Current or recent malaria infection is associated with elevated inflammation-adjusted ferritin concentrations in pre-school children: a secondary analysis of the BRINDA database.

Inflammation and infections such as malaria affect micronutrient biomarker concentrations and hence estimates of nutritional status. It is unknown whether correction for C-reactive protein (CRP) and α1-acid glycoprotein (AGP) fully captures the modification in ferritin concentrations during a malaria infection, or whether environmental and sociodemographic factors modify this association. Cross-sectional data from eight surveys in children aged 6-59 months (Cameroon, Cote d'Ivoire, Kenya, Liberia, Malawi, Nigeria and Zambia; n 6653) from the Biomarkers Reflecting Inflammation and Nutritional Determinants of Anaemia (BRINDA) project were pooled. Ferritin was adjusted using the BRINDA adjustment method, with values < 12 µg/l indicating iron deficiency. The association between current or recent malaria infection, detected by microscopy or rapid test kit, and inflammation-adjusted ferritin was estimated using pooled multivariable linear regression. Age, sex, malaria endemicity profile (defined by the Plasmodium falciparum infection prevalence) and malaria diagnostic methods were examined as effect modifiers. Unweighted pooled malaria prevalence was 26·0 % (95 % CI 25·0, 27·1) and unweighted pooled iron deficiency was 41·9 % (95 % CI 40·7, 43·1). Current or recent malaria infection was associated with a 44 % (95 % CI 39·0, 52·0; P < 0·001) increase in inflammation-adjusted ferritin after adjusting for age and study identifier. In children, ferritin increased less with malaria infection as age and malaria endemicity increased. Adjustment for malaria increased the prevalence of iron deficiency, but the effect was small. Additional information would help elucidate the underlying mechanisms of the role of endemicity and age in the association between malaria and ferritin.

Long-lasting insecticidal nets use and the prevalence of Plasmodium falciparum infection among pregnant women attending antenatal care at the Bonassama District Hospital, Littoral Region of Cameroon: a cross-sectional study.

BACKGROUND: Malaria during pregnancy continues to be a significant cause of morbidity and mortality for both infants and mothers, particularly in sub-Saharan African (SSA) countries, despite increased efforts to control it. The utilization of long-lasting insecticide-treated nets (LLINs) during pregnancy is a well-established strategy to reduce the prevalence of malaria. Nonetheless, inadequate adherence remains a persistent challenge in certain regions with high malaria endemicity. This research aimed to assess the effectiveness of long-lasting insecticidal nets in preventing asymptomatic malaria infections among pregnant women attending antenatal care at the Bonassama District Hospital in the Littoral Region of Cameroon. METHODS: A hospital-based cross-sectional study was conducted from March to June 2022. Data on sociodemographic characteristics and LLIN usage were collected through a structured questionnaire, while asymptomatic malaria infections were identified using a PfHRP2/pLDH malaria qualitative rapid diagnostic kit. The relationship between categorical variables was analyzed using the chi-square test and logistic regression at a significance level of 5%. RESULTS: Out of the 411 pregnant women included in the study, 35.4% were diagnosed with malaria. The LLIN utilization rate was 65.1%. The risk of malaria infection was 2.7 times higher (AOR = 2.75, 95% CI = 1.83-4.14, p < 0.001) among women who did not consistently use LLINs compared to those who did. Pregnant women in their first trimester (AOR = 3.40, 95% CI = 1.24-4.64, p = 0.010) and second trimester (AOR = 1.90, 95%CI = 0.99-3.62, p = 0.055) were more likely to sleep under net when compared to those in the third trimester. Younger women 20-29 years (71.4%), those in the first trimester (69.6%) and those who had the nets before pregnancy (68.9%) were amongst those who frequently used use the nets. Among the reasons reported for not frequently using LLINs were heat (55.2%), suffocation (13.6%) and the smell of nets (8.4%). CONCLUSION: The use of LLIN was moderately high among the participants in this study, though still below national target. Age group, religion and gestation period were the major factors determining the use of LLINs. Considering the proven effectiveness of LLINs in reducing malaria morbidity and mortality, it is imperative for the National Malaria Control Programme (NMCP) to remain focused in promoting both LLIN ownership and utilization to achieve the national target of 100% and 80%, respectively.

False Positive for Malaria Rapid Test in a Patient With Cytomegalovirus Infection.

There is a growing development of immunochromatographic tests for the detection of specific Plasmodium spp. antigens. These tests rely on capturing antigens from peripheral blood using monoclonal or polyclonal antibodies against specific targets. We present the case of a 28-year-old male patient with a history of two previous episodes of Plasmodium falciparum malaria, treated appropriately seven months and three years ago. He was referred to our institution with a six-day history of fever, epigastric pain, hematuria, and vomiting. Serial thick and thin blood smears were negative for hemoparasites, but a Bioline™ Malaria Ag P.f/Pan rapid test was positive for the Pan (pLDH) band. Given the clinical context and inability to visualize Plasmodium in blood smears, the positive pLDH band on the rapid malaria test was considered a possible false positive. Subsequent tests concluded that the patient was experiencing a cytomegalovirus (CMV) infection, which improved with supportive management, and he was discharged symptom-free. Malaria remains a major public health issue in tropical and subtropical regions. While rapid diagnostic tests are crucial for timely diagnosis, false positives due to cross-reactivity with other infections and conditions are reported. Our case highlights the potential for cross-reactivity with CMV infections, although direct evidence of active viral replication was not obtained. This phenomenon can lead to the overestimation of malaria cases and inappropriate treatment, underscoring the need for careful interpretation of rapid test results.

Plasmodium Vivax in a Healthy, Young Immigrant Male.

A young immigrant male presented to the hospital with multiple complaints and was found to be in septic shock with symptomatic anemia. After an extensive workup, the patient was found to have malaria, a disease caused by the bite of an infected mosquito. This case outlines the pertinent findings, relevant diagnostic tests, and appropriate treatment for a patient with malaria secondary to Plasmodium vivax. It also demonstrates the importance of social and travel history, especially when evaluating our immigrant populations.

Validation of malaria-attributed deaths using verbal autopsy studies: a systematic review.

BACKGROUND: Malaria contributes substantially to the persistent burden of child deaths in sub-Saharan Africa. Accurate and comprehensive malaria mortality data are crucial to monitor the progress in reducing malaria incidence and mortality. Verbal Autopsy (VA) ascertains the cause of death despite its limitations leading to misclassification errors. Minimally Invasive Tissue Sampling (MITS) is being conducted in some settings as an alternative to Complete Diagnostic Autopsy (CDA). The present study examines the validity of malaria-related deaths comparing VA diagnoses with those obtained through MITS and/or CDA. METHODS: A comprehensive literature search for original studies in English language using Ovid MEDLINE, Ovid Embase, CINAHL via EBSCO, Scopus, The Cochrane Library via Wiley, Google Scholar and searching the MITS Surveillance Alliance papers was carried out. The reference period was January 1, 1990-March 31, 2024. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were adopted. RESULTS: Among 71 articles identified in the databases, 21 matched the eligibility criteria. Qualitative syntheses showed that malaria Cause Specific Mortality Fractions (CSMFs) across various studies ranged from 2 to 31%. Plasmodium falciparum was mostly responsible for these deaths and the most common complications were anaemia and cerebral malaria. The sensitivity and specificity of the VA validation studies ranged from 18.4% to 33% and from 86.6% to 97%, respectively, and there was a high level of misclassification for both InSilico and Expert Algorithm VA for malaria compared to MITS. The overall concordance rates between MITS and CDA diagnoses ranged from 68 to 90%, with the highest concordance seen in deaths due to infectious diseases and malignant tumours. Clinical data increased diagnostic coincidence between MITS blind to clinical data and the gold standard CDA by 11%. CONCLUSIONS: The comprehensive review finds that MITS demonstrated better accuracy compared to VA in diagnosing malaria-attributed deaths, particularly in hospital settings. The high specificity of malaria in VA diagnosis suggests population-based estimates of the proportion of deaths due to malaria are broadly plausible.

Patterns and predictors of malaria among head porters: a mobile population in Ghana.

BACKGROUND: Head porters popularly known as 'Kayayeis in Ghana, face challenges in accessing essential health care services due to the mobile nature of their trade, low formal education, poor settlements, low-income among others. Kayayeis are predominantly females and form part of the mobile population who are at increased risk of malaria infection. Despite their increased risk of malaria, mobile populations are difficult to target for malaria interventions, hence serving as potential drivers of transmission even if malaria in the general population is controlled. The study, therefore, assessed the patterns and predictors of malaria among the Kayayei population in Ghana to inform policy decisions. METHODS: A mixed methods study was conducted among Head-porters and their leaders in the three main hubs of Head-porters in Ghana; namely Accra, Kumasi, and Tamale. Blood samples were collected from participants and tested for malaria parasites using Rapid Diagnostic Test (RDT). Additionally, data including socio-demographics, malaria knowledge, attitude and practice were collected using a semi-structured questionnaire. Associations between malaria status and participants characteristics were determined by logistic regression (p < 0.05). Thematic analysis was used to analyse transcripts from the key informant interviews. RESULTS: Out of 754 head porters studied, 10.48% (79) tested positive for malaria. The majority 43.10% (325/754) of the head porters were twenty years and below, and most 67.11% (506/754) had no formal education. Nearly half (50.4%) were not on any health insurance. Receiving malaria education in the past 6 months [AOR = 0.48, (0.26-0.88), p-value 0.02], and having poor knowledge of malaria [AOR = 2.23, (1.26-4.27), p < 0.02], were the factors significantly associated with malaria infection. CONCLUSION: The prevalence of malaria among 'Kayayei's was estimated at 10.46%. A majority of them sleeps outside and in structures without mosquito screens. Receiving malaria education in the past 6 months reduced the odds of malaria infection whilst poor knowledge of malaria increased the odds of malaria infection among the porters. The authors recommend that the National Malaria Elimination Programme and partners should provide long-lasting insecticidal nets (LLIN) and other outdoor interventions for use by this special group. Designated state institutions should arrange free National Health Insurance Scheme (NHIS) registration for 'Kayayeis' to narrow the health access gap.

Longitudinal changes in iron homeostasis in human experimental and clinical malaria.

BACKGROUND: The interaction between iron status and malaria is incompletely understood. We evaluated longitudinal changes in iron homeostasis in volunteers enrolled in malaria volunteer infection studies (VIS) and in Malaysian patients with falciparum and vivax malaria. METHODS: We retrieved data and samples from 55 participants (19 female) enrolled in malaria VIS, and 171 patients (45 female) with malaria and 30 healthy controls (13 female) enrolled in clinical studies in Malaysia. Ferritin, hepcidin, erythropoietin, and soluble transferrin receptor (sTfR) were measured by ELISA. FINDINGS: In the VIS, participants' parasitaemia was correlated with baseline mean corpuscular volume (MCV), but not iron status (ferritin, hepcidin or sTfR). Ferritin, hepcidin and sTfR all increased during the VIS. Ferritin and hepcidin normalised by day 28, while sTfR remained elevated. In VIS participants, baseline ferritin was associated with post-treatment increases in liver transaminase levels. In Malaysian patients with malaria, hepcidin and ferritin were elevated on admission compared to healthy controls, while sTfR increased following admission. By day 28, hepcidin had normalised; however, ferritin and sTfR both remained elevated. INTERPRETATION: Our findings demonstrate that parasitaemia is associated with an individual's MCV rather than iron status. The persistent elevation in sTfR 4 weeks post-infection in both malaria VIS and clinical malaria may reflect a causal link between malaria and iron deficiency. FUNDING: National Health and Medical Research Council (Program Grant 1037304, Project Grants 1045156 and 1156809; Investigator Grants 2016792 to BEB, 2016396 to JCM, 2017436 to MJG); US National Institute of Health (R01-AI116472-03); Malaysian Ministry of Health (BP00500420).

First experimental observation on biology of the avian malaria parasite Plasmodium (Novyella) homonucleophilum (lineage pSW2), with remarks on virulence and distribution.

Species of subgenus Novyella remain most fragmentarily studied amongst avian malaria agents. Transmission of the recently described Plasmodium (Novyella) homonucleophilum (lineage pSW2) occurs broadly in the Old World, including Europe, however biology of this pathogen remains insufficiently investigated. This study provided the first data on the development of P. homonucleophilum in the experimentally infected Eurasian siskins Spinus spinus exposed by inoculation of infected blood. The parasite strain was isolated from a naturally infected song thrush Turdus philomelos, multiplied in vivo, and inoculated to six Eurasian siskins. The same number of birds were used as negative controls. All exposed birds were susceptible, and the controls remained uninfected during the entire study (172 days). Prepatent period was 8-12 days post exposure (dpe). Maximum parasitaemia reached 50-90 % of infected erythrocytes between 20 and 44 dpe. Then, parasitaemia decreased but remained relatively high during the entire observation. Three of six exposed birds died, indicating high virulence of this infection. The parasitaemia increase coincided with a decline of haematocrit value, indicating anaemia. Polychromasia was evident in all infected birds but not in controls. Body mass of exposed birds increased, coinciding with increased food intake. The latter probably is an adaptation to compensate energy loss of hosts due to the long-lasting parasitism. Exo-erythrocytic stages were not found, suggesting that long-lasting parasitaemia was entirely due to erythrocytic merogony. The lineage pSW2 has been reported broadly in the Old World and is likely a generalist infection. Neglected avian Novyella malaria parasites are worth more attention of researchers due to their cosmopolitan distribution and high virulence.

Recombinant Full-length Plasmodium falciparum Circumsporozoite Protein-Based Vaccine Adjuvanted With Glucopyranosyl Lipid A-Liposome Quillaja saponaria 21: Results of Phase 1 Testing With Malaria Challenge.

BACKGROUND: Malaria is preventable yet causes >600 000 deaths annually. RTS,S, the first marketed malaria vaccine, has modest efficacy, but improvements are needed for eradication. METHODS: We conducted an open-label, dose escalation phase 1 study of a full-length recombinant circumsporozoite protein vaccine (rCSP) administered with adjuvant glucopyranosyl lipid A-liposome Quillaja saponaria 21 formulation (GLA-LSQ) on days 1, 29, and 85 or 1 and 490 to healthy, malaria-naive adults. The primary end points were safety and reactogenicity. The secondary end points were antibody responses and Plasmodium falciparum parasitemia after homologous controlled human malaria infection. RESULTS: Participants were enrolled into 4 groups receiving rCSP/GLA-LSQ: 10 µg × 3 (n = 20), 30 µg × 3 (n = 10), 60 µg × 3 (n = 10), or 60 µg × 2 (n = 9); 10 participants received 30 µg rCSP alone × 3, and there were 6 infectivity controls. Participants experienced no serious adverse events. Rates of solicited and unsolicited adverse events were similar among groups. All 26 participants who underwent controlled human malaria infection 28 days after final vaccinations developed malaria. Increasing vaccine doses induced higher immunoglobulin G titers but did not achieve previously established RTS,S benchmarks. CONCLUSIONS: rCSP/GLA-LSQ had favorable safety results. However, tested regimens did not induce protective immunity. Further investigation could assess whether adjuvant or schedule adjustments improve efficacy. CLINICAL TRIALS REGISTRATION: NCT03589794.

Plasmodium falciparum merozoite surface protein 1 as asexual blood stage malaria vaccine candidate.

INTRODUCTION: Malaria represents a public health challenge in tropical and subtropical regions, and currently deployed control strategies are likely insufficient to drive elimination of malaria. Development and improvement of malaria vaccines might be key to reduce disease burden. Vaccines targeting asexual blood stages of the parasite have shown limited efficacy when studied in human trials conducted over the past decades. AREAS COVERED: Vaccine candidates based on the merozoite surface protein 1 (MSP1) were initially envisioned as one of the most promising approaches to provide immune protection against asexual blood-stage malaria. Successful immunization studies in monkey involved the use of the full-length MSP1 (MSP1FL) as vaccine construct. Vaccines using MSP1FL for immunization have the potential benefit of including numerous conserved B-cell and T-cell epitopes. This could result in improved parasite strain-transcending, protective immunity in the field. We review outcomes of clinical trials that utilized a variety of MSP1 constructs and formulations, including MSP1FL, either alone or in combination with other antigens, in both animal models and humans. EXPERT OPINION: Novel approaches to analyze breadth and magnitude of effector functions of MSP1-targeting antibodies in volunteers undergoing experimental vaccination and controlled human malaria infection will help to define correlates of protective immunity.

Prevalence and risk factors associated with malaria infection in children under two years of age in southern Togo prior to perennial malaria chemoprevention implementation.

BACKGROUND: Malaria remains the leading cause of mortality and morbidity in young children in sub-Saharan Africa. To prevent malaria in children living in moderate-to-high malaria transmission areas, the World Health Organization has recommended perennial malaria chemoprevention (PMC). Prior to piloting PMC implementation in southern Togo, a household survey was conducted to estimate malaria infection prevalence in children under 2 years of age (U2). METHODS: A cross-sectional community-based household survey was conducted in the Haho district in the Togo Plateaux region. A three-stage random sampling method was used to select study participants aged 10-23 months whose caretakers gave informed consent. The prevalence of Plasmodium infection, defined as a positive rapid diagnostic test (RDT), was estimated with 95% confidence interval (CI). Clinical malaria was defined as having a positive RDT plus fever (≥ 37.5 °C) or history of fever in the last 24 h. Mixed-effects logistic regression models were used to assess the child's, caretaker's, and household's factors associated with malaria infection. RESULTS: A total of 685 children were included in the survey conducted January-February in 2022 (dry season). Median age was 17 months (interquartile range: 13-21). About 80% of the children slept under a bed net the night before the interview. Malaria infection prevalence was 32.1% (95% CI 27.7-37.0) with significant area variation (cluster range: 0.0-73.3). Prevalence of clinical malaria was 15.4% (95% CI 12.2-19.2). Children whose caretakers were animist (aOR: 1.71, 95% CI 1.19-2.46) and those living in mother-headed households (aOR: 2.39, 95% CI 1.43-3.99) were more likely to have a positive RDT. Living more than 5 km away from the nearest health facility (aOR: 1.60, 95% CI 1.04-2.44) and presence of two or more under-5-years children in the household (aOR: 1.44, 95% CI 1.01-2.07) were also associated with increased risk of infection. CONCLUSION: One-third of the children U2 who participated in this survey had malaria infection, thus PMC could be a promising strategy to reduce malaria burden in young children in Plateaux region. Reinforcement of outreach services and targeting the poorest households should be prioritized to reduce the inequity in malaria prevention in children exposed to the infection.

Human transcriptional signature of protection after Plasmodium falciparum immunization and infectious challenge via mosquito bites.

The identification of immune correlates of protection against infectious pathogens will accelerate the design and optimization of recombinant and subunit vaccines. Systematic analyses such as immunoprofiling including serological, cellular, and molecular assessments supported by computational tools are key to not only identify correlates of protection but also biomarkers of disease susceptibility. The current study expands our previous cellular and serological profiling of vaccine-induced responses to a whole parasite malaria vaccine. The irradiated sporozoite model was chosen as it is considered the most effective vaccine against malaria. In contrast to whole blood transcriptomics analysis, we stimulated peripheral blood mononuclear cells (PBMC) with sporozoites and enriched for antigen-specific cells prior to conducting transcriptomics analysis. By focusing on transcriptional events triggered by antigen-specific stimulation, we were able to uncover quantitative and qualitative differences between protected and non-protected individuals to controlled human malaria infections and identified differentially expressed genes associated with sporozoite-specific responses. Further analyses including pathway and gene set enrichment analysis revealed that vaccination with irradiated sporozoites induced a transcriptomic profile associated with Th1-responses, Interferon-signaling, antigen-presentation, and inflammation. Analyzing longitudinal time points not only post-vaccination but also post-controlled human malaria infection further revealed that the transcriptomic profile of protected vs non-protected individuals was not static but continued to diverge over time. The results lay the foundation for comparing protective immune signatures induced by various vaccine platforms to uncover immune correlates of protection that are common across platforms.

Assessing caregivers' perceptions of treatment-seeking for suspected severe malaria in the Democratic Republic of the Congo.

BACKGROUND: Malaria remains a major public health issue in the Democratic Republic of the Congo (DRC), accounting for 44% deaths among outpatient visits in children < 5 years of age, and 22% of facility deaths. Understanding determinants of caregivers' treatment-seeking patterns and decision-making is crucial in reducing the malaria burden. METHODS: In the frame of the Community Access to Rectal Artesunate for Malaria (CARAMAL) project, cross-sectional household surveys that randomly sampled villages and households were carried-out in three rural DRC health zones prior to the rollout of pre-referral Rectal Artesunate (RAS) and then 9 and 19 months after RAS rollout (post-RAS). Data were captured electronically through face-to-face interviews with the main caregivers of children < 5 years. Capillary blood samples of the children were tested for malaria and anaemia. The main study outcome was whether caregiver "sought treatment outside home" when the child had fever. Multilevel mixed effects logistic regression models using village as random effect and health zone as a fixed effect was performed to assess treatment-seeking predictors. RESULTS: 2439 household interviews were completed (pre-RAS 888 and post-RAS 1551), including 316 and 653 treatment-seeking interviews. Overall, 3499 children < 5 years were tested for malaria and anaemia (pre-RAS 1,315 and post-RAS 2184). Caregiver's recognition of severe malaria signs was poor, while knowledge of symptoms of uncomplicated malaria seemed high. Despite this, danger signs significantly increased the odds of seeking treatment (aOR = 2.12, 95%CI 1.03-4.38), the same was found for the "least poor" quintile (aOR = 3.01, 95%CI 1.03-8.82), as well as residents of Kingandu (aOR = 2.78, 95%CI 1.01-7.65). "Doing something at home" against fever negatively affected treatment-seeking in both study phases. RAS acceptance was high, at almost 100%. Malaria prevalence was higher post-RAS (45.2%) compared to pre-RAS (34.4%), p = 0.003, but anaemia, although high (≥ 75%), was similar in both study phases (p = 0.92). CONCLUSION: In remote communities with high malaria prevalence in the DRC, malaria remains a major problem. Improving the recognition of danger signs of severe disease and introducing pre-referral RAS may improve treatment-seeking and contribute to reducing malaria-related mortality among children-if quality of care can be guaranteed.

Effectiveness of Intermittent Preventive Treatment with Sulfadoxine-Pyrimethamine in Pregnancy: Low Coverage and High Prevalence of Plasmodium falciparum dhfr-dhps Quintuple Mutants as Major Challenges in Douala, an Urban Setting in Cameroon.

Intermittent preventive treatment in pregnancy with sulfadoxine and pyrimethamine (IPTp-SP) is a key component in the malaria control strategy implemented in Africa. The aim of this study was to determine IPTp-SP adherence and coverage, and the impact on maternal infection and birth outcomes in the context of widespread SP resistance in the city of Douala, Cameroon. Clinical and demographic information were documented among 888 pregnant women attending 3 health facilities, from the antenatal care visit to delivery. Positive samples were genotyped for P. falciparum gene (dhfr, dhps, and k13) mutations. The overall IPTp-SP coverage (≥three doses) was 17.5%, and 5.1% received no dose. P. falciparum prevalence was 16%, with a predominance of submicroscopic infections (89.3%). Malaria infection was significantly associated with locality and history of malaria, and it was reduced among women using indoor residual spraying. Optimal doses of IPTp-SP were significantly associated with reduced infection among newborns and women (secundiparous and multiparous), but there was no impact of IPTp-SP on the newborn bodyweight. Pfdhfr-Pfdhps quintuple mutants were over-represented (IRNI-FGKAA, IRNI-AGKAA), and sextuple mutants (IRNI-AGKAS, IRNI-FGEAA, IRNI-AGKGS) were also reported. The Pfk13 gene mutations associated with artemisinin resistance were not detected. This study highlights the role of ANC in achieving optimal SP coverage in pregnant women, the mitigated impact of IPTp-SP on malaria outcomes, and the high prevalence of multiple SP-resistant P. falciparum parasites in the city of Douala that could compromise the efficacy of IPTp-SP.

Plasmodium 18S Ribosomal RNA Biomarker Clearance After Food and Drug Administration-Approved Antimalarial Treatment in Controlled Human Malaria Infection Trials.

Background: Sensitive molecular assays, such as quantitative reverse-transcription polymerase chain reaction (qRT-PCR) of Plasmodium 18S ribosomal RNA (rRNA), are increasingly the primary method of detecting infections in controlled human malaria infection (CHMI) trials. However, thick blood smears (TBSs) remain the main method for confirming clearance of parasites after curative treatment, in part owing to uncertainty regarding biomarker clearance rates. Methods: For this analysis, 18S rRNA qRT-PCR data were compiled from 127 Plasmodium falciparum-infected participants treated with chloroquine or atovaquone-proguanil in 6 CHMI studies conducted in Seattle, Washington, over the past decade. A survival analysis approach was used to compare biomarker and TBS clearance times among studies. The effect of the parasite density at which treatment was initiated on clearance time was estimated using linear regression. Results: The median time to biomarker clearance was 3 days (interquartile range, 3-5 days), while the median time to TBS clearance was 1 day (1-2 days). Time to biomarker clearance increased with the parasite density at which treatment was initiated. Parasite density did not have a significant effect on TBS clearance. Conclusions: The Plasmodium 18S rRNA biomarker clears quickly and can be relied on to confirm the adequacy of Food and Drug Administration-approved treatments in CHMI studies at nonendemic sites.

Dual-pharmacophore artezomibs hijack the Plasmodium ubiquitin-proteasome system to kill malaria parasites while overcoming drug resistance.

Artemisinins (ART) are critical anti-malarials and despite their use in combination therapy, ART-resistant Plasmodium falciparum is spreading globally. To counter ART resistance, we designed artezomibs (ATZs), molecules that link an ART with a proteasome inhibitor (PI) via a non-labile amide bond and hijack parasite's own ubiquitin-proteasome system to create novel anti-malarials in situ. Upon activation of the ART moiety, ATZs covalently attach to and damage multiple parasite proteins, marking them for proteasomal degradation. When damaged proteins enter the proteasome, their attached PIs inhibit protease function, potentiating the parasiticidal action of ART and overcoming ART resistance. Binding of the PI moiety to the proteasome active site is enhanced by distal interactions of the extended attached peptides, providing a mechanism to overcome PI resistance. ATZs have an extra mode of action beyond that of each component, thereby overcoming resistance to both components, while avoiding transient monotherapy seen when individual agents have disparate pharmacokinetic profiles.

Baseline TGF-ß correlates with protection after immunization with Plasmodium falciparum sporozoites in the controlled human malaria infection model.

BACKGROUND: Here we assessed a possible relationship between baseline TGF-ß concentrations and acquisition of sterile immunity after Plasmodium falciparum sporozoite immunization. METHODS: TGF-ß concentrations were determined in samples of 65 malaria-naive volunteers in 4 studies either prior to and after challenge infection, or prior to and after first immunizing infection under chemoprophylaxis with P. falciparum sporozoites. RESULTS: High baseline TGF-ß concentrations were associated with rapid acquisition of sterile protection (p = 0.028). CONCLUSION: Baseline TGF-ß concentrations predict the efficiency of acquisition of sterile immunity following sporozoite immunization and may represent a steady-state regulatory mechanism to keep in check immune systems with a low threshold for activation.

Distinctive Kaposi Sarcoma-Associated Herpesvirus Serological Profile during Acute Plasmodium falciparum Malaria Episodes.

The seroprevalence of Kaposi sarcoma-associated herpesvirus (KSHV) and the incidence of endemic Kaposi sarcoma (KS) overlap with regions of malaria endemicity in sub-Saharan Africa. Multiple studies have shown an increased risk of KSHV seroconversion in children from high malaria compared to low malaria regions; however, the impact of acute episodes of Plasmodium falciparum (P. falciparum) malaria on KSHV's biphasic life cycle and lytic reactivation has not been determined. Here, we examined KSHV serological profiles and viral loads in 134 children with acute malaria and 221 healthy children from high malaria regions in Kisumu, as well as 77 healthy children from low malaria regions in Nandi. We assayed KSHV, Epstein-Barr virus (EBV), and P. falciparum malaria antibody responses in these three by multiplexed Luminex assay. We confirmed that KSHV seroprevalence was significantly associated with malaria endemicity (OR = 1.95, 1.18-3.24 95% CI, p = 0.01) with 71-77% seropositivity in high-malaria (Kisumu) compared to 28% in low-malaria (Nandi) regions. Furthermore, KSHV serological profiles during acute malaria episodes were distinct from age-matched non-malaria-infected children from the same region. Paired IgG levels also varied after malaria treatment, with significantly higher anti-ORF59 at day 0 but elevated ORF38, ORF73, and K8.1 at day 3. Acute malaria episodes is characterized by perturbation of KSHV latency in seropositive children, providing further evidence that malaria endemicity contributes to the observed increase in endemic KS incidence in sub-Saharan Africa.

Malaria infection and the risk of epilepsy: a meta-analysis.

Epilepsy, a chronic disease of the central nervous system, is highly prevalent in malaria-endemic regions. Therefore, several studies have evaluated the associations between malaria infection and epilepsy development. A meta-analysis of observational studies published from inception to 10 May 2022 has been conducted to synthesize and pool the existing data on this topic. The relevant publications were systematically searched in PubMed/Medline, Scopus, Embase and Web of Science database collections. A random-effects meta-analysis model (REM) was utilized to generate the pooled odds ratio (OR) at 95% confidence intervals (CIs). The between-studies heterogeneity was assessed with I2, as well as several subgroups, meta-regression and sensitivity analysis were performed to identify the source of heterogeneity. Overall, 17 eligible studies containing 6285 cases and 13 909 healthy controls were included. The REM showed a significant positive association between malaria infection and epilepsy development (OR 2.36; 95% CI 1.44­3.88). In subgroup analyses, significant positive associations were observed in studies that: epilepsy was the outcome in the follow-up of patients with cerebral malaria (OR 7.10; 95% CI 3.50­14.38); used blood smear to diagnose malaria (OR 4.80; 95% CI 2.36­9.77); included only children (OR 3.92; 95% CI 1.81­8.50); published before 2010 (OR 6.39; 95% CI 4.25­9.62). Our findings indicated that patients with malaria, especially those with cerebral malaria, are at a high risk of epilepsy development; however, further well-designed and controlled studies are needed to verify the strength of the association.