Evaluation of seasonal malaria chemoprevention in two areas of intense seasonal malaria transmission: Secondary analysis of a household-randomised, placebo-controlled trial in Houndé District, Burkina Faso and Bougouni District, Mali.

BACKGROUND: Seasonal malaria chemoprevention (SMC) is now widely deployed in the Sahel, including several countries that are major contributors to the global burden of malaria. Consequently, it is important to understand whether SMC continues to provide a high level of protection and how SMC might be improved. SMC was evaluated using data from a large, household-randomised trial in Houndé, Burkina Faso and Bougouni, Mali. METHODS AND FINDINGS: The parent trial evaluated monthly SMC plus either azithromycin (AZ) or placebo, administered as directly observed therapy 4 times per year between August and November (2014-2016). In July 2014, 19,578 children aged 3-59 months were randomised by household to study group. Children who remained within the age range 3-59 months in August each year, plus children born into study households or who moved into the study area, received study drugs in 2015 and 2016. These analyses focus on the approximately 10,000 children (5,000 per country) under observation each year in the SMC plus placebo group. Despite high coverage and high adherence to SMC, the incidence of hospitalisations or deaths due to malaria and uncomplicated clinical malaria remained high in the study areas (overall incidence rates 12.5 [95% confidence interval (CI): 11.2, 14.1] and 871.1 [95% CI: 852.3, 890.6] cases per 1,000 person-years, respectively) and peaked in July each year, before SMC delivery began in August. The incidence rate ratio comparing SMC within the past 28 days with SMC more than 35 days ago-adjusted for age, country, and household clustering-was 0.13 (95% CI: 0.08, 0.20), P < 0.001 for malaria hospitalisations and deaths from malaria and 0.21 (95% CI 0.20, 0.23), P < 0.001 for uncomplicated malaria, indicating protective efficacy of 87.4% (95% CI: 79.6%, 92.2%) and 78.3% (95% CI: 76.8%, 79.6%), respectively. The prevalence of malaria parasitaemia at weekly surveys during the rainy season and at the end of the transmission season was several times higher in children who missed the SMC course preceding the survey contact, and the smallest prevalence ratio observed was 2.98 (95% CI: 1.95, 4.54), P < 0.001. The frequency of molecular markers of sulfadoxine-pyrimethamine (SP) and amodiaquine (AQ) resistance did not increase markedly over the study period either amongst study children or amongst school-age children resident in the study areas. After 3 years of SMC deployment, the day 28 PCR-unadjusted adequate clinical and parasitological response rate of the SP + AQ regimen in children with asymptomatic malaria was 98.3% (95% CI: 88.6%, 99.8%) in Burkina Faso and 96.1% (95% CI: 91.5%, 98.2%) in Mali. Key limitations of this study are the potential overdiagnosis of uncomplicated malaria by rapid diagnostic tests and the potential for residual confounding from factors related to adherence to the monthly SMC schedule. CONCLUSION: Despite strong evidence that SMC is providing a high level of protection, the burden of malaria remains substantial in the 2 study areas. These results emphasise the need for continuing support of SMC programmes. A fifth monthly SMC course is needed to adequately cover the whole transmission season in the study areas and in settings with similar epidemiology. TRIAL REGISTRATION: The AZ-SMC trial in which these data were collected was registered at clinicaltrials.gov: NCT02211729

Overall and Gender-Specific Effects of Intermittent Preventive Treatment of Malaria with Artemisinin-Based Combination Therapies among Schoolchildren in Mali: A Three-Group Open Label Randomized Controlled Trial.

Intermittent preventive treatment of malaria among schoolchildren (IPTsc) reduces clinical malaria, asymptomatic parasitemia, and anemia. The effects of IPTsc by gender have not been studied longitudinally. We investigated overall IPTsc efficacy and conducted a secondary analysis to explore gender-specific differences. We enrolled schoolchildren aged 6-13 years in an open-label, rolling-cohort randomized controlled trial between September 2007 and February 2013 in Kolle, Mali. Annually, schoolchildren received two full-treatment courses of sulfadoxine-pyrimethamine (SP) plus artesunate, or amodiaquine (AQ) plus artesunate, or no malaria treatment as control. We used mixed-effects generalized linear models to estimate differences in treatment outcomes across groups with interaction terms to explore gender-specific differences associated with Plasmodium falciparum infection, hemoglobin, and grade point averages (GPA) based on standardized testing. Overall, 305 students contributed 4,564 observations. Compared with the control, SP plus artesunate and AQ plus artesunate reduced the odds of P. falciparum infection (odds ratio [OR]: 0.33, 95% CI: 0.26-0.43; OR: 0.46, 95% CI: 0.36-0.59). We found strong evidence of increased mean hemoglobin concentrations (g/dL) in the SP plus artesunate group versus control (difference +0.37, 95% CI: 0.13-0.58). Collectively, schoolchildren given AQ plus artesunate had higher mean GPA (difference +0.36, 95% CI: 0.02-0.69) relative to control. Schoolgirls, compared with schoolboys, given SP plus artesunate had greater improvement in GPA (+0.50, 95% CI: -0.02 to 1.02 versus -0.27, 95% CI: -0.71 to 0.16); interaction P = 0.048, respectively. The IPTsc decreases P. falciparum infections in schoolchildren. Treatment regimens that include longer-acting drugs may be more effective at decreasing malaria-related anemia and improving educational outcomes as observed among girls in this setting

The evolving SARS-CoV-2 epidemic in Africa: Insights from rapidly expanding genomic surveillance

INTRODUCTION Investment in Africa over the past year with regard to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) sequencing has led to a massive increase in the number of sequences, which, to date, exceeds 100,000 sequences generated to track the pandemic on the continent. These sequences have profoundly affected how public health officials in Africa have navigated the COVID-19 pandemic. RATIONALE We demonstrate how the first 100,000 SARS-CoV-2 sequences from Africa have helped monitor the epidemic on the continent, how genomic surveillance expanded over the course of the pandemic, and how we adapted our sequencing methods to deal with an evolving virus. Finally, we also examine how viral lineages have spread across the continent in a phylogeographic framework to gain insights into the underlying temporal and spatial transmission dynamics for several variants of concern (VOCs). RESULTS Our results indicate that the number of countries in Africa that can sequence the virus within their own borders is growing and that this is coupled with a shorter turnaround time from the time of sampling to sequence submission. Ongoing evolution necessitated the continual updating of primer sets, and, as a result, eight primer sets were designed in tandem with viral evolution and used to ensure effective sequencing of the virus. The pandemic unfolded through multiple waves of infection that were each driven by distinct genetic lineages, with B.1-like ancestral strains associated with the first pandemic wave of infections in 2020. Successive waves on the continent were fueled by different VOCs, with Alpha and Beta cocirculating in distinct spatial patterns during the second wave and Delta and Omicron affecting the whole continent during the third and fourth waves, respectively. Phylogeographic reconstruction points toward distinct differences in viral importation and exportation patterns associated with the Alpha, Beta, Delta, and Omicron variants and subvariants, when considering both Africa versus the rest of the world and viral dissemination within the continent. Our epidemiological and phylogenetic inferences therefore underscore the heterogeneous nature of the pandemic on the continent and highlight key insights and challenges, for instance, recognizing the limitations of low testing proportions. We also highlight the early warning capacity that genomic surveillance in Africa has had for the rest of the world with the detection of new lineages and variants, the most recent being the characterization of various Omicron subvariants. CONCLUSION Sustained investment for diagnostics and genomic surveillance in Africa is needed as the virus continues to evolve. This is important not only to help combat SARS-CoV-2 on the continent but also because it can be used as a platform to help address the many emerging and reemerging infectious disease threats in Africa. In particular, capacity building for local sequencing within countries or within the continent should be prioritized because this is generally associated with shorter turnaround times, providing the most benefit to local public health authorities tasked with pandemic response and mitigation and allowing for the fastest reaction to localized outbreaks. These investments are crucial for pandemic preparedness and response and will serve the health of the continent well into the 21st century

Two-Year Scale-Up of Seasonal Malaria Chemoprevention Reduced Malaria Morbidity among Children in the Health District of Koutiala, Mali

International audienceBackground: Previous controlled studies demonstrated seasonal malaria chemoprevention (SMC) reduces malaria morbidity by >80% in children aged 3-59 months. Here, we assessed malaria morbidity after large-scale SMC implementation during a pilot campaign in the health district of Koutiala, Mali.Methods: Starting in August 2012, children received three rounds of SMC with sulfadoxine-pyrimethamine (SP) and amodiaquine (AQ). From July 2013 onward, children received four rounds of SMC. Prevalence of malaria infection, clinical malaria and anemia were assessed during two cross-sectional surveys conducted in August 2012 and June 2014. Investigations involved 20 randomly selected clusters in 2012 against 10 clusters in 2014.Results: Overall, 662 children were included in 2012, and 670 in 2014. Children in 2014 versus those surveyed in 2012 showed reduced proportions of malaria infection (12.4% in 2014 versus 28.7% in 2012 (p = 0.001)), clinical malaria (0.3% versus 4.2%, respectively (p < 0.001)), and anemia (50.1% versus 67.4%, respectively (p = 0.001)). A propensity score approach that accounts for environmental differences showed that SMC conveyed a significant protective effect against malaria infection (IR = 0.01, 95% CI (0.0001; 0.09), clinical malaria (OR = 0.25, 95% CI (0.06; 0.85)), and hemoglobin concentration (β = 1.3, 95% CI (0.69; 1.96)) in 2012 and 2014, respectively.Conclusion: SMC significantly reduced frequency of malaria infection, clinical malaria and anemia two years after SMC scale-up in Koutiala

Impact of Three-Year Intermittent Preventive Treatment Using Artemisinin-Based Combination Therapies on Malaria Morbidity in Malian Schoolchildren

Previous studies have shown that a single season of intermittent preventive treatment in schoolchildren (IPTsc) targeting the transmission season has reduced the rates of clinical malaria, all-cause clinic visits, asymptomatic parasitemia, and anemia. Efficacy over the course of multiple years of IPTsc has been scantly investigated. Methods: An open, randomized-controlled trial among schoolchildren aged 6–13 years was conducted from September 2007 to January 2010 in Kolle, Mali. Students were included in three arms: sulphadoxine-pyrimethamine+artesunate (SP+AS), amodiaquine+artesunate (AQ+AS), and control (C). All students received two full doses, given 2 months apart, and were compared with respect to the incidence of clinical malaria, all-cause clinic visits, asymptomatic parasitemia, and anemia. Results: A total of 296 students were randomized. All-cause clinic visits were in the SP+AS versus control (29 (20.1%) vs. 68 (47.2%); 20 (21.7%) vs. 41 (44.6%); and 14 (21.2%) vs. 30 (44.6%); p &lt; 0.02) in 2007, 2008, and 2009, respectively. The prevalence of asymptomatic parasitemia was lower in the SP+AS compared to control (38 (7.5%) vs. 143 (28.7%); and 47 (12.7%) vs. 75 (21.2%); p &lt; 0.002) in 2007 and 2008, respectively. Hemoglobin concentration was significantly higher in children receiving SP+AS (11.96, 12.06, and 12.62 g/dL) than in control children (11.60, 11.64, and 12.15 g/dL; p &lt; 0.001) in 2007, 2008, and 2009, respectively. No impact on clinical malaria was observed. Conclusion: IPTsc with SP+AS reduced the rates of all-cause clinic visits and anemia during a three-year implementation

Characterization of the effect of retinol on Plasmodium falciparum in vitro

A preliminary study from our laboratory found retinol (vitamin A alcohol) to have in vitro activity against Plasmodium falciparum at concentrations close to those in normal human serum (1-3 muM). To characterize the antimalarial potential of retinol in more detail, the 3D7 and K1 laboratory strains of P. falciparum were maintained in continuous culture and [H-3]hypoxanthine incorporation and microscopy were used to assess the effect of retinol against asexual stages of the parasite life-cycle. Losses of retinol and retinol-associated hemolysis were also quantified in the in vitro culture system. There were retinol losses of >50% but no hemolysis was observed with added retinol concentrations up to 100 M. All stages of parasite development showed comparable sensitivity to retinol including merozoite invasion (range of mean IC50 values 10.1-21.4 muM after adjustment for losses). Retinol pre-treatment of uninfected RBC did not inhibit merozoite invasion. Retinol treatment was associated with increased vacuolization within the parasite food vacuole and evidence of parasite membrane rupture. These appearances were similar to those seen with quinoline and artemisinin compounds. Although these data do not support a role for acute retinol supplementation in the treatment of falciparum malaria, they add to knowledge regarding potential antimalarial therapies and justify assessment of more potent synthetic retinoids and their metabolites. (C) 2004 Elsevier Inc. All rights reserved

Prevalence of molecular markers of resistance to sulphadoxine, pyrimethamine and amodiaquine at baseline and post intervention period in Non-SMC patient population.

<p>Prevalence of molecular markers of resistance to sulphadoxine, pyrimethamine and amodiaquine at baseline and post intervention period in Non-SMC patient population.</p

Prevalence of molecular markers of resistance to sulphadoxine, pyrimethamine and amodiaquine at baseline and post-SMC in the SMC population.

<p>Prevalence of molecular markers of resistance to sulphadoxine, pyrimethamine and amodiaquine at baseline and post-SMC in the SMC population.</p

Prevalence of molecular markers of resistance to sulphadoxine, pyrimethamine and amodiaquine at post-SMC in the SMC population <i>vs</i>. concurrent Non-SMC patient population.

<p>Prevalence of molecular markers of resistance to sulphadoxine, pyrimethamine and amodiaquine at post-SMC in the SMC population <i>vs</i>. concurrent Non-SMC patient population.</p