dose intravenous group had ≥99% parasite clearance, this regimen was not shown to be non-inferior to the conventional five-dose regimen. What Do These Findings Mean? These findings when combined with the findings of several secondary analyses suggest that, in African children, a three-dose intramuscular artesunate regimen is non-inferior to the WHO-recommended regimen for the treatment of severe malaria. The study’s open-label design may limit the accuracy of its findings, as may its use of a primary endpoint midway through drug treatment rather than at the end (the researchers note that 60% of deaths from severe malaria occur during the first 24 hours of illness and that parasitemia is harder to measure later during treatment) and its use of parasite clearance rather than death as the primary endpoint (case fatality rates in severe malaria treatment trials are very low, so a much larger study would be needed if death were used as the primary endpoint). Overall, these findings support the use of the three-dose intramuscular artesunate regimen for the treatment of severe malaria. Importantly, however, 22% of the children in the study developed delayed anemia, irrespective of treatment regimen. Thus, although further studies are needed to clarify whether treatment with artesunate or the malaria infection itself was responsible for the delayed anemia, patients treated with artesunate for severe malaria should be routinely monitored for this complication. Additional Information This list of resources contains links that can be accessed when viewing the PDF on a device or via the online version of the article at http://dx.doi.org/10.1371/journal.pmed.1001938. Information is available from the World Health Organization on malaria (in several languages); the World Malaria Report 2014 provides details of the current global malaria situation, including information on malaria in individual African countries; WHO’s Guidelines for the Treatment of Malaria and its Management of Severe Malaria: A Practical Handbook are available The US Centers for Disease Control and Prevention provides information on malaria (in English and Spanish), including personal stories about malaria The UK National Health Service Choices website also provides information about malaria, including a personal story Information is available from the Roll Back Malaria Partnership on the global control of malaria The Scientists Against Malaria collaboration applies modern drug design and modeling techniques to develop new treatments against malaria; its website includes information about many aspects of malaria Public Health England provides a collection of guidance and research and analysis on malaria MedlinePlus provides links to additional information on malaria (in English and Spanish) More information about this trial is available

The candidate malaria vaccine RTS,S/AS01 is being evaluated in order to inform a decision regarding its inclusion in routine vaccination schedules.We conducted 7 years of follow-up in children who had been randomly assigned, at 5 to 17 months of age, to receive three doses of either the RTS,S/AS01 vaccine or a rabies (control) vaccine. The end point was clinical malaria (temperature of ≥37.5°C and infection with Plasmodium falciparum of2500 parasites per cubic millimeter). In an analysis that was not prespecified, the malaria exposure of each child was estimated with the use of information on the prevalence of malaria among residents within a 1-km radius of the child's home. Vaccine efficacy was defined as 1 minus the hazard ratio or the incidence-rate ratio, multiplied by 100, in the RTS,S/AS01 group versus the control group.Over 7 years of follow-up, we identified 1002 episodes of clinical malaria among 223 children randomly assigned to the RTS,S/AS01 group and 992 episodes among 224 children randomly assigned to the control group. The vaccine efficacy, as assessed by negative binomial regression, was 4.4% (95% confidence interval [CI], -17.0 to 21.9; P=0.66) in the intention-to-treat analysis and 7.0% (95% CI, -14.5 to 24.6; P=0.52) in the per-protocol analysis. Vaccine efficacy waned over time (P=0.006 for the interaction between vaccination and time), including negative efficacy during the fifth year among children with higher-than-average exposure to malaria parasites (intention-to-treat analysis: -43.5%; 95% CI, -100.3 to -2.8 [P=0.03]; per-protocol analysis: -56.8%; 95% CI, -118.7 to -12.3 [P=0.008]).A three-dose vaccination with RTS,S/AS01 was initially protective against clinical malaria, but this result was offset by rebound in later years in areas with higher-than-average exposure to malaria parasites. (Funded by the PATH Malaria Vaccine Initiative and others; ClinicalTrials.gov number, NCT00872963.).

BACKGROUND: The RTS,S/AS01 vaccine targets the circumsporozoite protein of Plasmodium falciparum and has partial protective efficacy against clinical and severe malaria disease in infants and children. We investigated whether the vaccine efficacy was specific to certain parasite genotypes at the circumsporozoite protein locus. METHODS: We used polymerase chain reaction-based next-generation sequencing of DNA extracted from samples from 4985 participants to survey circumsporozoite protein polymorphisms. We evaluated the effect that polymorphic positions and haplotypic regions within the circumsporozoite protein had on vaccine efficacy against first episodes of clinical malaria within 1 year after vaccination. RESULTS: In the per-protocol group of 4577 RTS,S/AS01-vaccinated participants and 2335 control-vaccinated participants who were 5 to 17 months of age, the 1-year cumulative vaccine efficacy was 50.3% (95% confidence interval [CI], 34.6 to 62.3) against clinical malaria in which parasites matched the vaccine in the entire circumsporozoite protein C-terminal (139 infections), as compared with 33.4% (95% CI, 29.3 to 37.2) against mismatched malaria (1951 infections) (P=0.04 for differential vaccine efficacy). The vaccine efficacy based on the hazard ratio was 62.7% (95% CI, 51.6 to 71.3) against matched infections versus 54.2% (95% CI, 49.9 to 58.1) against mismatched infections (P=0.06). In the group of infants 6 to 12 weeks of age, there was no evidence of differential allele-specific vaccine efficacy. CONCLUSIONS: These results suggest that among children 5 to 17 months of age, the RTS,S vaccine has greater activity against malaria parasites with the matched circumsporozoite protein allele than against mismatched malaria. The overall vaccine efficacy in this age category will depend on the proportion of matched alleles in the local parasite population; in this trial, less than 10% of parasites had matched alleles. (Funded by the National Institutes of Health and others.).

BACKGROUND: The RTS,S/AS01 malaria vaccine targets the circumsporozoite protein, inducing antibodies associated with the prevention of Plasmodium falciparum infection. We assessed the association between anti-circumsporozoite antibody titres and the magnitude and duration of vaccine efficacy using data from a phase 3 trial done between 2009 and 2014. METHODS: Using data from 8922 African children aged 5-17 months and 6537 African infants aged 6-12 weeks at first vaccination, we analysed the determinants of immunogenicity after RTS,S/AS01 vaccination with or without a booster dose. We assessed the association between the incidence of clinical malaria and anti-circumsporozoite antibody titres using a model of anti-circumsporozoite antibody dynamics and the natural acquisition of protective immunity over time. FINDINGS: RTS,S/AS01-induced anti-circumsporozoite antibody titres were greater in children aged 5-17 months than in those aged 6-12 weeks. Pre-vaccination anti-circumsporozoite titres were associated with lower immunogenicity in children aged 6-12 weeks and higher immunogenicity in those aged 5-17 months. The immunogenicity of the booster dose was strongly associated with immunogenicity after primary vaccination. Anti-circumsporozoite titres wane according to a biphasic exponential distribution. In participants aged 5-17 months, the half-life of the short-lived component of the antibody response was 45 days (95% credible interval 42-48) and that of the long-lived component was 591 days (557-632). After primary vaccination 12% (11-13) of the response was estimated to be long-lived, rising to 30% (28-32%) after a booster dose. An anti-circumsporozoite antibody titre of 121 EU/mL (98-153) was estimated to prevent 50% of infections. Waning anti-circumsporozoite antibody titres predict the duration of efficacy against clinical malaria across different age categories and transmission intensities, and efficacy wanes more rapidly at higher transmission intensity. INTERPRETATION: Anti-circumsporozoite antibody titres are a surrogate of protection for the magnitude and duration of RTS,S/AS01 efficacy, with or without a booster dose, providing a valuable surrogate of effectiveness for new RTS,S formulations in the age groups considered. FUNDING: UK Medical Research Council.

BACKGROUND: To date, information about the frequency of electrolyte disturbances among children with severe falciparum malaria is limited. METHODS: We describe changes in potassium, calcium, magnesium, and phosphate levels in 56 Kenyan children (42 who survived and 14 who died) admitted to the hospital with clinical features of severe malaria (impaired consciousness or deep breathing) complicated by acidosis (base deficit, >8 mmol/L). RESULTS: Mild-to-moderate hypercalcemia was common at admission, particularly among children with severe anemia. Severe hyperkalemia complicated falciparum malaria in 9 children (16%), of whom 7 (78%) died, generally soon after admission. Hypokalemia, hypomagnesemia, and hypophosphatemia were uncommon (30% of children within 24 h. Hypocalcemia was infrequent (

Background Benefit sharing in health research has been the focus of international debates for many years, particularly in developing countries. Whilst increasing attention is being given to frameworks that can guide researchers to determine levels of benefits to participants, there is little empirical research from developing countries on the practical application of these frameworks, including in situations of extreme poverty and vulnerability. In addition, the voices of those who often negotiate and face issues related to benefits in practice - frontline researchers and fieldworkers (FWs) - are rarely included in these debates. Against this background, this paper reports on experiences of negotiating research participation and benefits as described by fieldworkers, research participants and researchers in two community based studies. Methods The findings reported here are from a broader social science study that explored the nature of interactions between fieldworkers and participants in two community based studies on the Kenyan Coast. Between January and July 2010, data were collected using participant observation, and through group discussions and in-depth interviews with 42 fieldworkers, 4 researchers, and 40 study participants. Results Participants highly appreciated the benefits provided by studies, particularly health care benefits. Fieldworkers were seen by participants and other community members as the gatekeepers and conduits of benefits, even though those were not their formal roles. Fieldworkers found it challenging to ignore participant and community requests for more benefits, especially in situations of extreme poverty. However, responding to requests by providing different sorts and levels of benefits over time, as inadvertently happened in one study, raised expectations of further benefits and led to continuous negotiations between fieldworkers and participants. Conclusions Fieldworkers play an important intermediary role in research; a role imbued with multiple challenges and ethical dilemmas for which they require appropriate support. Further more specific empirical research is needed to inform the development of guidance for researchers on benefit sharing, and on responding to emergency humanitarian needs for this and other similar settings.

Background Podoconiosis is one of the forgotten types of leg swelling (elephantiasis) in the tropics. Unlike the other, better-known types of leg swelling, podoconiosis is not caused by any parasite, virus or bacterium, but by an abnormal reaction to minerals found in the clay soils of some tropical highland areas. Non-governmental Organizations (NGOs) have been responsible for the development of simple treatment methods without systematic evaluation of its effectiveness. It is essential that a large scale, fully controlled, pragmatic trial of the intervention is conducted. We aim to test the hypothesis that community-based treatment of podoconiosis lymphoedema reduces the frequency of acute dermatolymphangioadenitis episodes (‘acute attacks’) and improves other clinical, social and economic outcomes. Methods/Design This is a pragmatic, individually randomised controlled trial. We plan to randomly allocate 680 podoconiosis patients from the East Gojjam Zone in northern Ethiopia to one of two groups: ‘Standard Treatment’ or ‘Delayed Treatment’. Those randomised to standard treatment will receive the hygiene and foot-care intervention from May 2015 for one year, whereas those in the control arm will be followed through 2015 and be offered the intervention in 2016. The trial will be preceded by an economic context survey and a Rapid Ethical Assessment to identify optimal methods of conveying information about the trial and the approaches to obtaining informed consent preferred by the community. The primary outcome will be measured by recording patient recall and using a simple, patient-held diary that will be developed to record episodes of acute attacks. Adherence to treatment, clinical stage of disease, quality of life, disability and stigma will be considered secondary outcome measures. Other outcomes will include adverse events and economic productivity. Assessments will be made at baseline and at 3, 6, 9 and 12 months thereafter. Discussion The evidence is highly likely to inform implementation of the new master plan for integrated control of Neglected Tropical Diseases (NTDs), in which podoconiosis is identified as one of eight NTDs prioritised for control. Potentially, an estimated 3 million patients in Ethiopia will therefore benefit from the results of this trial. Trial registration International Standard Randomised Controlled Trial Number. Registration number: ISRCTN67805210. Date of registration: 24 January 2013.

Background Clinical trials data management (CTDM) remains one of the many challenges in running state of the art trials in resource-poor settings since most trials do not allocate, or have available, sufficient resources for CTDM and because of poor internet connectivity. Open-source software like OpenClinica could be a solution in such scenarios. Findings In 2007, the KEMRI-Wellcome Trust Research Programme (KWTRP) adopted OpenClinica (OC) community edition, an open-source software system and we share our experience and lessons learnt since its adoption. We have used OC in three different modes; direct remote data entry from sites through Global System for Mobile Communications (GSM) modems, a centralized data centre approach where all data from paper records were entered at a central location and an off-line approach where data entry was done from a copy of database hosted on a field-site server laptop, then data uploaded to a centralized server later. We have used OC in eleven trials/studies with a cumulative number of participants in excess of 6000. These include large and complex trials, with multiple sites recruiting in different regions of East Africa. In the process, we have developed substantial local capacity through hands-on training and mentorship, which we have now begun to share with other institutions in the region. Conclusions Our experience demonstrates that an open source data management system to manage trials’ data can be utilized to international industry standards in resource-poor countries.

Background Community engagement (CE) is increasingly promoted for biomedical research conducted in resource poor settings for both intrinsic and instrumental purposes. Given the potential importance of CE, but also complexities and possibilities of unexpected negative outcomes, there is need for more documentation of CE processes in practice. We share experiences of formal CE for a paediatric randomized controlled malaria vaccine trial conducted in three sites within Kilifi County, Kenya. Methods Social scientists independent of the trial held in-depth individual interviews with trial researchers (n = 5), community leaders (n = 8) and parents (15 with enrolled children and 4 without); and group discussions with fieldworkers (n = 6) and facility staff (n = 2). We conducted a survey of participating households (n = 200) and observed over 150 CE activities. Results The overall CE plan was similar across the three study sites. The majority of respondents felt that CE activities helped to clear pre-existing concerns and misconceptions, and increase familiarity with and trust in trial staff. Challenges included: some community leaders attempting to exert pressure on people to enrol; local wording in information sheets and consent forms feeding into serious anxieties about the trial; and concerns about reduced CE over time. Negative effects of these challenges were mitigated through changes to on-going CE activities, and final information sharing and consent being conducted individually by trained clinical staff. One year after enrolment, 31% (n = 62) of participants’ parents reported malaria prevention as the main aim of the activities their children were involved in, and 93% wanted their children to remain involved. Conclusion The trial teams’ goals for CE were relatively clear from the outset. Other actors’ hopes and expectations (like higher allowances and future employment) were not openly discussed, but emerged over the course of engagements. Encouraging open discussion of all actors’ intentions and goals from the outset takes time, risks raising expectations that cannot be met, and is complex. However, doing so in future similar trials may allow successes here to be built upon, and some challenges to be minimized or avoided. Trial registration ClinicalTrials.gov NCT00866619 (registration 19-Mar-2009).

Background: The nature of protective immune responses elicited by immunization with the candidate malaria vaccine RTS, S is still incompletely understood. Antibody levels correlate with protection against malaria infection, but considerable variation in outcome is unexplained (e.g., children may experience malaria despite high anticircumsporozoite [CS] titers). Methods and Findings: We measured the avidity index (AI) of the anti-CS antibodies raised in subgroup of 5-17 month old children in Kenya who were vaccinated with three doses of RTS, S/AS01(E) between March and August 2007. We evaluated the association between the AI and the subsequent risk of clinical malaria. We selected 19 cases (i.e., with clinical malaria) and 42 controls (i.e., without clinical malaria), matching for anti-CS antibody levels and malaria exposure. We assessed their sera collected 1 month after the third dose of the vaccine, in March 2008 (range 4-10 months after the third vaccine), and at 12 months after the third vaccine dose. The mean AI was 45.2 (95% CI: 42.4 to 48.1), 45.3 (95% CI: 41.4 to 49.1) and 46.2 (95% CI; 43.2 to 49.3) at 1 month, in March 2008 (4-10 months), and at 12 months after the third vaccination, respectively (p=0.9 by ANOVA test for variation over time). The AI was not associated with protection from clinical malaria (OR=0.90; 95% CI: 0.49 to 1.66; p=0.74). The AI was higher in children with high malaria exposure, as measured using the weighted local prevalence of malaria, compared to those with low malaria exposure at 1 month post dose 3 (p=0.035). Conclusion: Our data suggest that in RTS, S/AS01(E)-vaccinated children residing in malaria endemic countries, the avidity of anti-circumsporozoite antibodies, as measured using an elution ELISA method, was not associated with protection from clinical malaria. Prior natural malaria exposure might have primed the response to RTS, S/AS01(E) vaccination.

Community engagement is increasingly emphasized in biomedical research, as a right in itself, and to strengthen ethical practice. We draw on interviews and observations to consider the practical and ethical implications of involving Community Health Workers (CHWs) as part of a community engagement strategy for a vaccine trial on the Kenyan Coast. CHWs were initially engaged as an important network to be informed about the trial. However over time, and in response to community advice, they became involved in trial information sharing and identifying potential participants; thereby taking on roles that overlapped with those of employed fieldworkers (FWs). While CHWs involvement was generally perceived as positive and appreciated, there were challenges in their relations with FWs and other community members, partly related to levels and forms of remuneration. Specifically, payment of CHWs was not as high as for FWs and was based on ‘performance’. This extrinsic motivation had the potential to crowd out CHWs intrinsic motivation to perform their pre-existing community roles. CHWs remuneration potentially also contributed to CHWs distorting trial information to encourage community members to participate; and to researchers encouraging CHWs to utilize their social connections and status to increase the numbers of people who attended information giving sessions. Individual consent processes were protected in this trial through final information sharing and consent being conducted by trained clinical staff who were not embedded in study communities. However, our experiences suggest that roles and remuneration of all front line staff and volunteers involved in trials need careful consideration from the outset, and monitoring and discussion over time.

Background Encouraging progress has been seen with reductions in Plasmodium falciparum malaria transmission in some parts of Africa. Reduced transmission might lead to increasing susceptibility to malaria among older children due to lower acquired immunity, and this has implications for ongoing control strategies. Methods and Findings We conducted a longitudinal observational study of children admitted to Kilifi County Hospital in Kenya and linked it to data on residence and insecticide-treated net (ITN) use. This included data from 69,104 children aged from 3 mo to 13 y admitted to Kilifi County Hospital between 1 January 1990 and 31 December 2014. The variation in malaria slide positivity among admissions was examined in logistic regression models using the following predictors: location of the residence, calendar time, the child’s age, ITN use, and the enhanced vegetation index (a proxy for soil moisture). The proportion of malaria slide-positive admissions declined from 0.56 (95% confidence interval [CI] 0.54–0.58) in 1998 to 0.07 (95% CI 0.06–0.08) in 2009 but then increased again through to 0.24 (95% CI 0.22–0.25) in 2014. Older children accounted for most of the increase after 2009 (0.035 [95% CI 0.030–0.040] among young children compared to 0.22 [95% CI 0.21–0.23] in older children). There was a nonlinear relationship between malaria risk and prevalence of ITN use within a 2 km radius of an admitted child’s residence such that the predicted malaria positive fraction varied from ~0.4 to, Using observational data over 25 years, Polycarp Mogeni and colleagues examine the age, spatial, and temporal variations in malaria hospital admissions in Kilifi County, Kenya., Author Summary Why Was This Study Done? The past decade has seen a marked decline in malaria transmission in some parts of Africa alongside substantial investments to control malaria. However, malaria remains a public health emergency in sub-Saharan Africa. As malaria declines in some parts of Africa, older children may become more susceptible to clinical malaria because reduced exposure earlier in life decreases opportunities for acquired immunity. Insecticide-treated net (ITN) use in randomized controlled trials and observational studies of effectiveness has been associated with reduced malaria morbidity and mortality. Given the ongoing global campaign to increase coverage, there is need for continuous assessment of ITN effectiveness in field conditions. What Did the Researchers Do and Find? We analyzed 25 y of longitudinal surveillance data of hospital admissions to Kilifi County Hospital in the Kenyan Coast between 1990 and 2014. We included 69,104 children between 3 mo and 13 y of age in the analysis. We observed a decline in the proportion of admitted children with malaria parasites on blood testing from 1998 to 2009. However, there was a steady and marked increase in the proportion of admitted children with malaria parasites in their blood from 2009 to 2014. This coincided with a shift of malaria burden from younger to older children. Fortunately, there was no increase in malaria-related mortality. The proportion of children with malaria parasites was consistently higher in the southern region of Kilifi County compared to the north, thereby providing an opportunity for targeted interventions. However, within the northern and southern regions there was substantial geographical variability from year to year, which would complicate targeted control. Community ITN use around the admitted child’s residence was highly effective—i.e., children presenting for admission surrounded by high ITN usage at the community level were less likely to present with malaria parasites compared with those surrounded by low ITN usage. What Do These Findings Mean? These findings suggest that further reductions of malaria transmission are needed to mitigate the increasing burden among older children and that universal ITN coverage is a promising strategy to achieve this goal.

BACKGROUND: The candidate malaria vaccine RTS,S/AS01 reduced episodes of both clinical and severe malaria in children 5 to 17 months of age by approximately 50% in an ongoing phase 3 trial. We studied infants 6 to 12 weeks of age recruited for the same trial. METHODS: We administered RTS,S/AS01 or a comparator vaccine to 6537 infants who were 6 to 12 weeks of age at the time of the first vaccination in conjunction with Expanded Program on Immunization (EPI) vaccines in a three-dose monthly schedule. Vaccine efficacy against the first or only episode of clinical malaria during the 12 months after vaccination, a coprimary end point, was analyzed with the use of Cox regression. Vaccine efficacy against all malaria episodes, vaccine efficacy against severe malaria, safety, and immunogenicity were also assessed. RESULTS: The incidence of the first or only episode of clinical malaria in the intention-to-treat population during the 14 months after the first dose of vaccine was 0.31 per person-year in the RTS,S/AS01 group and 0.40 per person-year in the control group, for a vaccine efficacy of 30.1% (95% confidence interval [CI], 23.6 to 36.1). Vaccine efficacy in the per-protocol population was 31.3% (97.5% CI, 23.6 to 38.3). Vaccine efficacy against severe malaria was 26.0% (95% CI, -7.4 to 48.6) in the intention-to-treat population and 36.6% (95% CI, 4.6 to 57.7) in the per-protocol population. Serious adverse events occurred with a similar frequency in the two study groups. One month after administration of the third dose of RTS,S/AS01, 99.7% of children were positive for anti-circumsporozoite antibodies, with a geometric mean titer of 209 EU per milliliter (95% CI, 197 to 222). CONCLUSIONS: The RTS,S/AS01 vaccine coadministered with EPI vaccines provided modest protection against both clinical and severe malaria in young infants. (Funded by GlaxoSmithKline Biologicals and the PATH Malaria Vaccine Initiative; RTS,S ClinicalTrials.gov number, NCT00866619.).

OBJECTIVE: To explore excess paediatric mortality after discharge from Kilifi District Hospital, Kenya, and its duration and risk factors. METHODS: Hospital and demographic data were used to describe post-discharge mortality and survival probability in children aged -4 but 13 days (HR: 1.8). Older age was protective (reference

The malaria vaccine candidate, RTS,S/AS01E, showed promising protective efficacy in a trial of Kenyan and Tanzanian children aged 5 to 17 months. Here we report on the vaccine's safety and tolerability. The experimental design was a Phase 2b, two-centre, double-blind (observer- and participant-blind), randomised (1∶1 ratio) controlled trial. Three doses of study or control (rabies) vaccines were administered intramuscularly at 1 month intervals. Solicited adverse events (AEs) were collected for 7 days after each vaccination. There was surveillance and reporting for unsolicited adverse events for 30 days after each vaccination. Serious adverse events (SAEs) were recorded throughout the study period which lasted for 14 months after dose 1 in Korogwe, Tanzania and an average of 18 months post-dose 1 in Kilifi, Kenya. Blood samples for safety monitoring of haematological, renal and hepatic functions were taken at baseline, 3, 10 and 14 months after dose 1. A total of 894 children received RTS,S/AS01E or rabies vaccine between March and August 2007. Overall, children vaccinated with RTS,S/AS01E had fewer SAEs (51/447) than children in the control group (88/447). One SAE episode in a RTS,S/AS01E recipient and nine episodes among eight rabies vaccine recipients met the criteria for severe malaria. Unsolicited AEs were reported in 78% of subjects in the RTS,S/AS01E group and 74% of subjects in the rabies vaccine group. In both vaccine groups, gastroenteritis and pneumonia were the most frequently reported unsolicited AE. Fever was the most frequently observed solicited AE and was recorded after 11% of RTS,S/AS01E doses compared to 31% of doses of rabies vaccine. The candidate vaccine RTS,S/AS01E showed an acceptable safety profile in children living in a malaria-endemic area in East Africa. More data on the safety of RTS,S/AS01E will become available from the Phase 3 programme. Trial Registration ClinicalTrials.gov NCT00380393

BACKGROUND: Plasmodium falciparum malaria is a pressing global health problem. A previous study of the malaria vaccine RTS,S (which targets the circumsporozoite protein), given with an adjuvant system (AS02A), showed a 30% rate of protection against clinical malaria in children 1 to 4 years of age. We evaluated the efficacy of RTS,S given with a more immunogenic adjuvant system (AS01E) in children 5 to 17 months of age, a target population for vaccine licensure. METHODS: We conducted a double-blind, randomized trial of RTS,S/AS01E vaccine as compared with rabies vaccine in children in Kilifi, Kenya, and Korogwe, Tanzania. The primary end point was fever with a falciparum parasitemia density of more than 2500 parasites per microliter, and the mean duration of follow-up was 7.9 months (range, 4.5 to 10.5). RESULTS: A total of 894 children were randomly assigned to receive the RTS,S/AS01E vaccine or the control (rabies) vaccine. Among the 809 children who completed the study procedures according to the protocol, the cumulative number in whom clinical malaria developed was 32 of 402 assigned to receive RTS,S/AS01E and 66 of 407 assigned to receive the rabies vaccine; the adjusted efficacy rate for RTS,S/AS01E was 53% (95% confidence interval [CI], 28 to 69; P

Summary Background There is little data on the burden or causes of epilepsy in developing countries, particularly in children living in sub-Saharan Africa. Methods We conducted two surveys to estimate the prevalence, incidence and risk factors of epilepsy in children in a rural district of Kenya. All children born between 1991 and 1995 were screened with a questionnaire in 2001 and 2003, and those with a positive response were then assessed for epilepsy by a clinician. Active epilepsy was defined as two or more unprovoked seizures with one in the last year. Results In the first survey 10,218 children were identified from a census, of whom 110 had epilepsy. The adjusted prevalence estimates of lifetime and active epilepsy were 41/1000 (95% CI: 31–51) and 11/1000 (95% CI: 5–15), respectively. Overall two-thirds of children had either generalized tonic-clonic and/or secondary generalized seizures. A positive history of febrile seizures (OR=3.01; 95% CI: 1.50–6.01) and family history of epilepsy (OR=2.55; 95% CI: 1.19–5.46) were important risk factors for active epilepsy. After the second survey, 39 children from the same birth cohort with previously undiagnosed epilepsy were identified, thus the incidence rate of active epilepsy is 187 per 100,000 per year (95% CI: 133–256) in children aged 6–12 years. Conclusions There is a considerable burden of epilepsy in older children living in this area of rural Kenya, with a family history of seizures and a history of febrile seizures identified as risk factors for developing epilepsy.

Neurological impairment is common in resource-poor countries, but its causes are not clear. Computerized tomography (CT) of the brain has been used to determine the cause of brain insults that may manifest as neurological impairments. The authors conducted a community survey in Kilifi of 10 218 children aged 6 to 9 years to detect neurological impairment. From this survey, 34 children were identified, of whom 16 had motor deficits, 11 complex partial seizures, 4 microcephaly or macrocephaly, and 3 severe developmental delay. These children were assessed with elicitation of history, physical examination, and CT scan of the brain. Sixteen (47%) of the scans showed abnormalities: cerebral atrophy (n = 9), schizencephaly (n = 3), periventricular leukomalacia (n = 2), porencephalic cyst (n = 1), and agenesis of the corpus callosum (n = 1). The minimum prevalence of abnormalities on the CT scan of the brain is 1.56 of 1000, and the prevalence of schizencephaly is 0.29 of 1000. Motor impairments were more likely to show abnormality than the other indications. CT abnormalities are common in children with neurological impairment in Kenya, but the appearances did not identify a major cause.

BACKGROUND: There is little data on the burden of neurological impairment (NI) in developing countries, particularly in children of Africa. METHODS: We conducted a survey of NI in children aged 6-9 years in a rural district of Kenya. First, we screened for neurological disability by administering the Ten Questions Questionnaire (TQQ) to parents/guardians of children in a defined population. In phase two, we performed a comprehensive clinical and psychological assessment on children who tested positive on TQQ and on a similar number of children who tested negative. RESULTS: A total of 10 218 children were screened, of whom 955 (9.3%) were positive on TQQ. Of these, 810 (84.8%) were assessed, and of those who tested negative 766 (8.3%) were assessed. The prevalence for moderate/severe NI was 61/1000 [95% confidence interval (95% CI) 48-74]. The most common domains affected were epilepsy (41/1000), cognition (31/1000), and hearing (14/1000). Motor (5/1000) and vision (2/1000) impairments were less common. Of the neurologically impaired children (n = 251), 56 (22%) had more than one impairment. Neonatal insults were found to have a significant association with moderate/severe NI in both the univariate [odds ratio (OR) = 1.70; 95% CI 1.12-2.47] and multivariate analyses (OR = 1.30; 95% CI 1.09-1.65). CONCLUSIONS: There is a considerable burden of moderate/severe NI in this area of rural Kenya, with epilepsy, cognition, and hearing being the most common domains affected. Neonatal insults were identified as an important risk factor.

Background GlaxoSmithKline Biologicals and the PATH Malaria Vaccine Initiative are working in partnership to develop a malaria vaccine to protect infants and children living in malaria endemic regions of sub-Saharan Africa, which can be delivered through the Expanded Programme on Immunization. The RTS,S/AS candidate vaccine has been evaluated in multiple phase I/II studies and shown to have a favourable safety profile and to be well-tolerated in both adults and children. This paper details the design of the phase III multicentre efficacy trial of the RTS,S/AS01 malaria vaccine candidate, which is pivotal for licensure and policy decision-making. Methods The phase III trial is a randomized, controlled, multicentre, participant- and observer-blind study on-going in 11 centres associated with different malaria transmission settings in seven countries in sub-Saharan Africa. A minimum of 6,000 children in each of two age categories (6-12 weeks, 5-17 months) have been enrolled. Children were randomized 1:1:1 to one of three study groups: (1) primary vaccination with RTS,S/AS01 and booster dose of RTS,S/AS01; (2) primary vaccination with RTS,S/AS01 and a control vaccine at time of booster; (3) primary vaccination with control vaccine and a control vaccine at time of booster. Primary vaccination comprises three doses at monthly intervals; the booster dose is administered at 18 months post-primary course. Subjects will be followed to study month 32. The co-primary objectives are the evaluation of efficacy over one year post-dose 3 against clinical malaria when primary immunization is delivered at: (1) 6-12 weeks of age, with co-administration of DTPwHepB/Hib antigens and OPV; (2) 5-17 months of age. Secondary objectives include evaluation of vaccine efficacy against severe malaria, anaemia, malaria hospitalization, fatal malaria, all-cause mortality and other serious illnesses including sepsis and pneumonia. Efficacy of the vaccine against clinical malaria under different transmission settings, the evolution of efficacy over time and the potential benefit of a booster will be evaluated. In addition, the effect of RTS,S/AS01 vaccination on growth, and the safety and immunogenicity in HIV-infected and malnourished children will be assessed. Safety of the primary course of immunization and the booster dose will be documented in both age categories. Conclusions This pivotal phase III study of the RTS,S/AS01 candidate malaria vaccine in African children was designed and implemented by the Clinical Trials Partnership Committee. The study will provide efficacy and safety data to fulfil regulatory requirements, together with data on a broad range of endpoints that will facilitate the evaluation of the public health impact of the vaccine and will aid policy and implementation decisions. Trial registration Clinicaltrials.gov NCT00866619

Summary Background In sub-Saharan Africa, community-acquired bacteraemia is an important cause of illness and death in children. Our aim was to establish the magnitude and causes of hospital-acquired (nosocomial) bacteraemia in African children. Methods We reviewed prospectively collected surveillance data of 33 188 admissions to Kilifi District Hospital, Kenya, between April 16, 2002, and Sept 30, 2009. We defined bacteraemia as nosocomial if it occurred 48 h or more after admission. We estimated the per-admission risk, daily rate, effect on mortality, and microbial cause of nosocomial bacteraemia and analysed risk factors by multivariable Cox regression. The effect on morbidity was measured as the increase in hospital stay by comparison with time-matched patients without bacteraemia. Findings The overall risk of nosocomial bacteraemia during this period was 5·9/1000 admissions (95% CI 5·2–6·9) but we recorded an underlying rise in risk of 27% per year. The incidence was 1·0/1000 days in hospital (0·87–1·14), which is about 40 times higher than that of community-acquired bacteraemia in the same region. Mortality in patients with nosocomial bacteraemia was 53%, compared with 24% in community-acquired bacteraemia and 6% in patients without bacteraemia. In survivors, nosocomial bacteraemia lengthened hospital stay by 10·1 days (3·0–17·2). Klebsiella pneumoniae, Escherichia coli, Staphylococcus aureus, Acinetobacter spp, group D streptococci, and Pseudomonas aeruginosa accounted for three-quarters of nosocomial infections. Nosocomial bacteraemia was significantly associated with severe malnutrition (hazard ratio 2·52, 95% CI 1·79–3·57) and blood transfusion in children without severe anaemia (4·99; 3·39–7·37). Interpretation Our findings show that although nosocomial bacteraemia is rare, it has serious effects on morbidity and mortality, and the microbiological causes are distinct from those of community-acquired bacteraemia. Nosocomial infections are largely unrecognised or undocumented as a health risk in low-income countries, but they are likely to become public health priorities as awareness of their occurrence increases and as other prominent childhood diseases are progressively controlled. Funding Wellcome Trust.

Background Targeted malaria control interventions are expected to be cost-effective. Clinical, parasitological and serological markers of malaria transmission have been used to detect malaria transmission hotspots, but few studies have examined the relationship between the different potential markers in low transmission areas. The present study reports on the relationships between clinical, parasitological, serological and entomological markers of malaria transmission in an area of low transmission intensity in Coastal Kenya. Methods Longitudinal data collected from 831 children aged 5–17 months, cross-sectional survey data from 800 older children and adults, and entomological survey data collected in Ganze on the Kenyan Coast were used in the present study. The spatial scan statistic test used to detect malaria transmission hotspots was based on incidence of clinical malaria episodes, prevalence of asymptomatic asexual parasites carriage detected by microscopy and polymerase chain reaction (PCR), seroprevalence of antibodies to two Plasmodium falciparum merozoite antigens (AMA1 and MSP1-19) and densities of Anopheles mosquitoes in CDC light-trap catches. Results There was considerable overlapping of hotspots by these different markers, but only weak to moderate correlation between parasitological and serological markers. PCR prevalence and seroprevalence of antibodies to AMA1 or MSP1-19 appeared to be more sensitive markers of hotspots at very low transmission intensity. Conclusion These findings may support the choice of either serology or PCR as markers in the detection of malaria transmission hotspots for targeted interventions. Electronic supplementary material The online version of this article (doi:10.1186/s12936-016-1260-3) contains supplementary material, which is available to authorized users.