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BioRxiv : the Preprint Server For... Sep 2023, the malaria-causing parasite, is a leading cause of infection-induced deaths worldwide. The preferred treatment approach is artemisinin-combination therapy, which...
, the malaria-causing parasite, is a leading cause of infection-induced deaths worldwide. The preferred treatment approach is artemisinin-combination therapy, which couples fast-acting artemisinin derivatives with longer-acting drugs like lumefantrine, mefloquine, and amodiaquine. However, the urgency for new treatments has risen due to the parasite's growing resistance to existing therapies. Our study shows that a common characteristic of the proteome - stretches of poly-lysine residues such as those found in proteins related to adhesion and pathogenicity - can serve as an effective peptide treatment for infected erythrocytes. A single dose of these poly-basic peptides can successfully diminish parasitemia in human erythrocytes with minimal toxicity. The effectiveness of the treatment correlates with the length of the poly-lysine peptide, with 30 lysine peptides supporting the eradication of erythrocytic parasites within 72 hours. PEG-ylation of the poly-lysine peptides or utilizing poly-lysine dendrimers and polymers further increases parasite clearance efficiency and bolsters the stability of these potential new therapeutics. Lastly, our affinity pull-downs and mass-spectrometry identify outer membrane proteins as likely targets for polybasic peptide medications. Since poly-lysine dendrimers are already FDA-approved for drug delivery, their adaptation as antimalarial drugs presents a promising new therapeutic strategy.
PubMed: 37745508
DOI: 10.1101/2023.09.16.558069 -
The American Journal of Tropical... Nov 2023Integration of vertical programs for the control of malaria, schistosomiasis, and soil-transmitted helminthiasis has been recommended to achieve elimination of malaria... (Randomized Controlled Trial)
Randomized Controlled Trial
Integration of vertical programs for the control of malaria, schistosomiasis, and soil-transmitted helminthiasis has been recommended to achieve elimination of malaria and neglected tropical diseases (NTD) by 2030. This qualitative study was conducted within the context of a randomized controlled trial to explore the perceptions and views of parents/caregivers of at-risk children and healthcare providers to determine their acceptability of the integrated malaria-helminth treatment approach. Randomly selected parents/caregivers of children enrolled in the trial, healthcare providers, trial staff, malaria, and NTD program managers were interviewed using purpose-designed topic guides. Transcripts obtained from the interviews were coded and common themes identified using content analysis were triangulated. Fifty-seven study participants comprising 26 parents/caregivers, 10 study children aged ≥ 10 years, 15 trial staff, four healthcare providers, and two managers from the Senegal Ministry of Health were interviewed. Thirty-eight of the participants (66.7%) were males, and their ages ranged from 10 to 65 years. Overall, the integrated malaria-helminth treatment approach was considered acceptable, but the study participants expressed concerns about the taste, smell, and side effects associated with amodiaquine and praziquantel in the combination package. Reluctance to accept the medications was also observed among children aged 10 to 14 years due to peer influence and gender-sensitive cultural beliefs. Addressing concerns about the taste and smell of amodiaquine and praziquantel is needed to optimize the uptake of the integrated treatment program. Also, culturally appropriate strategies need to be put in place to cater for the inclusion of children aged 10 to 14 years in this approach.
Topics: Child; Male; Animals; Humans; Adolescent; Young Adult; Adult; Middle Aged; Aged; Female; Praziquantel; Amodiaquine; Senegal; Helminthiasis; Helminths; Malaria
PubMed: 37722662
DOI: 10.4269/ajtmh.23-0113 -
Malaria Journal Sep 2023The routine surveillance of asymptomatic malaria using nucleic acid-based amplification tests is essential in obtaining reliable data that would inform malaria policy...
BACKGROUND
The routine surveillance of asymptomatic malaria using nucleic acid-based amplification tests is essential in obtaining reliable data that would inform malaria policy formulation and the implementation of appropriate control measures.
METHODS
In this study, the prevalence rate and the dynamics of Plasmodium species among asymptomatic children (n = 1697) under 5 years from 30 communities within the Hohoe municipality in Ghana were determined.
RESULTS AND DISCUSSION
The observed prevalence of Plasmodium parasite infection by polymerase chain reaction (PCR) was 33.6% (571/1697), which was significantly higher compared to that obtained by microscopy [26.6% (451/1697)] (P < 0.0001). Based on species-specific analysis by nested PCR, Plasmodium falciparum infection [33.6% (570/1697)] was dominant, with Plasmodium malariae, Plasmodium ovale and Plasmodium vivax infections accounting for 0.1% (1/1697), 0.0% (0/1697), and 0.0% (0/1697), respectively. The prevalence of P. falciparum infection among the 30 communities ranged from 0.0 to 82.5%. Following artesunate-amodiaquine (AS + AQ, 25 mg/kg) treatment of a sub-population of the participants (n = 184), there was a substantial reduction in Plasmodium parasite prevalence by 100% and 79.2% on day 7 based on microscopy and nested PCR analysis, respectively. However, there was an increase in parasite prevalence from day 14 to day 42, with a subsequent decline on day 70 by both microscopy and nested PCR. For parasite clearance rate analysis, we found a significant proportion of the participants harbouring residual Plasmodium parasites or parasite genomic DNA on day 1 [65.0% (13/20)], day 2 [65.0% (13/20)] and day 3 [60.0% (12/20)] after initiating treatment. Of note, gametocyte carriage among participants was low before and after treatment.
CONCLUSION
Taken together, the results indicate that a significant number of individuals could harbour residual Plasmodium parasites or parasite genomic DNA after treatment. The study demonstrates the importance of routine surveillance of asymptomatic malaria using sensitive nucleic acid-based amplification techniques.
Topics: Child; Humans; Ghana; Malaria; Artemisinins; Malaria, Falciparum; Plasmodium malariae; Nucleic Acids
PubMed: 37710288
DOI: 10.1186/s12936-023-04712-1 -
The Journal of Infectious Diseases Jan 2024Owing to the increased cases of malaria in older children, the World Health Organization has recently recommended extending seasonal malaria chemoprevention (SMC) to... (Randomized Controlled Trial)
Randomized Controlled Trial
Randomized Field Trial to Assess the Safety and Efficacy of Dihydroartemisinin-Piperaquine for Seasonal Malaria Chemoprevention in School-Aged Children in Bandiagara, Mali.
BACKGROUND
Owing to the increased cases of malaria in older children, the World Health Organization has recently recommended extending seasonal malaria chemoprevention (SMC) to children >5 years of age and using other effective drugs for malaria. In this study, we report the safety and efficacy of dihydroartemisinin-piperaquine (DHA-PQ) for SMC in school-aged children in Mali.
METHOD
This randomized, controlled trial included 345 participants aged 6-15 years randomized to receive DHA-PQ, sulfadoxine-pyrimethamine plus amodiaquine (SP-AQ), or no chemoprevention (albendazole) at a 1:1:1 ratio. Four rounds of SMC were conducted from September to December 2021. The participants were assessed 7 days after each round for safety and efficacy of the interventions.
RESULTS
Abdominal pain (11.8% vs 29.2%), headache (11.2% vs 19.2%), and vomiting (5.7% vs 15.2%) were frequently reported in the DHA-PQ and SP-AQ arms. On Day 120 of follow up, the incidence of clinical malaria was 0.01 episodes/person-month in the DHA-PQ and SP-AQ arms and 0.17 episodes/person-month in the control arm (P < .0001). Gametocytes were detected in 37 participants in all arms.
CONCLUSIONS
Children in DHA-PQ arm reported less adverse events compared to the SP-AQ arm. Both drugs were effective against clinical malaria and infection.
Topics: Child; Humans; Infant; Child, Preschool; Antimalarials; Mali; Seasons; Malaria; Sulfadoxine; Amodiaquine; Drug Combinations; Chemoprevention; Piperazines; Quinolines; Artemisinins
PubMed: 37682871
DOI: 10.1093/infdis/jiad387 -
Parasite (Paris, France) 2023Malaria is a major public health problem in Madagascar, particularly in coastal areas. We conducted a randomized, controlled, parallel-group study of artemisinin-based... (Randomized Controlled Trial)
Randomized Controlled Trial
Therapeutic efficacy and safety of artesunate + amodiaquine and artemether + lumefantrine in treating uncomplicated Plasmodium falciparum malaria in children on the rainy south-east coast of Madagascar.
Malaria is a major public health problem in Madagascar, particularly in coastal areas. We conducted a randomized, controlled, parallel-group study of artemisinin-based combination therapy (ACT) in Mananjary and Farafangana, two localities on the rainy south-east coast of Madagascar, from March to September 2018. The efficacy and safety of artesunate + amodiaquine (ASAQ) and artemether + lumefantrine (AL) were assessed according to the WHO protocol with a 28-day follow-up. Children aged 6 months to 14 years with uncomplicated Plasmodium falciparum malaria were randomized to receive ASAQ or AL for three days (1:1). 347/352 (98.5%) randomized patients reached the study endpoint on day 28. Crude adequate clinical and parasitological response (ACPR) rates were 100% (95% CI: 98.8-100%) in the ASAQ group and 96% (95% CI: 93.1-98.9%) in the AL group (per protocol population). However, the PCR-corrected ACPR rate was 97.7% (95% CI: 95.4-100%) in the AL group. Two cases of recrudescence and three of re-infection were observed. Mild and moderate adverse events, including gastrointestinal and/or nervous disorders, were reported in 11.9% (42/352) of patients. We found that ASAQ and AL were safe and efficacious for treating uncomplicated P. falciparum malaria. They may be used for treatment at health facilities and at the community level, and for mass drug administration campaigns.
Topics: Humans; Child; Artesunate; Madagascar; Amodiaquine; Malaria, Falciparum; Artemether, Lumefantrine Drug Combination
PubMed: 37646608
DOI: 10.1051/parasite/2023034 -
The Lancet. Infectious Diseases Jan 2024Seasonal vaccination with the RTS,S/AS01 vaccine combined with seasonal malaria chemoprevention (SMC) prevented malaria in young children more effectively than either... (Randomized Controlled Trial)
Randomized Controlled Trial
Seasonal vaccination with RTS,S/AS01 vaccine with or without seasonal malaria chemoprevention in children up to the age of 5 years in Burkina Faso and Mali: a double-blind, randomised, controlled, phase 3 trial.
BACKGROUND
Seasonal vaccination with the RTS,S/AS01 vaccine combined with seasonal malaria chemoprevention (SMC) prevented malaria in young children more effectively than either intervention given alone over a 3 year period. The objective of this study was to establish whether the added protection provided by the combination could be sustained for a further 2 years.
METHODS
This was a double-blind, individually randomised, controlled, non-inferiority and superiority, phase 3 trial done at two sites: the Bougouni district and neighbouring areas in Mali and Houndé district, Burkina Faso. Children who had been enrolled in the initial 3-year trial when aged 5-17 months were initially randomly assigned individually to receive SMC with sulphadoxine-pyrimethamine and amodiaquine plus control vaccines, RTS,S/AS01 plus placebo SMC, or SMC plus RTS,S/AS01. They continued to receive the same interventions until the age of 5 years. The primary trial endpoint was the incidence of clinical malaria over the 5-year trial period in both the modified intention-to-treat and per-protocol populations. Over the 5-year period, non-inferiority was defined as a 20% increase in clinical malaria in the RTS,S/AS01-alone group compared with the SMC alone group. Superiority was defined as a 12% difference in the incidence of clinical malaria between the combined and single intervention groups. The study is registered with ClinicalTrials.gov, NCT04319380, and is complete.
FINDINGS
In April, 2020, of 6861 children originally recruited, 5098 (94%) of the 5433 children who completed the initial 3-year follow-up were re-enrolled in the extension study. Over 5 years, the incidence of clinical malaria per 1000 person-years at risk was 313 in the SMC alone group, 320 in the RTS,S/AS01-alone group, and 133 in the combined group. The combination of RTS,S/AS01 and SMC was superior to SMC (protective efficacy 57·7%, 95% CI 53·3 to 61·7) and to RTS,S/AS01 (protective efficacy 59·0%, 54·7 to 62·8) in preventing clinical malaria. RTS,S/AS01 was non-inferior to SMC (hazard ratio 1·03 [95% CI 0·95 to 1·12]). The protective efficacy of the combination versus SMC over the 5-year period of the study was very similar to that seen in the first 3 years with the protective efficacy of the combination versus SMC being 57·7% (53·3 to 61·7) and versus RTS/AS01-alone being 59·0% (54·7 to 62·8). The comparable figures for the first 3 years of the study were 62·8% (58·4 to 66·8) and 59·6% (54·7 to 64·0%), respectively. Hospital admissions for WHO-defined severe malaria were reduced by 66·8% (95% CI 40·3 to 81·5), for malarial anaemia by 65·9% (34·1 to 82·4), for blood transfusion by 68·1% (32·6 to 84·9), for all-cause deaths by 44·5% (2·8 to 68·3), for deaths excluding external causes or surgery by 41·1% (-9·2 to 68·3), and for deaths from malaria by 66·8% (-2·7 to 89·3) in the combined group compared with the SMC alone group. No safety signals were detected.
INTERPRETATION
Substantial protection against malaria was sustained over 5 years by combining seasonal malaria vaccination with seasonal chemoprevention, offering a potential new approach to malaria control in areas with seasonal malaria transmission.
FUNDING
UK Joint Global Health Trials and PATH's Malaria Vaccine Initiative (through a grant from the Bill & Melinda Gates Foundation).
TRANSLATION
For the French translation of the abstract see Supplementary Materials section.
Topics: Child; Humans; Infant; Child, Preschool; Mali; Burkina Faso; Seasons; Malaria; Malaria Vaccines; Vaccination; Chemoprevention; Malaria, Falciparum
PubMed: 37625434
DOI: 10.1016/S1473-3099(23)00368-7 -
Malaria Journal Aug 2023Artesunate-amodiaquine (AS-AQ) and artemether-lumefantrine (AL) are the currently recommended first-and second-line therapies for uncomplicated Plasmodium falciparum...
Therapeutic efficacy of artesunate-amodiaquine and artemether-lumefantrine for the treatment of uncomplicated falciparum malaria in Chad: clinical and genetic surveillance.
BACKGROUND
Artesunate-amodiaquine (AS-AQ) and artemether-lumefantrine (AL) are the currently recommended first-and second-line therapies for uncomplicated Plasmodium falciparum infections in Chad. This study assessed the efficacy of these artemisinin-based combinations, proportion of day 3 positive patients, proportions of molecular markers associated with P. falciparum resistance to anti-malarial drugs and variable performance of HRP2-based malaria rapid diagnostic tests (RDTs).
METHODS
A single-arm prospective study assessing the efficacy of AS-AQ and AL at three sites (Doba, Kelo and Koyom) was conducted between November 2020 to January 2021. Febrile children aged 6 to 59 months with confirmed uncomplicated P. falciparum infection were enrolled sequentially first to AS-AQ and then AL at each site and followed up for 28 days. The primary endpoint was PCR-adjusted adequate clinical and parasitological response (ACPR). Samples collected on day 0 were analysed for mutations in pfkelch13, pfcrt, pfmdr-1, pfdhfr, pfdhps genes and deletions in pfhrp2/pfhrp3 genes.
RESULTS
By the end of 28-day follow-up, per-protocol PCR corrected ACPR of 97.8% (CI 95% 88.2-100) in Kelo and 100% in Doba and Kayoma were observed among AL treated patients. For ASAQ, 100% ACPR was found in all sites. All, but one patient, did not have parasites detected on day 3. Out of the 215 day 0 samples, 96.7% showed pfkelch13 wild type allele. Seven isolates carried nonsynonymous mutations not known to be associated artemisinin partial resistance (ART-R). Most of samples had a pfcrt wild type allele (79% to 89%). The most prevalent pfmdr-1 allele detected was the single mutant 184F (51.2%). For pfdhfr and pfdhps mutations, the quintuple mutant allele N51I/C59R/S108N + G437A/540E responsible for SP treatment failures in adults and children was not detected. Single deletion in the pfhrp2 and pfhrp3 gene were detected in 10/215 (4.7%) and 2/215 (0.9%), respectively. Dual pfhrp2/pfhrp3 deletions, potentially threatening the efficacy of HRP2-based RDTs, were observed in 5/215 (2.3%) isolates.
CONCLUSION
The results of this study confirm that AS-AQ and AL treatments are highly efficacious in study areas in Chad. The absence of known pfkelch13 mutations in the study sites and the high parasite clearance rate at day 3 suggest the absence of ART-R. The absence of pfdhfr/pfdhps quintuple or sextuple (quintuple + 581G) mutant supports the continued use of SP for IPTp during pregnancy. The presence of parasites with dual pfhrp2/pfhrp3 deletions, potentially threatening the efficacy of HRP2-based RDTs, warrants the continued surveillance. Trial registration ACTRN12622001476729.
Topics: Adult; Female; Pregnancy; Humans; Artesunate; Antimalarials; Amodiaquine; Artemether, Lumefantrine Drug Combination; Chad; Prospective Studies; Artemether; Malaria, Falciparum; Artemisinins
PubMed: 37612601
DOI: 10.1186/s12936-023-04644-w -
RSC Chemical Biology Aug 2023Bloodstream infections caused by invasive, non-typhoidal (iNTS) are a major global health concern, particularly in Africa where the pathogenic variant of Typhimurium...
Bloodstream infections caused by invasive, non-typhoidal (iNTS) are a major global health concern, particularly in Africa where the pathogenic variant of Typhimurium sequence type (ST) 313 is dominant. Unlike Typhimurium strains that cause gastroenteritis, iNTS strains cause bloodstream infections and are resistant to multiple first-line antibiotics, thus limiting current treatment options. Here, we developed and implemented multiple small molecule screens under physiological, infection-relevant conditions to reveal chemical sensitivities in ST313 and to identify host-directed therapeutics as entry points to drug discovery to combat the clinical burden of iNTS. Screening ST313 iNTS under host-mimicking growth conditions identified 92 compounds with antimicrobial activity despite inherent multidrug resistance. We characterized the antimicrobial activity of the nucleoside analog 3'-azido-3'-deoxythymidine as an exemplary compound from this screen, which depended on bacterial thymidine kinase activity for antimicrobial activity. In a companion macrophage-based screening platform designed to enrich for host-directed therapeutics, we identified three compounds (amodiaquine, berbamine, and indatraline) as actives that required the presence of host cells for antibacterial activity. These three compounds had antimicrobial activity only in the presence of host cells that significantly inhibited intracellular ST313 iNTS replication in macrophages. This work provides evidence that despite high invasiveness and multidrug resistance, ST313 iNTS remains susceptible to unconventional drug discovery approaches.
PubMed: 37547457
DOI: 10.1039/d3cb00014a -
Nature Communications Jul 2023Increasing levels of artemisinin and partner drug resistance threaten malaria control and elimination globally. Triple artemisinin-based combination therapies (TACTs)...
Increasing levels of artemisinin and partner drug resistance threaten malaria control and elimination globally. Triple artemisinin-based combination therapies (TACTs) which combine artemisinin derivatives with two partner drugs are efficacious and well tolerated in clinical trials, including in areas of multidrug-resistant malaria. Whether early TACT adoption could delay the emergence and spread of antimalarial drug resistance is a question of vital importance. Using two independent individual-based models of Plasmodium falciparum epidemiology and evolution, we evaluated whether introduction of either artesunate-mefloquine-piperaquine or artemether-lumefantrine-amodiaquine resulted in lower long-term artemisinin-resistance levels and treatment failure rates compared with continued ACT use. We show that introduction of TACTs could significantly delay the emergence and spread of artemisinin resistance and treatment failure, extending the useful therapeutic life of current antimalarial drugs, and improving the chances of malaria elimination. We conclude that immediate introduction of TACTs should be considered by policy makers in areas of emerging artemisinin resistance.
Topics: Antimalarials; Artemether; Artemether, Lumefantrine Drug Combination; Artemisinins; Folic Acid Antagonists
PubMed: 37516752
DOI: 10.1038/s41467-023-39914-3 -
Malaria Journal Jul 2023Artemisinin-based combinations therapy (ACT) is the current frontline curative therapy for uncomplicated malaria in Burkina Faso. Sulfadoxine-pyrimethamine (SP) is used...
BACKGROUND
Artemisinin-based combinations therapy (ACT) is the current frontline curative therapy for uncomplicated malaria in Burkina Faso. Sulfadoxine-pyrimethamine (SP) is used for the preventive treatment of pregnant women (IPTp), while SP plus amodiaquine (SP-AQ) is recommended for children under five in seasonal malaria chemoprevention (SMC). This study aimed to assess the proportions of mutations in the P. falciparum multidrug-resistance 1 (Pfmdr1), P. falciparum chloroquine resistance transporter (Pfcrt), P. falciparum dihydrofolate reductase (pfdhfr), and P. falciparum dihydropteroate synthase (pfdhps), genes from isolates collected during household surveys in Burkina Faso.
METHODS
Dried blood spots from Plasmodium falciparum-positive cases at three sites (Orodara, Gaoua, and Banfora) collected during the peak of transmission were analysed for mutations in Pfcrt (codons 72-76, 93, 97, 145, 218, 343, 350 and 353), Pfmdr-1 (codons 86, 184, 1034, 1042 and 1246) dhfr (codons 51, 59, 108, 164) and dhps (at codons 431, 436, 437, 540, 581, 613) genes using deep sequencing of multiplexed Polymerase chaine reaction (PCR) amplicons.
RESULTS
Of the 377 samples analysed, 346 (91.7%), 369 (97.9%), 368 (97.6%), and 374 (99.2%) were successfully sequenced for Pfcrt, Pfmdr-1, dhfr, and dhps, respectively. Most of the samples had a Pfcrt wild-type allele (89.3%). The 76T mutation was below 10%. The most frequent Pfmdr-1 mutation was detected at codon 184 (Y > F, 30.9%). The single mutant genotype (NFSND) predominated (66.7%), followed by the wild-type genotype (NYSND, 30.4%). The highest dhfr mutations were observed at codon 59R (69.8%), followed by codons 51I (66.6%) and 108 N (14.7%). The double mutant genotype (ACIRSI) predominated (52.4%). For mutation in the dhps gene, the highest frequency was observed at codon 437 K (89.3%), followed by codons 436 A (61.2%), and 613 S (14.4%). The double mutant genotype (IAKKAA) and the single mutant genotype (ISKKAA) were predominant (37.7% and 37.2%, respectively). The most frequent dhfr/dhps haplotypes were the triple mutant ACIRSI/IAKKAA (23%), the wild-type ACNCSI/ISKKAA (19%) and the double mutant ACIRSI/ISKKAA (14%). A septuple mutant ACIRNI/VAKKGA was observed in 2 isolates from Gaoua (0.5%).
CONCLUSION
The efficacy of ACT partner drugs and drugs used in IPTp and SMC does not appear to be affected by the low proportion of highly resistant mutants observed in this study. Continued monitoring, including molecular surveillance, is critical for decision-making on effective treatment policy in Burkina Faso.
Topics: Humans; Child; Female; Pregnancy; Plasmodium falciparum; Antimalarials; Burkina Faso; Pyrimethamine; Sulfadoxine; Malaria, Falciparum; Malaria; Mutation; Tetrahydrofolate Dehydrogenase; Drug Combinations; Drug Resistance; Codon
PubMed: 37474966
DOI: 10.1186/s12936-023-04645-9