Two decades of molecular surveillance in Senegal reveal changes in known drug resistance mutations associated with historical drug use and seasonal malaria chemoprevention

Ndiaye, Yaye Dié; Wong, Waichi; Thwing, Julie; Schaffner, Stephen; Tine, Abdoulaye; Diallo, Mamadou Alpha; Déme, Awa B.; Sy, Mouhammad; Bei, Amy K.; Thiaw, Alphonse Birane; Daniels, Rachel F.; Ndiaye, Tolla; Gaye, Amy; Ndiaye, Ibrahima; Toure, Mariama; Gadiaga, Nogaye; Sene, Aita; Garba, Mamane Nassirou; Yade, Mamadou Samba; Dièye, Baba; Diongue, Khadim; Zoumarou, Daba; Ndiaye, Aliou; Gomis, Jules F.; Fall, Fatou; Ndiop, Médoune; Diallo, Ibrahima; Sène, Doudou; MacInnis, Bronwyn; Seck, Mame Cheikh; Ndiaye, Mouhamadou; Badiane, Aïda Sadikh; Hartl, Daniel L.; Volkman, Sarah K.; Wirth, Dyann F.; Ndiaye, Daouda

doi:10.1101/2023.04.24.23288820

Cited by 4 publications

(3 citation statements)

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“…In Senegal, SMC is administered under 3-day supervision, which increases drastically the number of children receiving the complete SP-AQ regimen including all 3 doses of AQ. Recent analyses on genetic markers of Plasmodium falciparum drug resistance reported evidence of selection on genetic loci associated with SP resistance (19). Our results also highlight a high incidence observed in individuals aged 10-19 years old, who now represent the most affected group.…”

Section: (Which Was Not Certified By Peer Review)supporting

confidence: 65%

Impact of seasonal malaria chemoprevention timing on clinical malaria incidence dynamics in the Kedougou region, Senegal

Kazanga,

Ba,

Legendre

et al. 2024

Preprint

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Seasonal malaria chemoprevention (SMC) with sulfadoxine-pyrimethamine and amodiaquine is recommended by the World Health Organization since 2012 for clinical malaria prevention in children in the Sahelian region of Africa. In Senegal, SMC implementation began in 2013 and is given to children under 10 years old. This study aimed to describe clinical malaria incidence in the general population during routine SMC implementation and to analyse how SMC timing impacted clinical malaria dynamics in eligible children. We conducted an ecological study in the Kedougou region of Senegal in 27 villages included in the Bandafassi Health and Demographic Surveillance System (HDSS). We calculated weekly Plasmodium falciparum malaria incidence by age group using malaria case data recorded by community health workers and health-posts, and population denominators obtained from Bandafassi Health and Demographic Surveillance System. We used negative binomial generalized additive multilevel models to analyse the incidence of clinical episodes in children under 10 years during the expected SMC prophylactic period and at the end of the transmission period. Malaria incidence was strongly seasonal with a high transmission period starting in June. Children under SMC presented an overall lower incidence compared to older children and young adults. Among children eligible for SMC, the incidence was lowest for approximately 3 weeks after treatment administration and increased subsequently, suggesting a gradual loss of protection. At the end of the high transmission period, a higher malaria incidence was recorded from the 3rd to 6th week after the week of administration of the fourth (final) SMC round. While protecting children under 10 years, SMC warrants adjustment to reduce exposure before the next round, to increase protection of 5-9 years, and to cover the high transmission period completely. The addition of a 5th round of SMC in 2023 was necessary to cover the end of the transmission season, but individual-level studies are required to ensure that drug efficacy and adequate dosing are maintained.

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Section: (Which Was Not Certified By Peer Review)supporting

confidence: 65%

Impact of seasonal malaria chemoprevention timing on clinical malaria incidence dynamics in the Kedougou region, Senegal

Kazanga,

Ba,

Legendre

et al. 2024

Preprint

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“…This study tested samples from two different regions of Senegal: Thiès, a low transmission area with an EIR of <5 infectious bites per person per year [34,38,39], and Kédougou, a moderate transmission area with an EIR ~250 [35]. The low malaria transmission in Thiès has been tracked over time [40,41], and in the longitudinal cohort tested here, only four of seventy individuals had malaria reinfections over two years of follow-up.…”

Section: Cohorts In Contextmentioning

confidence: 96%

Two mosquito salivary antigens demonstrate promise as biomarkers of recent exposure toP. falciparuminfected mosquito bites

Lapidus,

Goheen,

et al. 2024

Preprint

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Background: Measuring malaria transmission intensity using the traditional entomological inoculation rate is difficult. Antibody responses to mosquito salivary proteins such as SG6 have previously been used as biomarkers of exposure to Anopheles mosquito bites. Here, we investigate four mosquito salivary proteins as potential biomarkers of human exposure to mosquitoes infected with P. falciparum: mosGILT, SAMSP1, AgSAP, and AgTRIO. Methods: We tested population-level human immune responses in longitudinal and cross-sectional plasma samples from individuals with known P. falciparum infection from low and moderate transmission areas in Senegal using a multiplexed magnetic bead-based assay. Results: AgSAP and AgTRIO were the best indicators of recent exposure to infected mosquitoes. Antibody responses to AgSAP, in a moderate endemic area, and to AgTRIO in both low and moderate endemic areas, were significantly higher than responses in a healthy non-endemic control cohort (p-values = 0.0245, 0.0064, and <0.0001 respectively). No antibody responses significantly differed between the low and moderate transmission area, or between equivalent groups during and outside the malaria transmission seasons. For AgSAP and AgTRIO, reactivity peaked 2-4 weeks after clinical P. falciparum infection and declined 3 months after infection. Discussion: Reactivity to both AgSAP and AgTRIO peaked after infection and did not differ seasonally nor between areas of low and moderate transmission, suggesting reactivity is likely reflective of exposure to infectious mosquitos or recent biting rather than general mosquito exposure. Kinetics suggest reactivity is relatively short-lived. AgSAP and AgTRIO are promising candidates to incorporate into multiplexed assays for serosurveillance of population-level changes in P. falciparum-infected mosquito exposure.

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“…SMC deployment is currently limited to the sub-Sahel region due to a high prevalence of SPAQ-resistant P. falciparum in southern, central, and eastern Africa (Amimo et al 2020). Moreover, the increased prevalence of molecular markers of drug resistance in areas where SPAQ is currently deployed for SMC is concerning (Ndiaye et al 2023).…”

Section: Introductionmentioning

confidence: 99%

A randomized, open-label two-period crossover pilot study to evaluate the relative bioavailability in the fed state of atovaquone-proguanil (Atoguanil™) versus atovaquone-proguanil hydrochloride (Malarone®) in healthy adult participants

Kuemmerle,

Gossen,

Marx

et al. 2024

Naunyn-Schmiedeberg's Arch Pharmacol

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Atoguanil™ is a novel complex of atovaquone (ATV) and proguanil (PG) with enhanced ATV bioavailability compared to Malarone®. This pilot study assessed whether the relative bioavailability (Frel) of ATV, PG, and the primary PG metabolite cycloguanil (CG) following a single oral dose in the fed state of Atoguanil was similar to Malarone despite a 50% lower ATV dose. This open-label, single-dose, randomized 2-period, 2-treatment, balanced crossover study was conducted between 17th November 2021 and 18th March 2022. Eligible participants (aged 18–55 years) were randomized (1:1) in period 1 to Atoguanil (ATV/PG 500/348 mg) or Malarone (ATV/PG hydrochloride 1000/400 mg) administered following a high-fat, high caloric meal. After a 24-day washout period, participants crossed treatment arms. For the doses tested, Frel was assumed similar if 90%CIs were between 80 and 125% for the geometric mean ratio of the least square mean differences for each exposure parameter. In 15 evaluable participants, Frel was similar for ATV Cmax (93.6% [90%CI 83.6, 104.9]) but not AUC0-inf (77.8% [67.4, 89.8]), for PG AUC0-inf (95.6% [92.1, 99.2]) but not Cmax (82.4% [75.8, 89.5]), and for both CG Cmax (100.8% [95.0, 107.0]) and AUC0-inf (102.9% [98.4, 107.7]). Nine adverse events occurred; all were of mild severity and not considered treatment related. At the doses tested, ATV Frel was lower following Atoguanil versus Malarone based on AUC0-inf, though when adjusted for dose Frel increased by 156%. Both drugs were well tolerated with no safety concerns. ClinicalTrials.gov: NCT04866602 (April 26th, 2021)

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Two decades of molecular surveillance in Senegal reveal changes in known drug resistance mutations associated with historical drug use and seasonal malaria chemoprevention

Cited by 4 publications

References 54 publications

Impact of seasonal malaria chemoprevention timing on clinical malaria incidence dynamics in the Kedougou region, Senegal

Impact of seasonal malaria chemoprevention timing on clinical malaria incidence dynamics in the Kedougou region, Senegal

Two mosquito salivary antigens demonstrate promise as biomarkers of recent exposure toP. falciparuminfected mosquito bites

A randomized, open-label two-period crossover pilot study to evaluate the relative bioavailability in the fed state of atovaquone-proguanil (Atoguanil™) versus atovaquone-proguanil hydrochloride (Malarone®) in healthy adult participants

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