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Shigella is associated with a significant burden of disease worldwide among individuals of all ages and is the major cause of moderate and severe diarrhea in children under five years of age in low- and middle-income countries. Several candidate vaccines against Shigella species are currently under clinical development. The investigational 1790GAHB vaccine against Shigella sonnei is based on GMMA (Generalized Modules for Membrane Antigens) technology. The vaccine was well tolerated and induced high antibody levels in early-phase clinical trials in both Shigella-endemic and non-endemic settings. The present analysis assessed the bactericidal activity of antibodies induced by 1790GAHB in healthy Kenyan adults during a phase 2a, controlled, randomized study (NCT02676895). Participants received two doses of 1790GAHB 4 weeks apart containing either 1.5/25 µg or 6/100 µg O antigen/protein, or active comparator vaccines (Control). Serum bactericidal activity (SBA) against S. sonnei was assessed at pre-vaccination (D1), 28 days post-first dose (D29) and 28 days post-second dose (D57), using a luminescence-based assay. Most participants had SBA titers above the lower limit of quantification of the assay at D1. SBA geometric mean titers increased 3.4-fold in the 1.5/25 µg group and 6.3-fold in the 6/100 µg group by D29 and were maintained at D57. There was no increase in SBA geometric mean titers in the Control group. A strong correlation was observed between SBA titers and anti-S. sonnei lipopolysaccharide serum immunoglobulin G antibody concentrations (Pearson correlation coefficient = 0.918), indicating that SBA can effectively complement enzyme-linked immunosorbent assay data by indicating the functionality of 1790GAHB-induced antibodies.

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 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: 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.).

Background: To restrict trial endpoints to infections acquired after vaccination in Phase IIb trials of candidate malaria vaccines, participants are treated with anti-malarial drugs to clear existing infections. Anti-malarial drugs with a long half-life may inhibit the acquisition of new infections. This study evaluated the effects of three anti-malarial drug regimens on the clearance of existing infections and acquisition of new infections. Methods: An open-label randomised controlled trial (MalPaC) was conducted between November 2013 and February 2014. Ninety adults were randomised 1:1:1 to receive one of three treatments: atovaquone/proguanil and artesunate (AP+AS); artesunate (AS); or sulphadoxine-pyrimethamine, artesunate, and primaquine (SP+AS+PQ). Parasite monitoring was determined over 84-day follow-up by assessing Plasmodium falciparum positivity by 18s qPCR, live and sexual stage parasites by RT-PCR, and recrudescence of infections by msp2 genotyping. Results: At enrolment, parasite prevalence by qPCR was 44% (40/90, day 0), which fell to 10% (9/90, day 16), then rose to almost the initial rates by day 84 (39%, 35/90). Individuals treated with AS and SP+AS+PQ were more likely to have higher qPCR positive rates compared to participants treated with AP+AS in the immediate post-treatment phase (days 16-28) (OR=7.7 [95%CI 4.6-12.8] p Conclusion: Falciparum DNA remained detectable by PCR post-treatment with incomplete parasite clearance regardless of drug regimen. Though AP+AS drug regimen may also have partially suppressed the acquisition of new infections during post-treatment follow-up. Trial registration: Pan African Clinical Trials Registry, 22nd of August 2013, PACTR201309000625311.

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.

Performing a genome-wide association study of Salmonella enterica serovar Typhi ( S. Typhi) invasion, Alvarez et al. (1) identify a trait-associated SNP, rs8060947, in VAC14 . rs8060947 is an expression quantitative trait locus for VAC14 RNA expression, and carriage of the A allele is associated with reduced VAC14 RNA and protein expression, and increased invasion of S . Typhi. VAC14-associated inhibition of S . Typhi invasion is mediated by a reduction in host cell membrane cholesterol. Carriage of the A allele at rs8060947 is associated with typhoid fever in Vietnamese individuals [cases = 496, controls = 500; P = 0.01, additive odds ratio (OR) = 1.38]. The authors further identify a SNP in high linkage disequilibrium with rs8060947 and rs8044133, located in a transcription factor binding site, which merits further investigation as the causative SNP. Alvarez et al. (1) note that cholesterol has been implicated in the invasion and pathogenesis of a wide range of pathogens (2⇓⇓–5). We therefore used previously published genome-wide association study data, describing susceptibility to bacteraemia secondary to diverse pathogens in Kenyan children (6), to explore whether genetic variation at the VAC14 locus is associated with susceptibility to invasive bacterial infections other than typhoid fever. In Kenyan children (cases = 1,536, controls = 2,677), rs8060947 (Fig. 1 A ) is significantly associated with all-cause bacteremia: P additive = 0.02, OR = 1.11 [95% confidence interval (CI) 1.02–1.22]. In keeping with the effect observed in typhoid, carriage of the A allele at rs8060947 increases risk of bacteremia. Fig. 1. rs8060947 and major causes of bacteremia … [↵][1]1To whom correspondence should be addressed. Email: james.gilchrist{at}well.ox.ac.uk. [1]: #xref-corresp-1-1

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

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 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: The range and amount of volunteer infection studies, known as Controlled Human Infection Model (CHMI) studies, in Low-Middle Income Countries (LMICs) is increasing with rapid technological advancement, world-class laboratory facilities and increasing capacity development initiatives. However, the ethical issues these studies present in LMICs have not been empirically studied. We present findings of a descriptive social science study nested within a malaria volunteer infection study, on-going at the time of writing, at the KEMRI-Wellcome Trust Research Programme (KWTRP) on the Kenyan Coast. Methods: The study included non-participant observations, five group discussions with more than half of the CHMI study participants, two in-depth interviews with study team members, and an exit questionnaire administered to the participants. Results: Participants understood the key elements of the study, including that they would be deliberately infected with malaria parasites and may get malaria as a result, there would be regular blood draws, and they would spend up to 24 days in a residence facility away from their homes. The greatest motivation for participation was the monetary compensation of 20 USD per overnight stay given as a lump-sum at the end of their residency stay. Also appreciated were the health screening tests prior to enrolment and the positive relations with the study team. Concerns raised included the amount and regularity of blood draws experienced, and concerns that this type of research may feed into on-going rumours about research generally. Conclusion: With the increasing range and number of CHMI studies being conducted in LMICs, current ethical guidance for more than minimal risk studies is inadequate. This study highlights some of the ethical issues that could emerge in these settings, emphasizing the heavy responsibility placed on research review and regulatory systems, researchers and funders, as well as the importance of carefully tailored community engagement and consent processes.

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 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).

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.

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

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: RTS,S/AS01 E, the most advanced malaria vaccine confers partial immunity. The vaccine-induced pre-erythrocytic immunity reduces exposure to blood-stage parasites, delaying acquisition of antibodies to blood-stage antigens. However, the duration of this effect is unknown. Methods: We measured, by enzyme-linked immunosorbent assay, IgG-antibodies to 4 Plasmodium falciparum blood-stage antigens (AMA1, MSP142, EBA175, and MSP3) on 314 children randomized to receive RTS,S/AS01 E or Rabies vaccine at 5 – 17 months of age in a phase 2b trial in Kenya, and thereafter participated in a 7-year study of the duration of vaccine immunity. Results: Antibody levels to MSP142, AMA1 and EBA175 were slightly lower among the RTS,S/AS01 E recipients, relative to the Rabies-control vaccinees, during the first 48 months of surveillance. Irrespective of vaccine arm, antibody levels to merozoite antigens were positively associated with the risk for malaria. However, this was only apparent at high levels for EBA175 and AMA1 and was not evident after adjusting for heterogeneity in malaria-exposure. Among children with asymptomatic parasitaemia, antibody levels were associated with reduced clinical malaria. Conclusions: The reduction in levels of antibodies to blood-stage antigens induced by vaccination with RTS,S/AS01 E can last for several years. In absence of asymptomatic infection, anti-merozoite antibody levels were unreliable correlates of clinical immunity.