Design, synthesis and biological evaluation of Rac1-targeting carbazole-pyrimidines as host-directed antimalarials.

Iron-oxide nanoparticles (SPIONs) enhance malaria vaccine antibody response.

Computational evaluation of indole alkaloids as inhibitors of 3-hydroxykynurenine transaminase in malaria vector control.

Cardiovascular Risk from Altered Lipid Profile and Atherogenic Indices in Children with Uncomplicated Plasmodium falciparum Malaria in Owo, Nigeria

Malaria is a public health problem in Sudan, with more than 89% of cases caused by Plasmodium falciparum. In 2024 Sudan introduced R21/Matrix-M malaria vaccine in two states through routine immunization system. This study aimed to determine and identify the factors affecting the utilization of the vaccine. A cross-sectional mixed -methods study was conducted in Gedarif and Blue Nile States of Sudan. Quantitative data were collected through pre-tested, pre-coded, structured questionnaire from samples of mothers or caregivers of children under the age of five. Additionally, Focus Group Discussions (FGDs) with school teachers and in-depth interviews with key Informants (KIIs) were conducted. Quantitative data were analyzed using SPSS, where univariate and multivariate analyses were performed. Qualitative thematic analysis was undertaken to identify barriers and drivers for each target group's behavior related to the malaria vaccine. A total of 416 mothers or caregivers (with a 99.0% response rate) who had children under the age of five were interviewed. The median age was 27.0years. Of 256 children eligible for the malaria vaccine, only 36.7%, 95% CI 31.1-42.8% or 94 received it, with no difference between states or residence. Attitudes towards vaccination were generally positive. Perceptions of malaria and awareness of the vaccine were low: 53.1% of mothers perceive malaria as not a significant health problem; 57.7% were aware of the malaria vaccine; 36.7% knew the number of required doses; 25.7% knew the recommended starting dose age. FGDs and KIIs highlighted vaccine stockouts and geographic access as additional barriers, indicating the importance of sustaining supply chains. The suboptimal uptake of the malaria vaccine was not attributed to vaccine hesitancy or behavioral and social determinants, but rather to limited educational efforts and a lack of focus on the malaria vaccine as a new intervention. Reviewing the communication strategy and addressing health system barriers might help achieve the vaccine targets set by the Ministry of Health. Furthermore, assessing vaccine acceptability and identifying the enabling and inhibiting factors for vaccination before introducing the malaria vaccine in addition to engagement of higher authorities will lead to better vaccine uptake. Further research to test the effectiveness of culturally tailored communication interventions and the use of reminders or small incentives to raise the uptake is highly needed.

Coenzyme A (CoA) is essential for the intraerythrocytic stage of Plasmodium falciparum. Phosphopantothenoylcysteine synthetase (PPCS) catalyzes the second of five steps of the CoA biosynthesis pathway. Most apicomplexan parasites express one PPCS, whereas two PPCSs are expressed in P. falciparum. Here, we demonstrate that the two P. falciparum PPCSs (PfPPCSs) associate into a single, functional PPCS heteromeric complex that, unlike any other eukaryotic PPCS reported to date, is unable to use adenosine 5'-triphosphate. We identify a prokaryote-like helical component of PfPPCS as important for the nucleotide specificity and potentially holding the key for its stringency for cytidine 5'-triphosphate. Moreover, we show that the complex is the target of multiple antiplasmodial pantothenate analogs and interacts with other analogs that target different steps in CoA biosynthesis/utilization. Our study provides opportunities for designing inhibitors that exploit the unique features of the PfPPCS complex while, at the same time, avoiding the human counterpart, paving the way for additional therapies to combat malaria.

The recommendation of the RTS,S/AS01 malaria vaccine for use in children in moderate to high transmission areas by the WHO in 2021 provided another crucial tool in reducing malaria morbidity and mortality. As countries introduce the RTS,S/AS01 vaccine, there is an interest in exploring vaccination schedules that align with existing routine health touchpoints and to optimize vaccine coverage. This study used OpenMalaria, an individual-based, stochastic model of malaria transmission and disease progression, to assess the impact of different vaccination timing schedules and coverage on uncomplicated malaria cases, severe malaria cases, and malaria-related deaths across different archetypal transmission settings. We ran simulations comparing fourth dose protection against infection and timings at 6-, 9-, 12-, 15- and 18-month intervals following the primary series, including exploring ranges of plausible protection assumptions for many of the dose timings. The primary series substantially reduces the malaria burden across transmission settings, regardless of timing of the fourth vaccine dose. For example, at a baseline Plasmodium falciparum prevalence in 2-10year olds (PfPR2-10) of 20%, our modeling suggests that the primary series is responsible for around 73-93% of the total uncomplicated and 74%-92% of severe cases averted regardless of fourth dose timing in perennial settings. Additionally, a fourth dose of the vaccine in this transmission setting could avert additional 8-38% of uncomplicated and 9-36% of severe malaria cases in addition to the primary series alone. While the number of cases averted varies by baseline prevalence, we find potential flexibility in timing this dose, especially when focused on 6 to 12months following the primary series. A fourth dose delivered between 15- and 21-months of age (corresponding to a 6-12month interval after the third dose) with high population coverage will likely avert the largest proportion of cases of uncomplicated malaria, severe malaria, and deaths in perennial settings, across transmission intensities.Therefore, the delivery of the fourth dose of the RTS,S/AS01 vaccine can be tailored to country-specific context and linked to existing health touchpoints to ensure adequate coverage of this dose to optimize its impact.

Differential expression of mitochondria-associated genes in clinical samples of Plasmodium falciparum showing severe manifestations.

There is dual endemicity of malaria and helminthic infections in low- and middle-income countries. Coinfection with both infectious diseases may have compounding negative effects on the health of school-aged children (SAC) in endemic areas. The prevalence of coinfection with malaria and intestinal helminths, including soil-transmitted helminths, Schistosoma mansoni, and Hymenolepis nana, was assessed among SAC in rural northern Uganda. A school-based cross-sectional study was conducted at four randomly selected schools from June 2 to June 10, 2025 in Nwoya District, Uganda. Children aged 5-18 years provided stool and blood samples, and were surveyed to assess demographic, environmental, and health-related factors. Intestinal helminth diagnosis was performed using a modified Kato-Katz method (Odongo-Aginya stain); malaria was detected using Plasmodium falciparum (P. falciparum) histidine-rich protein 2 rapid diagnostic tests (RDTs) and blood smears. Overall, 190 SAC with a median age of 13 years were enrolled. Although 75.3% (n = 143) of SAC tested positive for P. falciparum on an RDT, only 13.2% (n = 25) had microscopically detected parasitemia. Intestinal helminth infections were uncommon and involved Ascaris lumbricoides (0.5%; n = 1), Hymenolepis nana (1.6%; n = 3), and Schistosoma mansoni (1.1%; n = 2). All SAC with intestinal helminth infections (3.2%; n = 6) had positive malaria RDT results. The high rate of malaria RDT positivity with negative blood smears may be due to persistent antigenemia post-treatment or false negative blood smear results due to chronic low-grade parasitemia. The low rate of malaria-helminth coinfection among SAC observed in the present study is supported by other recent studies in Uganda and suggests a high efficacy of national mass drug administration programming for the control of intestinal helminths.

Intravenous drug abuse - a concern for falciparum malaria along with HIV.

Mefloquine (MQ) is an important component for antiparasitic therapy. Herein, the synthesis and antiplasmodial and antischistosomal activities of MQ-metal complexes of the general formula [M(II)(L)(MQ)]PF6 are described. Variation of the metal center (platinum and palladium) and coligand (phosphine or bipyridine) consistently yielded MQ coordinated as a N,O-bidentate ligand. Biological evaluation against Plasmodium falciparum and Schistosoma mansoni revealed that the metal center augmented the antiparasitic property of MQ by functioning as a thioredoxin/glutathione reductase-targeting moiety, while the coligand modulated chemical reactivity and physicochemical properties. MQ-Pt complexes displayed high in vivo efficacy. The intracellular accumulation of the metal in parasite cells contributed to the abrogation of essential biochemical pathways. Notably, despite being isostructural, Pd complexes differed from their Pt counterparts in their ligand dissociation behavior. The current work establishes a new structural framework for developing metal-based antiparasitic agents capable of selectively targeting essential parasite biochemical pathways while sparing mammalian cells.

Pyrimethamine resistance in Plasmodium falciparum is driven by mutations at dihydrofolate reductase (DHFR) residues N51I, C59R, S108N/T, and I164L, with parallel substitutions in P. vivax (N50I, S58R, S117N/T, S173L). To evaluate the influence of drug pressure on parasite evolution, we compared the dihydrofolate reductase-thymidylate synthase (dhfr-ts) genes of human and zoonotic malaria parasites exposed to different drug environments. Blood samples were collected from patients with symptomatic malaria in Thailand (P. falciparum, n = 241; P. vivax, n = 115) and from sympatric zoonotic infections, mainly in naturally infected macaques (P. knowlesi, n = 18; P. inui, n = 64). Complete dhfr-ts sequences were determined and validated. Among 356 human and 145 zoonotic dhfr-ts sequences, zoonotic parasites exhibited markedly higher mutation counts, haplotype diversity, and nucleotide diversity. In P. falciparum, the high prevalence of the quadruple IRNL mutant indicated strong directional selection. In P. vivax, the coexistence of wild-type alleles and mutations outside resistance-associated residues suggests incomplete fixation. In zoonotic parasites, elevated rates of synonymous versus nonsynonymous substitutions, along with an excess of rare variants, indicate that purifying selection and genetic drift act against slightly deleterious mutations, likely due to protein functional or structural constraints. Antifolate drug pressure has driven human malaria dhfr-ts genes toward fixation, whereas zoonotic orthologues evolve under a mutation-selection-drift balance. These findings highlight both the potential utility of antifolates against zoonotic malaria and the evolutionary consequences of sustained drug pressure.

BackgroundHistidine-rich protein 2 (HRP2)-based rapid diagnostic tests (RDTs) are critical for malaria diagnosis in Africa, particularly in resource-limited settings. However, the spread of Plasmodium falciparum parasites with pfhrp2 and pfhrp3 gene deletions challenges their effectiveness, raising concerns in affected areas. Therefore, this study aimed to assess the prevalence of pfhrp2 and pfhrp3 gene deletions and evaluate the diagnostic performance of HRP2-based RDTs in detecting asymptomatic malaria infections in Tanzania. MethodThis cross-sectional community survey study aimed to determine the prevalence of pfhrp2/3 gene deletions from asymptomatic malaria population in Tanzania. Moreover, the study intended to assess the performance of HRP2-based RDT and light microscopy (LM) in detecting asymptomatic malaria infections. The survey was conducted from December 2022 to July 2023 in twelve villages (8 villages from high malaria transmission areas and 4 in low endemicity). Diagnosis was done by RDT, LM and quantitative polymerase chain reaction (qPCR). A multiplex qPCR was employed on P. falciparum mono-infection isolates to assess the prevalence of pfhrp2/3 gene deletions. Unpaired t-tests and one-way ANOVA were performed to evaluate associations between log10-transformed parasitaemia levels and gene deletion profiles.ResultsAmong 3489 participants, RDT detected 710 (77.6%) of 915 qPCR-positive cases, compared to 492 (53.8%) by LM. Compared with qPCR, RDT produced 143 (5.6%) false positives and 205 (22.4%) false negatives, whereas LM had 60 (2.3%) false positives and 423 (46.2%) false negatives. Overall accuracy was similar for RDT (90.0%) and LM (86.2%), with higher sensitivity for RDT. Agreement with qPCR in asymptomatic cases was substantial for RDT (κ = 0.736), whereas it was moderate for LM (κ = 0.590). Multiplex qPCR revealed pfhrp2 or pfhrp3 deletions in 93 (11.8%) of 787 samples, including 19 (2.4%) dual-deletion isolates, all of which were RDT negative. Deletions were more frequent in high-transmission villages (76 cases, 9.7%) than in low-transmission villages (17 cases, 2.2%).ConclusionThe findings support the continued effectiveness of HRP2-based RDTs in detecting asymptomatic P. falciparum infections in Tanzania, despite the presence of some pfhrp2/3 gene deletions. However, the potential increase in deletion prevalence and the limitations of cross-sectional data highlight the need for ongoing molecular surveillance. Collectively, these findings provide a critical foundation for sustained surveillance and for clarifying the epidemiological significance of asymptomatic malaria in Tanzania.Graphical Supplementary InformationThe online version contains supplementary material available at 10.1186/s40249-025-01397-3.

Malaria remains a major public health concern in Jayapura, Indonesia. Limited microscopy availability in primary healthcare facilities has increased reliance on rapid diagnostic tests (RDTs) for early case detection. This study aimed to evaluate the diagnostic performance of two malaria RDTs, AllCheck® and Orient Gene®, using microscopy as the reference standard. A cross-sectional study was conducted at a primary healthcare center in Jayapura in December 2025, involving 49 patients with clinical symptoms suggestive of malaria. Capillary blood samples were collected for RDT testing and preparation of thick and thin blood smears. Diagnostic accuracy was assessed by calculating sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV), as well as agreement analysis using Cohen’s Kappa and McNemar test. Both RDTs demonstrated comparable diagnostic performance, with sensitivities of 93.75% (95% CI: 69.77–99.84) and specificities of 100% (95% CI: 89.42–100.00). The PPV was 100% (95% CI: 78.20–100.00), and the NPV was 97.06% (95% CI: 84.67–99.93). Agreement analysis showed almost perfect concordance between each RDT and microscopy (? = 0.953; p < 0.001). No significant difference was observed between AllCheck® and Orient Gene® results based on the McNemar test (p = 1.000). No significant association was found between diagnostic outcomes and patient sex or age group (p > 0.05). The RDTs showed good performance in detecting Plasmodium falciparum and Plasmodium vivax, but reduced sensitivity for Plasmodium malariae. In conclusion, AllCheck® and Orient Gene® RDTs demonstrate strong diagnostic performance and almost perfect agreement with microscopy, supporting their suitability for malaria screening and initial diagnosis in primary healthcare settings in Jayapura. Nevertheless, microscopy remains essential for confirming non-falciparum infections and ensuring comprehensive case detection.

The emergence of multi-drug resistant Plasmodium falciparum underscores the urgent need for new antimalarial therapies. SC83288, a chemically distinct antimalarial compound, is highly effective against P. falciparum both in vivo and in vitro, including strains resistant to artemisinin and partner drugs. Here, we show that SC83288 disrupts blood-stage development by blocking DNA replication and arresting karyokinesis. We identify the parasite's DNA and tRNAAsp methyltransferase PfDNMT2 as a primary molecular target, linking drug action to impaired epigenetic regulation, altered S-adenosylmethionine fluxes, and compensatory transcriptional responses. Resistance to SC83288 arises through mutations in the parasite's SERCA-type Ca²⁺ ATPase PfATP6, which enable transport of the compound into the endoplasmic reticulum, away from its nuclear targets. This resistance mechanism carries a substantial fitness cost, limiting its potential for spread. Together, target validation, a unique resistance profile, and high fitness cost strengthen SC83288's potential as a promising clinical development candidate for malaria treatment.

After substantial progress in malaria control, Ethiopia's Amhara Region experienced a marked resurgence since 2018. The relative contributions of climate variability, environmental context, intervention coverage, and unmeasured factors to this resurgence remain inadequately quantified. This study used a Bayesian spatiotemporal framework to estimate factor associations with malaria incidence, decompose spatial versus temporal climate effects, and identify persistent hotspots. We conducted an ecological district-level panel analysis of 13,944 district-month observations from 166 districts (January 2018-December 2024). Monthly confirmed malaria counts (total,Plasmodium falciparum,P. vivax) were modelled using Bayesian hierarchical negative binomial regression with BYM2 spatial and AR(1) temporal random effects, fitted with integrated nested Laplace approximation. Covariates included lagged rainfall, temperature, NDVI, elevation, and programmatic indicators (ITN ownership, IRS protection, and larval source management [LSM] intensity). Climate covariates were decomposed into between-district (spatial) means and within-district (temporal) deviations. Sensitivity analyses included alternative IRS protection windows and district fixed-effects models. A total of 5,746,571 confirmed cases were reported (64.3%P. falciparum, 35.7%P. vivax). Mean monthly incidence increased 5.5-fold from 1.19 per 1,000 (2018) to 6.53 per 1,000 (2024), while regional mean maximum temperature showed a small declining trend over the period. In fully adjusted models, higher lagged maximum temperature and rainfall were associated with higher incidence, and elevation was protective. IRS protection, higher ITN ownership, and higher LSM intensity were each associated with lower incidence; effect directions were consistent in within-district sensitivity analyses, although residual confounding and measurement error cannot be excluded. Climate-incidence associations were predominantly spatial (between-district) rather than temporal (within-district), suggesting that geographic ecological suitability explains much of the spatial patterning, rather than temporal warming trends explaining the resurgence. Districts with persistently elevated residual spatial risk (exceedance probability of residual RR > 1.25) clustered in low-elevation western border areas. Malaria resurgence in Amhara (2018-2024) occurred alongside strong spatial climatic and elevational gradients and was not consistent with a temporal warming-driven explanation at the regional scale. Remaining unexplained spatiotemporal variation highlights the likely importance of unmeasured drivers (e.g., conflict-related service disruption, vector/insecticide resistance dynamics, and population mobility). Climate-informed, spatially targeted intervention packages prioritizing districts with persistently high residual risk are warranted.

After the expansion of the World Health Organization's guidelines on eligibility for the seasonal malaria chemoprevention (SMC), the government of Kenya prepared to implement SMC for a first time in Turkana Central Subcounty in 2024. To inform the design of SMC, we conducted a baseline qualitative and quantitative study. Using stratified cluster sampling, we enrolled 198 households with children of ages 6 months to 5 years and tested all individuals six months and older using a rapid diagnostic test (RDT) and polymerase chain reaction (PCR) for Plasmodium falciparum. We performed 78 key informant interviews; 31 focus group discussions with community health workers, elders, and caretakers of children; and 60 in-depth interviews with caretakers. Prevalence of P. falciparum infection was 21% (9-42%) by RDT and 21% (11-38%) by PCR. Prevalence varied across villages, with the highest positivity of 73% by PCR. Although SMC was perceived positively, the identified challenges included physical access (households far from village centers, pastoralists, children living in the streets), stigma (children living with disabilities, households with members struggling with alcohol use), and acceptability (traditionalists, highly educated households). Despite the high malaria burden in the region, SMC may be a feasible approach to reduce its burden and transmission. However, implementation of SMC should be tailored, combining centralized distribution with door-to-door delivery and outreach to pastoralists and people living in the interior. Using existing grassroots structures, such as pastoralist leadership structures and religious and group leaders, and intensive mobilization will be critical for success of this intervention.

It is currently unclear whether repeated mosquito feeding attempts achieve pathogen transmission. We measured Plasmodium falciparum sporozoite expelling in Anopheles stephensi mosquitoes during two interrupted feeding attempts. The number of expelled sporozoites was positively correlated with salivary gland sporozoite load during the first feeding effort (ρ= 0.36, p= 0.0181) but less so during subsequent feeding (ρ= 0.06, p= 0.6811). The median number of expelled sporozoites was of similar magnitude during the first and second feeding event, with a strong correlation between them (ρ= 0.56, p= 0.0002). We conclude that repeated feeding results in repeated sporozoite inoculation at similar intensity.

Two new lyngbyabellin analogs, Q (1) and R (2), were isolated from a marine cyanobacterial biomat dominated by Moorena sp. Their structures were established primarily through a combination of spectroscopic analyses and degradation reactions. Lyngbyabellin Q (1) inhibited the growth of HeLa cells and disrupted actin dynamics. In addition, lyngbyabellin Q (1) exhibited potent antimalarial activity with an IC50 value of 22 nM, and a new structure-activity relationship enhancing selectivity for the growth inhibition of Plasmodium falciparum over mammalian cells was identified.

Inhibiting catalytic activity of Plasmodium falciparum aspartate protease plasmepsin V: A biochemical approach to malaria intervention.