By Dr. Derick Pasternak, Ambassador, Malaria Science & Research Coordinator, MPI
As published on 13 June by Medicines for Malaria Venture (a Swiss NGO), Calibr-Skaggs, a team of scientists from Scripps Research, have been awarded “Project of the Year” honors for their work on Compound CMP069, which is said to be a major potential innovation in malaria prevention, because it can be given orally once a month. The press release, https://www.mmv.org/newsroom/news-resources-search/calibr-skaggs-scripps-research-receives-mmvs-prestigious-2023 does not go further in detail about how the drug works, but it is about to go into Phase 1 testing.
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Nolen S, Malaria Vaccine Rollout in Africa Is a Cautionary Tale, an article in the New York Times on July 5, recounts the history of development and deployment of the RTS,S vaccine over 35 years since the initial collaboration by the US Army and GlaxoSmithKline (now GSK). The author demonstrates the vacillation of project supporters and eventually the manufacturer, in supporting the product, which was initially thought to be less than 35% effective, even after a series of four shots. Finally, after yet another pilot program in three sub-Saharan countries demonstrated increased efficacy and safety, WHO endorsed the vaccine. However, by then GSK had lost interest and then had to hurriedly restart the manufacturing process. Even today, there is no scenario in which it will be capable to produce the volume of vaccine that would be required to make the kind of impact initially envisioned for a vaccine. GSK has licensed the RTS,S vaccine to a company in India with far lesser manufacturing costs. “But until the end of 2025 [when the new company will be able to start production], there will be enough doses for only 4.5 million children, which could mean many more may fall ill and die.” Fortunately, the second vaccine to be approved by the WHO, R21, has had fewer bumps in the road, and its manufacturing company promises 100 million doses per year. Also, “[t]he malaria vaccines we have now won’t be the last. There are 65 new candidate vaccines in the development pipeline. They will all face this question of how to raise funds for production before we know they work … There is still no system that solves the fundamental problem of how to pay for at-risk production of a tool that is vitally important for the health of millions of people who can’t afford to pay for it.”
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On 11 July, MalariaWorld published the summary of a presentation by Olubagmegiba AO & al., made in April at a meeting of the MIM {Multilateral Initiative on Malaria} Society. The title of the presentation was Cost of Delivering Pyrethroid-Piperonyl Butoxide Insecticide-Treated Nets to Households in Ondo and Anambra States in Nigeria Through Universal Campaigns. The most interesting part of the paper (at least to this reviewer) was a detailed analysis of the cost of purchasing, shipping, distributing, and installing the nets. Although the two states had different costs for their specific campaign components, the total cost per net was USD 3.19 in one state, USD 3.22 in the other.
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Oxford University announced (https://www.ox.ac.uk/news/2024-07-15-c-te-d-ivoire-makes-history-first-nation-deploy-r21matrix-m-malaria-vaccine) that 17 July “marks the official rollout of the new R21/Matrix-M™ malaria vaccine – co-developed by the University of Oxford and Serum Institute of India, leveraging Novavax’s Matrix-M™ adjuvant technology … 15 African countries are expected to introduce malaria vaccines with Gavi support in 2024, and countries plan to reach around 6.6 million children with the malaria vaccine in 2024 and 2025 … The new vaccine has been authorised by Ghana, Nigeria, Burkina Faso and the Central African Republic, and many others are preparing to receive shipments …R21/Matrix-M™ is a low-dose, highly effective and affordable vaccine which can be manufactured at speed and scale[, w]ith the Serum Institute of India committed to producing 100 million vaccines.”
PEER REVIEWED ARTICLES (see notes after citations from non-peer-reviewed publications)
Prevention
Vaccines
Laurenson AJ & Laurens MB pose and answer five questions about the current status of malaria vaccine development and deployment in A New Landscape for Malaria Vaccine Development. PLoS Pathog, 2024 Jun 27, 20(6): e1012309, https://doi.org/10.1371/journal.ppat.1012309 and conclude that the “first 2 malaria vaccines recommended by the WHO in 2021 and 2023 may have arrived just in time, as current malaria case counts remain essentially unchanged since 2015, reports of first-line antimalarial resistance are becoming more common, and climate change threatens recent advances in malaria control. … Next-generation vaccines are needed to provide enhanced and sustained efficacy that will improve child health, increase educational outcomes for children, save lives, and advance elimination efforts. Preclinical work to define new and improved vaccine antigens can be informed by computational biology pipelines to increase efficiency. … Malaria vaccines represent a high-impact intervention that can reduce clinical disease, prevent severe malaria illness, decrease hospitalizations, and improve child survival. Vaccines epitomize a viable strategy that can be furthered and advanced through continued research and innovation to accelerate malaria elimination efforts and shrink existing health disparities in resource-limited areas, paving the way toward a malaria-free future.”
Duffy PE & al., Malaria Vaccines: A New Era of Prevention and Control, Nat Rev Microbiol, 2024 Jul 18, https://doi.org/10.1038/s41579-024-01065-7 is yet another review of the current state of anti-malaria vaccine development. “Next-generation vaccines are needed to provide enhanced and sustained efficacy that will improve child health, increase educational outcomes for children, save lives, and advance elimination efforts. … Malaria vaccines represent a high-impact intervention that can reduce clinical disease, prevent severe malaria illness, decrease hospitalizations, and improve child survival.”
Two of the 60+ potential new vaccines are the topic of King LDW & al., Preclinical Development of a Stabilized RH5 Virus-Like Particle Vaccine that Induces Improved Antimalarial Antibodies, Cell Rep Med, 2024 Jul 16; 5(7):101654, https://doi.org/10.1016/j.xcrm.2024.101654. “Plasmodium falciparum reticulocyte-binding protein homolog 5 (RH5) is a leading blood-stage malaria vaccine antigen target, currently in a phase 2b clinical trial as a full-length soluble protein/adjuvant vaccine candidate called RH5.1/Matrix-M.” The authors cite three preclinical studies that used a slight variation, referred to as RH5.2/Matrix-M, which is slated to enter Phase 1a-b clinical trials
“Current understanding of genetic polymorphisms and natural selection in Plasmodium falciparum circumsporozoite (PfCSP), the [basis for the] leading malaria vaccine, is crucial for the development of next-generation vaccines, and such data is lacking in Africa, according to Pradel Kojom Foko L & al., Genetic Analysis of the Circumsporozoite Gene in Plasmodium falciparum Isolates from Cameroon: Implications for Efficacy and Deployment of RTS,S/AS01 Vaccine, Gene. 2024 Jul 2: 148744, https://doi.org/10.1016/j.gene.2024.148744. Although the article is focused primarily on the genetic polymorphism of the protein, the potential impact of the results of the investigation on future vaccine development is noted.
“Transmission-blocking vaccines interrupting malaria transmission within mosquitoes represent an ideal public health tool to eliminate malaria at the population level.” Cao Y & al., Evaluation of Combination Vaccines Targeting Transmission of Plasmodium falciparum and P. vivax, Vaccine, 2024 Jul 19: 126140, https://doi.org/10.1016/j.vaccine.2024.07.041 recounts an unsuccessful effort to develop a DNA-based vaccine that may inhibit transmission of gametocytes of either of the two most prevalent causes of malaria.
Vectors
“Pyrethroid bednets treated with the synergist piperonyl butoxide (PBO) offer the possibility of improved vector control in mosquito populations with metabolic resistance. In 2017-2019, [Lynd A & al.] conducted a large-scale, cluster-randomised trial (LLINEUP) to evaluate long-lasting insecticidal nets (LLINs) treated with a pyrethroid insecticide plus PBO (PBO LLINs), as compared to conventional, pyrethroid-only LLINs across 104 health sub-districts (HSDs) in Uganda… Overall, 5395 female Anopheles mosquitoes were collected from 5046 households. The proportion of mosquitoes infected (PCR-positive) with Plasmodium falciparum did not change significantly over time, while infection with non-falciparum malaria decreased in An. gambiae s.s., but not An. funestus. The frequency of genetic markers associated with pyrethroid resistance increased significantly over time, but the rate of change was not different between the two LLIN types. The paper is LLIN Evaluation In Uganda Project (LLINEUP)-Effects of a Vector Control Trial on Plasmodium Infection Prevalence and Genotypic Markers of Insecticide Resistance in Anopheles Vectors from 48 Districts of Uganda, Sci Rep. 2024 Jun 24; 14(1):14488, https://doi.org/10.1038/s41598-024-65050-z
“Dual-Active Ingredient long-lasting insecticidal nets (Dual-AI LLINs) have been developed to counteract the reduced efficacy of pyrethroid (PY)-only nets due to widespread pyrethroid insecticide resistance in malaria vector mosquitoes… However, their effectiveness once they develop holes is unclear, particularly in pyrethroid-resistant settings.” Lukole EA & al., Will a Lack of Fabric Durability Be Their Downfall? Impact of Textile Durability on the Efficacy of Three Types of Dual-Active-Ingredient Long-Lasting Insecticidal Nets: A Secondary Analysis on Malaria Prevalence and Incidence from a Cluster-Randomized Trial in North-West Tanzania, Malaria J, 2024 Jun 28, 23:199, https://doi.org/10.1186/s12936-024-05020-y “evaluates the textile integrity of three dual-AI LLINs compared to standard PY LLN, over 3 years of use in a community in Tanzania and the associated impact on malaria prevalence and incidence.” As a result of data analysis from 2019 to 2021, the authors conclude that “sleeping under a chlorfenapyr-PY LLIN or PBO-PY LLIN offered superior protection to pyrethroid-only nets even when torn. Preventing the development of holes is essential as they impact the level of protection offered against malaria infection.”
Dako-Gyeke P & al., Assessing LLIN Distribution Implementation Using Evidence-Informed Intervention Core Elements: a Qualitative Study in a Resource-Constrained Setting, BMC Health Serv Res. 2024 Jul 9; 24(1):790, https://doi.org/10.1186/s12913-024-11223-5 is a study based on focus group discussions with heads of households and caregivers of small children. The authors regard “core elements” to be “implementation, content, and pedagogy.” Based on the conclusion, this last element is what is usually referred to as training in use of the nets and it is found wanting in the view of the authors.
ITNs almost invariably contain pyrethroids either by themselves or with other insecticides. Kambou SS & al. investigated whether some of the apparent resistance of mosquitoes to pyrethroids may be due to the non-contact repellent effect of pyrethroids on Anopheles mosquitoes. Their paper, Non-Contact Detection of Pyrethroids Widely Used in Vector Control by Anopheles Mosquitoes, PLoS One. 2024 Jul 12; 19(7):e0298512, https://doi.org/10.1371/journal.pone.0298512, reports that they studied “takeoff response of Anopheles gambiae pyrethroid-sensitive and resistant laboratory strains, as well as field collected mosquitoes from the Gambiae Complex, when exposed to the headspace of bottles containing different doses of the insecticides at 25 and 35°C, … Sensitive mosquitoes were significantly more prone to take off only in the presence of ⍺-cypermethrin, whereas sensitive and resistant mosquitoes showed similar responses to permethrin and deltamethrin. Field-collected mosquitoes of the Gambiae Complex were also responsive to permethrin, independently of the species identity (An. gambiae, An. coluzzii and An. arabiensis).”
“Indoor residual spraying (IRS) has been implemented to prevent malaria in Zambia for several decades, but its effectiveness has not been evaluated long term and in Vubwi District yet.” Zhang WX & al., Association Between Indoor Residual Spraying and the Malaria Burden in Zambia and Factors Associated with IRS Refusals: A Case-Control Study in Vubwi District, Parasit Vectors. 2024 Jun 27; 17(1):274, https://doi.org/10.1186/s13071-024-06328-z “aimed to assess the association between IRS and the malaria burden in Zambia and Vubwi District and to explore the factors associated with refusing IRS… A significantly negative correlation between the percentage of population protected by the IRS against the total population in Zambia (coverage) and the average malaria incidence in the whole population was observed in 2005-2020.” Interestingly, “those with a secondary education level … had a higher risk of refusing IRS implementation compared to those who had never been to school.” However unlike the rest of Zambia, the data from the district studied do not show association between IRS and lower malaria incidence.
Chemoprophylaxis
“Intermittent preventive treatment in pregnancy with sulfadoxine-pyrimethamine (IPTp-SP) is known to improve pregnancy outcomes. However, the coverage of IPTp-SP in antenatal care (ANC) in sub-Saharan Africa remains well below the target.” Xu X & al., The Readiness of Malaria Services and Uptake of Intermittent Preventive Treatment in Pregnancy in Six Sub-Saharan Countries, J Glob Health. 2024 Jun 28; 14:04112, https://doi.org/10.7189/jogh.14.04112 “aims to estimate to what extent malaria service readiness affects the uptake of IPTp-SP during ANC visits in sub-Saharan African countries.” Studying data from Senegal, the DRC, Kenya, Tanzania, Malawi and Namibia from various different dates, the authors conclude that “[f]or better IPTp-SP coverage, strategies should be customised. High uptake countries should focus on provider training, while low uptake ones should ensure IPTp-SP availability and service integration.”
According to Mlugu EM & al., “[d]ihydroartemisinin-piperaquine (DHP) recently showed superior effectiveness over sulfadoxine-pyrimethamine for malaria intermittent preventive treatment in pregnancy (IPTp). [The authors] investigated day 7 piperaquine pharmacokinetics and its therapeutic efficacy in preventing malaria during pregnancy. They report in Pharmacokinetics of Piperaquine and Its Association with Intermittent Malaria Preventive Therapy Outcomes During Pregnancy, BMC Pharmacol Toxicol. 2024 Jul 8; 25(1):38, https://doi.org/10.1186/s40360-024-00762-6 that they studied 400 malaria-free pregnant women who received DHP during their pregnancies. The prevalence of malaria at delivery was 9.8% and 3% of placentae harbored the parasite. The 7-day concentration of piperaquine was below acceptable threshold in 7 % of women after the first dose of IPT but diminished afterwards. The authors recommend monitoring plasma levels 7 days after IPT, but do not comment on the feasibility of their recommendation.
Masserey T & al., Seasonal Malaria Chemoprevention and the Spread of Plasmodium falciparum Quintuple-Mutant Parasites Resistant to Sulfadoxine-Pyrimethamine: A Modelling Study, Lancet Microbe. 2024 Jul 9: S2666-5247(24)00115-0, https://doi.org/10.1016/s2666-5247(24)00115-0 also explores possible remedies to the development of resistance to the SP regimen for intermittent chemoprevention. The authors “used an individual-based malaria transmission model with explicit parasite dynamics and drug pharmacological models to identify and quantify the influence of factors driving quintuple-mutant spread and predict the time needed for the mutant to spread from 1% to 50% of inoculations for several SMC deployment strategies.” Based on evidence presented in the article but not the abstract, “SMC with sulfadoxine-pyrimethamine plus amodiaquine should be considered in seasonal settings where this mutant is already prevalent” is the authors’ conclusion.
“Recommended since 2012 by the World Health Organization (WHO), seasonal malaria chemoprevention (SMC) is a community-based intervention to prevent malaria in children in African regions where malaria transmission follows a seasonal pattern.” Lasmi K & al. used focus groups of “caregivers and community distributors … [to] identify potential barriers to quality delivery of SMC.” The results indicate “barriers to the quality delivery of SMC were identified including difficulty ensuring adherence to the SMC administration protocol; difficulties reaching mobile populations; concerns around adverse drug reactions; rumours, and concerns about SMC safety; and community distributors’ working conditions. Context-specific barriers included: the suboptimal timeliness of the SMC round in Burkina Faso, and the lack of involvement of female caregivers in mobilization activities in Chad.” The article is Barriers to the Quality Delivery of Seasonal Malaria Chemoprevention in Chad and Burkina Faso: a Qualitative Exploration of Caregivers and Community Distributors’ Perspectives, Malaria J, 2024 Jul 19, 23:216, https://doi.org/10.1186/s12936-024-0cc5034-6.
Rogerson SJ & Aitken EH, Malaria in Pregnancy: Baby Steps, Curr Opin Infect Dis, 2024 Jul 11, https://doi.org/10.1097/QCO.0000000000001037 is a general overview of the problems posed by malaria in pregnant women. “Artemether-lumefantrine has been endorsed for treatment in first trimester, but many women attend antenatal clinics later in pregnancy, and reaching high-risk young, first-time mothers is particularly difficult. Small-for-gestational-age babies frequently result from malaria, which affects the placenta’s development and its functions such as nutrient transport. Resistance to continues to increase to sulphadoxine-pyrimethamine, the mainstay of intermittent preventive treatment in pregnancy. The alternative, dihydroartemisinin-piperaquine controls malaria better, but does not improve pregnancy outcomes, suggesting that sulphadoxine-pyrimethamine may have nonmalarial effects including improving gut function or reducing dangerous inflammation.” Artemether-lumefantrine has been endorsed for treatment in first trimester, but many women attend antenatal clinics later in pregnancy, and reaching high-risk young, first-time mothers is particularly difficult. Small-for-gestational-age babies frequently result from malaria, which affects the placenta’s development and its functions such as nutrient transport. Resistance to continues to increase to sulphadoxine-pyrimethamine, the mainstay of intermittent preventive treatment in pregnancy. The alternative, dihydroartemisinin-piperaquine controls malaria better, but does not improve pregnancy outcomes, suggesting that sulphadoxine-pyrimethamine may have nonmalarial effects including improving gut function or reducing dangerous inflammation.
Other
“Sterile insect technique (SIT) is a powerful suppression approach that has successfully eradicated a number of insect pests, … [it] relies on iterative mass releases of nonbiting, nondriving, sterile males which seek out and mate with monandrous wild females. Once mated, females are permanently sterilized due to mating-induced refractoriness, which results in population suppression of the subsequent generation.” Apte RA & al., Eliminating Malaria Vectors with Precision-Guided Sterile Males, Proc Natl Acad Sci U S A. 2024 Jul 2; 121(27):e2312456121, https://doi.org/10.1073/pnas.2312456121 states that “sterilization by traditional methods renders males unfit, making the creation of precise genetic sterilization methods imperative. [The authors] introduce a vector control technology termed precision-guided sterile insect technique (pgSIT), in A. gambiae; … genetically sterilized males {that they produce} have good longevity, are able to induce sustained population suppression in cage trials, and are predicted to eliminate wild A. gambiae populations using mathematical models, making them ideal candidates for release.”
“Attractive Targeted Sugar Baits (ATSBs) offer a complementary vector control strategy to interventions targeting blood feeding or larval control by attacking the sugar feeding behaviour of adult mosquitoes using an attract-and-kill approach.” Two articles from Zambia report on a major ATSB project: Orange E & al., Deployment of Attractive Targeted Sugar Baits in Western Zambia: Installation, Monitoring, Removal, and Disposal Procedures During a Phase III Cluster Randomized Controlled Trial, Malaria J, 2024 Jul 9, 23:204, https://doi.org/10.1186/s12936-024-05030-w “describes ATSB station installation, monitoring, removal, and disposal, quantifies ATSB station coverage, and reports major reasons for ATSB station replacement.” Over 130,000 such stations were installed; the “primary reasons for ATSB station replacement due to damage were holes/tears and presence of mold.” Then, Wagman J & al., Entomological Effects of Attractive Targeted Sugar Bait Station Deployment in Western Zambia: Vector Surveillance Findings from a Two-Arm Cluster Randomized Phase III Trial, Malaria J, 2024 Jul 18, 23:214, https://doi.org/10.1186/s12936-024-05045-3 covers the “results of the vector surveillance component of the study, conducted in a subset of 20 clusters” of ATSB stations. “During the study 20,337 female An. funestus were collected, 11,229 from control and 9,108 from intervention clusters. … [An.] funestus parity did not differ across study arms, but ATSB deployment was associated with a non-significant 35% reduction in vector LT {light trap} density, results that are consistent with the epidemiological impact reported elsewhere. Additional research is needed to better understand how to maximize the potential impact of ATSB approaches in Zambia and other contexts.”
Diagnosis
General diagnostics
The reliability of rapid diagnostic tests (RDTs) relying on histidine-rich protein (HRP) for P. falciparum (Pf) is known to be poor in communities where the parasites contain certain genetic deletions. Oyegoke OO & al., Molecular Detection of Sub-Microscopic Infections and Plasmodium falciparum Histidine-Rich Protein-2 and 3 Gene Deletions in Pre-Elimination Settings of South Africa, Sci Rep. 2024 Jul 11; 14(1):16024, https://doi.org/10.1038/s41598-024-60007-8 report results from a community where out of 354 samples collected from patients with known sub-microscopic P. falciparum infections, “339 were tested negative with PfHRP2 based RDTs.” Thegene deletions were then confirmed on analysis. In these communities, “[m]olecular-based test is recommended as an essential surveillance tool for malaria management programs as the target focuses on elimination.”
Individuals who are negative at testing for Duffy antigens on their red blood cells have long been held to be resistant to infection by Plasmodium vivax. This belief is not supported by the findings reported in Abagero BR & al., Detection of Duffy Blood Group Genotypes and Submicroscopic Plasmodium Infections Using Molecular Diagnostic Assays in Febrile Malaria Patients, Malaria J, 2024 Jun 20, 23:194, https://doi.org/10.1186/s12936-024-04875-5. When using quantitative polymerase chain reaction (qPCR) as a diagnostic test among 300 febrile patients, “[a]mong the 48 qPCR-positive samples, 39 … were negative by microscopy.” While P. falciparum and P. vivax infections in Duffy negative individuals were generally “submicroscopic,” their infections were clinically evident. Even when patients with P. vivax have no symptoms, treatment is indicated since the parasite may be dormant in the liver.
Yakubu MN & al. report on finding metabolic clues to the recurrence of P. vivax in their paper, Host Metabolomic Responses in Recurrent P. vivax Malaria, Sci Rep. 2024 Mar 27; 14(1):7249, https://doi.org/10.1038/s41598-024-54231-5. Their findings suggest that there may be biomarkers that signal recurrence of vivax malaria before it becomes clinically evident.
Field diagnostics
“Microscopic detection of malaria parasites is labour-intensive, time-consuming, and expertise-demanding. Moreover, the slide interpretation is highly dependent on the staining technique and the technician’s expertise. Therefore, there is a growing interest in next-generation, fully- or semi-integrated microscopes that can improve slide preparation and examination.” Abdel Hamid MM & al. “aimed to evaluate the clinical performance of miLab™ (Noul Inc., Republic of Korea), a fully integrated automated microscopy device for the detection of malaria parasites in symptomatic patients at point-of-care in Sudan.” They report “a prospective, case–control diagnostic accuracy study conducted in primary health care facilities in rural Khartoum” in Diagnostic Accuracy of an Automated Microscope Solution (MiLab™) in Detecting Malaria Parasites in Symptomatic Patients at Point-of-Care in Sudan: A Case–Control Study, Malaria J, 2024 Jun 28, 23:200, https://doi.org/10.1186/s12936-024-05029-3. Of 190 patients reported, 100 were malaria positive on routine microscopy and 112 on PCR testing. Using the MiLab automated diagnosis for the same population, the authors report 91.1% sensitivity and 66.7% specificity. They conclude that “[b]efore clinical application, more refinement is needed to ensure full workflow automation and eliminate human intervention.”
Amoah LE & al., Diagnostic Performance of an Ultra-Sensitive RDT and a Conventional RDT in Malaria Mass Testing, Treatment and Tracking Interventions in Southern Ghana, Parasit Vectors. 2024 Jul 1;17(1):280, https://doi.org/10.1186/s13071-024-06354-x is an assessment of “the effectiveness of using the Ultra-sensitive NxTek eliminate RDT (uRDT) and conventional SD Bioline HRP2 RDT (cRDT) in diagnosing asymptomatic parasitaemia while measuring the impact of mass testing, treatment and tracking (MTTT) on the prevalence of asymptomatic malaria over a 1-year period in Ghana.” Although the report verifies that uRDT was more sensitive (between 52 and 60%) than cRDT (41 to 49%), neither was acceptable, as compared to PCR testing. The authors therefore recommend the use of a highly sensitive PCR test in these circumstances instead.
“The accuracy of malaria rapid diagnostic tests is threatened by Plasmodium falciparum with pfhrp2/3 deletions.” Gatton ML & al., Comparison of Prevalence Estimates of pfhrp2 and pfhrp3 Deletions in Plasmodium falciparum Determined by Conventional PCR and Multiplex QPCR and Implications for Surveillance and Monitoring, Int J Infect Dis. 2024 Jul; 144:107061, https://doi.org/10.1016/j.ijid.2024.107061 “compares gene deletion prevalence determined by multiplex real time polymerase chain reaction (qPCR) and conventional polymerase chain reaction (cPCR).” In two of three collections of samples, the two diagnostic methods were equivalent; however, in one collection of samples, qPCR was much more sensitive in detecting multiclonal infections.
New diagnostic methods
None this month
Treatment
Treatment results
Gebrie H & al. describe treatment results for P. vivax in Ethiopia, where the parasite infects a significant proportion of the population. “Unlike [P.] falciparum, P. vivax has a dormant liver stage (hypnozoite) that can be a risk of recurrent vivax malaria unless treated by radical cure with primaquine.” However, the latter drug may have serious hematological complications in patients with glucose-6-dehydrogenase (G6PD) deficiency, which is not rare in the population studied. Their paper, Efficacy and Safety of Chloroquine Plus Primaquine for the Treatment of Plasmodium vivax Malaria in Hamusit Site, Northwestern Ethiopia, Malaria J, 2024 Jul 6, 23:202, https://doi.org/10.1186/s12936-024-05031-9 reports that in a specific health center, among 100 enrolled patients, “co-administration of chloroquine with primaquine {‘using the standard World Health Organization (WHO) protocol’} was efficacious and well-tolerated with fast resolution of fever and high parasites clearance rate. However, the 7.4% failure [rate] reported is alarming that warrant[s] further monitoring of the therapeutic efficacy study of P. vivax.” Neither the abstract, nor the article mention the G6PD status of the patients studied.
Guidelines
None this month
Side effects and complications
“To interrupt residual malaria transmission and achieve successful elimination of Plasmodium falciparum in low-transmission settings, the World Health Organization (WHO) recommends the administration of a single dose of 0.25 mg/kg (or 15 mg/kg for adults) primaquine (PQ) combined with artemisinin-based combination therapy (ACT), without glucose-6-phosphate dehydrogenase (G6PD) testing.” Habtamu K & al. tested the side effect of single low dose of PQ in 166 patients (PQ + ACT) versus 83 patients on ACT alone. All patients had uncomplicated P. falciparum infections. The authors report in The Effect of Single Low-Dose Primaquine Treatment for Uncomplicated Plasmodium falciparum Malaria on Haemoglobin Levels in Ethiopia: A Longitudinal Cohort Study, Malaria J, 2024 Jul 12, 23:208, https://10.1186/s12936-024-05021-x that although there was slightly greater reduction of hemoglobin (Hb) in the PQ cohort than in the ACT cohort, the difference was not significant. However, it must be mentioned that the frequency of G6PD deficiency in the study population was low (around 7% in each cohort) and the paper, but not the abstract, demonstrates that the G6PD deficient group within each cohort had a greater drop in Hb as compared with the G6PD normal group within the same cohort, with “p” values close to the significant range after 7 days, but greater (i.e. non-significant) on days 14, 21, and 28.
Thio J, & al., Artemisinin-Induced Cholestatic Liver Injury and Intrahepatic Ductopenia, Oxf Med Case Reports, 2024 Jul 13; 2024(7):omae070, https://doi.org/10.1093/omcr/omae070 is a report of liver injury following artemisinin use. The authors state that “[t]here have been few reports of artemisinin-induced liver injury. Most of these instances of hepatotoxicity are reportedly due to prolonged use of herbal remedies containing artemisinin. To [the authors’ knowledge, they] report the first case of intrahepatic ductopenia in a patient with cholestatic liver injury after artemisinin use.”
Drug resistance
Tukwasibwe S & al. studied drug resistance in refugees with malaria from DRC and South Sudan and report in Varied Prevalence of Antimalarial Drug Resistance Markers in Different Populations of Newly Arrived Refugees in Uganda, J Infect Dis. 2024 Jun 14: jiae288, https://doi.org/10.1093/infdis/jiae288 that there were strains of P. falciparum ( from both countries) and P. malariae (from DRC) that were resistant to different antimalarial compounds, including artemisinin partial resistance (ART-R). “Prevalences of most mutations differed from those seen in Ugandans attending health centers near the refugee centers. Refugee evaluations yielded insights into varied malaria epidemiology and identified markers of ART-R in two previously little-studied countries.”
Shoaib R & al., Prefoldins are Novel Regulators of the Unfolded Protein Response in Artemisinin Resistant P. falciparum Malaria, J Biol Chem. 2024 Jun 24: 107496, https://doi.org/10.1016/j.jbc.2024.107496 is a basic science paper that demonstrated one pathway by which P. falciparum may become resistant to artemisinins. The mechanism is stated to be dependent on Prefoldins, which are involved in folding of proteins. The authors also note that the “FDA approved drug ‘Biperiden’ … inhibits the parasite growth in ART sensitive Pf3D7 and resistant Pf3D7k13R539T strains.”
Awor P & al. assessed genetic “K13 polymorphisms … [and performed} parasite editing and phenotyping … to assess the impact of mutations on parasite resistance. Whole-genome sequencing was performed, and haplotype networks were constructed to determine the geographic origin of k13 mutations. They report in Indigenous Emergence and Spread of Kelch13 C469Y Artemisinin-Resistant Plasmodium falciparum in Uganda, Antimicrob Agents Chemother, 2024 Jul 19: e0165923, https://doi.org/10.1128/aac.01659-23 that their data “provide evidence of selection for the artemisinin-resistant C469Y mutation. The realistic threat of multiresistant parasites emerging in Africa should encourage careful monitoring of the efficacy of artemisinin derivatives and strict adherence to ACT treatment regimens.”
Chloroquine and artesunates are not the only drugs whose effectiveness is challenged by the emergence of resistant parasites, as seen in two articles from Senegal. Ndiaye M & al., P. falciparum Genetic Markers Associated with Drug Resistance from Patients with Treatment Failure in the Southern Part of Senegal in 2017, Int J Mol Epidemiol Genet, 2024 Jun 15; 15(3):22-30, https://doi.org/10.62347/RWLA6562 evaluated genetic markers of resistance in patients with P. falciparum malaria recurring shortly after treatment with three different combinations of antimalarials. The failures occurred in combinations that included amodiaquine. Ndiaye YD & al. report on genetic shifts in P. falciparum in Senegal over the past ten years. Two Decades of Molecular Surveillance in Senegal Reveal Rapid Changes in Known Drug Resistance Mutations over Time, Malaria J, 2024 Jul 9, 23:205, https://doi.org/10.1186/s12936-024-05024-8 reports “[c]hanges in the mutation frequency at Pfcrt K76T and Pfdhps A437G coinciding with the 2014 introduction of seasonal malaria chemoprevention (SMC) in Senegal were observed. In 2014, the frequency of Pfcrt K76T increased while the frequency of Pfdhps A437G declined. Haplotype-based analyses of Pfcrt K76T showed that this rapid increase was due to a recent selective sweep that started after 2014.” They than conclude that the “rapid increase in Pfcrt K76T is troubling and could be a sign of emerging amodiaquine (AQ) resistance in Senegal. Emerging AQ resistance may threaten the future clinical efficacy of artesunate-amodiaquine (ASAQ) and AQ-dependent SMC chemoprevention.”
In a more broadly-based review of the literature, Milong Malong CS & al. “evaluate the published evidence concerning validated, candidate, and novel Pfk13 polymorphisms in ten Central African countries. Results show that four validated non-synonymous polymorphisms …, directly associated with a delayed therapy response, have been reported in the region. Also, two Pfk13 polymorphisms associated to artemisinin resistance but not validated … have been reported.” The article is An Overview of Artemisinin-Resistant Malaria and Associated Pfk13 Gene Mutations in Central Africa, Parasitol Res, 2024 Jul 18; 123(7):277, https://doi.org/10.1007/s00436-024-08301-2.
New drug research
In a highly technical paper, Pradhan D & al. describe “utilizing pH-responsive acetal-dextran nanoparticles (Ac-Dex NPs) as carriers for the delivery of withaferin-A (WS-3) and artesunate (Art) to improve treatment efficacy of malaria.” As reported in Development, Characterization, and Evaluation of Withaferin-A and Artesunate-Loaded PH-Responsive Acetal-Dextran Polymeric Nanoparticles for the Management of Malaria, Int J Biol Macromol. 2024 Jun 17: 133220, https://doi.org/10.1016/j.ijbiomac.2024.133220, “the combination therapy comprised of Art and WS-3 Ac-Dex NPs achieved complete inhibition of parasitemia even at a half dose of Art, indicating the synergistic potential of the combinations. However, further investigations are necessary to confirm the safety and effectiveness of WS-3 and Art Ac-Dex NPs for their successful clinical implications.”
The overarching premise of Karunakaran D & al. is that injectable, long-acting antimalarial medication would encourage adherence to a dosage regimen for populations at risk of contracting the disease. To advance support for this goal, [the authors] developed oil-based formulations of ELQ-331 (a prodrug of ELQ-300) that perform as long-acting, injectable chemoprophylactics with drug loading as high as 160 mg/ml of ELQ-331. As reported in Long-Acting Intramuscular Injections of ELQ-331, an Antimalarial Agent, Eur J Pharm Sci. 2024 Jul 1; 198:106795, https://doi.org/10.1016/j.ejps.2024.106795, “[i]n a pharmacokinetic study performed with rats, a single intramuscular injection of 12.14 mg/kg maintained higher plasma levels than the previously established minimum fully protective plasma concentration (33.25 ng/ml) of ELQ-300 for more than 4 weeks. The formulations were well tolerated by the rats and the tested dose produced no adverse reactions.” The authors suggest that “ELQ-331 can offer a more accessible, low-cost option for long-acting disease prevention and reduced transmission in malaria-endemic regions and may also be of use to travelers.”
Alkhaibari AM & al. “aimed to produce and analyze zinc oxide nanoparticles (ZNPs) loaded with linalool (LZNPs), and to evaluate their in vitro and in vivo efficacy through targeting the inflammation and oxidative stress… LZNPs demonstrated noteworthy (P<0.001) antiplasmodial activity against both susceptible and resistant strains of P. falciparum. P. berghei NK65 strain-infected mice treated with the ZNPs and LZNPs at doses of 5-15 mg/kg notably (p<0.001) increased the survival rates and parasite growth suppression. … The current experimental study demonstrated the potent in vitro antiplasmodial activity of LZNPs against chloroquine-resistant and sensitive strains of P. falciparum compared to ZNPs alone. Additionally, the study identified the potential benefits of this nanocomposite in suppressing the parasite and extending the survival rate in mice infected with P. berghei …. It also showed minimal toxicity in liver and kidney function in healthy mice.” The paper is Zinc Oxide Nanoparticles Loaded with Linalool as a Potential Control Agent of Malaria Infection, Acta Trop. 2024 Jul 5: 107312, https://doi.org/10.1016/j.actatropica.2024.107312.
Plant extracts and traditional treatments
Coriandrum sativum, known the world over as coriander or cilantro, is the subject of Habte G & al., Antimalarial Efficacy Test of the Aqueous Crude Leaf Extract of Coriandrum sativum Linn.: An in vivo Multiple Model Experimental Study in Mice Infected with Plasmodium berghei, BMC Complement Med Ther. 2024 Jul 12; 24(1):267, https://doi.org/10.1186/s12906-024-04577-0. The authors tested the extract in the laboratory on malaria infected mice and conclude that “the aqueous crude leaf extract of C. sativum exhibits significant antimalarial efficacy in multiple in vivo models involving mice infected with P. berghei. Given this promising therapeutic attribute, in-depth investigation on the plant is recommended.”
Campaigns and Policies
Despite its title, Bakai TA & al., Proactive Home-Based Malaria Management in Rural Communities of Bassar Health District in Northern Togo From 2014 to 2017: PECADOM +, a Pilot Experiment, Malaria J, 2024 Jul 7, 23:203, https://doi.org/10.1186/s12936-024-04988-x is actually a report on home-based diagnosis and occasional treatment by rural community health workers during an experimental campaign. In the population under study, the 5 – 10 year old cohort had the highest number of positive tests. Positive tests were more likely during the wet season. The authors conclude that the “program will help Togo’s National Malaria Control Programme reduce malaria morbidity and mortality in remote and hard-to-reach communities.”
Silke F & al. used data from the Tufts University Center for the Evaluation of Value and Risk in Health … Cost-Effectiveness Registries (the CEA Registry beginning in 1976 and the Global Health CEA registry beginning in 1995) up to Jan 1, 2018 … [The authors] selected ratios for interventions with a minimum of two published articles and three published ICERs {incremental cost-effectiveness ratios} that mapped to one of five GBD {global burden of disease} causes (HIV/AIDS, malaria, syphilis, drug-susceptible tuberculosis, or multi-drug resistant tuberculosis) …” According to Cost-Effectiveness of Interventions for HIV/AIDS, Malaria, Syphilis, and Tuberculosis in 128 Countries: A Meta-Regression Analysis, Lancet Glob Health. 2024 Jul; 12(7):e1159-e1173, https://doi.org/10.1016/s2214-109x(24)00181-5 the four malaria preventive strategies studied (bednets, vaccination, IPTp, and IPT for infants) are in mostly in the middle in this analysis; however, in some sub-Saharan countries, bednets have very high ICER. This information is in the paper, but not mentioned in the abstract.
“Proactive community case management (ProCCM) is a new strategy in which a community health worker “sweeps” a village, visiting households at defined intervals to proactively provide diagnostic testing and treatment if indicated. Pilot experiments have shown the potential of ProCCM for controlling malaria transmission…” Wang Y & al., Modeling the Impact of Proactive Community Case Management on Reducing Confirmed Malaria Cases in Sub-Saharan African Countries, Am J Trop Med Hyg. 2024 Jul 9: tpmd230844, https://doi.org/10.4269/ajtmh.23-0844 reports an “agent-based simulation to model malaria transmission and the impact of various ProCCM strategies. … Various ProCCM strategies were tested to evaluate the potential for reducing parasitologically confirmed symptomatic malaria cases in the Senegal setting. … weekly ProCCM sweeps during a 21-week transmission season could reduce cases by 36.3% per year compared with no sweeps. Alternatively, two initial fortnightly sweeps, seven weekly sweeps, and finally four fortnightly sweeps (13 sweeps total) could reduce confirmed malaria cases by 30.5% per year while reducing the number of diagnostic tests and corresponding costs by about 33%. Under a highly seasonal transmission setting, starting the sweeps early with longer duration and higher frequency would increase the impact of ProCCM, though with diminishing returns…”
Epidemiology
Climate change, biodiversity and environment
Obeagu EI & Obeagu GU, Adapting to the Shifting Landscape: Implications of Climate Change for Malaria Control: A Review, Medicine (Baltimore), 2024 Jul 19; 103(29):e39010, https://doi.org/10.1097/MD.0000000000039010 is yet another analysis of climate change’s influence on malaria and its control. “The paper begins by dissecting the influence of climate change on malaria dynamics, including alterations in temperature, precipitation, and other climatic factors that impact the habitat and life cycle of malaria vectors. It delves into the evolving ecology and behavior of malaria vectors in response to changing climatic conditions, emphasizing the importance of understanding these adaptations. As a response to this shifting landscape, the review discusses adaptive strategies for malaria control, ranging from vector control measures to the utilization of climate data in early warning systems. Community engagement and education are highlighted as essential components of these strategies, recognizing the vital role of local communities in effective malaria control efforts.”
Amadi M & Erandi KKWH, Assessing the Relationship Between Malaria Incidence Levels and Meteorological Factors Using Cluster-Integrated Regression, BMC Infect Dis. 2024 Jul 3; 24(1):664, https://doi.org/10.1186/s12879-024-09570-z “introduces a novel approach to modeling malaria incidence in Nigeria by integrating clustering strategies with regression modeling and leveraging meteorological data. … [The authors’] findings reveal significant variability in malaria incidence, specific to certain geographic clusters and beyond what can be explained by observed weather variables alone. Notably, rainfall and temperature exhibit varying marginal effects across incidence clusters, indicating their differential impact on malaria transmission. High rainfall correlates with lower incidence, possibly due to its role in flushing mosquito breeding sites. On the other hand, temperature could not predict high-incidence cases, suggesting that other factors other than temperature contribute to high cases.” The article reports on conditions in Nigeria.
Ogunsakin RE & al. come to different conclusions, using their models in predicting the dependence of malaria incidence on temperature variation in Nigeria, in GIS-Based Spatiotemporal Mapping of Malaria Prevalence and Exploration of Environmental Inequalities, Parasitol Res. 2024 Jul 6; 123(7):262, https://doi.org/10.1007/s00436-024-08276-0. There has been “a shift in the distribution of malaria cases over the five years. According to the authors’ model, “[e]nvironmental factors such as the Enhanced Vegetation Index, annual land surface temperature, and precipitation exhibited a strong positive association with malaria cases …. Conversely, insecticide-treated bed net coverage and mean temperature negatively correlated with malaria cases in the same model.”
Gizaw Z & al., Impacts of Climate Change on Water-Related Mosquito-Borne Diseases in Temperate Regions: A Systematic Review of Literature and Meta-Analysis, Acta Trop, 2024 Jul 13: 107324, https://doi.org/10.1016/j.actatropica.2024.107324 is focused on the temperate zone but its review of the literature yields some important conclusions regarding malaria. Specifically, “[m]alaria establishment occurs when the consecutive average daily temperatures are above 16°C until the sum is above 210°C.”
In a massive, multi-year study on conditions in Africa and Asia, Villena OC & al. used modeling and concluded that “[b]oth temperature and precipitation exhibited unimodal relationships with malaria, with a positive effect up to a point after which a negative effect was observed as temperature and precipitation increased. Overall decline in malaria from 2000 to 2012 was well captured by the models, as was the resurgence after that. The models also indicated higher malaria in regions with lower economic and development indicators.” Their article is Influence of Environmental, Geographic, Socio-Demographic, and Epidemiological Factors on Presence of Malaria at the Community Level in Two Continents, Sci Rep, 2024 Jul 20; 14(1):16734, https://doi.org/10.1038/s41598-024-67452-5.
“Small dam impoundments provide communities with a continuous supply of water for domestic and agricultural activities across sub-Saharan Africa and are considered vital to food security and climate change resilience. However, these permanent water bodies also create ideal breeding sites for mosquitoes in typically arid landscapes.” Zembere K & al. focus “on a specific dam impoundment and its vicinity, aiming to assess its spatial and temporal influence on indoor vector densities.” As the authors report in their article, Small Dams Drive Anopheles Abundance During the Dry Season in a High Malaria Burden Area of Malawi, Med Vet Entomol, 2024 Jun 21, https://doi.org/10.1111/mve.12733, mosquito catches were most abundant during the wet season and also diminished as the community’s distance from the dams increased. The paper emphasizes the tradeoff between economic necessity and health concerns and recommends increasing control efforts near the small dams.
Risk factors
“Many infections, including malaria, are associated with an increase in autoantibodies (AAbs). Prior studies have reported an association between genetic markers of susceptibility to autoimmune disease and resistance to malaria…” Hagadorn KA & al., “performed a longitudinal study of children and adults (n = 602) in Mali” and report in Autoantibodies Inhibit Plasmodium falciparum Growth and Are Associated with Protection from Clinical Malaria, Immunity. 2024 Jun 13: S1074-7613(24)00278-4, https://doi.org/10.1016/j.immuni.2024.05.024 “that high levels of plasma AAbs before the malaria season independently predicted a reduced risk of clinical malaria in children during the ensuing malaria season. [The authors] found that AAbs purified from the plasma of protected individuals inhibit the growth of blood-stage parasites and bind P. falciparum proteins that mediate parasite invasion. … This study provides evidence in support of the hypothesis that a propensity toward autoimmunity offers a survival advantage against malaria.”
General epidemiology
It is somewhat unclear what the thrust of Prah DA & Laryea-Akrong E, Asymptomatic Low-Density Plasmodium falciparum Infections: Parasites Under the Host’s Immune Radar, J Infect Dis. 2024 Jun 14; 229(6):1913-1918, https://doi.org/10.1093/infdis/jiad58 is, given the following abstract, quoted in its entirety: “A large body of evidence suggests that low parasite carriage in Plasmodium falciparum asymptomatic infection is required for the maintenance of malaria immunity. However, the fact that treating such infections has little to no impact on subsequent clinical malaria is rarely noted. In this paper, we review data and argue that low-density parasite carriage in asymptomatic infection may not support host immune processes and that parasites are virtually under the host’s immunological radar. We also discuss factors that may be constraining parasitemia in asymptomatic infections from reaching the threshold required to cause clinical symptoms. A thorough understanding of this infectious reservoir is essential for malaria control and eradication because asymptomatic infections contribute significantly to Plasmodium transmission.” The article itself is not available for review.
Sima-Biyang YV & al. used five databases “to collect and identify all studies published between 1980 and 2023 on malaria prevalence, antimalarial drug resistance, markers of antimalarial drug resistance and insecticide resistance marker” and report in Epidemiology of Malaria in Gabon: A Systematic Review and Meta-Analysis from 1980 To 2023, J Infect Public Health. 2024 Jul; 17(7):102459, https://doi.org/10.1016/j.jiph.2024.05.047 that “Gabon continues to face malaria as an urgent public health problem, with persistently high prevalence rates. Markers of resistance to CQ {chloroquine} persist despite its withdrawal, and markers of resistance to SP {sulfadoxine-pyrimethamine} have emerged with a high frequency, reaching 100 %, while ACTs {artemisinin combination therapy} remain effective. Also, recent studies have identified markers of resistance to the insecticides Kdr-w and Kdr-e at frequencies ranging from 25 % to 100 %. Ace1R mutation was reported with a frequency of 0.4 %. In conclusion, the efficacy of ACTs remains above the threshold recommended by the WHO.”
The Plasmodium parasite travels from humans and other vertebrates in the form of gametocytes, whereas it is the sporozoite life form that is transmitted from mosquito vectors to the infected vertebrate. Therefore, Minwuyelet A & al. studied the prevalence of these two formats in their respective hosts in order to establish the propensity of the parasite to continue its life cycle despite antimalarial treatment and vector control efforts. Plasmodium Gametocyte Carriage in Humans and Sporozoite Rate in Anopheline Mosquitoes in Gondar Zuria District, Northwest Ethiopia, PLoS One. 2024 Jul 1; 19(7):e0306289, https://doi.org/10.1371/journal.pone.0306289, their paper, reports that 5.4% of 242 humans tested in the region studied and 11.6% of 515 female Anopheles mosquitoes caught harbored the relevant formats. The authors conclude that “frequent, and active community-based surveillance of gametocytemia and sporozoite infection rate is important,” in addition to preventive and treatment efforts, in order to obtain a full picture of the degree of success of malaria control.
According to Habibzadeh F, The Effect on the Equilibrium Sickle Cell Allele Frequency of the Probable Protection Conferred by Malaria and Sickle Cell Gene Against Other Infectious Diseases, Sci Rep. 2024 Jul 4; 14(1):15399, https://doi.org/10.1038/s41598-024-66289-2, “[i]f a mutated gene with heterozygous advantage against malaria, e.g., hemoglobin S (HbS) gene, is introduced in a small tribe, the gene (allele) frequency (fgene) increases until it reaches a steady state value (feq) where the total mortality from malaria and sickle cell disease is a minimum. This is a classic example of balanced-polymorphism named malaria hypothesis. In a previous in silico study, assuming realistic initial conditions, it has been shown that the feq is around 14%, far less than the fgene observed in certain parts of Africa, 24%.” The author argues that according to his analysis this discrepancy is explained if the coexistence of heterozygous HbS and malaria is protective against as yet unidentified other diseases.
Ranjbar M & Woldemariam YT summarize the world literature about malaria species other than falciparum infecting people in Uganda. They report in Non-Falciparum Malaria Infections in Uganda, Does It Matter? A Review of the Published Literature, Malaria J, 2024 Jul12, 23:207, https://doi.org/10.1186/s12936-024-05023-9 that the “literature reported a substantial prevalence of non-falciparum infections in Uganda. Plasmodium malariae and Plasmodium ovale spp. were the second and third most prevalent reported malaria species respectively after P. falciparum as dominant species. Non-falciparum malaria infections often occur as mixed infections rather than mono-infections.”
Spatiotemporal studies
Mandai SS & al., High Prevalence and Risk of Malaria Among Asymptomatic Individuals from Villages with High Prevalence of Artemisinin Partial Resistance in Kyerwa District of Kagera Region, North-Western Tanzania, Malaria J, 2024 Jun 26, 23:197, https://doi.org/10.1186/s12936-024-05.
Connelly SV & al., Strong Isolation by Distance and Evidence of Population Microstructure Reflect Ongoing Plasmodium falciparum Transmission in Zanzibar, Elife. 2024 Jun 27; 12:RP90173, https://doi.org/10.7554/elife.90173
Molla E & al., Seasonal Dynamics of Symptomatic and Asymptomatic Plasmodium falciparum and Plasmodium vivax Infections in Coendemic Low-Transmission Settings, South Ethiopia, Am J Trop Med Hyg. 2024 Jul 2: tpmd240021, https://doi.org/10.4269/ajtmh.24-0021
Govoetchan R & al., Malaria Prevalence and Transmission in the Zakpota Sub-District of Central Benin: Baseline Characteristics for a Community Randomised Trial of a New Insecticide for Indoor Residual Spraying, Parasit Vectors. 2024 Jul 13; 17(1):303, https://doi.org/10.1186/s13071-024-06342-1
Legesse G & al., Asymptomatic Malaria and Predictors Among Migrant Farmworkers East Shewa Zone Oromia Ethiopia, Sci Rep. 2024 Jul 13; 14(1):16187, https://doi.org/10.1038/s41598-024-65470-x
Alemayehu A & al., Asymptomatic Malaria in Pregnancy and Associated Risk Factors in Majang Zone, Gambella Region, Southwest Ethiopia: A Hard-to-Reach Malaria Hotspot, Malaria J, 2024 Jul 15, 23:210, https://10.1186/s12936-024-05041-7