75 results on '"Mainga Hamaluba"'
Search Results
2. Nutritional supplementation in children with severe pneumonia in Uganda and Kenya (COAST-Nutrition): a phase 2 randomised controlled trialResearch in context
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Sarah Kiguli, Peter Olupot-Olupot, Mainga Hamaluba, Elisa Giallongo, Karen Thomas, Florence Alaroker, Robert O. Opoka, Abner Tagoola, Shela Oyella, Damalie Nalwanga, Eva Nabawanuka, William Okiror, Margaret Nakuya, Denis Amorut, Rita Muhindo, Ayub Mpoya, Hellen Mnjalla, Emmanuel Oguda, Thomas N. Williams, David A. Harrison, Kathy Rowan, Andre Briend, and Kathryn Maitland
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Children ,Africa ,Pneumonia randomised controlled trial ,Nutritional support ,Ready to use therapeutic feeds ,Anthropometry ,Medicine (General) ,R5-920 - Abstract
Summary: Background: Severe pneumonia in African children results in poor long-term outcomes (deaths/readmissions) with undernutrition as a key risk factor. We hypothesised additional energy/protein-rich Ready-to-Use Therapeutic Foods (RUTF) would meet additional nutritional requirements and improve outcomes. Methods: COAST-Nutrition was an open-label Phase 2 randomised controlled trial in children (aged 6 months-12 years) hospitalised with severe pneumonia (and hypoxaemia, SpO2 99%). By Day 90, there was no significant difference in the composite endpoint (probabilistic index 0.49, 95% CI 0.45–0.53, p = 0.74). Respective 90-day mortality (13/420 3.1% vs 14/421 3.3%) and MUAC increment (0.54 (SD 0.85) vs 0.55 (SD 0.81)) were similar between arms. There was no difference in any anthropometric secondary endpoints to Day 28, 90 or 180 except skinfold thickness at Day 28 and Day 90 was greater in the RUTF arm. Serious adverse events were higher in the RUTF arm (n = 164 vs 108), mainly due to hospital readmission for acute illness (54/387 (14%) vs 37/375 (10%). Interpretation: Our study suggested that nutritional supplementation with RUTF did not improve outcomes to 180 days in children with severe pneumonia. Funding: This trial is part of the EDCTP2 programme (grant number RIA-2016S-1636-COAST-Nutrition) supported by the European Union, and UK Joint Global Health Trials scheme: Medical Research Council, Department for International Development, Wellcome Trust (grant number MR/L004364/1, UK).
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- 2024
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3. A Phase I trial of Non-invasive Ventilation and seizure prophylaxis with levetiracetam In Children with Cerebral Malaria Trial (NOVICE-M Trial) [version 1; peer review: 2 approved]
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Mainga Hamaluba, Diana M. Gibb, Elizabeth C. George, Symon M. Kariuki, Kathryn Maitland, Roisin Connon, Nchafasto Obonyo, Christabel Mogaka, Thomas N. Williams, Emmanuel Ogoda, A. Sarah Walker, and Charles Newton
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severe malaria ,prophylactic anticonvulsants ,children ,Africa ,clinical trial ,non invasive ventilation ,eng ,Medicine ,Science - Abstract
Background African children with cerebral malaria and seizures caused Plasmodium falciparum are at greater risk of poor outcomes including death and neurological sequelae. The agonal events are severe hypoventilation and respiratory arrest often triggered by seizures. We hypothesised that prophylactic anti-seizure medication (ASM) could avert ‘spikes’ of intracranial pressure during or following seizures and that adequate ventilation could be supported by biphasic Cuirass Ventilation (BCV) which requires no intubation. Methods A Phase I trial conducted in Kilifi, Kenya designed to provide data on safety, feasibility and preliminary data on seizure control using prophylactic ASM (levetiracetam) and BCV as non-invasive ventilatory support in children with cerebral malaria. Children aged 3 months to 12-years hospitalised with P falciparum malaria (positive rapid diagnostic test or a malaria slide), a Blantyre Coma Score ≤2 and a history of acute seizures in this illness are eligible for the trial. In a phased evaluation we will study i) BCV alone for respiratory support (n=10); ii) prophylactic LVT: 40mg/kg loading dose then 30mg/kg every 12 hours given via nasogastric tube for 72 hours (or until fully conscious) plus BCV support (n=10) and; iii) prophylactic LVT: 60mg/kg loading dose then 45mg/kg every 12 hours given via nasogastric tube for 72 hours (or until fully conscious) plus BCV support (n=10). Primary outcome measure: cumulative time with a clinically detected seizures or number of observed seizures over 36 hours. Secondary outcomes will be assessed by feasibility or ability to implement BCV, and recovery from coma within 36 hours. Safety endpoints include: aspiration during admission; death at 28 days and 180 days; and de-novo neurological impairments at 180 days. Conclusions This is a Phase I trial largely designed to test the feasibility, tolerability and safety of using non-invasive ventilatory support and LVT prophylaxis in cerebral malaria. Registration ISRCTN76942974 (5.02.2019); PACTR202112749708968 (20.12.2021).
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- 2024
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4. Targeted amplicon deep sequencing of ama1 and mdr1 to track within-host P. falciparum diversity throughout treatment in a clinical drug trial [version 4; peer review: 2 approved, 2 approved with reservations]
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Mainga Hamaluba, Juliana Wambua, Arjen M. Dondorp, Jennifer Musyoki, Caroline Ngetsa, Oksana Kharabora, Leonard Ndwiga, Zaydah de Laurent, Kevin Wamae, Kelvin Kimenyi, Gabriel Mwambingu, Peter Kalume, Philip Bejon, Jeffrey Bailey, Rob van der Pluijm, Lynette Ochola-Oyier, Jonathan Juliano, and Victor Osoti
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Artemisinin-based combination therapy ,pfama1 ,Pfmdr1 ,artemisinin resistance ,antimalarial resistance ,targeted deep sequencing ,eng ,Medicine ,Science - Abstract
Introduction Antimalarial therapeutic efficacy studies are routinely conducted in malaria-endemic countries to assess the effectiveness of antimalarial treatment strategies. Targeted amplicon sequencing (AmpSeq) uniquely identifies and quantifies genetically distinct parasites within an infection. In this study, AmpSeq of Plasmodium falciparum apical membrane antigen 1 (ama1), and multidrug resistance gene 1 (mdr1), were used to characterise the complexity of infection (COI) and drug-resistance genotypes, respectively. Methods P. falciparum-positive samples were obtained from a triple artemisinin combination therapy clinical trial conducted in 30 children under 13 years of age between 2018 and 2019 in Kilifi, Kenya. Nine of the 30 participants presented with recurrent parasitemia from day 26 (624h) onwards. The ama1 and mdr1 genes were amplified and sequenced, while msp1, msp2 and glurp data were obtained from the original clinical study. Results The COI was comparable between ama1 and msp1, msp2 and glurp; overall, ama1 detected more microhaplotypes. Based on ama1, a stable number of microhaplotypes were detected throughout treatment until day 3. Additionally, a recrudescent infection was identified with an ama1 microhaplotype initially observed at 30h and later in an unscheduled follow-up visit. Using the relative frequencies of ama1 microhaplotypes and parasitemia, we identified a fast (5h) clearing microhaplotype. As expected, only two mdr1 microhaplotypes (NF and NY) were identified based on the combination of amino acid polymorphisms at codons 86 and 184. Conclusions This study highlights AmpSeq as a tool for highly-resolution tracking of parasite microhaplotypes throughout treatment and can detect variation in microhaplotype clearance estimates. AmpSeq can also identify slow-clearing microhaplotypes, a potential early sign of selection during treatment. Consequently, AmpSeq has the capability of improving the discriminatory power to distinguish recrudescences from reinfections accurately.
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- 2024
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5. Gastroenteritis Rehydration Of children with Severe Acute Malnutrition (GASTROSAM): A Phase II Randomised Controlled trial: Trial Protocol [version 2; peer review: 2 approved]
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Mainga Hamaluba, Matthew Coldiron, Kirsty Houston, Temmy Sunyoto, Marie-Francoise SCHERRER, Roisin Connon, Celine LANGENDORF, Roberta PETRUCCI, Nchafatso Obonyo, Diana M. Gibb, Peter Olupot-Olupot, Elizabeth C. George, Jennifer A Evans, Kathryn Maitland, Salifou Atti, Manuel Dewez, Florence Aloroker, San Maurice Ouattara, Ousmane Guindo, Hellen Mnjalla, Omokore Oluseyi Amos, Ayub Mpoya, Abdullahi Chara, Margaret Nakuya, Hadiza Alhaji Sainna, George Paasi, and Oluwakemi Ogundipe
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Severe Malnutrition ,Gastroenteritis ,African Children ,Intravenous fluids ,WHO guidelines ,Dehydration ,eng ,Medicine ,Science - Abstract
Background Children hospitalised with severe acute malnutrition (SAM) are frequently complicated (>50%) by diarrhoea ( ≥3 watery stools/day) which is accompanied by poor outcomes. Rehydration guidelines for SAM are exceptionally conservative and controversial, based upon expert opinion. The guidelines only permit use of intravenous fluids for cases with advanced shock and exclusive use of low sodium intravenous and oral rehydration solutions (ORS) for fear of fluid and/or sodium overload. Children managed in accordance to these guidelines have a very high mortality. The proposed GASTROSAM trial will reappraise current recommendations with mortality as the primary outcome. We hypothesize that liberal rehydration strategies for both intravenous and oral rehydration in SAM children with diarrhoea may reduce adverse outcomes. Methods An open Phase II trial, with a partial factorial design, enrolling children in Uganda, Kenya, Nigeria and Niger aged 6 months to 12 years with SAM hospitalised with gastroenteritis (>3 loose stools/day) and signs of moderate and severe dehydration. In Stratum A (severe dehydration) children will be randomised (1:1:2) to WHO plan C (100mls/kg Ringers Lactate (RL) with intravenous rehydration (IV) given over 3-6 hours according to age including boluses for shock), slow rehydration (100 mls/kg RL over 8 hours (no boluses)) or WHO SAM rehydration regime (ORS only (boluses for shock (standard of care)). Stratum B incorporates all children with moderate dehydration and severe dehydration post-intravenous rehydration and compares (1:1 ratio) standard WHO ORS given for non-SAM (experimental) versus WHO SAM-recommended low-sodium ReSoMal. The primary outcome for intravenous rehydration is mortality to 96 hours and for oral rehydration a change in sodium levels at 24 hours post-randomisation. Secondary outcomes include measures assessing safety (evidence of pulmonary oedema or heart failure); change in sodium from post-iv levels for those in Stratum A; perturbations of electrolyte abnormalities (severe hyponatraemia
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- 2024
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6. Where do those data go? Reuse of screening results from clinical trials to estimate population prevalence of HBV infection in adults in Kilifi, Kenya
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Louise O. Downs, Cori Campbell, Michael Abouyannis, Mark Otiende, Melissa Kapulu, Christina W. Obiero, Mainga Hamaluba, Caroline Ngetsa, Monique I. Andersson, George Githinji, George Warimwe, Kathy Baisley, J. Anthony G. Scott, Philippa C. Matthews, and Anthony Etyang
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Chronic hepatitis B ,Clinical trials ,Seroprevalence ,Elimination goals ,Clinical care ,Microbiology ,QR1-502 ,Public aspects of medicine ,RA1-1270 - Abstract
Chronic hepatitis B infection (CHB) is a significant problem worldwide with around 300 million people infected. Ambitious goals have been set towards its elimination as a public health threat by 2030. However, accurate seroprevalence estimates in many countries are lacking or fail to provide representative population estimates, particularly in the WHO African Region (AFRO). This means the full extent of HBV infection is not well described, leading to a lack of investment in diagnostics, treatment and disease prevention. Clinical trials in the WHO AFRO region have been increasing over time and many test for infectious diseases including hepatitis B virus (HBV) to determine baseline eligibility for participants, however these screening data are not reported. Here we review data from six clinical trials completed at the KEMRI-Wellcome Trust Research Programme between 2016 and 2023 that screened for HBV using hepatitis B surface antigen (HBsAg) as part of the trial exclusion criteria. 1727 people had HBsAg results available, of which 60 tested positive. We generated a crude period HBV prevalence estimate of 3.5% (95% CI 2.6–4.5%), and after standardisation for sex and age to account for the population structure of the Kilifi Health Demographics Surveillance System (KHDSS), the prevalence estimate increased to 5.0% (95% CI 3.4–6.6%). The underrepresentation of women in these trials was striking with 1263/1641 (77%) of participants being male. Alanine aminotransferase (ALT) was significantly higher in the HBsAg positive group but was not outside the normal range. We argue that routine collation and publishing of data from clinical trials could increase precision and geographical representation of global HBV prevalence estimates, enabling evidence-based provision of clinical care pathways and public health interventions to support progress towards global elimination targets. We do acknowledge when using clinical trials data for seroprevalence estimates, that local population structure data is necessary to allow standardisation of results, and the point of care tests used here are limited in sensitivity and specificity.
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- 2023
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7. Safety and immunogenicity of ChAdOx1 nCoV-19 (AZD1222) vaccine in adults in Kenya: a phase 1/2 single-blind, randomised controlled trial [version 2; peer review: 2 approved]
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Mainga Hamaluba, Cynthia Mauncho, Neema Mturi, Henry Karanja, Daisy Mugo, James Nyagwange, Caroline Ngetsa, Bernadette Kutima, Samuel Sang, John N. Gitonga, Benjamin Tsofa, Philip Bejon, Naomi Kamau, George Warimwe, Benedict Orindi, Irene Njau, Mwaganyuma Mwatasa, Lynette Ochola-Oyier, Donwilliams Omuoyo, Elizaphan Oloo, Stanley Cheruiyot, Eunice W. Nduati, Roselyne Namayi, Anthony Etyang, Nadia Aliyan, Adrian Hill, Amy Boyd, Marianne Munene, Alexander Douglas, Amek Nyaguara, Sarah Gilbert, Daniel Wright, Teresa Lambe, Charles Agoti, Kadondi Kasera, Alun Davies, Andrew Pollard, and Noni Mumba
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COVID-19 ,vaccine ,ChAdOx1-nCoV-19 ,Kenya ,eng ,Medicine ,Science - Abstract
Background There are limited data on the immunogenicity of coronavirus disease 2019 (COVID-19) vaccines in African populations. Here we report the immunogenicity and safety of the ChAdOx1 nCoV-19 (AZD1222) vaccine from a phase 1/2 single-blind, randomised, controlled trial among adults in Kenya conducted as part of the early studies assessing vaccine performance in different geographical settings to inform Emergency Use Authorisation. Methods We recruited and randomly assigned (1:1) 400 healthy adults aged ≥18 years in Kenya to receive ChAdOx1 nCoV-19 or control rabies vaccine, each as a two-dose schedule with a 3-month interval. The co-primary outcomes were safety, and immunogenicity assessed using total IgG enzyme-linked immunosorbent assay (ELISA) against SARS-CoV-2 spike protein 28 days after the second vaccination. Results Between 28th October 2020 and 19th August 2021, 400 participants were enrolled and assigned to receive ChAdOx1 nCoV-19 (n=200) or rabies vaccine (n=200). Local and systemic adverse events were self-limiting and mild or moderate in nature. Three serious adverse events were reported but these were deemed unrelated to vaccination. The geometric mean anti-spike IgG titres 28 days after second dose vaccination were higher in the ChAdOx1 group (2773 ELISA units [EU], 95% CI 2447, 3142) than in the rabies vaccine group (61 EU, 95% CI 45, 81) and persisted over the 12 months follow-up. We did not identify any symptomatic infections or hospital admissions with respiratory illness and so vaccine efficacy against clinically apparent infection could not be measured. Vaccine efficacy against asymptomatic SARS-CoV-2 infection was 38.4% (95% CI -26.8%, 70.1%; p=0.188). Conclusions The safety, immunogenicity and efficacy against asymptomatic infection of ChAdOx1 nCoV-19 among Kenyan adults was similar to that observed elsewhere in the world, but efficacy against symptomatic infection or severe disease could not be measured in this cohort. Pan-African Clinical Trials Registration PACTR202005681895696 (11/05/2020)
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- 2023
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8. SEVUparin as a potential Adjunctive Treatment in children with severe malaria: A phase I trial safety and dose finding trial (SEVUSMAART) [version 1; peer review: 1 approved, 2 approved with reservations]
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Mainga Hamaluba, Thomas N. Williams, Christabel Mogoka, Luc Kambale Kamavu, Mike Chaponda, Sam Miti, Nick White, Nick Day, Nchafatso Obonyo, Diana M. Gibb, Elizabeth C. George, Arjen Dondorp, Kathryn Maitland, Roisin Connon, A. Sarah Walker, and Emmanuel Oguda
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severe malaria ,adjunctive therapy ,children ,Africa ,clinical trial ,heparin-like molecule ,eng ,Medicine ,Science - Abstract
Background Even on the best antimalarial treatments (injectable artesunate) African children with severe malaria have poor outcomes with most deaths occurring early in the course of hospital admission ( 2mmol/l). Three intravenous doses will be given at admission (0 hours), 8 and 16 hours. APPT will be measured 1 hour after each dose (to assess maximum toxicity). Studying 20 children will allow sufficient data on safety to be generated across a range of doses to identify the maximum tolerated dose (MTD) using the Continual Reassessment Method, which adapts or informs subsequent doses for each child based on the data from previously enrolled children. The MTD will be identified based on the dose-toxicity model updated by each previous patient’s APTT results using standard methods. Conclusions The results of the Phase I trial will identify the final dose to be tested in a Phase II trial in terms of both efficacy and safety outcomes. Registration PACTR number: 202007890194806 (date 20/07/2020) ISRCTN32271864 (date 28/07/2021)
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- 2023
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9. Safety and immunogenicity of varied doses of R21/Matrix-M™ vaccine at three years follow-up: A phase 1b age de-escalation, dose-escalation trial in adults, children, and infants in Kilifi-Kenya [version 1; peer review: 2 approved]
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Omar Ngoto, Mainga Hamaluba, Emmaloise Gathuri, Sam Provstgaard-Morys, Janet Musembi, Jeremy Aboagye, Lisa Stockdale, Racheal Roberts, Daniel Woods, Francis Ndungu, Kelvias Keter, Adrian V.S. Hill, Katie J. Ewer, Alison Lawrie, Samuel Sang, Philip Bejon, Irene Njau, Benedict Orindi, Melissa Kapulu, Edward Otieno, Mehreen S. Datoo, Duncan Bellamy, Charles Muiruri, and Domtila Kimani
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R21 ,Matrix-M™ ,Adults ,children ,infants ,Kenya ,eng ,Medicine ,Science - Abstract
Background: Falciparum malaria remains a global health problem. Two vaccines, based on the circumsporozoite antigen, are available. RTS, S/AS01 was recommended for use in 2021 following the advice of the World Health Organisation (WHO) Strategic Advisory Group of Experts (SAGE) on Immunization and WHO Malaria Policy Advisory Group (MPAG). It has since been pre-qualified in 2022 by the WHO. R21 is similar to RTS, S/AS01, and recently licensed in Nigeria, Ghana and Burkina Faso following Phase 3 trial results. Methods: We conducted a Phase 1b age de-escalation, dose escalation bridging study after a change in the manufacturing process for R21. We recruited healthy adults and children and used a three dose primary vaccination series with a booster dose at 1–2 years. Variable doses of R21 and adjuvant (Matrix-M ™) were administered at 10µgR21/50 µg Matrix-M™, 5µgR21/25µg Matrix-M™ and 5µgR21/50µg Matrix-M™ to 20 adults, 20 children, and 51 infants. Results: Self-limiting adverse events were reported relating to the injection site and mild systemic symptoms. Two serious adverse events were reported, neither linked to vaccination. High levels of IgG antibodies to the circumsporozoite antigen were induced, and geometric mean titres in infants, the target group, were 1.1 (0.9 to 1.3) EU/mL at day 0, 10175 (7724 to 13404) EU/mL at day 84 and (following a booster dose at day 421) 6792 (5310 to 8687) EU/mL at day 456. Conclusions: R21/Matrix-M™ is safe, and immunogenic when given at varied doses with the peak immune response seen in infants 28 days after a three dose primary vaccination series given four weeks apart. Antibody responses were restored 28 days after a 4th dose given one year post a three dose primary series in the young children and infants. Registration: Clinicaltrials.gov (NCT03580824; 9th of July 2018; Pan African Clinical Trials Registry (PACTR202105682956280; 17th May 2021).
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- 2023
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10. Targeted amplicon deep sequencing of ama1 and mdr1 to track within-host P. falciparum diversity throughout treatment in a clinical drug trial [version 3; peer review: 2 approved, 2 approved with reservations]
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Mainga Hamaluba, Juliana Wambua, Arjen M. Dondorp, Jennifer Musyoki, Caroline Ngetsa, Oksana Kharabora, Leonard Ndwiga, Zaydah de Laurent, Kevin Wamae, Kelvin Kimenyi, Gabriel Mwambingu, Peter Kalume, Philip Bejon, Jeffrey Bailey, Rob van der Pluijm, Lynette Ochola-Oyier, Jonathan Juliano, and Victor Osoti
- Subjects
Artemisinin-based combination therapy ,pfama1 ,Pfmdr1 ,artemisinin resistance ,antimalarial resistance ,targeted deep sequencing ,eng ,Medicine ,Science - Abstract
Introduction Antimalarial therapeutic efficacy studies are routinely conducted in malaria-endemic countries to assess the effectiveness of antimalarial treatment strategies. Targeted amplicon sequencing (AmpSeq) uniquely identifies and quantifies genetically distinct parasites within an infection. In this study, AmpSeq of Plasmodium falciparum apical membrane antigen 1 (ama1), and multidrug resistance gene 1 (mdr1), were used to characterise the complexity of infection (COI) and drug-resistance genotypes, respectively. Methods P. falciparum-positive samples were obtained from a triple artemisinin combination therapy clinical trial conducted in 30 children under 13 years of age between 2018 and 2019 in Kilifi, Kenya. Nine of the 30 participants presented with recurrent parasitemia from day 26 (624h) onwards. The ama1 and mdr1 genes were amplified and sequenced, while msp1, msp2 and glurp data were obtained from the original clinical study. Results The COI was comparable between ama1 and msp1, msp2 and glurp; overall, ama1 detected more microhaplotypes. Based on ama1, a stable number of microhaplotypes were detected throughout treatment until day 3. Additionally, a recrudescent infection was identified with an ama1 microhaplotype initially observed at 30h and later in an unscheduled follow-up visit. Using the relative frequencies of ama1 microhaplotypes and parasitemia, we identified a fast (5h) clearing microhaplotype. As expected, only two mdr1 microhaplotypes (NF and NY) were identified based on the combination of amino acid polymorphisms at codons 86 and 184. Conclusions This study highlights AmpSeq as a tool for highly-resolution tracking of parasite microhaplotypes throughout treatment and can detect variation in microhaplotype clearance estimates. AmpSeq can also identify slow-clearing microhaplotypes, a potential early sign of selection during treatment. Consequently, AmpSeq has the capability of improving the discriminatory power to distinguish recrudescences from reinfections accurately.
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- 2023
- Full Text
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11. A long-term observational study of paediatric snakebite in Kilifi County, south-east Kenya.
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Michael Abouyannis, Mwanamvua Boga, David Amadi, Nelson Ouma, Amek Nyaguara, Neema Mturi, James A Berkley, Ifedayo M Adetifa, Nicholas R Casewell, David G Lalloo, and Mainga Hamaluba
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Arctic medicine. Tropical medicine ,RC955-962 ,Public aspects of medicine ,RA1-1270 - Abstract
IntroductionEstimates suggest that one-third of snakebite cases in sub-Saharan Africa affect children. Despite children being at a greater risk of disability and death, there are limited published data. This study has determined the: population-incidence and mortality rate of hospital-attended paediatric snakebite; clinical syndromes of snakebite envenoming; and predictors of severe local tissue damage.MethodsAll children presenting to Kilifi County Hospital, Kenya with snakebite were identified through the Kilifi Health and Demographic Surveillance System (KHDSS). Cases were prospectively registered, admitted for at least 24-hours, and managed on a paediatric high dependency unit (HDU). Households within the KHDSS study area have been included in 4-monthly surveillance and verbal autopsy, enabling calculation of population-incidence and mortality. Predictors of severe local tissue damage were identified using a multivariate logistic regression analysis.ResultsBetween 2003 and 2021, there were 19,606 admissions to the paediatric HDU, of which 584 were due to snakebite. Amongst young children (≤5-years age) the population-incidence of hospital-attended snakebite was 11.3/100,000 person-years; for children aged 6-12 years this was 29.1/100,000 person-years. Incidence remained consistent over the study period despite the population size increasing (98,967 person-years in 2006; and 153,453 person-years in 2021). Most cases had local envenoming alone, but there were five snakebite associated deaths. Low haemoglobin; raised white blood cell count; low serum sodium; high systolic blood pressure; and an upper limb bite-site were independently associated with the development of severe local tissue damage.ConclusionThere is a substantial burden of disease due to paediatric snakebite, and the annual number of cases has increased in-line with population growth. The mortality rate was low, which may reflect the species causing snakebite in this region. The identification of independent predictors of severe local tissue damage can help to inform future research to better understand the pathophysiology of this important complication.
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- 2023
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12. Phagocytosis of Plasmodium falciparum ring-stage parasites predicts protection against malaria
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Fauzia K. Musasia, Irene N. Nkumama, Roland Frank, Victor Kipkemboi, Martin Schneider, Kennedy Mwai, Dennis O. Odera, Micha Rosenkranz, Kristin Fürle, Domitila Kimani, James Tuju, Patricia Njuguna, Mainga Hamaluba, Melissa C. Kapulu, Hedda Wardemann, CHMI-SIKA Study Team, and Faith H. A. Osier
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Science - Abstract
Here the authors show that antibody-dependent phagocytosis of ring-stage P. falciparum parasites is mediated by merozoite antigens and is a strong predictor of protection following challenge in a controlled human malaria infection study in semi-immune Kenyan adults.
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- 2022
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13. Controlled human malaria infection (CHMI) outcomes in Kenyan adults is associated with prior history of malaria exposure and anti-schizont antibody response
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Melissa C. Kapulu, Domtila Kimani, Patricia Njuguna, Mainga Hamaluba, Edward Otieno, Rinter Kimathi, James Tuju, B. Kim Lee Sim, and CHMI-SIKA Study Team
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Malaria exposure ,Controlled human malaria infection ,Plasmodium falciparum ,Anti-schizont antibody response ,Infectious and parasitic diseases ,RC109-216 - Abstract
Abstract 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
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- 2022
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14. Targeted amplicon deep sequencing of ama1 and mdr1 to track within-host P. falciparum diversity throughout treatment in a clinical drug trial [version 2; peer review: 2 approved, 1 approved with reservations]
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Mainga Hamaluba, Juliana Wambua, Arjen M. Dondorp, Jennifer Musyoki, Caroline Ngetsa, Oksana Kharabora, Leonard Ndwiga, Zaydah de Laurent, Kevin Wamae, Kelvin Kimenyi, Gabriel Mwambingu, Peter Kalume, Philip Bejon, Jeffrey Bailey, Rob van der Pluijm, Lynette Ochola-Oyier, Jonathan Juliano, and Victor Osoti
- Subjects
Artemisinin-based combination therapy ,pfama1 ,Pfmdr1 ,artemisinin resistance ,antimalarial resistance ,targeted deep sequencing ,eng ,Medicine ,Science - Abstract
Introduction: Antimalarial therapeutic efficacy studies are routinely conducted in malaria-endemic countries to assess the effectiveness of antimalarial treatment strategies. Targeted amplicon sequencing (AmpSeq) uniquely identifies and quantifies genetically distinct parasites within an infection. In this study, AmpSeq of Plasmodium falciparum apical membrane antigen 1 (ama1), and multidrug resistance gene 1 (mdr1), were used to characterise the complexity of infection (COI) and drug-resistance genotypes, respectively. Methods: P. falciparum-positive samples were obtained from a triple artemisinin combination therapy clinical trial conducted in 30 children under 13 years of age between 2018 and 2019 in Kilifi, Kenya. Nine of the 30 participants presented with recurrent parasitemia from day 26 (624h) onwards. The ama1 and mdr1 genes were amplified and sequenced, while msp1, msp2 and glurp data were obtained from the original clinical study. Results: The COI was comparable between ama1 and msp1, msp2 and glurp; overall, ama1 detected more microhaplotypes. Based on ama1, a stable number of microhaplotypes were detected throughout treatment until day 3. Additionally, a recrudescent infection was identified with an ama1 microhaplotype initially observed at 30h and later in an unscheduled follow-up visit. Using the relative frequencies of ama1 microhaplotypes and parasitemia, we identified a fast (5h) clearing microhaplotype. As expected, only two mdr1 microhaplotypes (NF and NY) were identified based on the combination of amino acid polymorphisms at codons 86 and 184. Conclusions: This study highlights AmpSeq as a tool for highly-resolution tracking of parasite microhaplotypes throughout treatment and can detect variation in microhaplotype clearance estimates. AmpSeq can also identify slow-clearing microhaplotypes, a potential early sign of selection during treatment. Consequently, AmpSeq has the capability of improving the discriminatory power to distinguish recrudescences from reinfections accurately.
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- 2022
- Full Text
- View/download PDF
15. Undertaking Community Engagement for a Controlled Human Malaria Infection Study in Kenya: Approaches and Lessons Learnt
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Noni Mumba, Patricia Njuguna, Primus Chi, Vicki Marsh, Esther Awuor, Mainga Hamaluba, Cynthia Mauncho, Salim Mwalukore, Johnson Masha, Mary Mwangoma, Betty Kalama, Hassan Alphan, Juliana Wambua, Philip Bejon, Dorcas Kamuya, and Melissa C. Kapulu
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community engagement approaches ,human infection studies ,malaria ,stakeholder identification ,challenges and lessons ,Public aspects of medicine ,RA1-1270 - Abstract
Human infection studies (HIS) involve deliberately infecting healthy volunteers with disease-causing pathogens under controlled conditions. These studies are “controlled” by way of using specific types of pathogens, including dose, and the availability of emergency medical facilities to research volunteers. Most HIS involve diseases whose treatment is known and are done to accelerate the development of novel therapeutics such as vaccines, to address emerging and existing infectious diseases. Traditionally, HIS have been conducted primarily in high-income countries (HICs) but are now increasingly being conducted in low-and-middle income countries (LMICs). In LMICs settings, HIS are likely to raise concerns among various stakeholders including participating populations and regulatory bodies, that are unfamiliar with this type of research. Deliberately infecting a healthy individual with a disease-causing pathogen seems to go against the normal practice of medicine of “do no harm”. Such types of studies can give rise to increased rumors and jeopardize research participation in study activities, including non-HIS research. Community engagement can be one approach to address particular issues that HIS studies raise through meaningfully engaging with communities, where views and voices inform the conduct of HIS studies. In addition, engagement can inform the ethical conduct and acceptability of HIS studies in LMICs settings and provide opportunities for sharing information, listening to, and responding to concerns and views from potential participants, and the larger community in which the study would be conducted. Despite community engagement being an important aspect to consider, very few published and gray literature cover the types of approaches that have been used, and lessons learnt in engagement for HIS. This article outlinesthe community engagement approaches that were used to engage stakeholders and communities for malaria HIS-controlled human malaria infection (CHMI), undertaken in Kilifi, Kenya. It outlines the engagement activities across the research cycle, from activities conducted during protocol development, to planning, and implementation of the study. We discuss the challenges experienced, lessons learnt, and provide some recommendations for engagement around HIS.
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- 2022
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16. TRUE-1: Trial of Repurposed Unithiol for snakebite Envenoming phase 1 (safety, tolerability, pharmacokinetics and pharmacodynamics in healthy Kenyan adults) [version 1; peer review: 3 approved]
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Mainga Hamaluba, Debra Riako, Betty Kalama, Francis M. Ndungu, Hope Mwangudzah, Saye Khoo, David G. Lalloo, Lawrence Babu, Richard FitzGerald, Michael Abouyannis, Benedict Orindi, Samson Ngome, Mwanajuma Ngama, Yvonne K. Nyambura, Laura Else, Frida Lewa, Noni Mumba, Ifedayo Adetifa, Sujan Dily Penchala, and Nicholas R. Casewell
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Snakebite ,envenoming ,small molecule ,chelator ,phase I ,adaptive ,eng ,Medicine ,Science - Abstract
Background: Snakebites affect over 5 million people each year, and over 100,000 per year die as a result. The only available treatment is antivenom, which has many shortcomings including high cost, intravenous administration, and high risk of adverse events. One of the most abundant and harmful components of viper venoms are the zinc-dependent snake venom metalloproteinases (SVMPs). Unithiol is a chelating agent which is routinely used to treat heavy metal poisoning. In vivo experiments in small animal models have demonstrated that unithiol can prevent local tissue damage and death caused by a certain viper species. This phase I clinical trial will assess the safety of ascending doses of unithiol with a view for repurposing for snakebite indication. Methods: This open label, single agent, phase I clinical trial of a repurposed drug has a primary objective to evaluate the safety of escalating doses of unithiol, and a secondary objective to describe its pharmacokinetics. In total, 64 healthy Kenyan volunteers from Kilifi County will be dosed in consecutive groups of eight, with dose escalation decisions dependent on review of safety data by an independent data safety monitoring board. Four groups will receive ascending single oral doses, two will receive multiple oral doses, and two will receive single intravenous doses. Follow-up will be for 6-months and includes full adverse event reporting. Pharmacokinetic analysis will define the Cmax, Tmax, half-life and renal elimination. Conclusions: This clinical trial will assess the safety and tolerability of a promising oral therapeutic in a relevant setting where snakebites are prevalent. Unithiol is likely to be safer than antivenom, is easier to manufacture, has activity against diverse snake species, and can be administered orally, and thus shows promise for repurposing for tropical snakebite. Pan African Clinical Trials Registry: PACTR202103718625048 (3/3/2021)
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- 2022
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17. Children’s Oxygen Administration Strategies And Nutrition Trial (COAST-Nutrition): a protocol for a phase II randomised controlled trial [version 2; peer review: 2 approved]
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Sarah Kiguli, Peter Olopot-Olupot, Florence Alaroker, Charles Engoru, Robert O. Opoka, Abner Tagoola, Mainga Hamaluba, Hellen Mnjalla, Ayub Mpoya, Christabel Mogaka, Damalie Nalwanga, Eva Nabawanuka, James Nokes, Charles Nyaigoti, André Briend, Job B. M. van Woensel, Richard Grieve, Zia Sadique, Thomas N. Williams, Karen Thomas, David A. Harrison, Kathryn Rowan, and Kathryn Maitland
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Medicine ,Science - Abstract
Background: To prevent poor long-term outcomes (deaths and readmissions) the integrated global action plan for pneumonia and diarrhoea recommends under the ‘Treat’ element of Protect, Prevent and Treat interventions the importance of continued feeding but gives no specific recommendations for nutritional support. Early nutritional support has been practiced in a wide variety of critically ill patients to provide vital cell substrates, antioxidants, vitamins, and minerals essential for normal cell function and decreasing hypermetabolism. We hypothesise that the excess post-discharge mortality associated with pneumonia may relate to the catabolic response and muscle wasting induced by severe infection and inadequacy of the diet to aid recovery. We suggest that providing additional energy-rich, protein, fat and micronutrient ready-to-use therapeutic feeds (RUTF) to help meet additional nutritional requirements may improve outcome. Methods: COAST-Nutrition is an open, multicentre, Phase II randomised controlled trial in children aged 6 months to 12 years hospitalised with suspected severe pneumonia (and hypoxaemia, SpO2
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- 2021
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18. Safety and PCR monitoring in 161 semi-immune Kenyan adults following controlled human malaria infection
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Melissa C. Kapulu, Patricia Njuguna, Mainga Hamaluba, Domtila Kimani, Joyce M. Ngoi, Janet Musembi, Omar Ngoto, Edward Otieno, Peter F. Billingsley, and the Controlled Human Malaria Infection in Semi-Immune Kenyan Adults (CHMI-SIKA) Study Team
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Clinical trials ,Infectious disease ,Medicine - Abstract
BACKGROUND Naturally acquired immunity to malaria is incompletely understood. We used controlled human malaria infection (CHMI) to study the impact of past exposure on malaria in Kenyan adults in relation to infection with a non-Kenyan parasite strain.METHODS We administered 3.2 × 103 aseptic, purified, cryopreserved Plasmodium falciparum sporozoites (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 parasitemia reached 500 or more parasites per μL blood, clinically important symptoms were seen, or at 21 days after inoculation. All volunteers received antimalarial drug treatment upon meeting the endpoint.RESULTS One hundred and sixty-one volunteers underwent CHMI between August 4, 2016, and February 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 or more parasites per μL and were treated; 53 (37.3%) had parasitemia without meeting thresholds for treatment; and 33 (23.2%) remained qPCR negative.CONCLUSION We found 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.TRIAL REGISTRATION ClinicalTrials.gov NCT02739763.FUNDING Wellcome Trust.
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- 2021
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19. Clinical outcomes and outcome measurement tools reported in randomised controlled trials of treatment for snakebite envenoming: A systematic review.
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Michael Abouyannis, Dinesh Aggarwal, David G Lalloo, Nicholas R Casewell, Mainga Hamaluba, and Hanif Esmail
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Arctic medicine. Tropical medicine ,RC955-962 ,Public aspects of medicine ,RA1-1270 - Abstract
BackgroundSnakebite is a priority neglected tropical disease and causes a range of complications that vary depending on the snake species. Randomised clinical trials have used varied outcome measures that do not allow results to be compared or combined. In accordance with the Core Outcomes Measurements in Effectiveness Trials (COMET) initiative, this systematic review aims to support the development of a globally relevant core outcome set for snakebite.MethodsAll randomised controlled trials, secondary analyses of randomised controlled trials and study protocols investigating the efficacy of therapeutics for human snakebite envenoming were eligible for inclusion. Study screening and data extraction were conducted in duplicate by two independent reviewers. All primary and secondary outcome measures were extracted and compiled, as were adverse event outcome measures. Similar outcome measures were grouped into domains. The study was prospectively registered with PROSPERO: CRD42020196160.ResultsThis systematic review included 43 randomised controlled trials, two secondary analyses and 13 study protocols. A total of 382 outcome measures were extracted and, after duplicates were merged, there were 153 unique outcomes. The most frequently used outcome domain ('venom antigenaemia') was included in less than one third of the studies. The unique outcomes were classified into 60 outcome domains. Patient-centred outcomes were used in only three of the studies.DiscussionSignificant heterogeneity in outcome measures exists in snakebite clinical trials. Consensus is needed to select outcome measures that are valid, reliable, patient-centred and feasible. The results of this systematic review strongly support the development of a core outcome set for use in snakebite clinical trials.
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- 2021
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20. Gastroenteritis Rehydration Of children with Severe Acute Malnutrition (GASTROSAM): A Phase II Randomised Controlled trial: Trial Protocol [version 1; peer review: 2 approved]
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Peter Olupot-Olupot, Florence Aloroker, Ayub Mpoya, Hellen Mnjalla, George Passi, Margaret Nakuya, Kirsty Houston, Nchafatso Obonyo, Mainga Hamaluba, Jennifer A Evans, Roisin Connon, Elizabeth C George, Diana M Gibb, and Kathryn Maitland
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Medicine ,Science - Abstract
Background: Children hospitalised with severe acute malnutrition (SAM) are frequently complicated (>50%) by diarrhoea (≥3 watery stools/day) which is accompanied by poor outcomes. Rehydration guidelines for SAM are exceptionally conservative and controversial, based upon expert opinion. The guidelines only permit use of intravenous fluids for cases with advanced shock and exclusive use of low sodium intravenous and oral rehydration solutions (ORS) for fear of fluid and/or sodium overload. Children managed in accordance to these guidelines have a very high mortality. The proposed GASTROSAM trial is the first step in reappraising current recommendations. We hypothesize that liberal rehydration strategies for both intravenous and oral rehydration in SAM children with diarrhoea may reduce adverse outcomes. Methods An open Phase II trial, with a partial factorial design, enrolling Ugandan and Kenyan children aged 6 months to 12 years with SAM hospitalised with gastroenteritis (>3 loose stools/day) and signs of moderate and severe dehydration. In Stratum A (severe dehydration) children will be randomised (1:1:2) to WHO plan C (100mls/kg Ringers Lactate (RL) with intravenous rehydration given over 3-6 hours according to age including boluses for shock), slow rehydration (100 mls/kg RL over 8 hours (no boluses)) or WHO SAM rehydration regime (ORS only (boluses for shock (standard of care)). Stratum B incorporates all children with moderate dehydration and severe dehydration post-intravenous rehydration and compares (1:1 ratio) standard WHO ORS given for non-SAM (experimental) versus WHO SAM-recommended low-sodium ReSoMal. The primary outcome for intravenous rehydration is urine output (mls/kg/hour at 8 hours post-randomisation), and for oral rehydration a change in sodium levels at 24 hours post-randomisation. This trial will also generate feasibility, safety and preliminary data on survival to 28 days. Discussion. If current rehydration strategies for non-malnourished children are safe in SAM this could prompt future evaluation in Phase III trials.
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- 2021
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21. Observational study: 27 years of severe malaria surveillance in Kilifi, Kenya
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Patricia Njuguna, Kathryn Maitland, Amek Nyaguara, Daniel Mwanga, Polycarp Mogeni, Neema Mturi, Shebe Mohammed, Gabriel Mwambingu, Caroline Ngetsa, Kenedy Awuondo, Brett Lowe, Ifedayo Adetifa, J. Anthony G. Scott, Thomas N. Williams, Sarah Atkinson, Faith Osier, Robert W. Snow, Kevin Marsh, Benjamin Tsofa, Norbert Peshu, Mainga Hamaluba, James A. Berkley, Charles R. J. Newton, John Fondo, Anisa Omar, and Philip Bejon
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Severe malaria ,Secular trend ,Mortality ,Africa ,Longitudinal surveillance ,Medicine - Abstract
Abstract 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.
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- 2019
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22. Assessing the Level and Determinants of COVID-19 Vaccine Confidence in Kenya
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Stacey Orangi, Jessie Pinchoff, Daniel Mwanga, Timothy Abuya, Mainga Hamaluba, George Warimwe, Karen Austrian, and Edwine Barasa
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COVID-19 ,vaccination ,vaccine hesitancy ,vaccine confidence ,vaccine hesitancy predictors ,Kenya ,Medicine - Abstract
The government of Kenya has launched a phased rollout of COVID-19 vaccination. A major barrier is vaccine hesitancy; the refusal or delay of accepting vaccination. This study evaluated the level and determinants of vaccine hesitancy in Kenya. We conducted a cross-sectional study administered through a phone-based survey in February 2021 in four counties of Kenya. Multilevel logistic regression was used to identify individual perceived risks and influences, context-specific factors and vaccine-specific issues associated with COVID-19 vaccine hesitancy. COVID-19 vaccine hesitancy in Kenya was high: 36.5%. Factors associated with vaccine hesitancy included: Rural regions, perceived difficulty in adhering to government regulations on COVID-19 prevention, no perceived COVID-19 infection risk, concerns regarding vaccine safety and effectiveness, and religious and cultural reasons. There is a need for the prioritization of interventions to address vaccine hesitancy and improve vaccine confidence as part of the vaccine roll-out plan. These messaging and/or interventions should be holistic to include the value of other public health measures, be focused and targeted to specific groups, raise awareness on the risks of COVID-19 and effectively communicate the benefits and risks of vaccines.
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- 2021
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23. Streptococcus pneumoniae carriage prevalence in Nepal: evaluation of a method for delayed transport of samples from remote regions and implications for vaccine implementation.
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Sarah Hanieh, Mainga Hamaluba, Dominic F Kelly, Jane A Metz, Kelly L Wyres, Roberta Fisher, Rahul Pradhan, Disuja Shakya, Lochan Shrestha, Amrita Shrestha, Anip Joshi, Jocelyn Habens, Bishnu D Maharjan, Stephen Thorson, Erik Bohler, Ly-Mee Yu, Sarah Kelly, Emma Plested, Tessa John, Anja M Werno, Neelam Adhikari, David R Murdoch, Angela B Brueggemann, and Andrew J Pollard
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Medicine ,Science - Abstract
Pneumococcal disease is a significant cause of morbidity and mortality in young children in Nepal, and currently available pneumococcal conjugate vaccines offer moderate coverage of invasive disease isolates.A prevalence study of children aged 1.5 to 24 months in urban and rural Nepal was conducted. In the urban group, nasopharyngeal swabs (NPS) were transported using silica desiccant packages (SDP) with delayed processing (2 weeks), or skim-milk-tryptone-glucose-glycerin (STGG) with immediate processing (within 8 hours). Pneumococcal nasopharyngeal carriage prevalence, serogroup/type distribution and isolate genotypes (as defined by multilocus sequence typing) were determined.1101 children were enrolled into the study: 574 in the urban group and 527 in the rural group. Overall carriage prevalence based on culture from specimens transported and stored in STGG was 58.7% (337/574), compared to 40.9% (235/574) in SDP. There was concordance of detection of pneumococcus in 67% of samples. Using the SDP method, pneumococcal carriage prevalence was higher in the rural population (69.2%; 364/526) compared to the urban population (40.9%; 235/574). Serogroup/type distribution varied with geographical location. Over half of the genotypes identified in both the urban and rural pneumococcal populations were novel.The combination of delayed culture and transport using SDP underestimates the prevalence of pneumococcal carriage; however, in remote areas, this method could still provide a useful estimate of carriage prevalence and serogroup/type distribution. Vaccine impact is unpredictable in a setting with novel genotypes and limited serotype coverage as described here. Consequently, continued surveillance of pneumococcal isolates from carriage and disease in Nepali children following the planned introduction of pneumococcal conjugate vaccines introduction will be essential.
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- 2014
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24. A global core outcome measurement set for snakebite clinical trials
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Michael Abouyannis, Hanif Esmail, Mainga Hamaluba, Mwanajuma Ngama, Hope Mwangudzah, Noni Mumba, Betty K Yeri, Salim Mwalukore, Hassan J Alphan, Dinesh Aggarwal, Gabriel Alcoba, Nick Cammack, Jean-Philippe Chippaux, Matthew E Coldiron, José M Gutiérrez, Abdulrazaq G Habib, Robert A Harrison, Geoffrey K Isbister, Eric J Lavonas, Diogo Martins, Isabela Ribeiro, James A Watson, David J Williams, Nicholas R Casewell, Sarah A Walker, David G Lalloo, A Sarah Walker, Chanaveerappa Bammigatti, Rebecca W Carter, Charles J Gerardo, H Janaka de Silva, Thomas Lamb, Matthew R Lewin, Wuelton Monteiro, Ymkje Stienstra, and Group, Snakebite Global Core Outcome Set Study
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General Medicine - Abstract
Snakebite clinical trials have often used heterogeneous outcome measures and there is an urgent need for standardisation. A globally representative group of key stakeholders came together to reach consensus on a globally relevant set of core outcome measurements. Outcome domains and outcome measurement instruments were identified through searching the literature and a systematic review of snakebite clinical trials. Outcome domains were shortlisted by use of a questionnaire and consensus was reached among stakeholders and the patient group through facilitated discussions and voting. Five universal core outcome measures should be included in all future snakebite clinical trials—mortality, WHO disability assessment scale, patient-specific functional scale, acute allergic reaction by Brown criteria, and serum sickness by formal criteria. Additional syndrome-specific core outcome measures should be used depending on the biting species. This core outcome measurement set provides global standardisation, supports the priorities of patients and clinicians, enables meta-analysis, and is appropriate for use in low-income and middle-income settings.
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- 2023
25. Immunogenicity and safety of fractional doses of 17D-213 yellow fever vaccine in HIV-infected people in Kenya (YEFE): a randomised, double-blind, non-inferiority substudy of a phase 4 trial
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Derick Kimathi, Aitana Juan-Giner, Benedict Orindi, Kyra H Grantz, Ndeye S Bob, Stanley Cheruiyot, Mainga Hamaluba, Naomi Kamau, Gamou Fall, Moussa Dia, Moses Mosobo, Felix Moki, Kenneth Kiogora, Oscar Chirro, Alexander Thiong'o, Jane Mwendwa, Andrew Guantai, Henry K Karanja, John Gitonga, Daisy Mugo, Kelly Ramko, Ousmane Faye, Eduard J Sanders, Rebecca F Grais, Philip Bejon, and George M Warimwe
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Infectious Diseases - Published
- 2023
26. Randomised controlled trial of oxygen therapy and high-flow nasal therapy in African children with pneumonia
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Kathryn Maitland, Florence Alaroker, Mainga Hamaluba, Charles Engoru, Abner Tagoola, H Mnjella, David A Harrison, John F. Fraser, Karen Thomas, Bandika, Sarah Kiguli, Thomas N. Williams, Peter Olupot-Olupot, William Okiror, E Oguda, Kathy Rowan, Robert O. Opoka, Ayub Mpoya, Eva Nabawanuka, Denis Aromut, Margeret Nakuya, group, COAST trial, Medical Research Council (MRC), DFID/MRC/Wellcome Trust, European and Developing Countries Clinical Trials Partnership, and Wellcome Trust
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medicine.medical_specialty ,Original ,medicine.medical_treatment ,INFANTS ,Critical Care and Intensive Care Medicine ,1117 Public Health and Health Services ,law.invention ,03 medical and health sciences ,0302 clinical medicine ,Critical Care Medicine ,Randomized controlled trial ,High-flow nasal therapy ,law ,General & Internal Medicine ,Oxygen therapy ,Anesthesiology ,Internal medicine ,medicine ,Clinical endpoint ,Humans ,Child ,Hypoxia ,Science & Technology ,business.industry ,MORTALITY ,AIR ,Mortality rate ,Uncertainty ,Oxygen Inhalation Therapy ,1103 Clinical Sciences ,030208 emergency & critical care medicine ,Pneumonia ,HYPOXEMIA ,Odds ratio ,COAST trial group ,medicine.disease ,Kenya ,Emergency & Critical Care Medicine ,respiratory tract diseases ,Oxygen ,Clinical trial ,030228 respiratory system ,African children ,business ,Life Sciences & Biomedicine - Abstract
Purpose The life-saving role of oxygen therapy in African children with severe pneumonia is not yet established. Methods The open-label fractional-factorial COAST trial randomised eligible Ugandan and Kenyan children aged > 28 days with severe pneumonia and severe hypoxaemia stratum (SpO2 3 h receipt of oxygen were excluded. The primary endpoint was 48 h mortality; secondary endpoints included mortality or neurocognitive sequelae at 28 days. Results The trial was stopped early after enrolling 1852/4200 children, including 388 in the severe hypoxaemia stratum (median 7 months; median SpO2 75%) randomised to HFNT (n = 194) or LFO (n = 194) and 1454 in the hypoxaemia stratum (median 9 months; median SpO2 88%) randomised to HFNT (n = 363) vs LFO (n = 364) vs permissive hypoxaemia (n = 727). Per-protocol 15% of patients in the permissive hypoxaemia group received oxygen (when SpO2
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- 2021
27. Is triple artemisinin-based combination therapy necessary for uncomplicated malaria?
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Rob W van der Pluijm, Thomas J Peto, Mainga Hamaluba, James J Callery, Rupam Tripura, Nicholas J White, Arjen M Dondorp, Intensive Care Medicine, and Amsterdam institute for Infection and Immunity
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Infectious Diseases ,Humans ,Artemisinins ,Malaria - Published
- 2022
28. Arterolane–piperaquine–mefloquine versus arterolane–piperaquine and artemether–lumefantrine in the treatment of uncomplicated Plasmodium falciparum malaria in Kenyan children: a single-centre, open-label, randomised, non-inferiority trial
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Patricia Njuguna, Peter Kalume, Mwanajuma Ngama, Gabriel Mwambingu, Arjen M. Dondorp, Neema Mturi, Nicholas P. J. Day, Mwanamvua Boga, Nicholas J. White, Mallika Imwong, Sónia Gonçalves, Joseph Weya, Brian Mutinda, Altaf A. Lal, Olivo Miotto, Juliana Wambua, Philip Bejon, Joel Tarning, Arshad Khuroo, Mainga Hamaluba, Mavuto Mukaka, Rob W. van der Pluijm, Mehul Dhorda, Naomi Waithira, Richard M. Hoglund, Walter R. J. Taylor, Caroline Ngetsa, and Intensive Care Medicine
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0301 basic medicine ,education.field_of_study ,medicine.medical_specialty ,Artemether/lumefantrine ,business.industry ,Mefloquine ,030231 tropical medicine ,030106 microbiology ,Population ,Articles ,Lumefantrine ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Infectious Diseases ,Tolerability ,chemistry ,Internal medicine ,Piperaquine ,Medicine ,Artemether ,Arterolane ,business ,education ,medicine.drug - Abstract
Summary Background Triple antimalarial combination therapies combine potent and rapidly cleared artemisinins or related synthetic ozonides, such as arterolane, with two, more slowly eliminated partner drugs to reduce the risk of resistance. We aimed to assess the safety, tolerability, and efficacy of arterolane–piperaquine–mefloquine versus arterolane–piperaquine and artemether–lumefantrine for the treatment of uncomplicated falciparum malaria in Kenyan children. Methods In this single-centre, open-label, randomised, non-inferiority trial done in Kilifi County Hospital, Kilifi, coastal Kenya, children with uncomplicated Plasmodium falciparum malaria were recruited. Eligible patients were aged 2–12 years and had an asexual parasitaemia of 5000–250 000 parasites per μL. The exclusion criteria included the presence of an acute illness other than malaria, the inability to tolerate oral medications, treatment with an artemisinin derivative in the previous 7 days, a known hypersensitivity or contraindication to any of the study drugs, and a QT interval corrected for heart rate (QTc interval) longer than 450 ms. Patients were randomly assigned (1:1:1), by use of blocks of six, nine, and 12, and opaque, sealed, and sequentially numbered envelopes, to receive either arterolane–piperaquine, arterolane–piperaquine–mefloquine, or artemether–lumefantrine. Laboratory staff, but not the patients, the patients' parents or caregivers, clinical or medical officers, nurses, or trial statistician, were masked to the intervention groups. For 3 days, oral artemether–lumefantrine was administered twice daily (target dose 5–24 mg/kg of bodyweight of artemether and 29–144 mg/kg of bodyweight of lumefantrine), and oral arterolane–piperaquine (arterolane dose 4 mg/kg of bodyweight; piperaquine dose 20 mg/kg of bodyweight) and oral arterolane–piperaquine–mefloquine (mefloquine dose 8 mg/kg of bodyweight) were administered once daily. All patients received 0·25 mg/kg of bodyweight of oral primaquine at hour 24. All patients were admitted to Kilifi County Hospital for at least 3 consecutive days and followed up at day 7 and, thereafter, weekly for up to 42 days. The primary endpoint was 42-day PCR-corrected efficacy, defined as the absence of treatment failure in the first 42 days post-treatment, of arterolane–piperaquine–mefloquine versus artemether–lumefantrine, and, along with safety, was analysed in the intention-to-treat population, which comprised all patients who received at least one dose of a study drug. The 42-day PCR-corrected efficacy of arterolane–piperaquine–mefloquine versus arterolane–piperaquine was an important secondary endpoint and was also analysed in the intention-to-treat population. The non-inferiority margin for the risk difference between treatments was −7%. The study is registered in ClinicalTrials.gov , NCT03452475 , and is completed. Findings Between March 7, 2018, and May 2, 2019, 533 children with P falciparum were screened, of whom 217 were randomly assigned to receive either arterolane–piperaquine (n=73), arterolane–piperaquine–mefloquine (n=72), or artemether–lumefantrine (n=72) and comprised the intention-to-treat population. The 42-day PCR-corrected efficacy after treatment with arterolane–piperaquine–mefloquine (100%, 95% CI 95–100; 72/72) was non-inferior to that after treatment with artemether–lumefantrine (96%, 95% CI 88–99; 69/72; risk difference 4%, 95% CI 0–9; p=0·25). The 42-day PCR-corrected efficacy of arterolane–piperaquine–mefloquine was non-inferior to that of arterolane–piperaquine (100%, 95% CI 95–100; 73/73; risk difference 0%). Vomiting rates in the first hour post-drug administration were significantly higher in patients treated with arterolane–piperaquine (5%, 95% CI 2–9; ten of 203 drug administrations; p=0·0013) or arterolane–piperaquine–mefloquine (5%, 3–9; 11 of 209 drug administrations; p=0·0006) than in patients treated with artemether–lumefantrine (1%, 0–2; three of 415 drug administrations). Upper respiratory tract complaints (n=26 for artemether–lumefantrine; n=19 for arterolane–piperaquine–mefloquine; n=23 for arterolane–piperaquine), headache (n=13; n=4; n=5), and abdominal pain (n=7; n=5; n=5) were the most frequently reported adverse events. There were no deaths. Interpretation This study shows that arterolane–piperaquine–mefloquine is an efficacious and safe treatment for uncomplicated falciparum malaria in children and could potentially be used to prevent or delay the emergence of antimalarial resistance. Funding UK Department for International Development, The Wellcome Trust, The Bill & Melinda Gates Foundation, Sun Pharmaceutical Industries
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- 2021
29. Breadth of Fc-Mediated Effector Function Delineates Grades of Clinical Immunity Following Human Malaria Challenge
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Irene Nkumama, Dennis Odero, Fauzia Musasia, Kennedy Mwai Wambui, Lydia Nyamako, Linda Murungi, James Tuju, Kristin Fürle, Micha Rosenkranz, Rinter Kimathi, Patricia Njuguna, Mainga Hamaluba, Melissa C. Kapulu, Roland Frank, CHMI-SIKA Study Team, and Faith Hope Among'in Osier
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History ,Polymers and Plastics ,Business and International Management ,Industrial and Manufacturing Engineering - Published
- 2022
30. Deliberately infecting healthy volunteers with malaria parasites: Perceptions and experiences of participants and other stakeholders in a Kenyan‐based malaria infection study
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Mainga Hamaluba, Philip Bejon, Irene Jao, Vicki Marsh, Sassy Molyneux, Dorcas Kamuya, Primus Che Chi, and Melissa C. Kapulu
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Health (social science) ,Context (language use) ,0603 philosophy, ethics and religion ,Special Issue: Ethics of Human Challenge Trials ,deliberate infection ,Nursing ,Informed consent ,medicine ,Cognitive dissonance ,Animals ,Humans ,Parasites ,Special Issue: Ethics of Controlled Human Infection Studies ,Community engagement ,Health Policy ,challenge studies ,developing countries ,06 humanities and the arts ,medicine.disease ,ethics ,Kenya ,Focus group ,Healthy Volunteers ,Malaria ,3. Good health ,Philosophy ,Incentive ,Africa ,Perception ,060301 applied ethics ,Psychology ,controlled human infection studies ,Qualitative research - Abstract
Controlled human malaria infection (CHMI) studies involve the deliberate infection of healthy volunteers with malaria parasites under controlled conditions to study immune responses and/or test drug or vaccine efficacy. An empirical ethics study was embedded in a CHMI study at a Kenyan research programme to explore stakeholders' perceptions and experiences of deliberate infection and moral implications of these. Data for this qualitative study were collected through focus group discussions, in-depth interviews and non-participant observation. Sixty-nine participants were involved, including CHMI study volunteers, community representatives and research staff. Data were managed using QSR Nvivo 10 and analysed using an inductive-deductive approach, guided by ethics literature. CHMI volunteers had reasonable understanding of the study procedures. Decisions to join were influenced by study incentives, trust in the research institution, their assessment of associated burdens and motivation to support malaria vaccine development. However, deliberate malaria infection was a highly unusual research strategy for volunteers, community representatives and some study staff. Volunteers' experiences of physical, emotional and social burdens or harms were often greater than anticipated initially, and fluctuated over time, related to specific procedures and events. Although unlikely to deter volunteers' participation in similar studies in furture, we argue that the dissonance between level of understanding of the burdens involved and actual experiences are morally relevant in relation to community engagement, informed consent processes, and ongoing support for volunteers and research staff. We further argue that ethics oversight of CHMI studies should take account of these issues in deciding whether consent, engagement and the balance of benefits and harms are reasonable in a given context.
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- 2020
31. Antibodies targeting merozoites induce natural killer cell degranulation and interferon gamma secretion and are associated with immunity against malaria
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Kennedy Mwai, Mainga Hamaluba, and Timothy Chege Kuria
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parasitic diseases - Abstract
Natural killer cells are potent immune effectors that can be activated via antibody mediated Fc receptor engagement. Using multiparameter flow cytometry, we found that natural killer (NK) cells degranulate and release IFNγ upon stimulation with antibody-opsonized Plasmodium falciparum merozoites. Antibody-dependent NK activity (Ab-NK) was largely strain-transcending and enhanced the inhibition of invasion into erythrocytes. Ab-NK was associated with the successful control of parasitemia following experimental malaria challenge in African adults. In an independent cohort study in children, Ab-NK increased with age, was boosted by concurrent falciparum infections and associated with a lower risk of clinical episodes of malaria. Nine of 14 vaccine candidates tested induced Ab-NK including some less well-studied antigens - P41, P113, MSP11, RHOPH3, and Pf_11363200. These data highlight an important role for ab-NK in immunity against malaria and provide a new mechanism for the evaluation of vaccine candidatesOne Sentence SummaryAntibody-dependent natural killer activation is induced by merozoites and associated with immunity against malaria
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- 2021
32. A pragmatic randomized controlled trial of standard care versus steroids plus standard care for treatment of pneumonia in adults admitted to Kenyan hospitals (SONIA)
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Ruth Lucinde, Abdirahman Abdi, Benedict Orindi, Stella Mwakio, Henry Gathuri, Edwin Onyango, Salome Chira, Morris Ogero, Lynda Isaaka, Jimmy Shangala, Irene Njeri Oginga, Alvin Wachira, Evans Manuthu, Hazel Kariuki, Jared Nyikuli, Cyprian Wekesa, Amos Otedo, Hannah Bosire, Steve Biko Okoth, Winston Ongalo, David Mukabi, Wilber Lusamba, Beatrice Muthui, Nicholas Kirui, Isaac Adembesa, Caroline Mithi, Mohammed Sood, Nadia Ahmed, Bernard Gituma, Vera Bina Ongaki, Matiko Giabe, Charles Omondi, Loice Achieng Ombajo, Wangeci Kagucia, Mike English, Mainga Hamaluba, Lynette Isabella Ochola-Oyier, Dorcas Kamuya, Philip Bejon, Ambrose Agweyu, Samuel Akech, and Anthony Oliwa Etyang
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Medicine (miscellaneous) ,General Biochemistry, Genetics and Molecular Biology - Abstract
Background: It is unclear if adjunctive steroid therapy reduces mortality in community-acquired pneumonia, as very few studies have had mortality as a primary outcome. This question has become even more relevant following demonstration of a mortality benefit of dexamethasone when used in patients with COVID-19 who had severe disease. This has led to increased prescription of steroids in adults with community acquired pneumonia in low-resource settings even when their COVID-19 diagnosis is uncertain due to low testing rates. This pragmatic parallel randomised-controlled open-label trial will determine if adjunctive low-dose steroids for treatment of adults admitted to hospital with community acquired pneumonia whose SARS-CoV-2 status is either unknown or negative reduces mortality. Methods: We will enroll and randomize 2180 patients admitted with a clinical diagnosis of community acquired pneumonia into two arms; in Stratum A-participants will receive standard care for the treatment of community acquired pneumonia. In Stratum B-participants will receive a 10-day course of low-dose oral corticosteroids in addition to standard care. All participants will be followed up to 30 days post randomization and their final status recorded (alive or dead). An immunology sub study will be conducted on a subset of the trial participants (50 per arm) to determine the correlation of pre-existing and treatment induced immune and metabolic changes with study outcomes. Discussion: Mortality among adults admitted to hospital with community acquired pneumonia in resource-limited settings is high. Steroids are readily available in these settings. If the addition of steroids to standard care for community acquired pneumonia is found to be beneficial, this easily scalable intervention would significantly reduce the currently high mortality associated with the illness.
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- 2022
33. Safety and PCR monitoring in 161 semi-immune Kenyan adults following controlled human malaria infection
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Peter F. Billingsley, Omar Ngoto, Mainga Hamaluba, Patricia Njuguna, Domtila Kimani, Edward Otieno, Janet Musembi, Joyce M. Ngoi, and Melissa C. Kapulu
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Adult ,Male ,medicine.medical_specialty ,030231 tropical medicine ,Plasmodium falciparum ,Adaptive Immunity ,Polymerase Chain Reaction ,03 medical and health sciences ,Minimum inhibitory concentration ,0302 clinical medicine ,Immune system ,Internal medicine ,parasitic diseases ,medicine ,Animals ,Humans ,Clinical Trials ,030212 general & internal medicine ,Malaria, Falciparum ,Adverse effect ,Aged ,Retrospective Studies ,Infectious disease ,biology ,business.industry ,Incidence ,General Medicine ,DNA, Protozoan ,Middle Aged ,medicine.disease ,biology.organism_classification ,Kenya ,3. Good health ,Malaria ,Clinical trial ,Real-time polymerase chain reaction ,Parasitology ,Female ,Clinical Medicine ,business ,Follow-Up Studies - Abstract
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.
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- 2021
34. Clinical outcomes and outcome measurement tools reported in randomised controlled trials of treatment for snakebite envenoming: A systematic review
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Nicholas R. Casewell, David G. Lalloo, Mainga Hamaluba, Michael Abouyannis, Hanif Esmail, Dinesh Aggarwal, Abouyannis, Michael [0000-0003-4856-4334], Aggarwal, Dinesh [0000-0002-5938-8172], Lalloo, David G [0000-0001-7680-2200], Hamaluba, Mainga [0000-0002-0266-1414], and Apollo - University of Cambridge Repository
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RC955-962 ,Snake Bites ,Cardiovascular Medicine ,Toxicology ,Pathology and Laboratory Medicine ,Outcome (game theory) ,Vascular Medicine ,law.invention ,0302 clinical medicine ,Medical Conditions ,Randomized controlled trial ,law ,Coagulopathy ,Arctic medicine. Tropical medicine ,Allergies ,Outcome Assessment, Health Care ,Medicine and Health Sciences ,Toxins ,030212 general & internal medicine ,Snakebite ,Randomized Controlled Trials as Topic ,Outcome measures ,Hematology ,w_20.5 ,Infectious Diseases ,Systematic review ,Treatment Outcome ,Data extraction ,Cardiovascular Diseases ,Research Design ,Public aspects of medicine ,RA1-1270 ,wd_410 ,Research Article ,Neglected Tropical Diseases ,medicine.medical_specialty ,Drug Research and Development ,Clinical Research Design ,030231 tropical medicine ,Immunology ,Toxic Agents ,MEDLINE ,Cardiology ,Hemorrhage ,Research and Analysis Methods ,03 medical and health sciences ,Signs and Symptoms ,medicine ,Animals ,Humans ,Clinical Trials ,Patient Reported Outcome Measures ,Intensive care medicine ,Adverse effect ,Blood Coagulation ,Anaphylaxis ,Pharmacology ,Coagulation Disorders ,business.industry ,Venoms ,Public Health, Environmental and Occupational Health ,Biology and Life Sciences ,Tropical Diseases ,Randomized Controlled Trials ,Clinical trial ,Clinical Immunology ,Adverse Events ,Clinical Medicine ,business - Abstract
Background Snakebite is a priority neglected tropical disease and causes a range of complications that vary depending on the snake species. Randomised clinical trials have used varied outcome measures that do not allow results to be compared or combined. In accordance with the Core Outcomes Measurements in Effectiveness Trials (COMET) initiative, this systematic review aims to support the development of a globally relevant core outcome set for snakebite. Methods All randomised controlled trials, secondary analyses of randomised controlled trials and study protocols investigating the efficacy of therapeutics for human snakebite envenoming were eligible for inclusion. Study screening and data extraction were conducted in duplicate by two independent reviewers. All primary and secondary outcome measures were extracted and compiled, as were adverse event outcome measures. Similar outcome measures were grouped into domains. The study was prospectively registered with PROSPERO: CRD42020196160. Results This systematic review included 43 randomised controlled trials, two secondary analyses and 13 study protocols. A total of 382 outcome measures were extracted and, after duplicates were merged, there were 153 unique outcomes. The most frequently used outcome domain (‘venom antigenaemia’) was included in less than one third of the studies. The unique outcomes were classified into 60 outcome domains. Patient-centred outcomes were used in only three of the studies. Discussion Significant heterogeneity in outcome measures exists in snakebite clinical trials. Consensus is needed to select outcome measures that are valid, reliable, patient-centred and feasible. The results of this systematic review strongly support the development of a core outcome set for use in snakebite clinical trials., Author summary Standardised outcome measures for snakebite randomised controlled trials are needed to enable results to be compared and combined between studies. This systematic review was conducted to understand the variations in outcome measure use in snakebite randomised controlled trials, and to create a comprehensive list of outcome measures from which to develop a core outcome set (COS). A total of 153 unique outcome measures were extracted from the 58 studies identified in this systematic review. Of these 153 unique outcome measures, 91 were used in only in a single study. Although a form of bedside whole blood clotting test was used in 30 of the 58 studies, 18 unique methods of measurement were identified. Only three studies, all conducted in the USA, included patient-centred outcomes. This systematic review demonstrates the strong need for a snakebite core outcome set, which will support the adoption of valid, reproducible, and patient-centred outcome measures, and enable downstream meta-analyses.
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- 2021
35. Gastroenteritis rehydration of children with severe acute malnutrition (GASTROSAM): a phase II randomised controlled trial: trial protocol
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Nchafatso G. Obonyo, Diana M. Gibb, Kathryn Maitland, Jennifer Evans, Mainga Hamaluba, Kirsty A. Houston, George Passi, Hellen Mnjalla, Elizabeth C. George, Roisin Connon, Florence Aloroker, Peter Olupot-Olupot, Ayub Mpoya, and Margaret Nakuya
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0301 basic medicine ,WHO guidelines ,Pediatrics ,medicine.medical_specialty ,viruses ,Severe Acute Malnutrition ,Trial protocol ,Medicine (miscellaneous) ,General Biochemistry, Genetics and Molecular Biology ,Severe dehydration ,law.invention ,03 medical and health sciences ,Study Protocol ,0302 clinical medicine ,Randomized controlled trial ,law ,Severe Malnutrition ,medicine ,030212 general & internal medicine ,Dehydration ,business.industry ,virus diseases ,Articles ,biochemical phenomena, metabolism, and nutrition ,Intravenous fluids ,Rehydration ,medicine.disease ,digestive system diseases ,Gastroenteritis ,030104 developmental biology ,Oral rehydration solutions ,Shock (circulatory) ,medicine.symptom ,business ,African Children ,Low sodium - Abstract
Background: Children hospitalised with severe acute malnutrition (SAM) are frequently complicated (>50%) by diarrhoea (≥3 watery stools/day) which is accompanied by poor outcomes. Rehydration guidelines for SAM are exceptionally conservative and controversial, based upon expert opinion. The guidelines only permit use of intravenous fluids for cases with advanced shock and exclusive use of low sodium intravenous and oral rehydration solutions (ORS) for fear of fluid and/or sodium overload. Children managed in accordance to these guidelines have a very high mortality. The proposed GASTROSAM trial is the first step in reappraising current recommendations. We hypothesize that liberal rehydration strategies for both intravenous and oral rehydration in SAM children with diarrhoea may reduce adverse outcomes. Methods An open Phase II trial, with a partial factorial design, enrolling Ugandan and Kenyan children aged 6 months to 12 years with SAM hospitalised with gastroenteritis (>3 loose stools/day) and signs of moderate and severe dehydration. In Stratum A (severe dehydration) children will be randomised (1:1:2) to WHO plan C (100mls/kg Ringers Lactate (RL) with intravenous rehydration given over 3-6 hours according to age including boluses for shock), slow rehydration (100 mls/kg RL over 8 hours (no boluses)) or WHO SAM rehydration regime (ORS only (boluses for shock (standard of care)). Stratum B incorporates all children with moderate dehydration and severe dehydration post-intravenous rehydration and compares (1:1 ratio) standard WHO ORS given for non-SAM (experimental) versus WHO SAM-recommended low-sodium ReSoMal. The primary outcome for intravenous rehydration is urine output (mls/kg/hour at 8 hours post-randomisation), and for oral rehydration a change in sodium levels at 24 hours post-randomisation. This trial will also generate feasibility, safety and preliminary data on survival to 28 days. Discussion. If current rehydration strategies for non-malnourished children are safe in SAM this could prompt future evaluation in Phase III trials.
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- 2021
36. Assessing the level and determinants of COVID-19 Vaccine Confidence in Kenya
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Mainga Hamaluba, Jessie Pinchoff, George M. Warimwe, Stacey Orangi, Timothy Abuya, Daniel Mwanga, Karen Austrian, and Edwine Barasa
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Vaccine safety ,Vaccination ,Government ,medicine.medical_specialty ,Coronavirus disease 2019 (COVID-19) ,Phone ,business.industry ,Environmental health ,Public health ,Psychological intervention ,medicine ,Logistic regression ,business - Abstract
The government of Kenya has launched a phased rollout of COVID-19 vaccination. A major barrier is vaccine hesitancy; the refusal or delay of accepting vaccination. This study evaluated the level and determinants of vaccine hesitancy in Kenya. We conducted a cross-sectional study administered through a phone-based survey in February 2021 in four counties of Kenya. Multivariate logistic regression was used to identify individual perceived risks and influences, context-specific factors, and vaccine-specific issues associated with COVID-19 vaccine hesitancy. COVID-19 vaccine hesitancy in Kenya was high: 60.1%. Factors associated with vaccine hesitancy included: older age, lower education level, perceived difficulty in adhering to government regulations on COVID-19 prevention, less adherence to wearing of face masks, not having ever been tested for COVID-19, no reported socio-economic loss as a result of COVID public-health restriction measures, and concerns regarding vaccine safety and effectiveness. There is a need for the prioritization of interventions to address vaccine hesitancy and improve vaccine confidence as part of the vaccine roll-out plan. These messaging and/or interventions should be holistic to include the value of other public health measures, be focused and targeted to specific groups, raise awareness on the risks of COVID-19 and effectively communicate the benefits and risks of vaccines.
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- 2021
37. Incidence of chikungunya virus infections among Kenyan children with neurological disease: a prospective cohort study
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Samuel M. Thumbi, Barnes Kitsao, Mainga Hamaluba, Doris K. Nyamwaya, George Githinji, John N. Gitonga, Donwilliams O. Omuoyo, Henry K. Karanja, Symon M. Kariuki, Charles R. Newton, Charles N. Agoti, B Otieno, Salim Mwarumba, Philip Bejon, George M. Warimwe, Z R de Laurent, L Mwango, Mark Otiende, and A Davies
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Coma ,education.field_of_study ,Pediatrics ,medicine.medical_specialty ,business.industry ,Incidence (epidemiology) ,Public health ,Population ,virus diseases ,Disease ,medicine.disease_cause ,Cerebral Malaria ,Medicine ,Chikungunya ,medicine.symptom ,business ,education ,Prospective cohort study - Abstract
BackgroundNeurological complications due to chikungunya virus (CHIKV) infection have been described in different parts of the world, with children being disproportionately affected. However, the burden of CHIKV-associated neurological disease in Africa is currently unknown.MethodsWe estimated the incidence of CHIKV infection among children hospitalised with neurological disease in coastal Kenya. We used reverse-transcriptase polymerase chain reaction (RT-PCR) to systematically test for CHIKV in cerebrospinal fluid (CSF) samples from children aged FindingsThere were 18,341 paediatric admissions during the 5-year study period, of which 4,332 (24%) had CSF collected. The most common clinical reasons for CSF collection were impaired consciousness, seizures and coma (47%, 22% and 21% of all collections, respectively). After acute investigations done for immediate clinical care, CSF samples were available for 3,980 admissions, of which 367 (9.2%) were CHIKV RT-PCR positive. The annual incidence of CHIKV-associated neurological disease varied between 13 to 58 episodes per 100,000 person-years among all children InterpretationAlthough not previously recognized, CHIKV-associated neurological disease is common in coastal Kenya and a significant public health burden.
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- 2021
38. Complications and mortality of non-typhoidal salmonella invasive disease: a global systematic review and meta-analysis
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Christian S Marchello, Megan Birkhold, John A Crump, Laura B. Martin, Michael O. Ansah, Gianluca Breghi, Rocio Canals, Fabio Fiorino, Melita A. Gordon, Jong-Hoon Kim, Mainga Hamaluba, Brama Hanumunthadu, Jan Jacobs, Samuel Kariuki, Stefano Malvolti, Carsten Mantel, Florian Marks, Donata Medaglini, Vittal Mogasale, Chisomo L. Msefula, Esther Muthumbi, Tonney S. Niyrenda, Robert Onsare, Ellis Owusu-Dabo, Elena Pettini, Maheshi N. Ramasamy, Bassiahi A. Soura, Tiziana Spadafina, and Bieke Tack
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Science & Technology ,ANTIMICROBIAL RESISTANCE ,Asia ,CLINICAL-FEATURES ,INFANTS ,CHILDREN ,NONTYPHOID SALMONELLA ,Europe ,PROGNOSTIC-FACTORS ,Infectious Diseases ,Salmonella ,Africa ,COMMUNITY-ACQUIRED BACTEREMIA ,RISK-FACTORS ,Prevalence ,Humans ,ADULT PATIENTS ,BLOOD-STREAM INFECTIONS ,Life Sciences & Biomedicine - Abstract
BACKGROUND: Non-typhoidal salmonella can cause serious, life-threatening invasive infections involving the bloodstream and other normally sterile sites. We aimed to systematically review the prevalence of complications and case-fatality ratio (CFR) of non-typhoidal salmonella invasive disease to provide contemporary global estimates and inform the development of vaccine and non-vaccine interventions. METHODS: We did a global systematic review and meta-analysis of studies investigating the complications and mortality associated with non-typhoidal salmonella invasive disease. We searched Embase, MEDLINE, Web of Science, and PubMed for peer-reviewed, primary research articles published from database inception up to June 4, 2021, with no restrictions on language, country, date, or participant demographics. Only studies reporting the proportion of complications or deaths associated with non-typhoidal salmonella invasive disease, confirmed by culture of samples taken from a normally sterile site (eg, blood or bone marrow) were included. We excluded case reports, case series, policy reports, commentaries, editorials, and conference abstracts. Data on the prevalence of complications and CFR were abstracted. The primary outcomes were to estimate the prevalence of complications and CFR of non-typhoidal salmonella invasive disease. We calculated an overall pooled CFR estimate and pooled CFR stratified by UN region, subregion, age group, and by serovar when available with a random-effects meta-analysis. A risk-of-bias assessment was done, and heterogeneity was assessed with Cochran's Q Test, I2, and τ2. This study was done in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses, and is registered with PROSPERO, CRD42020202293. FINDINGS: The systematic review returned a total of 8770 records. After duplicates were removed, 5837 titles and abstracts were screened, yielding 84 studies from 35 countries after exclusions. Of these included studies, 77 (91·7%) were hospital-based and 66 (78·6%) were located in Africa or Asia. Among 55 studies reporting non-typhoidal salmonella disease-associated complications, a total of 45 different complications were reported and 1824 complication events were identified among 6974 study participants. The most prevalent complication was septicaemia, occurring in 171 (57·2%) of 299 participants, followed by anaemia in 580 (47·3%) of 1225 participants. From 81 studies reporting the CFR of non-typhoidal salmonella invasive disease, the overall pooled CFR estimate was 14·7% (95% CI 12·2-17·3). When stratified by UN region, the pooled CFR was 17·1% (13·6-21·0) in Africa, 14·0% (9·4-19·4) in Asia, 9·9% (6·4-14·0) in Europe, and 9·6% (0·0-25·1) in the Americas. Of all 84 studies, 66 (78·6%) had an overall high risk of bias, 18 (21·4%) had a moderate risk, and none had a low risk. Substantial heterogeneity (I2>80%) was observed in most (15 [65·2%] of 23) CFR estimates. INTERPRETATION: Complications were frequent among individuals with non-typhoidal salmonella invasive disease and approximately 15% of patients died. Clinicians, especially in African countries, should be aware of non-typhoidal salmonella invasive disease as a cause of severe febrile illness. Prompt diagnoses and management decisions, including empiric antimicrobial therapy, would improve patient outcomes. Additionally, investments in improving clinical microbiology facilities to identify non-typhoidal salmonella and research efforts towards vaccine development and non-vaccine prevention measures would prevent non-typhoidal salmonella invasive disease-associated illness and death. FUNDING: EU Horizon 2020 research and innovation programme. ispartof: LANCET INFECTIOUS DISEASES vol:22 issue:5 pages:692-705 ispartof: location:United States status: published
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- 2021
39. Referee report. For: Continuous research monitoring improves the quality of research conduct and compliance among research trainees: internal evaluation of a monitoring programme [version 1; peer review: 1 approved with reservations]
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Mainga Hamaluba, Munene, Marianne, and Kivaya, Esther
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- 2021
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40. Understanding the benefits and burdens associated with a malaria human infection study in Kenya: experiences of study volunteers and other stakeholders
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E A Owino, S C Murphy, Jennifer N. Musyoki, Philip Bejon, Z R de Laurent, Khadija Said Mohammed, L Murungi, P Billingsley, E James, M Winterberg, G Kamuyu, Johnstone Makale, J Oloo, Kevin Marsh, Melissa C. Kapulu, George Nyangweso, J Ongecha, S H Hodgson, Francis M. Ndungu, Juliana Wambua, Faith H. A. Osier, Donwilliams O. Omuoyo, Patricia Njuguna, N Kibinge, Michelle K. Muthui, Samson M. Kinyanjui, J Musembi, M Njue, J Mwongeli, Bernhards Ogutu, J Tarning, M O Ongas, Dorcas Kamuya, N Koskei, R Kimathi, Domtila Kimani, B Lowe, C Kivisi, F Olewe, Mainga Hamaluba, M Mosobo, Jedidah Mwacharo, D Mwanga, Stephen L. Hoffman, Mallika Imwong, James Tuju, M Ooko, J Shangala, Simon Kariuki, Edward Otieno, P C Chi, Abdirahman I. Abdi, Thomas N. Williams, I Jao, A Audi, Sim Bkl., Peter C. Bull, O Ngoto, Vicki Marsh, Y Abebe, Joyce M. Ngoi, and Team, CHMI-SIKA Study
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Volunteers ,Medicine (General) ,media_common.quotation_subject ,Medicine (miscellaneous) ,Stakeholder engagement ,Context (language use) ,Interpersonal communication ,0603 philosophy, ethics and religion ,Challenge studies ,Developing countries ,03 medical and health sciences ,R5-920 ,0302 clinical medicine ,General & Internal Medicine ,Controlled human infection studies ,CHMI-SIKA Study Team ,Medicine ,Humans ,Pharmacology (medical) ,030212 general & internal medicine ,1102 Cardiorespiratory Medicine and Haematology ,Socioeconomic status ,media_common ,Ethics ,Medical education ,Human infection studies ,business.industry ,Research ,1103 Clinical Sciences ,06 humanities and the arts ,Focus Groups ,Focus group ,Kenya ,Benefits ,Malaria ,Cardiovascular System & Hematology ,Research Design ,Burdens ,060301 applied ethics ,business ,Qualitative research ,Reputation ,Diversity (politics) - Abstract
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.
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- 2020
41. Safety and efficacy of the ChAdOx1 nCoV-19 vaccine (AZD1222) against SARS-CoV-2: an interim analysis of four randomised controlled trials in Brazil, South Africa, and the UK
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Merryn Voysey, Sue Ann Costa Clemens, Shabir A Madhi, Lily Y Weckx, Pedro M Folegatti, Parvinder K Aley, Brian Angus, Vicky L Baillie, Shaun L Barnabas, Qasim E Bhorat, Sagida Bibi, Carmen Briner, Paola Cicconi, Andrea M Collins, Rachel Colin-Jones, Clare L Cutland, Thomas C Darton, Keertan Dheda, Christopher J A Duncan, Katherine R W Emary, Katie J Ewer, Lee Fairlie, Saul N Faust, Shuo Feng, Daniela M Ferreira, Adam Finn, Anna L Goodman, Catherine M Green, Christopher A Green, Paul T Heath, Catherine Hill, Helen Hill, Ian Hirsch, Susanne H C Hodgson, Alane Izu, Susan Jackson, Daniel Jenkin, Carina C D Joe, Simon Kerridge, Anthonet Koen, Gaurav Kwatra, Rajeka Lazarus, Alison M Lawrie, Alice Lelliott, Vincenzo Libri, Patrick J Lillie, Raburn Mallory, Ana V A Mendes, Eveline P Milan, Angela M Minassian, Alastair McGregor, Hazel Morrison, Yama F Mujadidi, Anusha Nana, Peter J O’Reilly, Sherman D Padayachee, Ana Pittella, Emma Plested, Katrina M Pollock, Maheshi N Ramasamy, Sarah Rhead, Alexandre V Schwarzbold, Nisha Singh, Andrew Smith, Rinn Song, Matthew D Snape, Eduardo Sprinz, Rebecca K Sutherland, Richard Tarrant, Emma C Thomson, M Estée Török, Mark Toshner, David P J Turner, Johan Vekemans, Tonya L Villafana, Marion E E Watson, Christopher J Williams, Alexander D Douglas, Adrian V S Hill, Teresa Lambe, Sarah C Gilbert, Andrew J Pollard, Marites Aban, Fatola Abayomi, Kushala Abeyskera, Jeremy Aboagye, Matthew Adam, Kirsty Adams, James Adamson, Yemi A. Adelaja, Gbadebo Adewetan, Syed Adlou, Khatija Ahmed, Yasmeen Akhalwaya, Saajida Akhalwaya, Andrew Alcock, Aabidah Ali, Elizabeth R. Allen, Lauren Allen, Thamires C. D. S. C Almeida, Mariana P.S. Alves, Fabio Amorim, Foteini Andritsou, Rachel Anslow, Matthew Appleby, Edward H. Arbe-Barnes, Mark P. Ariaans, Beatriz Arns, Laiana Arruda, Paula Azi, Lorena Azi, Gavin Babbage, Catherine Bailey, Kenneth F. Baker, Megan Baker, Natalie Baker, Philip Baker, Lisa Baldwin, Ioana Baleanu, Danieli Bandeira, Anna Bara, Marcella A.S. Barbosa, Debbie Barker, Gavin D. Barlow, Eleanor Barnes, Andrew S. Barr, Jordan R. Barrett, Jessica Barrett, Louise Bates, Alexander Batten, Kirsten Beadon, Emily Beales, Rebecca Beckley, Sandra Belij-Rammerstorfer, Jonathan Bell, Duncan Bellamy, Nancy Bellei, Sue Belton, Adam Berg, Laura Bermejo, Eleanor Berrie, Lisa Berry, Daniella Berzenyi, Amy Beveridge, Kevin R. Bewley, Helen Bexhell, Sutika Bhikha, Asad E. Bhorat, Zaheda E. Bhorat, Else Bijker, Geeta Birch, Sarah Birch, Adam Bird, Olivia Bird, Karen Bisnauthsing, Mustapha Bittaye, Katherine Blackstone, Luke Blackwell, Heather Bletchly, Caitlin L. Blundell, Susannah R. Blundell, Pritesh Bodalia, Bruno C. Boettger, Emma Bolam, Elena Boland, Daan Bormans, Nicola Borthwick, Francesca Bowring, Amy Boyd, Penny Bradley, Tanja Brenner, Phillip Brown, Claire Brown, Charlie Brown-O'Sullivan, Scott Bruce, Emily Brunt, Ruaridh Buchan, William Budd, Yusuf A. Bulbulia, Melanie Bull, Jamie Burbage, Hassan Burhan, Aileen Burn, Karen R. Buttigieg, Nicholas Byard, Ingrid Cabera Puig, Gloria Calderon, Anna Calvert, Susana Camara, Michelangelo Cao, Federica Cappuccini, João R. Cardoso, Melanie Carr, Miles W. Carroll, Andrew Carson-Stevens, Yasmin de M. Carvalho, José A.M. Carvalho, Helen R. Casey, Paul Cashen, Thais Castro, Lucia Carratala Castro, Katrina Cathie, Ana Cavey, José Cerbino-Neto, Jim Chadwick, David Chapman, Sue Charlton, Irina Chelysheva, Oliver Chester, Sunder Chita, Jee-Sun Cho, Liliana Cifuentes, Elizabeth Clark, Matthew Clark, Andrea Clarke, Elizabeth A. Clutterbuck, Sarah L.K. Collins, Christopher P. Conlon, Sean Connarty, Naomi Coombes, Cushla Cooper, Rachel Cooper, Lynne Cornelissen, Tumena Corrah, Catherine Cosgrove, Tony Cox, Wendy E.M. Crocker, Sarah Crosbie, Lorraine Cullen, Dan Cullen, Debora R.M.F. Cunha, Christina Cunningham, Fiona C. Cuthbertson, Suzete N. Farias Da Guarda, Larissa P. da Silva, Brad E. Damratoski, Zsofia Danos, Maria T.D.C. Dantas, Paula Darroch, Mehreen S. Datoo, Chandrabali Datta, Malika Davids, Sarah L. Davies, Hannah Davies, Elizabeth Davis, Judith Davis, John Davis, Maristela M.D. De Nobrega, Lis Moreno De Oliveira Kalid, David Dearlove, Tesfaye Demissie, Amisha Desai, Stefania Di Marco, Claudio Di Maso, Maria I.S. Dinelli, Tanya Dinesh, Claire Docksey, Christina Dold, Tao Dong, Francesca R. Donnellan, Tannyth Dos Santos, Thainá G. dos Santos, Erika Pachecho Dos Santos, Naomi Douglas, Charlotte Downing, Jonathan Drake, Rachael Drake-Brockman, Kimberley Driver, Ruth Drury, Susanna J. Dunachie, Benjamin S. Durham, Lidiana Dutra, Nicholas J.W. Easom, Samual van Eck, Mandy Edwards, Nick J. Edwards, Omar M. El Muhanna, Sean C. Elias, Mike Elmore, Marcus English, Alisgair Esmail, Yakub Moosa Essack, Eoghan Farmer, Mutjaba Farooq, Madi Farrar, Leonard Farrugia, Beverley Faulkner, Sofiya Fedosyuk, Sally Felle, Carla Ferreira Da Silva, Samantha Field, Richard Fisher, Amy Flaxman, James Fletcher, Hazel Fofie, Henry Fok, Karen J. Ford, Jamie Fowler, Pedro H.A. Fraiman, Emma Francis, Marilia M. Franco, John Frater, Marilúcia S.M. Freire, Samantha H. Fry, Sabrina Fudge, Julie Furze, Michelle Fuskova, Pablo Galian-Rubio, Eva Galiza, Harriet Garlant, Madita Gavrila, Ailsa Geddes, Karyna A. Gibbons, Ciaran Gilbride, Hardeep Gill, Sharon Glynn, Kerry Godwin, Karishma Gokani, Ursula Carvalho Goldoni, Maria Goncalves, Isabela G.S. Gonzalez, Jayne Goodwin, Amina Goondiwala, Katherine Gordon-Quayle, Giacomo Gorini, Janet Grab, Lara Gracie, Melanie Greenland, Nicola Greenwood, Johann Greffrath, Marisa M. Groenewald, Leonardo Grossi, Gaurav Gupta, Mark Hackett, Bassam Hallis, Mainga Hamaluba, Elizabeth Hamilton, Joseph Hamlyn, Daniel Hammersley, Aidan T. Hanrath, Brama Hanumunthadu, Stephanie A. Harris, Clair Harris, Tara Harris, Thomas D. Harrison, Daisy Harrison, Thomas C. Hart, Birgit Hartnell, Shadin Hassan, John Haughney, Sophia Hawkins, Jodie Hay, Ian Head, John Henry, Macarena Hermosin Herrera, David B. Hettle, Jennifer Hill, Gina Hodges, Elizea Horne, Mimi M. Hou, Catherine Houlihan, Elizabeth Howe, Nicola Howell, Jonathan Humphreys, Holly E. Humphries, Katrina Hurley, Claire Huson, Angela Hyder-Wright, Catherine Hyams, Sabina Ikram, Alka Ishwarbhai, Monica Ivan, Poppy Iveson, Vidyashankara Iyer, Frederic Jackson, Jeanne De Jager, Shameem Jaumdally, Helen Jeffers, Natasha Jesudason, Bryony Jones, Kathryn Jones, Elizabeth Jones, Christopher Jones, Marianna Rocha Jorge, Aylin Jose, Amar Joshi, Eduardo A.M.S. Júnior, Joanne Kadziola, Reshma Kailath, Faeeza Kana, Konstantinos Karampatsas, Mwila Kasanyinga, Jade Keen, Elizabeth J. Kelly, Dearbhla M. Kelly, Debbie Kelly, Sarah Kelly, David Kerr, Renato de Ávila Kfouri, Liaquat Khan, Baktash Khozoee, Sarah Kidd, Annabel Killen, Jasmin Kinch, Patrick Kinch, Lloyd D.W. King, Thomas B. King, Lucy Kingham, Paul Klenerman, Francesca Knapper, Julian C. Knight, Daniel Knott, Stanislava Koleva, Matilda Lang, Gail Lang, Colin W. Larkworthy, Jessica P.J. Larwood, Rebecca Law, Erica M. Lazarus, Amanda Leach, Emily A. Lees, Nana-Marie Lemm, Alvaro Lessa, Stephanie Leung, Yuanyuan Li, Amelia M. Lias, Kostas Liatsikos, Aline Linder, Samuel Lipworth, Shuchang Liu, Xinxue Liu, Adam Lloyd, Stephanie Lloyd, Lisa Loew, Raquel Lopez Ramon, Leandro Lora, Vicki Lowthorpe, Kleber Luz, Jonathan C. MacDonald, Gordon MacGregor, Meera Madhavan, David O. Mainwaring, Edson Makambwa, Rebecca Makinson, Mookho Malahleha, Ross Malamatsho, Garry Mallett, Kushal Mansatta, Takalani Maoko, Katlego Mapetla, Natalie G. Marchevsky, Spyridoula Marinou, Emma Marlow, Gabriela N. Marques, Paula Marriott, Richard P. Marshall, Julia L. Marshall, Flávia J. Martins, Masebole Masenya, Mduduzi Masilela, Shauna K. Masters, Moncy Mathew, Hosea Matlebjane, Kedidimetse Matshidiso, Olga Mazur, Andrea Mazzella, Hugh McCaughan, Joanne McEwan, Joanna McGlashan, Lorna McInroy, Zoe McIntyre, Daniela McLenaghan, Nicky McRobert, Steve McSwiggan, Clare Megson, Savviz Mehdipour, Wilma Meijs, Renata N.Á. Mendonça, Alexander J. Mentzer, Neginsadat Mirtorabi, Celia Mitton, Sibusiso Mnyakeni, Fiona Moghaddas, Kgaogelo Molapo, Mapule Moloi, Maria Moore, M. Isabel Moraes-Pinto, Marni Moran, Ella Morey, Róisín Morgans, Susan Morris, Sheila Morris, Helen C. Morris, Franca Morselli, Gertraud Morshead, Richard Morter, Lynelle Mottal, Andrew Moultrie, Nathifa Moya, Mushiya Mpelembue, Sibekezelo Msomi, Yvonne Mugodi, Ekta Mukhopadhyay, Jilly Muller, Alasdair Munro, Claire Munro, Sarah Murphy, Philomena Mweu, Celia Hatsuko Myasaki, Gurudutt Naik, Kush Naker, Eleni Nastouli, Abida Nazir, Bongani Ndlovu, Fabio Neffa, Cecilia Njenga, Helena Noal, Andrés Noé, Gabrielle Novaes, Fay L. Nugent, Géssika Nunes, Katie O'Brien, Daniel O'Connor, Miranda Odam, Suzette Oelofse, Blanche Oguti, Victoria Olchawski, Neil J. Oldfield, Marianne G. Oliveira, Catarina Oliveira, Angela Oosthuizen, Paula O'Reilly, Piper Osborne, David R.J. Owen, Lydia Owen, Daniel Owens, Nelly Owino, Mihaela Pacurar, Brenda V.B. Paiva, Edna M.F. Palhares, Susan Palmer, Sivapriyai Parkinson, Helena M.R.T. Parracho, Karen Parsons, Dipak Patel, Bhumika Patel, Faeezah Patel, Kelly Patel, Maia Patrick-Smith, Ruth O. Payne, Yanchun Peng, Elizabeth J. Penn, Anna Pennington, Marco Polo Peralta Alvarez, James Perring, Nicola Perry, Rubeshan Perumal, Sahir Petkar, Tricia Philip, Daniel J. Phillips, Jennifer Phillips, Mary Kgomotso Phohu, Lorinda Pickup, Sonja Pieterse, Jo Piper, Dimitra Pipini, Mary Plank, Joan Du Plessis, Samuel Pollard, Jennifer Pooley, Anil Pooran, Ian Poulton, Claire Powers, Fernando B. Presa, David A. Price, Vivien Price, Marcelo Primeira, Pamela C. Proud, Samuel Provstgaard-Morys, Sophie Pueschel, David Pulido, Sheena Quaid, Ria Rabara, Alexandra Radford, Kajal Radia, Durga Rajapaska, Thurkka Rajeswaran, Alberto San Francisco Ramos, Fernando Ramos Lopez, Tommy Rampling, Jade Rand, Helen Ratcliffe, Tom Rawlinson, David Rea, Byron Rees, Jesús Reiné, Mila Resuello-Dauti, Emilia Reyes Pabon, Carla M. Ribiero, Marivic Ricamara, Alex Richter, Neil Ritchie, Adam J. Ritchie, Alexander J. Robbins, Hannah Roberts, Ryan E. Robinson, Hannah Robinson, Talita T. Rocchetti, Beatriz Pinho Rocha, Sophie Roche, Christine Rollier, Louisa Rose, Amy L. Ross Russell, Lindie Rossouw, Simon Royal, Indra Rudiansyah, Sarah Ruiz, Stephen Saich, Claudia Sala, Jessica Sale, Ahmed M. Salman, Natalia Salvador, Stephannie Salvador, Milla Sampaio, Annette D. Samson, Amada Sanchez-Gonzalez, Helen Sanders, Katherine Sanders, Erika Santos, Mayara F.S. Santos Guerra, Iman Satti, Jack E. Saunders, Caroline Saunders, Aakifah Sayed, Ina Schim van der Loeff, Annina B. Schmid, Ella Schofield, Gavin Screaton, Samiullah Seddiqi, Rameswara R. Segireddy, Roberta Senger, Sonia Serrano, Rajiv Shah, Imam Shaik, Hannah E. Sharpe, Katherine Sharrocks, Robert Shaw, Adam Shea, Amy Shepherd, James G. Shepherd, Farah Shiham, Emad Sidhom, Sarah E. Silk, Antonio Carlos da Silva Moraes, Gilberto Silva-Junior, Laura Silva-Reyes, Anderson D. Silveira, Mariana B.V. Silveira, Jaisi Sinha, Donal T. Skelly, Daniel C. Smith, Nick Smith, Holly E. Smith, David J. Smith, Catherine C. Smith, Airanuédida Soares, Tiago Soares, Carla Solórzano, Guilherme L. Sorio, Kim Sorley, Tiffany Sosa-Rodriguez, Cinthia M.C.D.L. Souza, Bruno S.D.F. Souza, Alessandra R. Souza, Alexandra J. Spencer, Fernanda Spina, Louise Spoors, Lizzie Stafford, Imogen Stamford, Igor Starinskij, Ricardo Stein, Jill Steven, Lisa Stockdale, Lisa V. Stockwell, Louise H. Strickland, Arabella C. Stuart, Ann Sturdy, Natalina Sutton, Anna Szigeti, Abdessamad Tahiri-Alaoui, Rachel Tanner, Carol Taoushanis, Alexander W. Tarr, Keja Taylor, Ursula Taylor, Iona Jennifer Taylor, Justin Taylor, Rebecca te Water Naude, Yrene Themistocleous, Andreas Themistocleous, Merin Thomas, Kelly Thomas, Tonia M. Thomas, Asha Thombrayil, Fawziyah Thompson, Amber Thompson, Kevin Thompson, Ameeka Thompson, Julia Thomson, Viv Thornton-Jones, Patrick J. Tighe, Lygia Accioly Tinoco, Gerlynn Tiongson, Bonolo Tladinyane, Michele Tomasicchio, Adriana Tomic, Susan Tonks, James Towner, Nguyen Tran, Julia Tree, Gerry Trillana, Charlotte Trinham, Rose Trivett, Adam Truby, Betty Lebogang Tsheko, Aadil Turabi, Richard Turner, Cheryl Turner, Marta Ulaszewska, Benjamin R. Underwood, Rachel Varughese, Dennis Verbart, Marije Verheul, Iason Vichos, Taiane Vieira, Claire S. Waddington, Laura Walker, Erica Wallis, Matthew Wand, Deborah Warbick, Theresa Wardell, George Warimwe, Sarah C. Warren, Bridget Watkins, Ekaterina Watson, Stewart Webb, Alice Webb-Bridges, Angela Webster, Jessica Welch, Jeanette Wells, Alison West, Caroline White, Rachel White, Paul Williams, Rachel L. Williams, Rebecca Winslow, Mark Woodyer, Andrew T. Worth, Danny Wright, Marzena Wroblewska, Andy Yao, Rafael Zimmer, Dalila Zizi, Peter Zuidewind, Group, Oxford COVID Vaccine Trial, Toshner, Mark [0000-0002-3969-6143], and Apollo - University of Cambridge Repository
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Male ,COVID-19/prevention & control ,030204 cardiovascular system & hematology ,law.invention ,South Africa ,0302 clinical medicine ,Randomized controlled trial ,law ,Oxford COVID Vaccine Trial Group ,wc_505 ,Single-Blind Method ,030212 general & internal medicine ,Young adult ,11 Medical and Health Sciences ,wa_105 ,Covid19 ,General Medicine ,Articles ,Middle Aged ,Treatment Outcome ,Cohort ,Perspective ,Female ,Brazil ,Adult ,medicine.medical_specialty ,COVID-19 Vaccines ,Adolescent ,qw_806 ,qw_805 ,03 medical and health sciences ,Young Adult ,Double-Blind Method ,Conjugate vaccine ,Internal medicine ,General & Internal Medicine ,ChAdOx1 nCoV-19 ,medicine ,Humans ,Adverse effect ,Aged ,business.industry ,SARS-CoV-2 ,COVID-19 ,Viral Vaccines ,Vaccine efficacy ,Interim analysis ,United Kingdom ,Clinical trial ,bf023de6 ,business ,COVID-19 Vaccines/adverse effects - Abstract
BACKGROUND: A safe and efficacious vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), if deployed with high coverage, could contribute to the control of the COVID-19 pandemic. We evaluated the safety and efficacy of the ChAdOx1 nCoV-19 vaccine in a pooled interim analysis of four trials. \ud \ud \ud METHODS: This analysis includes data from four ongoing blinded, randomised, controlled trials done across the UK, Brazil, and South Africa. Participants aged 18 years and older were randomly assigned (1:1) to ChAdOx1 nCoV-19 vaccine or control (meningococcal group A, C, W, and Y conjugate vaccine or saline). Participants in the ChAdOx1 nCoV-19 group received two doses containing 5 × 1010 viral particles (standard dose; SD/SD cohort); a subset in the UK trial received a half dose as their first dose (low dose) and a standard dose as their second dose (LD/SD cohort). The primary efficacy analysis included symptomatic COVID-19 in seronegative participants with a nucleic acid amplification test-positive swab more than 14 days after a second dose of vaccine. Participants were analysed according to treatment received, with data cutoff on Nov 4, 2020. Vaccine efficacy was calculated as 1 - relative risk derived from a robust Poisson regression model adjusted for age. Studies are registered at ISRCTN89951424 and ClinicalTrials.gov, NCT04324606, NCT04400838, and NCT04444674. \ud \ud \ud FINDINGS: Between April 23 and Nov 4, 2020, 23 848 participants were enrolled and 11 636 participants (7548 in the UK, 4088 in Brazil) were included in the interim primary efficacy analysis. In participants who received two standard doses, vaccine efficacy was 62·1% (95% CI 41·0-75·7; 27 [0·6%] of 4440 in the ChAdOx1 nCoV-19 group vs71 [1·6%] of 4455 in the control group) and in participants who received a low dose followed by a standard dose, efficacy was 90·0% (67·4-97·0; three [0·2%] of 1367 vs 30 [2·2%] of 1374; pinteraction=0·010). Overall vaccine efficacy across both groups was 70·4% (95·8% CI 54·8-80·6; 30 [0·5%] of 5807 vs 101 [1·7%] of 5829). From 21 days after the first dose, there were ten cases hospitalised for COVID-19, all in the control arm; two were classified as severe COVID-19, including one death. There were 74 341 person-months of safety follow-up (median 3·4 months, IQR 1·3-4·8): 175 severe adverse events occurred in 168 participants, 84 events in the ChAdOx1 nCoV-19 group and 91 in the control group. Three events were classified as possibly related to a vaccine: one in the ChAdOx1 nCoV-19 group, one in the control group, and one in a participant who remains masked to group allocation. \ud \ud \ud INTERPRETATION: ChAdOx1 nCoV-19 has an acceptable safety profile and has been found to be efficacious against symptomatic COVID-19 in this interim analysis of ongoing clinical trials. \ud \ud \ud FUNDING: UK Research and Innovation, National Institutes for Health Research (NIHR), Coalition for Epidemic Preparedness Innovations, Bill & Melinda Gates Foundation, Lemann Foundation, Rede D'Or, Brava and Telles Foundation, NIHR Oxford Biomedical Research Centre, Thames Valley and South Midland's NIHR Clinical Research Network, and AstraZeneca.
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42. Title: Controlled human malaria infection (CHMI) outcomes in Kenyan adults associated with prior history of malaria exposure and anti-schizont antibody response
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Kim Lee Sim, James Tuju, Domtila Kimani, Chmi-Sika Study, Melissa C. Kapulu, Mainga Hamaluba, Patricia Njuguna, Edward Otieno, and Rinter Kimathi
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Kenya ,Antibody response ,business.industry ,Immunology ,medicine ,medicine.disease ,business ,Malaria - Published
- 2020
43. Immunogenicity and safety of fractional doses of yellow fever vaccines: a randomised, double-blind, non-inferiority trial
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Ndeye Sakha Bob, Patrick Kazooba, Derek A. T. Cummings, Philip Bejon, Immaculate Ampeire, Kyra H. Grantz, Alan D.T. Barrett, Moussa Dia, Thomas P. Monath, Derick Kimathi, Henry K. Karanja, Mainga Hamaluba, Edgar Mulogo, Patricia Njuguna, Rebecca F. Grais, George M. Warimwe, Juliet Mwanga-Amumpaire, Joachim Hombach, Gamou Fall, Dan Nyehangane, and Aitana Juan-Giner
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myalgia ,Adult ,Male ,medicine.medical_specialty ,Population ,Yellow fever vaccine ,030204 cardiovascular system & hematology ,03 medical and health sciences ,Plaque reduction neutralization test ,0302 clinical medicine ,Double-Blind Method ,Internal medicine ,Yellow Fever ,Medicine ,Humans ,Uganda ,Dosing ,030212 general & internal medicine ,Seroconversion ,Adverse effect ,education ,education.field_of_study ,business.industry ,Immunogenicity ,Yellow fever ,Yellow Fever Vaccine ,General Medicine ,Off-Label Use ,medicine.disease ,Antibodies, Neutralizing ,Kenya ,Poliomyelitis ,Vaccination ,Female ,medicine.symptom ,business ,medicine.drug - Abstract
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.
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- 2020
44. Naturally acquired immunity among Kenyan adults suppresses the West African P. falciparum NF54 strain in controlled human malaria infection (CHMI)
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J Musembi, Melissa C. Kapulu, Mainga Hamaluba, Joyce M. Ngoi, Domtila Kimani, Edward Otieno, P F Billingsley, O Ngoto, and Patricia Njuguna
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Kenya ,biology ,Strain (chemistry) ,Plasmodium falciparum ,biology.organism_classification ,Acquired immune system ,medicine.disease ,Virology ,Real-time polymerase chain reaction ,Immunity ,parasitic diseases ,medicine ,Parasite hosting ,Malaria - Abstract
We used controlled human malaria infection (CHMI) to study naturally acquired immunity of Kenyan adults. We administered 3.2×103 cryopreserved Plasmodium falciparum sporozoites (SPZ, NF54 West African strain) and undertook clinical monitoring and serial quantitative PCR (qPCR). 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. We find that the immunity acquired by some Kenyan adults can completely suppress in vivo growth of a parasite strain originating from outside Kenya.
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- 2020
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45. Evaluation of Near Infrared Spectroscopy for Sporozoite Detection in Mosquitoes Infected With Wild-strain Parasites From Asymptomatic Gametocyte Carriers in Kilifi Kenya
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Marta Ferreira Maia, Martin G. Wagah, Jonathan Karisa, Robert Mwakesi, Festus Mure, Martha Muturi, Juliana Wambua, Mainga Hamaluba, Floyd E. Dowell, Philip Bejon, and Melissa C. Kapulu
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parasitic diseases - Abstract
Background: Screening for Plasmodium spp. sporozoite infection in mosquitoes is routinely done using ELISA (enzyme-linked immunosorbent assay). Near infrared spectroscopy (NIRS), a fast and non-destructive method, has recently been shown to distinguish, with 95% accuracy, between uninfected and sporozoite-infected mosquitoes using laboratory strains of Plasmodium falciparum (PfN54). The aim of this present study was to further investigate the reproducibility of NIRS to identify sporozoite infection in mosquitoes infected using field isolates of P. falciparum gametocytes from asymptomatic carriers. Methods: Healthy individuals (aged 5 years and above) were screened for gametocytaemia by thick-smear microscopy in an area of moderate transmission along the Coast of Kenya between May and September 2018. Asymptomatic gametocyte carriers were recruited for mosquito feeding assays, direct membrane feeding (DMFA) and direct skin feeding (DFA), using insectary-reared Anopheles gambiae s.s (Kilifi strain). Mosquitoes were kept for 14-days post feeding after which they were scanned using NIRS and subsequently analysed for sporozoite infection using circumsporozoite-ELISA. Predictive models were explored using partial least square regressions (PLS).Results: Two hundred and ninety-nine (299) individuals were screened for malaria parasites, 74 (24.8%) were found with circulating asexual parasites, and 16 (5.4%) with P. falciparum gametocyte stages.Fourteen (14) asymptomatic gametocyte carriers were recruited to the study for mosquito feeding assays. A total of 134 (7%, 134/1881) sporozoite-infected mosquitoes were obtained from 9 successful experiments. Three different training datasets composed of infected and uninfected mosquitoes were analysed. The PLS models were unable to distinguish between sporozoite-infected and uninfected mosquitoes. A predictive model could not be generated.Conclusions: The results of this study were not consistent with previous published research on NIRS for detection of sporozoite infection in the same mosquito species and may reflect differences between laboratory and field conditions. The current findings indicate that methods for sporozoite detection should be tested on field isolates at an early stage in their development and are informative for future research seeking novel high-throughput methods for parasite detection in mosquitoes.
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- 2020
46. Evaluation of near infrared spectroscopy for sporozoite detection in mosquitoes infected with wild-strain parasites from asymptomatic gametocyte carriers in Kilifi Kenya
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Marta F. Maia, F Mure, Floyd E. Dowell, R Mwakesi, Martin G. Wagah, Juliana Wambua, Mainga Hamaluba, M Muturi, Melissa C. Kapulu, J Karisa, and Philip Bejon
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biology ,Transmission (medicine) ,Plasmodium falciparum ,medicine.disease ,biology.organism_classification ,Virology ,Asymptomatic ,Plasmodium ,parasitic diseases ,medicine ,Gametocyte ,Parasite hosting ,medicine.symptom ,Asymptomatic carrier ,Malaria - Abstract
BackgroundScreening for Plasmodium spp. sporozoite infection in mosquitoes is routinely done using ELISA (enzyme-linked immunosorbent assay). Near infrared spectroscopy (NIRS), a fast and non-destructive method, has recently been shown to distinguish, with 95% accuracy, between uninfected and sporozoite-infected mosquitoes using laboratory strains of Plasmodium falciparum (PfN54). The aim of this present study was to further investigate the reproducibility of NIRS to identify sporozoite infection in mosquitoes infected using field isolates of P. falciparum gametocytes from asymptomatic carriers.MethodsHealthy individuals (aged 5 years and above) were screened for gametocytaemia by thick-smear microscopy in an area of moderate transmission along the Coast of Kenya between May and September 2018. Asymptomatic gametocyte carriers were recruited for mosquito feeding assays, direct membrane feeding (DMFA) and direct skin feeding (DFA), using insectary-reared Anopheles gambiae s.s (Kilifi strain). Mosquitoes were kept for 14-days post feeding after which they were scanned using NIRS and subsequently analysed for sporozoite infection using circumsporozoite-ELISA. Predictive models were explored using partial least square regressions (PLS).ResultsTwo hundred and ninety-nine (299) individuals were screened for malaria parasites, 74 (24.8%) were found with circulating asexual parasites, and 16 (5.4%) with P. falciparum gametocyte stages. Fourteen (14) asymptomatic gametocyte carriers were recruited to the study for mosquito feeding assays. A total of 134 (7%, 134/1881) sporozoite-infected mosquitoes were obtained from 9 successful experiments. Three different training datasets composed of infected and uninfected mosquitoes were analysed. The PLS models were unable to distinguish between sporozoite-infected and uninfected mosquitoes. A predictive model could not be generated.ConclusionsThe results of this study were not consistent with previous published research on NIRS for detection of sporozoite infection in the same mosquito species and may reflect differences between laboratory and field conditions. The current findings indicate that methods for sporozoite detection should be tested on field isolates at an early stage in their development and are informative for future research seeking novel high-throughput methods for parasite detection in mosquitoes.
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- 2020
47. The Children's Oxygen Administration Strategies Trial (COAST)
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Kathryn Maitland, Sarah Kiguli, Peter Olupot Oluput, Mainga Hamaluba, Karen Thomas, Florence Alaroker, Robert O. Opoka, Abner Tagoola, Victor Bandika, Ayub Mpoya, Hellen Mnjella, Eva Nabawanuka, William Okiror, Margaret Nakuya, Denis Aromut, Charles Engoru, Emmanuel Oguda, John F Fraser, Thomas N. Williams, David A. Harrison, and Kathy Rowan
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- 2020
48. The Children's Oxygen Administration Strategies Trial (COAST)
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Denis Aromut, Sarah Kiguli, Kathryn M Rowan, Peter Olupot Oluput, William Okiror, Robert O. Opoka, Karen Thomas, Mainga Hamaluba, Hellen Mnjella, Charles Engoru, Thomas N. Williams, Ayub Mpoya, Kathryn Maitland, David A Harrison, Victor Bandika, Margeret Nakuya, Abner Tagoola, Emmanuel Oguda, Florence Alaroker, Eva Nabawanuka, and John F. Fraser
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medicine.medical_specialty ,Kenya ,business.industry ,medicine.medical_treatment ,Mortality rate ,Ethics committee ,Odds ratio ,law.invention ,Randomized controlled trial ,law ,Internal medicine ,Oxygen therapy ,medicine ,Clinical endpoint ,business ,Trial registration - Abstract
Background: The life-saving role of oxygen therapy in children with clinically-defined severe pneumonia is not yet established. We hypothesised liberal oxygenation strategies and/or respiratory support may improve the high in-hospital mortality. Methods: The open-label fractional-factorial COAST trial in Ugandan and Kenyan children aged >28 days with feature of severe pneumonia. In stratum A (severe hypoxaemia: SpO2 3hours receipt of oxygen were excluded. The primary endpoint was 48-hour mortality; secondary endpoints included mortality or neurocognitive sequelae at 28 days. Findings: The Trial Steering Committee recommended halting recruitment for feasibility after 1842/4200 (44%) children enrolled. Of 1852 recruited, 388 in stratum A (median 7 months; median age SpO2 75%) were randomised to HFNT (n=194) or LFO (n=194) and 1454 in stratum B (median 9 months; median SpO2 88%) were randomised to HFNT (n=363) vs LFO (n=364) vs control (n=727). Per-protocol 109/726(15%) of controls received oxygen (when SpO2
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- 2020
49. Controlled Human Malaria Infection in Semi-Immune Kenyan Adults (CHMI-SIKA): A study protocol to investigate in vivo Plasmodium falciparum malaria parasite growth in the context of pre-existing immunity
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Patricia Njuguna, Melissa C. Kapulu, Chmi-Sika Study Team, and Mainga Hamaluba
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0301 basic medicine ,medicine.medical_specialty ,PfSPZ Challenge ,Plasmodium falciparum ,030231 tropical medicine ,Medicine (miscellaneous) ,Context (language use) ,General Biochemistry, Genetics and Molecular Biology ,Study Protocol ,03 medical and health sciences ,Immune system ,blood-stage ,0302 clinical medicine ,Antigen ,Immunity ,parasitic diseases ,medicine ,controlled human malaria infection ,biology ,business.industry ,Malaria vaccine ,Public health ,Articles ,medicine.disease ,biology.organism_classification ,immunity ,Kenya ,parasite growth ,3. Good health ,030104 developmental biology ,Immunology ,quantitative PCR ,business ,Malaria - Abstract
Malaria remains a major public health burden despite approval for implementation of a partially effective pre-erythrocytic malaria vaccine. There is an urgent need to accelerate development of a more effective multi-stage vaccine. Adults in malaria endemic areas may have substantial immunity provided by responses to the blood stages of malaria parasites, but field trials conducted on several blood-stage vaccines have not shown high levels of efficacy. We will use the controlled human malaria infection (CHMI) models with malaria-exposed volunteers to identify correlations between immune responses and parasite growth rates in vivo. Immune responses more strongly associated with control of parasite growth should be prioritized to accelerate malaria vaccine development. We aim to recruit up to 200 healthy adult volunteers from areas of differing malaria transmission in Kenya, and after confirming their health status through clinical examination and routine haematology and biochemistry, we will comprehensively characterize immunity to malaria using >100 blood-stage antigens. We will administer 3,200 aseptic, purified, cryopreserved Plasmodium falciparum sporozoites (PfSPZ Challenge) by direct venous inoculation. Serial quantitative polymerase chain reaction to measure parasite growth rate in vivo will be undertaken. Clinical and laboratory monitoring will be undertaken to ensure volunteer safety. In addition, we will also explore the perceptions and experiences of volunteers and other stakeholders in participating in a malaria volunteer infection study. Serum, plasma, peripheral blood mononuclear cells and whole blood will be stored to allow a comprehensive assessment of adaptive and innate host immunity. We will use CHMI in semi-immune adult volunteers to relate parasite growth outcomes with antibody responses and other markers of host immunity. Registration: ClinicalTrials.gov identifier NCT02739763.
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- 2019
50. Congenital microcephaly unrelated to flavivirus exposure in coastal Kenya
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Donwilliams O. Omuoyo, Everlyn Kamau, Philip Bejon, Amek Nyaguara, Anna C. Seale, Charles N. Agoti, George M. Warimwe, Daniel B. Wright, Joyce U. Nyiro, Stella Mwakio, James A. Berkley, Charles R. Newton, Barnes Kitsao, Mainga Hamaluba, Rosemary Sang, Hellen C. Barsosio, Henry K. Karanja, Doris K. Nyamwaya, Eduard J. Sanders, and John N. Gitonga
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Microcephaly ,Pediatrics ,medicine.medical_specialty ,030231 tropical medicine ,Population ,Medicine (miscellaneous) ,wc_524 ,Dengue virus ,medicine.disease_cause ,General Biochemistry, Genetics and Molecular Biology ,Zika virus ,03 medical and health sciences ,0302 clinical medicine ,medicine ,030212 general & internal medicine ,education ,education.field_of_study ,biology ,business.industry ,Flavivirus ,Congenital microcephaly ,Gestational age ,Articles ,qs_675 ,biology.organism_classification ,medicine.disease ,3. Good health ,Cohort ,Population study ,Small for gestational age ,qw_160 ,business ,Research Article - Abstract
Background: Zika virus (ZIKV) was first discovered in East Africa in 1947. ZIKV has caused microcephaly in the Americas, but it is not known whether ZIKV is a cause of microcephaly in East Africa. Methods: We used surveillance data from 11,061 live births at Kilifi County Hospital in coastal Kenya between January 2012 and October 2016 to identify microcephaly cases and conducted a nested case-control study to determine risk factors for microcephaly. Gestational age at birth was estimated based on antenatal ultrasound scanning (‘Scanned cohort’) or last menstrual period (‘LMP cohort’, including births ≥37 weeks’ gestation only). Controls were newborns with head circumference Z scores between >-2 and ≤2 SD that were compared to microcephaly cases in relation to ZIKV exposure and other maternal and newborn factors. Results: Of the 11,061 newborns, 214 (1.9%, 95%CI 1.69, 2.21) had microcephaly. Microcephaly prevalence was 1.0% (95%CI 0.64, 1.70, n=1529) and 2.1% (95%CI 1.81, 2.38, n=9532) in the scanned and LMP cohorts, respectively. After excluding babies Conclusions: Microcephaly was prevalent in coastal Kenya, but does not appear to be related to ZIKV exposure; the ZIKV response observed in our study population was largely due to cross-reactive responses to DENV or other related flaviviruses. Further research into potential causes and the clinical consequences of microcephaly in this population is urgently needed.
- Published
- 2019
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