Last data update: Oct 07, 2024. (Total: 47845 publications since 2009)
Records 1-30 (of 45 Records) |
Query Trace: Samuels AM[original query] |
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Estimation of vaccine effectiveness against SARS-CoV-2-associated hospitalization using sentinel surveillance in South Africa
Chiwandire N , Walaza S , von Gottberg A , Wolter N , Du Plessis M , Moosa F , Groome MJ , Nel J , Variava E , Dawood H , Makhasi M , Feldstein LR , Marcenac P , Lafond KE , Samuels AM , Cohen C . Int J Epidemiol 2024 53 (5) BACKGROUND: COVID-19 vaccine effectiveness (VE) studies leveraging systematic surveillance in sub-Saharan Africa are limited. We assessed the effectiveness of two vaccines (Pfizer BNT162b2 and Johnson & Johnson Ad26.COV2.S) against SARS-CoV-2-associated hospitalization in South African adults aged ≥18 years. METHODS: We conducted a test-negative case-control study using pneumonia surveillance data in South Africa. Inpatients with physician-diagnosed lower respiratory tract infection or suspected COVID-19, testing SARS-CoV-2 positive or negative from June 2021-March 2022, were cases or controls, respectively. Fully vaccinated individuals received one Ad26.COV2.S dose or two BNT162b2 doses ≥14-days before enrollment. VE was estimated using multivariable logistic regression for Delta- and Omicron BA.1/BA.2-predominant periods, stratified by age and HIV status. RESULTS: The study included 925 cases and 1890 controls; 38 (4%) cases and 186 (10%) controls were fully vaccinated with BNT162b2, and 30 (3%) cases and 94 (5%) controls with Ad26.COV2.S. The vaccine effectiveness of BNT162b2 against SARS-CoV-2-associated hospitalization over Delta and Omicron BA.1/BA.2 periods was 91% (95% CI: 52%, 98%) and 33% (-16%, 86%), respectively. The vaccine effectiveness of Ad26.COV2.S against hospitalization over Delta and Omicron BA.1/BA.2 periods was 72% (-36% ,94%), and -19% (-130%, 39%), respectively. The vaccine effectiveness of BNT162b2 against hospitalization over the Delta period was 94% (50%, 99%) and 89% (27%, 98%) among adults aged ≥60 years and HIV-uninfected, respectively. CONCLUSIONS: The BNT162b2 vaccine was effective against SARS-CoV-2-associated hospitalization during the Delta period for adults aged ≥18 years, ≥60 years and those HIV-uninfected. VE for Ad26.COV2.S was inconclusive, potentially due to limited sample size or residual confounding. These findings highlight the utility of sentinel surveillance for estimating VE. |
Genotypic analysis of RTS,S/AS01<inf>E</inf> malaria vaccine efficacy against parasite infection as a function of dosage regimen and baseline malaria infection status in children aged 5-17 months in Ghana and Kenya: a longitudinal phase 2b randomised controlled trial
Juraska M , Early AM , Li L , Schaffner SF , Lievens M , Khorgade A , Simpkins B , Hejazi NS , Benkeser D , Wang Q , Mercer LD , Adjei S , Agbenyega T , Anderson S , Ansong D , Bii DK , Buabeng PBY , English S , Fitzgerald N , Grimsby J , Kariuki SK , Otieno K , Roman F , Samuels AM , Westercamp N , Ockenhouse CF , Ofori-Anyinam O , Lee CK , MacInnis BL , Wirth DF , Gilbert PB , Neafsey DE . The Lancet Infectious Diseases 2024 24(9) 1025-1036 Background: The first licensed malaria vaccine, RTS,S/AS01<inf>E</inf>, confers moderate protection against symptomatic disease. Because many malaria infections are asymptomatic, we conducted a large-scale longitudinal parasite genotyping study of samples from a clinical trial exploring how vaccine dosing regimen affects vaccine efficacy. Method(s): Between Sept 28, 2017, and Sept 25, 2018, 1500 children aged 5-17 months were randomly assigned (1:1:1:1:1) to receive four different RTS,S/AS01<inf>E</inf> regimens or a rabies control vaccine in a phase 2b open-label clinical trial in Ghana and Kenya. Participants in the four RTS,S groups received two full doses at month 0 and month 1 and either full doses at month 2 and month 20 (group R012-20); full doses at month 2, month 14, month 26, and month 38 (group R012-14); fractional doses at month 2, month 14, month 26, and month 38 (group Fx012-14; early fourth dose); or fractional doses at month 7, month 20, and month 32 (group Fx017-20; delayed third dose). We evaluated the time to the first new genotypically detected infection and the total number of new infections during two follow-up periods (12 months and 20 months) in more than 36 000 dried blood spot specimens from 1500 participants. To study vaccine effects on time to the first new infection, we defined vaccine efficacy as one minus the hazard ratio (HR; RTS,S vs control) of the first new infection. We performed a post-hoc analysis of vaccine efficacy based on malaria infection status at first vaccination and force of infection by month 2. This trial (MAL-095) is registered with ClinicalTrials.gov, NCT03281291. Finding(s): We observed significant and similar vaccine efficacy (25-43%; 95% CI union 9-53) against first new infection for all four RTS,S/AS01<inf>E</inf> regimens across both follow-up periods (12 months and 20 months). Each RTS,S/AS01<inf>E</inf> regimen significantly reduced the mean number of new infections in the 20-month follow-up period by 1.1-1.6 infections (95% CI union 0.6-2.1). Vaccine efficacy against first new infection was significantly higher in participants who were infected with malaria (68%; 95% CI 50-80) than in those who were uninfected (37%; 23-48) at the first vaccination (p=0.0053). Interpretation(s): All tested dosing regimens blocked some infections to a similar degree. Improved vaccine efficacy in participants infected during vaccination could suggest new strategies for highly efficacious malaria vaccine development and implementation. Funding(s): GlaxoSmithKline Biologicals SA, PATH, Bill & Melinda Gates Foundation, and the German Federal Ministry of Education and Research. Copyright © 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license |
Acute febrile illness in Kenya: Clinical characteristics and pathogens detected among patients hospitalized with fever, 2017-2019
Verani JR , Eno EN , Hunsperger EA , Munyua P , Osoro E , Marwanga D , Bigogo G , Amon D , Ochieng M , Etau P , Bandika V , Zimbulu V , Kiogora J , Burton JW , Okunga E , Samuels AM , Njenga K , Montgomery JM , Widdowson MA . PLoS One 2024 19 (8) e0305700 Acute febrile illness (AFI) is a common reason for healthcare seeking and hospitalization in Sub-Saharan Africa and is often presumed to be malaria. However, a broad range of pathogens cause fever, and more comprehensive data on AFI etiology can improve clinical management, prevent unnecessary prescriptions, and guide public health interventions. We conducted surveillance for AFI (temperature ≥38.0°C <14 days duration) among hospitalized patients of all ages at four sites in Kenya (Nairobi, Mombasa, Kakamega, and Kakuma). For cases of undifferentiated fever (UF), defined as AFI without diarrhea (≥3 loose stools in 24 hours) or lower respiratory tract symptoms (cough/difficulty breathing plus oxygen saturation <90% or [in children <5 years] chest indrawing), we tested venous blood with real-time PCR-based TaqMan array cards (TAC) for 17 viral, 8 bacterial, and 3 protozoal fever-causing pathogens. From June 2017 to March 2019, we enrolled 3,232 AFI cases; 2,529 (78.2%) were aged <5 years. Among 3,021 with outcome data, 131 (4.3%) cases died while in hospital, including 106/2,369 (4.5%) among those <5 years. Among 1,735 (53.7%) UF cases, blood was collected from 1,340 (77.2%) of which 1,314 (98.1%) were tested by TAC; 715 (54.4%) had no pathogens detected, including 147/196 (75.0%) of those aged <12 months. The most common pathogen detected was Plasmodium, as a single pathogen in 471 (35.8%) cases and in combination with other pathogens in 38 (2.9%). HIV was detected in 51 (3.8%) UF cases tested by TAC and was most common in adults (25/236 [10.6%] ages 18-49, 4/40 [10.0%] ages ≥50 years). Chikungunya virus was found in 30 (2.3%) UF cases, detected only in the Mombasa site. Malaria prevention and control efforts are critical for reducing the burden of AFI, and improved diagnostic testing is needed to provide better insight into non-malarial causes of fever. The high case fatality of AFI underscores the need to optimize diagnosis and appropriate management of AFI to the local epidemiology. |
Genotypic analysis of RTS,S/AS01(E) malaria vaccine efficacy against parasite infection as a function of dosage regimen and baseline malaria infection status in children aged 5-17 months in Ghana and Kenya: a longitudinal phase 2b randomised controlled trial
Juraska M , Early AM , Li L , Schaffner SF , Lievens M , Khorgade A , Simpkins B , Hejazi NS , Benkeser D , Wang Q , Mercer LD , Adjei S , Agbenyega T , Anderson S , Ansong D , Bii DK , Buabeng PBY , English S , Fitzgerald N , Grimsby J , Kariuki SK , Otieno K , Roman F , Samuels AM , Westercamp N , Ockenhouse CF , Ofori-Anyinam O , Lee CK , MacInnis BL , Wirth DF , Gilbert PB , Neafsey DE . Lancet Infect Dis 2024 BACKGROUND: The first licensed malaria vaccine, RTS,S/AS01(E), confers moderate protection against symptomatic disease. Because many malaria infections are asymptomatic, we conducted a large-scale longitudinal parasite genotyping study of samples from a clinical trial exploring how vaccine dosing regimen affects vaccine efficacy. METHODS: Between Sept 28, 2017, and Sept 25, 2018, 1500 children aged 5-17 months were randomly assigned (1:1:1:1:1) to receive four different RTS,S/AS01(E) regimens or a rabies control vaccine in a phase 2b open-label clinical trial in Ghana and Kenya. Participants in the four RTS,S groups received two full doses at month 0 and month 1 and either full doses at month 2 and month 20 (group R012-20); full doses at month 2, month 14, month 26, and month 38 (group R012-14); fractional doses at month 2, month 14, month 26, and month 38 (group Fx012-14; early fourth dose); or fractional doses at month 7, month 20, and month 32 (group Fx017-20; delayed third dose). We evaluated the time to the first new genotypically detected infection and the total number of new infections during two follow-up periods (12 months and 20 months) in more than 36 000 dried blood spot specimens from 1500 participants. To study vaccine effects on time to the first new infection, we defined vaccine efficacy as one minus the hazard ratio (HR; RTS,S vs control) of the first new infection. We performed a post-hoc analysis of vaccine efficacy based on malaria infection status at first vaccination and force of infection by month 2. This trial (MAL-095) is registered with ClinicalTrials.gov, NCT03281291. FINDINGS: We observed significant and similar vaccine efficacy (25-43%; 95% CI union 9-53) against first new infection for all four RTS,S/AS01(E) regimens across both follow-up periods (12 months and 20 months). Each RTS,S/AS01(E) regimen significantly reduced the mean number of new infections in the 20-month follow-up period by 1·1-1·6 infections (95% CI union 0·6-2·1). Vaccine efficacy against first new infection was significantly higher in participants who were infected with malaria (68%; 95% CI 50-80) than in those who were uninfected (37%; 23-48) at the first vaccination (p=0·0053). INTERPRETATION: All tested dosing regimens blocked some infections to a similar degree. Improved vaccine efficacy in participants infected during vaccination could suggest new strategies for highly efficacious malaria vaccine development and implementation. FUNDING: GlaxoSmithKline Biologicals SA, PATH, Bill & Melinda Gates Foundation, and the German Federal Ministry of Education and Research. |
Feasibility, safety, and impact of the RTS,S/AS01(E) malaria vaccine when implemented through national immunisation programmes: evaluation of cluster-randomised introduction of the vaccine in Ghana, Kenya, and Malawi
Asante KP , Mathanga DP , Milligan P , Akech S , Oduro A , Mwapasa V , Moore KA , Kwambai TK , Hamel MJ , Gyan T , Westercamp N , Kapito-Tembo A , Njuguna P , Ansong D , Kariuki S , Mvalo T , Snell P , Schellenberg D , Welega P , Otieno L , Chimala A , Afari EA , Bejon P , Maleta K , Agbenyega T , Snow RW , Zulu M , Chinkhumba J , Samuels AM . Lancet 2024 403 (10437) 1660-1670 BACKGROUND: The RTS,S/AS01(E) malaria vaccine (RTS,S) was introduced by national immunisation programmes in Ghana, Kenya, and Malawi in 2019 in large-scale pilot schemes. We aimed to address questions about feasibility and impact, and to assess safety signals that had been observed in the phase 3 trial that included an excess of meningitis and cerebral malaria cases in RTS,S recipients, and the possibility of an excess of deaths among girls who received RTS,S than in controls, to inform decisions about wider use. METHODS: In this prospective evaluation, 158 geographical clusters (66 districts in Ghana; 46 sub-counties in Kenya; and 46 groups of immunisation clinic catchment areas in Malawi) were randomly assigned to early or delayed introduction of RTS,S, with three doses to be administered between the ages of 5 months and 9 months and a fourth dose at the age of approximately 2 years. Primary outcomes of the evaluation, planned over 4 years, were mortality from all causes except injury (impact), hospital admission with severe malaria (impact), hospital admission with meningitis or cerebral malaria (safety), deaths in girls compared with boys (safety), and vaccination coverage (feasibility). Mortality was monitored in children aged 1-59 months throughout the pilot areas. Surveillance for meningitis and severe malaria was established in eight sentinel hospitals in Ghana, six in Kenya, and four in Malawi. Vaccine uptake was measured in surveys of children aged 12-23 months about 18 months after vaccine introduction. We estimated that sufficient data would have accrued after 24 months to evaluate each of the safety signals and the impact on severe malaria in a pooled analysis of the data from the three countries. We estimated incidence rate ratios (IRRs) by comparing the ratio of the number of events in children age-eligible to have received at least one dose of the vaccine (for safety outcomes), or age-eligible to have received three doses (for impact outcomes), to that in non-eligible age groups in implementation areas with the equivalent ratio in comparison areas. To establish whether there was evidence of a difference between girls and boys in the vaccine's impact on mortality, the female-to-male mortality ratio in age groups eligible to receive the vaccine (relative to the ratio in non-eligible children) was compared between implementation and comparison areas. Preliminary findings contributed to WHO's recommendation in 2021 for widespread use of RTS,S in areas of moderate-to-high malaria transmission. FINDINGS: By April 30, 2021, 652 673 children had received at least one dose of RTS,S and 494 745 children had received three doses. Coverage of the first dose was 76% in Ghana, 79% in Kenya, and 73% in Malawi, and coverage of the third dose was 66% in Ghana, 62% in Kenya, and 62% in Malawi. 26 285 children aged 1-59 months were admitted to sentinel hospitals and 13 198 deaths were reported through mortality surveillance. Among children eligible to have received at least one dose of RTS,S, there was no evidence of an excess of meningitis or cerebral malaria cases in implementation areas compared with comparison areas (hospital admission with meningitis: IRR 0·63 [95% CI 0·22-1·79]; hospital admission with cerebral malaria: IRR 1·03 [95% CI 0·61-1·74]). The impact of RTS,S introduction on mortality was similar for girls and boys (relative mortality ratio 1·03 [95% CI 0·88-1·21]). Among children eligible for three vaccine doses, RTS,S introduction was associated with a 32% reduction (95% CI 5-51%) in hospital admission with severe malaria, and a 9% reduction (95% CI 0-18%) in all-cause mortality (excluding injury). INTERPRETATION: In the first 2 years of implementation of RTS,S, the three primary doses were effectively deployed through national immunisation programmes. There was no evidence of the safety signals that had been observed in the phase 3 trial, and introduction of the vaccine was associated with substantial reductions in hospital admission with severe malaria. Evaluation continues to assess the impact of four doses of RTS,S. FUNDING: Gavi, the Vaccine Alliance; the Global Fund to Fight AIDS, Tuberculosis and Malaria; and Unitaid. |
Risk factors for severe COVID-19 among children and adolescents enrolled in acute respiratory infection sentinel surveillance in South Africa, 2020-2022
Bishop K , Meiring S , Tempia S , von Gottberg A , Wolter N , Kleynhans J , Moosa F , du Plessis M , Moyes J , Makhasi M , Chuene B , Samuels AM , Dawood H , Reubenson G , Zar HJ , Quan V , Cohen C , Walaza S . Influenza Other Respir Viruses 2024 18 (5) e13300 BACKGROUND: Identifying children at risk for severe COVID-19 disease from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) may guide future mitigation interventions. Using sentinel surveillance data, we aimed to identify risk factors for SARS-CoV-2-associated hospitalisation among patients aged ≤ 18 years with respiratory illness. METHODS: From April 2020 to March 2022, patients meeting study case definitions were enrolled at four outpatient influenza-like illness (ILI) and five inpatient severe respiratory infection (SRI) surveillance sites and tested for SARS-CoV-2 infection using polymerase chain reaction (PCR). Each ILI clinic shared a catchment area with its corresponding SRI hospital. Potential risk factors for SARS-CoV-2-associated hospitalisation were analysed using multivariable logistic regression by comparing inpatient versus outpatient SARS-CoV-2 cases. RESULTS: Of 4688 participants aged ≤ 18 years, 4556 (97%) with complete PCR and HIV data were included in the analysis. Among patients with ILI and SRI, 92/1145 (8%) and 154/3411 (5%) tested SARS-CoV-2 positive, respectively. Compared to outpatients, hospitalised SARS-CoV-2 cases were associated with age < 6 months ([adjusted odds ratio (aOR) 8.0, 95% confidence interval (CI) 2.7-24.0] versus 1-4 years); underlying medical condition other than HIV [aOR 5.8, 95% CI 2.3-14.6]; laboratory-confirmed Omicron BA.1/BA.2 or Delta variant ([aOR 4.9, 95% CI 1.7-14.2] or [aOR 2.8, 95% CI 1.1-7.3] compared to ancestral SARS-CoV-2); and respiratory syncytial virus coinfection [aOR 6.2, 95% CI 1.0-38.5]. CONCLUSION: Aligning with previous research, we identified age < 6 months or having an underlying condition as risk factors for SARS-CoV-2-associated SRI hospitalisation and demonstrated the potential of sentinel surveillance to monitor COVID-19 in children. |
Could less be more? Accounting for fractional-dose regimens and different number of vaccine doses when measuring the impact of the RTS, S/AS01E malaria vaccine
Westercamp N , Osei-Tutu L , Schuerman L , Kariuki SK , Bollaerts A , Lee CK , Samuels AM , Ockenhouse C , Bii DK , Adjei S , Oneko M , Lievens M , Attobrah Sarfo MA , Atieno C , Bakari A , Sang T , Kotoh-Mortty MF , Otieno K , Roman F , Buabeng PBY , Ntiamoah Y , Ansong D , Agbenyega T , Ofori-Anyinam O . J Infect Dis 2024 BACKGROUND: The RTS, S/AS01E malaria vaccine (RTS, S) is recommended for children in moderate-to-high Plasmodium falciparum malaria transmission areas. This phase 2b trial (NCT03276962) evaluates RTS, S fractional- and full-dose regimens in Ghana and Kenya. METHODS: 1500 children aged 5-17 months were randomised (1:1:1:1:1) to receive RTS, S or rabies control vaccine. RTS, S groups received two full RTS, S doses at month (M)0/M1 followed by either full (groups R012-20, R012-14-26) or fractional (1/5) doses (groups Fx012-14-26, Fx017-20-32). RESULTS: At M32 post-first dose, vaccine efficacy (VE) against clinical malaria (all episodes) ranged from 38% (R012-20; 95%CI: 24-49) to 53% (R012-14-26; 95%CI: 42-62). Vaccine impact estimates (cumulative number of malaria cases averted/1000 children vaccinated) were 1344 (R012-20), 2450 (R012-14-26), 2273 (Fx012-14-26), 2112 (Fx017-20-32). To account for differences in vaccine volume (fractional- versus full-dose), in a post-hoc analysis, we also estimated cases averted/1000 RTS, S full-dose equivalents: 336 (R012-20), 490 (R012-14-26), 874 (Fx012-14-26), 880 (Fx017-20-32). CONCLUSIONS: VE against clinical malaria was similar in all RTS, S groups. Vaccine impact accounting for full-dose equivalence suggests that using fractional-dose regimens could be a viable dose-sparing strategy. If borne out through trial end (M50), these observations underscore the means to reduce cost per regimen with a goal of maximising impact and optimising supply. |
Burden of child mortality from malaria in high endemic areas: results from the CHAMPS Network using minimally invasive tissue sampling
Ogbuanu IU , Otieno K , Varo R , Sow SO , Ojulong J , Duduyemi B , Kowuor D , Cain CJ , Rogena EA , Onyango D , Akelo V , Tippett Barr BA , terKuile F , Kotloff KL , Tapia MD , Keita AM , Juma J , Assefa N , Assegid N , Acham Y , Madrid L , Scott JAG , Arifeen SE , Gurley ES , Mahtab S , Dangor Z , Wadula J , Dutoit J , Madhi SA , Mandomando I , Torres-Fernandez D , Kincardett M , Mabunda R , Mutevedzi P , Madewell ZJ , Blau DM , Whitney CG , Samuels AM , Bassat Q . J Infect 2024 BACKGROUND: Malaria is a leading cause of childhood mortality worldwide. However, accurate estimates of malaria prevalence and causality among patients who die at the country level are lacking due to the limited specificity of diagnostic tools used to attribute etiologies. Accurate estimates are crucial for prioritizing interventions and resources aimed at reducing malaria-related mortality. METHODS: Seven Child Health and Mortality Prevention Surveillance (CHAMPS) Network sites collected comprehensive data on stillbirths and children <5 years, using minimally invasive tissue sampling (MITS). A DeCoDe (Determination of Cause of Death) panel employed standardized protocols for assigning underlying, intermediate, and immediate causes of death, integrating sociodemographic, clinical, laboratory (including extensive microbiology, histopathology, and malaria testing), and verbal autopsy data. Analyses were conducted to ascertain the strength of evidence for cause of death (CoD), describe factors associated with malaria-related deaths, estimate malaria-specific mortality, and assess the proportion of preventable deaths. FINDINGS: Between December 3, 2016, and December 31, 2022, 2673 deaths underwent MITS and had a CoD attributed from four CHAMPS sites with at least 1 malaria-attributed death. No malaria-attributable deaths were documented among 891 stillbirths or 924 neonatal deaths, therefore this analysis concentrates on the remaining 858 deaths among children aged 1-59 months. Malaria was in the causal chain for 42.9% (126/294) of deaths from Sierra Leone, 31.4% (96/306) in Kenya, 18.2% (36/198) in Mozambique, 6.7% (4/60) in Mali, and 0.3% (1/292) in South Africa. Compared to non-malaria related deaths, malaria-related deaths skewed towards older infants and children (p<0.001), with 71.0% among ages 12-59 months. Malaria was the sole infecting pathogen in 184 (70.2%) of malaria-attributed deaths, whereas bacterial and viral co-infections were identified in the causal pathway in 24·0% and 12.2% of cases, respectively. Malnutrition was found at a similar level in the causal pathway of both malaria (26.7%) and non-malaria (30.7%, p=0.256) deaths. Less than two-thirds (164/262; 62.6%) of malaria deaths had received antimalarials prior to death. Nearly all (98·9%) malaria-related deaths were deemed preventable. INTERPRETATION: Malaria remains a significant cause of childhood mortality in the CHAMPS malaria-endemic sites. The high bacterial co-infection prevalence among malaria deaths underscores the potential benefits of antibiotics for severe malaria patients. Compared to non-malaria deaths, many of malaria-attributed deaths are preventable through accessible malaria control measures. FUNDING: This work was supported by the Bill & Melinda Gates Foundation [OPP1126780]. |
The role of asymptomatic infections in influenza transmission: what do we really know
Montgomery MP , Morris SE , Rolfes MA , Kittikraisak W , Samuels AM , Biggerstaff M , Davis WW , Reed C , Olsen SJ . Lancet Infect Dis 2023 Before the COVID-19 pandemic, the role of asymptomatic influenza virus infections in influenza transmission was uncertain. However, the importance of asymptomatic infection with SARS-CoV-2 for onward transmission of COVID-19 has led experts to question whether the role of asymptomatic influenza virus infections in transmission had been underappreciated. We discuss the existing evidence on the frequency of asymptomatic influenza virus infections, the extent to which they contribute to infection transmission, and remaining knowledge gaps. We propose priority areas for further evaluation, study designs, and case definitions to address existing knowledge gaps. |
Post-discharge risk of mortality in children under 5 years of age in western Kenya: A retrospective cohort study
Kwambai TK , Kariuki S , Smit MR , Nevitt S , Onyango E , Oneko M , Khagayi S , Samuels AM , Hamel MJ , Laserson K , Desai M , Ter Kuile FO . Am J Trop Med Hyg 2023 109 (3) 704-712 Limited evidence suggests that children in sub-Saharan Africa hospitalized with all-cause severe anemia or severe acute malnutrition (SAM) are at high risk of dying in the first few months after discharge. We aimed to compare the risks of post-discharge mortality by health condition among hospitalized children in an area with high malaria transmission in western Kenya. We conducted a retrospective cohort study among recently discharged children aged < 5 years using mortality data from a health and demographic surveillance system that included household and pediatric in-hospital surveillance. Cox regression was used to compare post-discharge mortality. Between 2008 and 2013, overall in-hospital mortality was 2.8% (101/3,639). The mortality by 6 months after discharge (primary outcome) was 6.2% (159/2,556) and was highest in children with SAM (21.6%), followed by severe anemia (15.5%), severe pneumonia (5.6%), "other conditions" (5.6%), and severe malaria (0.7%). Overall, the 6-month post-discharge mortality in children hospitalized with SAM (hazard ratio [HR] = 3.95, 2.60-6.00, P < 0.001) or severe anemia (HR = 2.55, 1.74-3.71, P < 0.001) was significantly higher than that in children without these conditions. Severe malaria was associated with lower 6-month post-discharge mortality than children without severe malaria (HR = 0.33, 0.21-0.53, P < 0.001). The odds of dying by 6 months after discharge tended to be higher than during the in-hospital period for all children, except for those admitted with severe malaria. The first 6 months after discharge is a high-risk period for mortality among children admitted with severe anemia and SAM in western Kenya. Strategies to address this risk period are urgently needed. |
Evaluation of community-based vector surveillance system for routine entomological monitoring under low malaria vector densities and high bed net coverage in western Kenya
Abong'o B , Stanton MC , Donnelly MJ , Ochomo E , Ter Kuile FO , Samuels AM , Kariuki S , Musula G , Oxborough R , Munga S , Torr SJ , Gimnig JE . Malar J 2023 22 (1) 203 BACKGROUND: Entomological surveillance is traditionally conducted by supervised teams of trained technicians. However, it is expensive and limiting in the number of sites visited. Surveillance through community-based collectors (CBC) may be more cost-effective and sustainable for longitudinal entomological monitoring. This study evaluated the efficiency of CBCs in monitoring mosquito densities compared to quality-assured sampling conducted by experienced entomology technicians. METHODS: Entomological surveillance employing CBCs was conducted in eighteen clusters of villages in western Kenya using indoor and outdoor CDC light traps and indoor Prokopack aspiration. Sixty houses in each cluster were enrolled and sampled once every month. Collected mosquitoes were initially identified to the genus level by CBCs, preserved in 70% ethanol and transferred to the laboratory every 2 weeks. Parallel, collections by experienced entomology field technicians were conducted monthly by indoor and outdoor CDC light traps and indoor Prokopack aspiration and served as a quality assurance of the CBCs. RESULTS: Per collection, the CBCs collected 80% fewer Anopheles gambiae sensu lato (s.l.) [RR = 0.2; (95% CI 0.14-0.27)] and Anopheles coustani [RR = 0.2; (95% CI 0.06-0.53)] and 90% fewer Anopheles funestus [RR = 0.1; (95% CI 0.08-0.19)] by CDC light traps compared to the quality assured (QA) entomology teams. Significant positive correlations were however observed between the monthly collections by CBCs and QA teams for both An. gambiae and An. funestus. In paired identifications of pooled mosquitoes, the CBCs identified 4.3 times more Anopheles compared to experienced technicians. The cost per person-night was lower in the community-based sampling at $9.1 compared to $89.3 by QA per collection effort. CONCLUSION: Unsupervised community-based mosquito surveillance collected substantially fewer mosquitoes per trap-night compared to quality-assured collection by experienced field teams, while consistently overestimating the number of Anopheles mosquitoes during identification. However, the numbers collected were significantly correlated between the CBCs and the QA teams suggesting that trends observed by CBCs and QA teams were similar. Further studies are needed to evaluate whether adopting low-cost, devolved supervision with spot checks, coupled with remedial training of the CBCs, can improve community-based collections to be considered a cost-effective alternative to surveillance conducted by experienced entomological technicians. |
Malaria in pregnancy (MiP) studies assessing the clinical performance of highly sensitive rapid diagnostic tests (HS-RDT) for Plasmodium falciparum detection.
Ding XC , Incardona S , Serra-Casas E , Charnaud SC , Slater HC , Domingo GJ , Adams ER , Ter Kuile FO , Samuels AM , Kariuki S , Dittrich S . Malar J 2023 22 (1) 60 BACKGROUND: Rapid diagnostic tests (RDTs) are effective tools to diagnose and inform the treatment of malaria in adults and children. The recent development of a highly sensitive rapid diagnostic test (HS-RDT) for Plasmodium falciparum has prompted questions over whether it could improve the diagnosis of malaria in pregnancy and pregnancy outcomes in malaria endemic areas. METHODS: This landscape review collates studies addressing the clinical performance of the HS-RDT. Thirteen studies were identified comparing the HS-RDT and conventional RDT (co-RDT) to molecular methods to detect malaria in pregnancy. Using data from five completed studies, the association of epidemiological and pregnancy-related factors on the sensitivity of HS-RDT, and comparisons with co-RDT were investigated. The studies were conducted in 4 countries over a range of transmission intensities in largely asymptomatic women. RESULTS: Sensitivity of both RDTs varied widely (HS-RDT range 19.6 to 85.7%, co-RDT range 22.8 to 82.8% compared to molecular testing) yet HS-RDT detected individuals with similar parasite densities across all the studies including different geographies and transmission areas [geometric mean parasitaemia around 100 parasites per µL (p/µL)]. HS-RDTs were capable of detecting low-density parasitaemias and in one study detected around 30% of infections with parasite densities of 0-2 p/µL compared to the co-RDT in the same study which detected around 15%. CONCLUSION: The HS-RDT has a slightly higher analytical sensitivity to detect malaria infections in pregnancy than co-RDT but this mostly translates to only fractional and not statistically significant improvement in clinical performance by gravidity, trimester, geography or transmission intensity. The analysis presented here highlights the need for larger and more studies to evaluate incremental improvements in RDTs. The HS-RDT could be used in any situation where co-RDT are currently used for P. falciparum diagnosis, if storage conditions can be adhered to. |
Natural sugar feeding rates of Anopheles mosquitoes collected by different methods in western Kenya
Omondi S , Kosgei J , Agumba S , Polo B , Yalla N , Moshi V , Abong'o B , Ombok M , McDermott DP , Entwistle J , Samuels AM , Ter Kuile FO , Gimnig JE , Ochomo E . Sci Rep 2022 12 (1) 20596 Attractive targeted sugar baits (ATSBs) are a potential vector control tool that exploits the sugar-feeding behaviour of mosquitoes. We evaluated the sugar-feeding behaviour of Anopheles mosquitoes as part of baseline studies for cluster randomised controlled trials of ATSBs. Mosquitoes were collected indoors and outdoors from two villages in western Kenya using prokopack aspirations, malaise tent traps and ultraviolet (UV) light traps. Individual mosquitoes were subjected to the cold anthrone test to assess the presence of sugar. Overall, 15.7% of collected mosquitoes had fed on natural sugar sources. By species and sex, the proportion sugar-fed was 41.3% and 27.7% in male and female Anopheles funestus, 27.2% and 12.8% in male and female An. arabiensis, and 9.7% and 8.3% in male and female An. coustani, respectively. Sugar-feeding was higher in unfed than blood-fed mosquitoes and higher in male than gravid mosquitoes. Anopheles mosquitoes obtained sugar meals from natural sources during all physiological stages, whether they rest indoors or outdoors. These findings offer a potential avenue to exploit for the control of mosquitoes, particularly with the advent of ATSBs, which have been shown to reduce mosquito densities in other regions. |
Novel application of one-step pooled molecular testing and maximum likelihood approaches to estimate the prevalence of malaria parasitaemia among rapid diagnostic test negative samples in western Kenya.
Shah MP , Chebore W , Lyles RH , Otieno K , Zhou Z , Plucinski M , Waller LA , Odongo W , Lindblade KA , Kariuki S , Samuels AM , Desai M , Mitchell RM , Shi YP . Malar J 2022 21 (1) 319 BACKGROUND: Detection of malaria parasitaemia in samples that are negative by rapid diagnostic tests (RDTs) requires resource-intensive molecular tools. While pooled testing using a two-step strategy provides a cost-saving alternative to the gold standard of individual sample testing, statistical adjustments are needed to improve accuracy of prevalence estimates for a single step pooled testing strategy. METHODS: A random sample of 4670 malaria RDT negative dried blood spot samples were selected from a mass testing and treatment trial in Asembo, Gem, and Karemo, western Kenya. Samples were tested for malaria individually and in pools of five, 934 pools, by one-step quantitative polymerase chain reaction (qPCR). Maximum likelihood approaches were used to estimate subpatent parasitaemia (RDT-negative, qPCR-positive) prevalence by pooling, assuming poolwise sensitivity and specificity was either 100% (strategy A) or imperfect (strategy B). To improve and illustrate the practicality of this estimation approach, a validation study was constructed from pools allocated at random into main (734 pools) and validation (200 pools) subsets. Prevalence was estimated using strategies A and B and an inverse-variance weighted estimator and estimates were weighted to account for differential sampling rates by area. RESULTS: The prevalence of subpatent parasitaemia was 14.5% (95% CI 13.6-15.3%) by individual qPCR, 9.5% (95% CI (8.5-10.5%) by strategy A, and 13.9% (95% CI 12.6-15.2%) by strategy B. In the validation study, the prevalence by individual qPCR was 13.5% (95% CI 12.4-14.7%) in the main subset, 8.9% (95% CI 7.9-9.9%) by strategy A, 11.4% (95% CI 9.9-12.9%) by strategy B, and 12.8% (95% CI 11.2-14.3%) using inverse-variance weighted estimator from poolwise validation. Pooling, including a 20% validation subset, reduced costs by 52% compared to individual testing. CONCLUSIONS: Compared to individual testing, a one-step pooled testing strategy with an internal validation subset can provide accurate prevalence estimates of PCR-positivity among RDT-negatives at a lower cost. |
Safety of single-dose primaquine as a Plasmodium falciparum gametocytocide: a systematic review and meta-analysis of individual patient data
Stepniewska K , Allen EN , Humphreys GS , Poirot E , Craig E , Kennon K , Yilma D , Bousema T , Guerin PJ , White NJ , Price RN , Raman J , Martensson A , Mwaiswelo RO , Bancone G , Bastiaens GJH , Bjorkman A , Brown JM , D'Alessandro U , Dicko AA , El-Sayed B , Elzaki SE , Eziefula AC , Gonçalves BP , Hamid MMA , Kaneko A , Kariuki S , Khan W , Kwambai TK , Ley B , Ngasala BE , Nosten F , Okebe J , Samuels AM , Smit MR , Stone WJR , Sutanto I , Ter Kuile F , Tine RC , Tiono AB , Drakeley CJ , Gosling R , Stergachis A , Barnes KI , Chen I . BMC Med 2022 20 (1) 350 BACKGROUND: In 2012, the World Health Organization (WHO) recommended single low-dose (SLD, 0.25 mg/kg) primaquine to be added as a Plasmodium (P.) falciparum gametocytocide to artemisinin-based combination therapy (ACT) without glucose-6-phosphate dehydrogenase (G6PD) testing, to accelerate malaria elimination efforts and avoid the spread of artemisinin resistance. Uptake of this recommendation has been relatively slow primarily due to safety concerns. METHODS: A systematic review and individual patient data (IPD) meta-analysis of single-dose (SD) primaquine studies for P. falciparum malaria were performed. Absolute and fractional changes in haemoglobin concentration within a week and adverse effects within 28 days of treatment initiation were characterised and compared between primaquine and no primaquine arms using random intercept models. RESULTS: Data comprised 20 studies that enrolled 6406 participants, of whom 5129 (80.1%) had received a single target dose of primaquine ranging between 0.0625 and 0.75 mg/kg. There was no effect of primaquine in G6PD-normal participants on haemoglobin concentrations. However, among 194 G6PD-deficient African participants, a 0.25 mg/kg primaquine target dose resulted in an additional 0.53 g/dL (95% CI 0.17-0.89) reduction in haemoglobin concentration by day 7, with a 0.27 (95% CI 0.19-0.34) g/dL haemoglobin drop estimated for every 0.1 mg/kg increase in primaquine dose. Baseline haemoglobin, young age, and hyperparasitaemia were the main determinants of becoming anaemic (Hb < 10 g/dL), with the nadir observed on ACT day 2 or 3, regardless of G6PD status and exposure to primaquine. Time to recovery from anaemia took longer in young children and those with baseline anaemia or hyperparasitaemia. Serious adverse haematological events after primaquine were few (9/3, 113, 0.3%) and transitory. One blood transfusion was reported in the primaquine arms, and there were no primaquine-related deaths. In controlled studies, the proportions with either haematological or any serious adverse event were similar between primaquine and no primaquine arms. CONCLUSIONS: Our results support the WHO recommendation to use 0.25 mg/kg of primaquine as a P. falciparum gametocytocide, including in G6PD-deficient individuals. Although primaquine is associated with a transient reduction in haemoglobin levels in G6PD-deficient individuals, haemoglobin levels at clinical presentation are the major determinants of anaemia in these patients. TRIAL REGISTRATION: PROSPERO, CRD42019128185. |
Temporal trends in molecular markers of drug resistance in Plasmodium falciparum in human blood and profiles of corresponding resistant markers in mosquito oocysts in Asembo, western Kenya.
Zhou Z , Gimnig JE , Sergent SB , Liu Y , Abong'o B , Otieno K , Chebore W , Shah MP , Williamson J , Ter Kuile FO , Hamel MJ , Kariuki S , Desai M , Samuels AM , Walker ED , Shi YP . Malar J 2022 21 (1) 265 BACKGROUND: Over the last two decades, the scale-up of vector control and changes in the first-line anti-malarial, from chloroquine (CQ) to sulfadoxine-pyrimethamine (SP) and then to artemether-lumefantrine (AL), have resulted in significant decreases in malaria burden in western Kenya. This study evaluated the long-term effects of control interventions on molecular markers of Plasmodium falciparum drug resistance using parasites obtained from humans and mosquitoes at discrete time points. METHODS: Dried blood spot samples collected in 2012 and 2017 community surveys in Asembo, Kenya were genotyped by Sanger sequencing for markers associated with resistance to SP (Pfdhfr, Pfdhps), CQ, AQ, lumefantrine (Pfcrt, Pfmdr1) and artemisinin (Pfk13). Temporal trends in the prevalence of these markers, including data from 2012 to 2017 as well as published data from 1996, 2001, 2007 from same area, were analysed. The same markers from mosquito oocysts collected in 2012 were compared with results from human blood samples. RESULTS: The prevalence of SP dhfr/dhps quintuple mutant haplotype C(50)I(51)R(59)N(108)I(164)/S(436)G(437)E(540)A(581)A(613) increased from 19.7% in 1996 to 86.0% in 2012, while an increase in the sextuple mutant haplotype C(50)I(51)R(59)N(108)I(164)/H(436)G(437)E(540)A(581)A(613) containing Pfdhps-436H was found from 10.5% in 2012 to 34.6% in 2017. Resistant Pfcrt-76 T declined from 94.6% in 2007 to 18.3% in 2012 and 0.9% in 2017. Mutant Pfmdr1-86Y decreased across years from 74.8% in 1996 to zero in 2017, mutant Pfmdr1-184F and wild Pfmdr1-D1246 increased from 17.9% to 58.9% in 2007 to 55.9% and 90.1% in 2017, respectively. Pfmdr1 haplotype N(86)F(184)S(1034)N(1042)D(1246) increased from 11.0% in 2007 to 49.6% in 2017. No resistant mutations in Pfk13 were found. Prevalence of Pfdhps-436H was lower while prevalence of Pfcrt-76 T was higher in mosquitoes than in human blood samples. CONCLUSION: This study showed an increased prevalence of dhfr/dhps resistant markers over 20 years with the emergence of Pfdhps-436H mutant a decade ago in Asembo. The reversal of Pfcrt from CQ-resistant to CQ-sensitive genotype occurred following 19 years of CQ withdrawal. No Pfk13 markers associated with artemisinin resistance were detected, but the increased haplotype of Pfmdr1 N(86)F(184)S(1034)N(1042)D(1246) was observed. The differences in prevalence of Pfdhps-436H and Pfcrt-76 T SNPs between two hosts and the role of mosquitoes in the transmission of drug resistant parasites require further investigation. |
Efficacy of artemether-lumefantrine and dihydroartemisinin-piperaquine for the treatment of uncomplicated plasmodium falciparum malaria among children in Western Kenya, 2016 to 2017
Westercamp N , Owidhi M , Otieno K , Chebore W , Buff AM , Desai M , Kariuki S , Samuels AM . Antimicrob Agents Chemother 2022 66 (9) e0020722 Antimalarial resistance threatens global malaria control efforts. The World Health Organization (WHO) recommends routine antimalarial efficacy monitoring through a standardized therapeutic efficacy study (TES) protocol. From June 2016 to March 2017, children with uncomplicated P. falciparum mono-infection in Siaya County, Kenya were enrolled into a standardized TES and randomized (1:1 ratio) to a 3-day course of artemether-lumefantrine (AL) or dihydroartemisinin-piperaquine (DP). Efficacy outcomes were measured at 28 and 42 days. A total of 340 children were enrolled. All but one child cleared parasites by day 3. PCR-corrected adequate clinical and parasitological response (ACPR) was 88.5% (95% CI: 80.9 to 93.3%) at day 28 for AL and 93.0% (95% CI: 86.9 to 96.4%) at day 42 for DP. There were 9.6 times (95% CI: 3.4 to 27.2) more reinfections in the AL arm compared to the DP arm at day 28, and 3.1 times (95% CI: 1.9 to 4.9) more reinfections at day 42. Both AL and DP were efficacious (per WHO 90% cutoff in the confidence interval) and well tolerated for the treatment of uncomplicated malaria in western Kenya, but AL efficacy appears to be waning. Further efficacy monitoring for AL, including pharmacokinetic studies, is recommended. |
Diagnostic performance of loop-mediated isothermal amplification and ultra-sensitive rapid diagnostic tests for malaria screening among pregnant women in Kenya.
Samuels AM , Towett O , Seda B , Wiegand RE , Otieno K , Chomba M , Lucchi N , Ljolje D , Schneider K , Gt P , Kwambai TK , Slutsker L , TerKuile FO , Kariuki SK . J Infect Dis 2022 226 (4) 696-707 BACKGROUND: Screen-and-treat strategies with sensitive diagnostic tests may reduce malaria-associated adverse pregnancy outcomes. We conducted a diagnostic accuracy study to evaluate new point-of-care tests to screen pregnant women for malaria at their first antenatal visit in western Kenya. METHODS: Consecutively women were tested for Plasmodium infection by expert-microscopy, conventional rapid diagnostic test (cRDT), ultra-sensitive RDT (usRDT), and loop-mediated isothermal amplification (LAMP). Photo-induced electron-transfer polymerase-chain-reaction (PET-PCR) served as the reference standard. Diagnostic performance was calculated and modelled at low parasite densities. RESULTS: Between May-September 2018, 172 out of 482 screened participants (35.7%) were PET-PCR positive. Relative to PET-PCR, expert-microscopy was least sensitive (40.1%, 95% CI 32.7-47.9), followed by cRDT (49.4%, 41.7-57.1), usRDT (54.7%, 46.9-62.2), and LAMP (68.6%, 61.1-75.5). Test sensitivities were comparable in febrile women (N=90). Among afebrile women (N=392), the geometric-mean parasite density was 29 parasites/L and LAMP (sensitivity=61.9%) and usRDT (43.2%) detected 1.74 (1.31-2.30) and 1.21 (0.88-2.21) more infections than cRDT (35.6%). Per our model, tests performed similarly at densities >200 parasites/L. At 50 parasites/L, the sensitivities were 45%, 56%, 62% and 74% with expert-microscopy, cRDT, usRDT, and LAMP, respectively. CONCLUSIONS: This first-generation usRDT provided moderate improvement in detecting low-density infections in afebrile pregnant women compared to cRDTs. |
Efficacy of RTS,S/AS01(E) malaria vaccine administered according to different full, fractional, and delayed third or early fourth dose regimens in children aged 5-17 months in Ghana and Kenya: an open-label, phase 2b, randomised controlled trial
Samuels AM , Ansong D , Kariuki SK , Adjei S , Bollaerts A , Ockenhouse C , Westercamp N , Lee CK , Schuerman L , Bii DK , Osei-Tutu L , Oneko M , Lievens M , Attobrah Sarfo MA , Atieno C , Morelle D , Bakari A , Sang T , Jongert E , Kotoh-Mortty MF , Otieno K , Roman F , Buabeng PBY , Ntiamoah Y , Ofori-Anyinam O , Agbenyega T . Lancet Infect Dis 2022 22 (9) 1329-1342 BACKGROUND: Controlled infection studies in malaria-naive adults suggest increased vaccine efficacy for fractional-dose versus full-dose regimens of RTS,S/AS01. We report first results of an ongoing trial assessing different fractional-dose regimens in children, in natural exposure settings. METHODS: This open-label, phase 2b, randomised controlled trial is conducted at the Malaria Research Center, Agogo, Ashanti Region (Ghana), and the Kenya Medical Research Institute and the US Centers for Disease Control and Prevention site in Siaya County (Kenya). We enrolled children aged 5-17 months without serious acute or chronic illness who had previously received three doses of diphtheria, tetanus, pertussis, and hepatitis B vaccine and at least three doses of oral polio vaccine. Children were randomly assigned (1:1:1:1:1) using a web-based randomisation system with a minimisation procedure accounting for centre to receive rabies control vaccine (M012 schedule) or two full doses of RTS,S/AS01(E) at month 0 and month 1, followed by either full doses at months 2 and 20 (group R012-20 [standard regimen]), full doses at months 2, 14, 26, and 38 (R012-14), fractional doses at months 2, 14, 26, and 38 (Fx012-14), or fractional doses at months 7, 20, and 32 (Fx017-20). The fractional doses were administered as one fifth (0·1 mL) of the full RTS,S dose (0·5 mL) after reconstitution. All vaccines were administered by intramuscular injection in the left deltoid. The primary outcome was occurrence of clinical malaria cases from month 2·5 until month 14 for the Fx012-14 group versus the pooled R012-14 and R012-20 groups in the per-protocol set. We assessed incremental vaccine efficacy of the Fx012-14 group versus the pooled R012-14 and R012-20 group over 12 months after dose three. Safety was assessed in all children who received at least one vaccine dose. This trial is registered with ClinicalTrials.gov, NCT03276962. FINDINGS: Between Sept 28, 2017, and Sept 25, 2018, 2157 children were enrolled, of whom 1609 were randomly assigned to a treatment group (322 to each RTS,S/AS01(E) group and 321 to the rabies vaccine control group). 1500 children received at least one study vaccine dose and the per-protocol set comprised 1332 children. Over 12 months after dose three, the incremental vaccine efficacy in the Fx012-14 group versus the pooled R012-14 and R12-20 groups was -21% (95% CI -57 to 7; p=0·15). Up to month 21, serious adverse events occurred in 48 (16%) of 298 children in the R012-20 group, 45 (15%) of 294 in the R012-14 group, 47 (15%) of 304 in the Fx012-14 group, 62 (20%) of 311 in the Fx017-20 group, and 71 (24%) of 293 in the control group, with no safety signals observed. INTERPRETATION: The Fx012-14 regimen was not superior to the standard regimen over 12 months after dose three. All RTS,S/AS01(E) regimens provided substantial, similar protection against clinical malaria, suggesting potential flexibility in the recommended dosing regimen and schedule. This, and the effect of annual boosters, will be further evaluated through 50 months of follow-up. FUNDING: GlaxoSmithKline Biologicals; PATH's Malaria Vaccine Initiative. |
Post-discharge morbidity and mortality in children admitted with severe anaemia and other health conditions in malaria-endemic settings in Africa: a systematic review and meta-analysis
Kwambai TK , Mori AT , Nevitt S , van Eijk AM , Samuels AM , Robberstad B , Phiri KS , Ter Kuile FO . Lancet Child Adolesc Health 2022 6 (7) 474-483 BACKGROUND: Severe anaemia is associated with high in-hospital mortality among young children. In malaria-endemic areas, surviving children also remain at increased risk of mortality for several months after hospital discharge. We aimed to compare the risks of morbidity and mortality among children discharged from hospital after recovery from severe anaemia versus other health conditions in malaria-endemic settings in Africa. METHODS: Following PRISMA guidelines, we searched PubMed, Scopus, Web of Science, and Cochrane Central from inception to Nov 30, 2021, without language restrictions, for prospective or retrospective cohort studies and randomised controlled trials that followed up children younger than 15 years for defined periods after hospital discharge in malaria-endemic countries in Africa. We excluded the intervention groups in trials and studies or subgroups involving children with sickle cell anaemia, malignancies, or surgery or trauma, or those reporting follow-up data that were combined with the in-hospital period. Two independent reviewers extracted the data and assessed the quality and risk of bias using the Newcastle Ottawa Scale or the Cochrane Collaboration's tool. The coprimary outcomes were all-cause death and all-cause readmissions 6 months after discharge. This study is registered with PROSPERO, CRD42017079282. FINDINGS: Of 2930 articles identified in our search, 27 studies were included. For children who were recently discharged following hospital admission with severe anaemia, all-cause mortality by 6 months was higher than during the in-hospital period (n=5 studies; Mantel-Haenszel odds ratio 1·72, 95% CI 1·22-2·44; p=0·0020; I(2)=51·5%) and more than two times higher than children previously admitted without severe anaemia (n=4 studies; relative risk [RR] 2·69, 95% CI 1·59-4·53; p<0·0001; I(2)=69·2%). Readmissions within 6 months of discharge were also more common in children admitted with severe anaemia than in children admitted with other conditions (n=1 study; RR 3·05, 1·12-8·35; p<0·0001). Children admitted with severe acute malnutrition (regardless of severe anaemia) also had a higher 6-month mortality after discharge than those admitted for other reasons (n=2 studies; RR=3·12, 2·02-4·68; p<0·0001; I(2)=54·7%). Other predictors of mortality after discharge included discharge against medical advice, HIV, bacteraemia, and hypoxia. INTERPRETATION: In malaria-endemic settings in Africa, children admitted to hospital with severe anaemia and severe acute malnutrition are at increased risk of mortality in the first 6 months after discharge compared with children admitted with other health conditions. Improved strategies are needed for the management of these high-risk groups during the period after discharge. FUNDING: Research Council of Norway and US Centers for Disease Control and Prevention. |
Evaluation of the protective efficacy of a spatial repellent to reduce malaria incidence in children in western Kenya compared to placebo: study protocol for a cluster-randomized double-blinded control trial (the AEGIS program)
Ochomo EO , Gimnig JE , Bhattarai A , Samuels AM , Kariuki S , Okello G , Abong'o B , Ouma EA , Kosgei J , Munga S , Njagi K , Odongo W , Liu F , Grieco JP , Achee NL . Trials 2022 23 (1) 260 BACKGROUND: Spatial repellents are widely used for prevention of mosquito bites and evidence is building on their public health value, but their efficacy against malaria incidence has never been evaluated in Africa. To address this knowledge gap, a trial to evaluate the efficacy of Mosquito Shield™, a spatial repellent incorporating transfluthrin, was developed for implementation in Busia County, western Kenya where long-lasting insecticidal net coverage is high and baseline malaria transmission is moderate to high year-round. METHODS: This trial is designed as a cluster-randomized, placebo-controlled, double-blinded clinical trial. Sixty clusters will be randomly assigned in a 1:1 ratio to receive spatial repellent or placebo. A total of 6120 children aged ≥6 months to 10 years of age will be randomly selected from the study clusters, enrolled into an active cohort (baseline, cohort 1, and cohort 2), and sampled monthly to determine time to first infection by smear microscopy. Each cohort following the implementation of the intervention will be split into two groups, one to estimate direct effect of the spatial repellent and the other to estimate degree of diversion of mosquitoes and malaria transmission to unprotected persons. Malaria incidence in each cohort will be estimated and compared (primary indicator) to determine benefit of using a spatial repellent in a high, year-round malaria transmission setting. Mosquitoes will be collected monthly using CDC light traps to determine if there are entomological correlates of spatial repellent efficacy that may be useful for the evaluation of new spatial repellents. Quarterly human landing catches will assess behavioral effects of the intervention. DISCUSSION: Findings will serve as the first cluster-randomized controlled trial powered to detect spatial repellent efficacy to reduce malaria in sub-Saharan Africa where transmission rates are high, insecticide-treated nets are widely deployed, and mosquitoes are resistant to insecticides. Results will be submitted to the World Health Organization Vector Control Advisory Group for assessment of public health value towards an endorsement to recommend inclusion of spatial repellents in malaria control programs. TRIAL REGISTRATION: ClinicalTrials.gov NCT04766879 . Registered February 23, 2021. |
Plasmodium falciparum pfhrp2 and pfhrp3 gene deletions from persons with symptomatic malaria infection in Ethiopia, Kenya, Madagascar, and Rwanda
Rogier E , McCaffery JN , Nace D , Svigel SS , Assefa A , Hwang J , Kariuki S , Samuels AM , Westercamp N , Ratsimbasoa A , Randrianarivelojosia M , Uwimana A , Udhayakumar V , Halsey ES . Emerg Infect Dis 2022 28 (3) 608-616 Histidine-rich protein 2 (HRP2)-based rapid diagnostic tests detect Plasmodium falciparum malaria and are used throughout sub-Saharan Africa. However, deletions in the pfhrp2 and related pfhrp3 (pfhrp2/3) genes threaten use of these tests. Therapeutic efficacy studies (TESs) enroll persons with symptomatic P. falciparum infection. We screened TES samples collected during 2016-2018 in Ethiopia, Kenya, Rwanda, and Madagascar for HRP2/3, pan-Plasmodium lactate dehydrogenase, and pan-Plasmodium aldolase antigen levels and selected samples with low levels of HRP2/3 for pfhrp2/3 genotyping. We observed deletion of pfhrp3 in samples from all countries except Kenya. Single-gene deletions in pfhrp2 were observed in 1.4% (95% CI 0.2%-4.8%) of Ethiopia samples and in 0.6% (95% CI 0.2%-1.6%) of Madagascar samples, and dual pfhrp2/3 deletions were noted in 2.0% (95% CI 0.4%-5.9%) of Ethiopia samples. Although this study was not powered for precise prevalence estimates, evaluating TES samples revealed a low prevalence of pfhrp2/3 deletions in most sites. |
Safety, immunogenicity and efficacy of PfSPZ vaccine against malaria in infants in western Kenya: a double-blind, randomized, placebo-controlled phase 2 trial
Oneko M , Steinhardt LC , Yego R , Wiegand RE , Swanson PA , Kc N , Akach D , Sang T , Gutman JR , Nzuu EL , Dungani A , Kim Lee Sim B , Oloo PN , Otieno K , Bii DK , Billingsley PF , James ER , Kariuki S , Samuels AM , Jongo S , Chebore W , Abdulla S , Daubenberger C , Mpina M , Styers D , Potter GE , Abarbanell G , Richie TL , Hoffman SL , Seder RA . Nat Med 2021 27 (9) 1636-1645 The radiation-attenuated Plasmodium falciparum sporozoite (PfSPZ) vaccine provides protection against P. falciparum infection in malaria-naïve adults. Preclinical studies show that T cell-mediated immunity is required for protection and is readily induced in humans after vaccination. However, previous malaria exposure can limit immune responses and vaccine efficacy (VE) in adults. We hypothesized that infants with less previous exposure to malaria would have improved immunity and protection. We conducted a multi-arm, randomized, double-blind, placebo-controlled trial in 336 infants aged 5-12 months to determine the safety, tolerability, immunogenicity and efficacy of the PfSPZ Vaccine in infants in a high-transmission malaria setting in western Kenya ( NCT02687373 ). Groups of 84 infants each received 4.5 × 10(5), 9.0 × 10(5) or 1.8 × 10(6) PfSPZ Vaccine or saline three times at 8-week intervals. The vaccine was well tolerated; 52 (20.6%) children in the vaccine groups and 20 (23.8%) in the placebo group experienced related solicited adverse events (AEs) within 28 d postvaccination and most were mild. There was 1 grade 3-related solicited AE in the vaccine group (0.4%) and 2 in the placebo group (2.4%). Seizures were more common in the highest-dose group (14.3%) compared to 6.0% of controls, with most being attributed to malaria. There was no significant protection against P. falciparum infection in any dose group at 6 months (VE in the 9.0 × 10(5) dose group = -6.5%, P = 0.598, the primary statistical end point of the study). VE against clinical malaria 3 months after the last dose in the highest-dose group was 45.8% (P = 0.027), an exploratory end point. There was a dose-dependent increase in antibody responses that correlated with VE at 6 months in the lowest- and highest-dose groups. T cell responses were undetectable across all dose groups. Detection of Vδ2(+)Vγ9(+) T cells, which have been correlated with induction of PfSPZ Vaccine T cell immunity and protection in adults, were infrequent. These data suggest that PfSPZ Vaccine-induced T cell immunity is age-dependent and may be influenced by Vδ2(+)Vγ9(+) T cell frequency. Since there was no significant VE at 6 months in these infants, these vaccine regimens will likely not be pursued further in this age group. |
Plasmodium falciparum kelch 13 Mutations, 9 Countries in Africa, 2014-2018.
Schmedes SE , Patel D , Dhal S , Kelley J , Svigel SS , Dimbu PR , Adeothy AL , Kahunu GM , Nkoli PM , Beavogui AH , Kariuki S , Mathanga DP , Koita O , Ishengoma D , Mohamad A , Hawela M , Moriarty LF , Samuels AM , Gutman J , Plucinski MM , Udhayakumar V , Zhou Z , Lucchi NW , Venkatesan M , Halsey ES , Talundzic E . Emerg Infect Dis 2021 27 (7) 1902-1908 The spread of drug resistance to antimalarial treatments poses a serious public health risk globally. To combat this risk, molecular surveillance of drug resistance is imperative. We report the prevalence of mutations in the Plasmodium falciparum kelch 13 propeller domain associated with partial artemisinin resistance, which we determined by using Sanger sequencing samples from patients enrolled in therapeutic efficacy studies from 9 sub-Saharan countries during 2014-2018. Of the 2,865 samples successfully sequenced before treatment (day of enrollment) and on the day of treatment failure, 29 (1.0%) samples contained 11 unique nonsynonymous mutations and 83 (2.9%) samples contained 27 unique synonymous mutations. Two samples from Kenya contained the S522C mutation, which has been associated with delayed parasite clearance; however, no samples contained validated or candidate artemisinin-resistance mutations. |
Mass testing and treatment on malaria in an area of western Kenya
Samuels AM , Odero NA , Odongo W , Otieno K , Were V , Shi YP , Sang T , Williamson J , Wiegand R , Hamel MJ , Kachur SP , Slutsker L , Lindblade KA , Kariuki SK , Desai MR . Clin Infect Dis 2021 72 (6) 1103-1104 We appreciate the thoughtful commentary provided by Hamer and Miller [1] and are pleased that they arrived at many of the same conclusions that we did; however, we would like to clarify a few points. | | First, we wish to correct the statement that, in our trial, mass testing and treatment (MTaT) was only implemented within the core areas of clusters. Rather, MTaT was implemented throughout intervention clusters, which included a core area ranging between 1 and 3 Km in diameter, and a 300-m buffer. As described, to limit contamination, inclusion criteria for the analytic sample required residence within the core area [2, 3]. |
Malaria chemoprevention in the postdischarge management of severe anemia
Kwambai TK , Dhabangi A , Idro R , Opoka R , Watson V , Kariuki S , Kuya NA , Onyango ED , Otieno K , Samuels AM , Desai MR , Boele van Hensbroek M , Wang D , John CC , Robberstad B , Phiri KS , Ter Kuile FO . N Engl J Med 2020 383 (23) 2242-2254 BACKGROUND: Children who have been hospitalized with severe anemia in areas of Africa in which malaria is endemic have a high risk of readmission and death within 6 months after discharge. No prevention strategy specifically addresses this period. METHODS: We conducted a multicenter, two-group, randomized, placebo-controlled trial in nine hospitals in Kenya and Uganda to determine whether 3 months of malaria chemoprevention could reduce morbidity and mortality after hospital discharge in children younger than 5 years of age who had been admitted with severe anemia. All children received standard in-hospital care for severe anemia and a 3-day course of artemether-lumefantrine at discharge. Two weeks after discharge, children were randomly assigned to receive dihydroartemisinin-piperaquine (chemoprevention group) or placebo, administered as 3-day courses at 2, 6, and 10 weeks after discharge. Children were followed for 26 weeks after discharge. The primary outcome was one or more hospital readmissions for any reason or death from the time of randomization to 6 months after discharge. Conditional risk-set modeling for recurrent events was used to calculate hazard ratios with the use of the Prentice-Williams-Peterson total-time approach. RESULTS: From May 2016 through May 2018, a total of 1049 children underwent randomization; 524 were assigned to the chemoprevention group and 525 to the placebo group. From week 3 through week 26, a total of 184 events of readmission or death occurred in the chemoprevention group and 316 occurred in the placebo group (hazard ratio, 0.65; 95% confidence interval [CI], 0.54 to 0.78; P<0.001). The lower incidence of readmission or death in the chemoprevention group than in the placebo group was restricted to the intervention period (week 3 through week 14) (hazard ratio, 0.30; 95% CI, 0.22 to 0.42) and was not sustained after that time (week 15 through week 26) (hazard ratio, 1.13; 95% CI, 0.87 to 1.47). No serious adverse events were attributed to dihydroartemisinin-piperaquine. CONCLUSIONS: In areas with intense malaria transmission, 3 months of postdischarge malaria chemoprevention with monthly dihydroartemisinin-piperaquine in children who had recently received treatment for severe anemia prevented more deaths or readmissions for any reason after discharge than placebo. (Funded by the Research Council of Norway and the Centers for Disease Control and Prevention; ClinicalTrials.gov number, NCT02671175.). |
Assessment of molecular markers of anti-malarial drug resistance among children participating in a therapeutic efficacy study in western Kenya.
Chebore W , Zhou Z , Westercamp N , Otieno K , Shi YP , Sergent SB , Rondini KA , Svigel SS , Guyah B , Udhayakumar V , Halsey ES , Samuels AM , Kariuki S . Malar J 2020 19 (1) 291 BACKGROUND: Anti-malarial drug resistance remains a major threat to global malaria control efforts. In Africa, Plasmodium falciparum remains susceptible to artemisinin-based combination therapy (ACT), but the emergence of resistant parasites in multiple countries in Southeast Asia and concerns over emergence and/or spread of resistant parasites in Africa warrants continuous monitoring. The World Health Organization recommends that surveillance for molecular markers of resistance be included within therapeutic efficacy studies (TES). The current study assessed molecular markers associated with resistance to Artemether-lumefantrine (AL) and Dihydroartemisinin-piperaquine (DP) from samples collected from children aged 6-59 months enrolled in a TES conducted in Siaya County, western Kenya from 2016 to 2017. METHODS: Three hundred and twenty-three samples collected pre-treatment (day-0) and 110 samples collected at the day of recurrent parasitaemia (up to day 42) were tested for the presence of drug resistance markers in the Pfk13 propeller domain, and the Pfmdr1 and Pfcrt genes by Sanger sequencing. Additionally, the Pfpm2 gene copy number was assessed by real-time polymerase chain reaction. RESULTS: No mutations previously associated with artemisinin resistance were detected in the Pfk13 propeller region. However, other non-synonymous mutations in the Pfk13 propeller region were detected. The most common mutation found on day-0 and at day of recurrence in the Pfmdr1 multidrug resistance marker was at codon 184F. Very few mutations were found in the Pfcrt marker (< 5%). Within the DP arm, all recrudescent cases (8 sample pairs) that were tested for Pfpm2 gene copy number had a single gene copy. None of the associations between observed mutations and treatment outcomes were statistically significant. CONCLUSION: The results indicate absence of Pfk13 mutations associated with parasite resistance to artemisinin in this area and a very high proportion of wild-type parasites for Pfcrt. Although the frequency of Pfmdr1 184F mutations was high in these samples, the association with treatment failure did not reach statistical significance. As the spread of artemisinin-resistant parasites remains a possibility, continued monitoring for molecular markers of ACT resistance is needed to complement clinical data to inform treatment policy in Kenya and other malaria-endemic regions. |
Efficacy of single dose primaquine with artemisinin combination therapy on P. falciparum gametocytes and transmission: A WWARN individual patient meta-analysis
Stepniewska K , Humphreys GS , Gonçalves BP , Craig E , Gosling R , Guerin PJ , Price RN , Barnes KI , Raman J , Smit MR , D'Alessandro U , Stone WJR , Bjorkman A , Samuels AM , Arroyo-Arroyo MI , Bastiaens GJH , Brown JM , Dicko A , El-Sayed BB , Elzaki SG , Eziefula AC , Kariuki S , Kwambai TK , Maestre AE , Martensson A , Mosha D , Mwaiswelo RO , Ngasala BE , Okebe J , Roh ME , Sawa P , Tiono AB , Chen I , Drakeley CJ , Bousema T . J Infect Dis 2020 225 (7) 1215-1226 BACKGROUND: Since the World Health Organization recommended single low-dose (0.25mg/kg) primaquine (PQ) in combination with artemisinin-based combination therapies (ACTs) in areas of low transmission or artemisinin-resistant P. falciparum, several single-site studies have been conducted to assess its efficacy. METHODS: An individual patient meta-analysis to assess the gametocytocidal and transmission-blocking efficacy of PQ used in combination with different ACTs was conducted. Random effects logistic regression was used to quantify PQ effect on (i) gametocyte carriage in the first two weeks post-treatment; (ii) the probability of infecting at least one mosquito or of a mosquito becoming infected. RESULTS: In 2,574 participants from fourteen studies, PQ reduced PCR-determined gametocyte carriage on days 7 and 14, most apparently in patients presenting with gametocytaemia on day 0 (Odds Ratio (OR)=0.22; 95%CI 0.17-0.28 and OR=0.12; 95%CI 0.08-0.16, respectively). The rate of decline in gametocyte carriage was faster when PQ was combined with artemether-lumefantrine (AL) compared to dihydroartemisinin-piperaquine (DP) (p=0.010 for day 7). Addition of 0.25mg/kg PQ was associated with near complete prevention of transmission to mosquitoes. CONCLUSION: Primaquine's transmission-blocking effects are achieved with 0.25 mg/kg PQ. Gametocyte persistence and infectivity are lower when PQ is combined with AL compared to DP. |
Malaria and Parasitic Neglected Tropical Diseases: Potential Syndemics with COVID-19?
Gutman JR , Lucchi NW , Cantey PT , Steinhardt LC , Samuels AM , Kamb ML , Kapella BK , McElroy PD , Udhayakumar V , Lindblade KA . Am J Trop Med Hyg 2020 103 (2) 572-577 The COVID-19 pandemic, caused by SARS-CoV-2, have surpassed 5 million cases globally. Current models suggest that low- and middle-income countries (LMICs) will have a similar incidence but substantially lower mortality rate than high-income countries. However, malaria and neglected tropical diseases (NTDs) are prevalent in LMICs, and coinfections are likely. Both malaria and parasitic NTDs can alter immunologic responses to other infectious agents. Malaria can induce a cytokine storm and pro-coagulant state similar to that seen in severe COVID-19. Consequently, coinfections with malaria parasites and SARS-CoV-2 could result in substantially worse outcomes than mono-infections with either pathogen, and could shift the age pattern of severe COVID-19 to younger age-groups. Enhancing surveillance platforms could provide signals that indicate whether malaria, NTDs, and COVID-19 are syndemics (synergistic epidemics). Based on the prevalence of malaria and NTDs in specific localities, efforts to characterize COVID-19 in LMICs could be expanded by adding testing for malaria and NTDs. Such additional testing would allow the determination of the rates of coinfection and comparison of severity of outcomes by infection status, greatly improving the understanding of the epidemiology of COVID-19 in LMICs and potentially helping to mitigate its impact. |
Feasibility of direct venous inoculation of the radiation-attenuated Plasmodium falciparum whole sporozoite vaccine in children and infants in Siaya, western Kenya
Oneko M , Cherop YR , Sang T , Gutman JR , Wiegand R , Nyang'au EM , Odila AD , Akach D , Hamel MJ , Samuels AM , Kariuki S , Abebe Y , Nzuu EL , Wijayalath W , James ER , Sim BKL , Billingsley PF , Richie TL , Hoffman SL , Seder RA , Steinhardt LC . Vaccine 2020 38 (29) 4592-4600 PfSPZ Vaccine, composed of radiation-attenuated, aseptic, purified, cryopreserved Plasmodium falciparum sporozoites, is administered by direct venous inoculation (DVI) for maximal efficacy against malaria. A critical issue for advancing vaccines that are administered intravenously is the ability to efficiently administer them across multiple age groups. As part of a pediatric safety, immunogenicity, and efficacy trial in western Kenya, we evaluated the feasibility and tolerability of DVI, including ease of venous access, injection time, and crying during the procedure across age groups. Part 1 was an age de-escalation, dose escalation trial in children aged 13 months-5 years and infants aged 5-12 months; part 2 was a vaccine efficacy trial including only infants, using the most skilled injectors from part 1. Injectors could use a vein viewer, if needed. A total of 1222 injections (target 0.5 mL) were initiated by DVI in 511 participants (36 were 5-9-year-olds, 65 were 13-59-month-olds, and 410 infants). The complete volume was injected in 1185/1222 (97.0%) vaccinations, 1083/1185 (91.4%) achieved with the first DVI. 474/511 (92.8%) participants received only complete injections, 27/511 (5.3%) received at least one partial injection (<0.5 mL), and in 10/511 (2.0%) venous access was not obtained. The rate of complete injections by single DVI for infants improved from 77.1% in part 1 to 92.8% in part 2. No crying occurred in 51/59 (86.4%) vaccinations in 5-9-year-olds, 25/86 (29.1%) vaccinations in 13-59-month-olds and 172/1067 (16.1%) vaccinations in infants. Mean administration time ranged from 2.6 to 4.6 minutes and was longer for younger age groups. These data show that vaccination by DVI was feasible and well tolerated in infants and children in this rural hospital in western Kenya, when performed by skilled injectors. We also report that shipping and storage in liquid nitrogen vapor phase was simple and efficient. (Clinicaltrials.gov NCT02687373). |
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