On 20 April, WHO published two pamphlets relating to malaria: (1) Monoclonal Antibodies for Malaria Prevention; Preferred Product Characteristics and Clinical Development Considerations and (2) Malaria Chemmoprevention; Preferred Product Characteristics. Both of these are available from the compiler of this column or from who.int.
PEER REVIEWED PUBLICATIONS:
Prevention
Vaccines
“With huge demand for new malaria vaccines, Gavi is concerned that scaling up production and affordability pose a formidable challenge,” according to Zarocostas J, Gavi Unveils Malaria Vaccine Plans, Lancet, 2023 May 6, 401(10387):P1485, https://doi.org/10.1016/S0140-6726(23)00902-9. “Gavi notes that 40–60 million doses are needed to meet demand by 2026, increasing to 80–100 million doses by 2030… Gavi says that applications from 14 countries for funding support to introduce RTS,S/AS01 have been reviewed and recommended by the Gavi Independent Review Committee for approval as of the end of March, 2023. In August, 2022, UNICEF announced that it had secured 18 million doses of RTS,S/AS01 (with funding from Gavi) over 3 years at a price of €9·30 per dose. GlaxoSmithKline is expected to increase the production of RTS,S/AS01 to 15 million doses per year during 2026–28 as a result of a product transfer agreement with the Indian company, Bharat Biotech. While supplies are limited, WHO has advised that countries with the greatest need will be prioritised. Gavi is also hopeful that the anticipated approval and prequalification by WHO of a second malaria vaccine, R21/Matrix-M—developed by Oxford University and to be manufactured by the Serum Institute of India—could help greatly reduce the price of malaria vaccines. It has already been approved by Ghana and Nigeria.”
Diawara H & al. prospectively estimated the “cost of seasonal malaria vaccine delivery in Mali and Burkina Faso… Three scenarios for seasonal vaccine delivery [were] costed (1) mass campaign only, (2) routine Expanded Programme on Immunisation (EPI) and (3) mixed delivery (mass campaign and routine EPI)), from the government’s perspective. They report in Cost of Introducing and Delivering Malaria Vaccine (RTS,S/AS01E) in Areas of Seasonal Malaria Transmission, Mali and Burkina Faso, BMJ Glob Health. 2023 Apr; 8(4):e011316, https://doi.org/10.1136/bmjgh-2022-011316 that at the “assumed vaccine price of US $5 per dose, the economic cost per dose administered ranges between $7.73 and $8.68 (mass campaign), $7.04 and $7.38 (routine EPI) and $7.26 and $7.93 (mixed delivery).”
Grant J & al. identified “potential strategies to deliver RTS,S/AS01E, and assess the considerations and recommendations for delivery of seasonal malaria vaccination in Mali, a country with highly seasonal malaria.” According to Delivery Strategies for Malaria Vaccination in Areas with Seasonal Malaria Transmission, BMJ Glob Health. 2023 May; 8(5):e011838, https://doi.org/10.1136/bmjgh-2023-011838 “[f]our delivery strategies were identified: age-based vaccination delivered via the Essential Programme on Immunisation (EPI); seasonal vaccination via EPI mass vaccination campaigns (MVCs); a combination of age-based priming vaccination doses delivered via the EPI clinics and seasonal booster doses delivered via MVCs; and a combination of age-based priming vaccination doses and seasonal booster doses, all delivered via the EPI clinics, which was the preferred strategy for delivery of RTS,S/AS01E in Mali identified during the national workshop.”
Topazian HM & al. found that the cost effectiveness of the RTS,S vaccine was maximal in the setting of reduced use of other preventive measures, such as insecticide treated nets, etc. The costs quoted in their report, Modelling the Relative Cost-Effectiveness of the RTS,S/AS01 Malaria Vaccine Compared to Investment in Vector Control or Chemoprophylaxis, Vaccine. 2023 Apr 18: S0264-410X(23)00394-8, https://doi.org/10.1016/j.vaccine.2023.04.011 are sightly above of those in Diawara & al. above.
Ngulube P reports on the Humoral Immune Responses to P. falciparum Circumsporozoite Protein (Pfcsp) Induced by the RTS,S Vaccine – Current Update, Infect Drug Resist. 2023 Apr 12; 16:2147-2157. https://doi.org/10.2147/idr.s401247. The abstract is unrevealing as to the findings of the study.
A different vaccine preparation is used to prevent malaria in Equatorial Guinea. According to Jongo SA & al., Safety and Immunogenicity of Radiation-Attenuated PfSPZ Vaccine in Equatoguinean Infants, Children, and Adults, Am J Trop Med Hyg, 2023 May 9; tpmd220773, https://doi.org/10.4269/ajtmh.22-0773, the “radiation-attenuated Plasmodium falciparum sporozoites (PfSPZ) Vaccine has demonstrated safety and immunogenicity in 5-month-old to 50-year-old Africans in multiple trials.” They conducted an age stratified double blind trial of three successive doses of vaccine and found in all age groups that the vaccine was safe and induced immune reactions, while those receiving placebo had no reactions at all. However, this was a very small study, including 69 subjects of all ages plus 15 controls of uncertain age.
Yet another approach to vaccine development is the prevention of transmission of Plasmodium to the vector. Such a vaccine would have to be aimed at the sexual stage of the parasite. Simons LM & al., Extending the Range of Plasmodium falciparum Transmission Blocking Antibodies, Vaccine. 2023 Apr 24: S0264-410X(23)00453-X, https://doi.org/10.1016/j.vaccine.2023.04.042 reviews the various aspects of antibodies that have been found to bind to the sexual stage.
Fotoran WL & al., Establishment of an Antiplasmodial Vaccine Based on PfRH5-Encoding RNA Replicons Stabilized by Cationic Liposomes, Pharmaceutics. 2023 Apr 12; 15(4):1223, https://doi.org/10.3390/pharmaceutics15041223 is one of two article this month on the applicability to mRNA vaccine technology to malaria prevention. They call their preparation “self-amplifying mRNA (samRNA)” and conclude that “[i]ntradermal delivery of cationic lipid-encapsulated samRNA constructs is a feasible approach for developing future malaria vaccines.”
Matarazzo L & Bettencourt PJG, mRNA Vaccines: a New Opportunity for Malaria, Tuberculosis and HIV, Front Immunol, 2023 Apr 24; 14:1172691, https://doi.org/10.3389/fimmu.2023.1172691. look more broadly at the applicability of mRNA technology. Tha euthors state that they “provide an up-to-date overview of the preclinical and clinical development of mRNA vaccines against infectious diseases, and discuss the immunogenicity, efficacy and correlates of protection of mRNA vaccines, with particular focus on research and development of mRNA vaccines against malaria, tuberculosis and HIV.”
Vector control and protection from vectors
Ibrahim M & al. claim that “Indoor Residual Spraying (IRS) has been the main tool used to control malaria. Reducing the life span and the density of the vector mosquitoes are direct effects of IRS towards restricting malaria transmission. Residents must not wash or re-plaster walls after the spray application for at least 6 months to fight against malaria with IRS.” In Altering of the Sprayed Wall After Indoor Residual Spraying and Associated Factors Among Households in Boricha District, Sidama Regional State, Ethiopia, 2019: Community-Based Cross-Sectional Study, Malar J, 2023 May 2, 22:144, https://doi.org/10.1186/s12936-023-04573-8 they report that among “608 sprayed houses included in the study, 37.3% … were found to have altered sprayed walls.” They advocate better information to be provided to the inhabitants of sprayed homes.
“In … two departments of high malaria incidence of Northern Benin, pirimiphos-methyl, mixture deltamethrin + clothianidin, as well as clothianidin were used at large scale for IRS.” Odjo EM & al., What Can Be Learned from the Residual Efficacy of Three Formulations of Insecticides (Pirimiphos-Methyl, Clothianidin and Deltamethrin Mixture, and Clothianidin Alone) Iin Large-Scale in Community Trial in North Benin, West Africa? Malar J, 2023 May 8, 22:150, https://doi.org/10.1186/s12936-023-04572-9 “aimed to assess the residual efficacy of these products… Over the three study years, deltamethrin resistance was observed in all the communes. With bendiocarb, resistance or possible resistance was observed. In 2019 and 2020, full susceptibility to pirimiphos-methyl was observed, while possible resistance to the same product was detected in 2021 …. With clothianidin, full susceptibility was observed 4–6 days post-exposure. The residual activity lasted 4–5 months for pirimiphos-methyl, and 8–10 months for clothianidin and the mixture deltamethrin + clothianidin.
“In … two departments of high malaria incidence of Northern Benin, pirimiphos-methyl, mixture deltamethrin + clothianidin, as well as clothianidin were used at large scale for IRS.” Odjo EM & al., What Can Be Learned from the Residual Efficacy of Three Formulations of Insecticides (Pirimiphos-Methyl, Clothianidin and Deltamethrin Mixture, and Clothianidin Alone) Iin Large-Scale in Community Trial in North Benin, West Africa? Malar J, 2023 May 8, 22:150, https://doi.org/10.1186/s12936-023-04572-9 “aimed to assess the residual efficacy of these products.
“Methods for evaluating efficacy of core malaria interventions in experimental and operational settings are well established but gaps exist for spatial repellents (SR). The objective of Swai JK & al.’s study, CDC light traps underestimate the protective efficacy of an indoor spatial repellent against bites from wild Anopheles arabiensis mosquitoes in Tanzania, Malar J, 2023 Apr 29, 22:141, https://doi.org/10.1186/s12936-023-04568-5 was to compare three different techniques: (1) collection of blood-fed mosquitoes (feeding), (2) human landing catch (HLC), and (3) CDC light trap (CDC-LT) collections for measuring the indoor protective efficacy (PE) of the volatile pyrethroid SR product Mosquito Shield™” The authors conclusion is inherent in the title of the paper.
“New long-lasting insecticidal nets (LLINs) containing two active ingredients (dual active-ingredient LLINs) have been developed to interrupt transmission in areas of pyrethroid resistance. [Matowo NS & al.] aimed to evaluate the effectiveness of three dual active-ingredient LLINs compared with standard pyrethroid LLINs against pyrethroid-resistant malaria vectors in rural Tanzania.” Differential Impact of Dual-Active Ingredient Long-Lasting Insecticidal Nets on Primary Malaria Vectors: A Secondary Analysis of a 3-Year, Single-Blind, Cluster-Randomised Controlled Trial in Rural Tanzania, Lancet Planet Health, 2023 May; 7(5): e370-e380. https://doi.org/10.1016/S2542-5196(23)00048-7 is the report on “a secondary analysis of entomological data from a four-group, 3 year, single-blind, cluster-randomised controlled trial carried out between Feb 18, 2019, and Dec 6, 2021… Chlorfenapyr pyrethroid LLINs were the most effective intervention against the main malaria vector An funestus sl over 3 years of community use, whereas the effect of piperonyl-butoxide pyrethroid LLIN was sustained for 2 years. The other vector, An arabiensis, was not controlled by any of the dual active-ingredient LLINs.”
In an analysis of “regional and socio-economic patterns of ITN {Insecticide Treated Nets} use among pregnant women in Kenya using data from the 2003, 2008 and 2014 Kenyan Demographic and Health Surveys (KDHSs),” Haileselassie W & al., Regional and Socio-Economic Disparity in Use of Insecticide-Treated Nets to Prevent Malaria Among Pregnant Women in Kenya, Int Health. 2023 May 2; 15(3):289-298, https://doi.org/10.1093/inthealth/ihac024 reports that “[s]ignificant inequality in ITN use among pregnant women was observed at a macro scale,” which should surprise on one.
Mrema S & al., Associations Between the Use of Insecticide-Treated Nets in Early Childhood and Educational Outcomes, Marriage and Child-Bearing in Early Adulthood: Evidence From a 22-Year Prospective Cohort Study in Tanzania, Malar J, 2023 Apr 25, 22:134, https://doi.org/10.1186/s12936-023-04560-z. is an interesting long-term study of over 5000 individuals who were born at the end of the 20th century. The authors “found that early life use of ITNs was strongly associated with increased school completion in both men and women. More marginal associations were found between early-life ITN use and both marriage and childbearing in early adulthood.”
Busari LO & al. studied a variety of insecticides and report in Investigating Insecticide Susceptibility Status of Adult Mosquitoes Against Some Class of Insecticides in Osogbo Metropolis, Osun State, Nigeria, PLoS One, 2023 May 11; 18(5):e0285605, https://doi.org/10.1371/journal.pone.0285605 that [f]our types of larval habitats were identified (tires, ground pools, gutters and plastic containers). Anopheles gambiae s. l. showed the highest resistance to Permethrin (49%) … while the highest susceptibility was recorded with Pirimiphos-methyl (69%) with the lowest against Permethrin (16%).
According to Gleave K & al., the “success of insecticide treated bed nets (ITNs) for malaria vector control in Africa relies on the behaviour of various species of Anopheles. Previous research has described mosquito behavioural alterations resulting from widespread ITN coverage, which could result in a decrease in net efficacy.” They studied the behavior of susceptible and resistant Anopheles mosquitoes around three different types of impregnated nets with human volunteers inside and conclude in Impacts of Dual Active-Ingredient Bed Nets on the Behavioural Responses of Pyrethroid Resistant Anopheles gambiae Determined by Room-Scale Infrared Video Tracking, Malar J, 2023 Apr 23, 22:132, https://doi.org/10.1186/s12936-023-04548-9 that there was no real difference between the behaviors of the two strains.
Carson J & al. noted that the increasing resistance of Anopheles to pyrethroids is mitigated by addition of heat-activated deltamethrin dispersed on chalk in North America and studied the effect of this preparation among five West African Anopheles strains. In Overcoming Insecticide Resistance in Anopheles Mosquitoes by Using Faster-Acting Solid Forms of Deltamethrin, Malar J, 2023 Apr 21, 22:129, https://doi.org/10.1186/s12936-023-04554-x they report that “[t]he heat-activated form of commercial deltamethrin D-Fense Dust outperformed the material as purchased, dramatically increasing efficacy against all tested pyrethroid-resistant strains. This increase in lethality was retained for 13 months of storage under ambient conditions in the laboratory.”
“Neonicotinoids are potential alternatives for targeting pyrethroid-resistant mosquitoes, but their efficacy against malaria vector populations of Sub-Saharan Africa has yet to be investigated. “Ashu FA & al., Enhancing the Efficacy of Neonicotinoids Against Mosquitoes and Overcoming Resistance Issues, bioRxiv. 2023 Apr 20: 2023.04.18.537427, https://doi.org/10.1101/2023.04.18.537427 report that there is differential susceptibility to these compounds between mosquitoes that are rural (mostly resistant) and urban (susceptible) to one of these compounds.
Tangi LN & al. found that in Cameroon “the population [is] considerably knowledgeable about the disease but poorly adherent to national malaria control guidelines. Knowledge, Attitude, and Adherence to Malaria Control Guidelines and the Prevalence of Plasmodium Species Infection in Localities Across Transmission and Ecological Zones in Cameroon, Front Public Health, 2023 Apr 27; 11:1060479, https://doi.org/10.3389/fpubh.2023.1060479. A total of 3,360 participants were enrolled in their study, “45.0% (1,513) of whom were mRDT positive, with 14.0% (451/3,216) and 29.6% (951/3,216) having asymptomatic parasitaemia and malaria, respectively. Although most participants knew the cause, symptoms, and control strategies, with 53.6% (1,000/1,867) expertly knowledgeable about malaria overall, only 0.1% (2/1,763) individuals were fully adherent to malaria control measures.”
Chemoprophylaxis
The conclusions reported in Koné S & al., Improving Coverage of Antenatal Iron and Folic Acid Supplementation and Malaria Prophylaxis Through Targeted Information and Home Deliveries in Côte D’Ivoire: A Cluster Randomised Controlled Trial, BMJ Glob Health. 2023 Apr; 8(4):e010934, https://doi.org/10.1136/bmjgh-2022-010934 are difficult to assess. It is unclear how home deliveries enhanced compliance with IPTp, which must have occurred prior to the deliveries. Unfortunately, the entire article was not available to review.
In a study carried out with questionnaires, Cardona-Arias JA, Synthesis of Qualitative Evidence on Malaria in Pregnancy, 2005-2022: A Systematic Review, Trop Med Infect Dis. 2023 Apr 20; 8(4):235, https://doi.org/10.3390/tropicalmed8040235 report that “[e]xtensive knowledge was demonstrated on ITN and case management, but it was lacking on SP-IPTp, risks and consequences of MiP. Attitudes were negative towards ANC and MiP prevention.”
Solanke BL & al., Using Andersen’s Behavioral Model of Health Care Use for Intermittent Preventive Treatment of Malaria in Pregnancy in Nigeria, BMC Pregnancy Childbirth. 2023 May 4;23(1):315, https://doi.org/10.1186/s12884-023-05648-9 documents the inadequacy of current optimal compliance with IPTp practice in Nigeria, which is reported at 21.8%. The survey included a sample of over 4500 women from throughout the country, based on data extracted from the 2018 Nigeria Demographic and Health Survey (NDHS).
Blumenröder S & al. report in Neonatal Infection in Sub-Saharan Africa: A Cross-Sectional Pilot Study on Bacterial Pathogens and Maternal Risk Factors, Front Microbiol, 2023 Apr 25; 14:1171651, https://doi.org/10.3389/fmicb.2023.1171651, a study based in Tanzania that broadly examined maternal risk factors for neonatal infections, that “[t]he prevalence of maternal infection with helminths or Plasmodium was low, indicating that anti-worming strategies and intermittent preventive treatment of malaria for pregnant women (IPTp) are effective.” This conclusion is interesting in that the majority of papers on IPTp so far reported on these monthly summaries (including the two immediately above) indicate inadequate compliance with the prophylaxis.
Fombah AE & al. conducted a “cross-sectional, community-based, multi-stage cluster household survey … from November to December 2021 in selected districts of … of Sierra Leone among 10–23 months old children” to establish compliance with the recommendation to administer Intermittent Preventive Treatment of malaria in infants (IPTi). They conclude in Coverage of Intermittent Preventive Treatment of Malaria in Infants After Four Years of Implementation in Sierra Leone, Malar J, 2023 May 2, 22:145, https://doi.org/10.1186/s12936-023-04575-6 that “half of the children received the three recommended doses of IPTi, indicating an increase in its uptake compared to previous data of just a third of children receiving the intervention.”
Ibinaiye T & al. state that in the Sahel, “seasonal malaria chemoprevention (SMC) is delivered door-to-door in monthly cycles. In each cycle, children are administered sulfadoxine–pyrimethamine (SP) plus amodiaquine (AQ) on Day 1 by community distributors, and AQ on Day 2 and Day 3 by caregivers. … Previous adverse reaction to SMC medicines by eligible children…, awareness of the importance of administering Day 2 and Day 3 AQ …, caregiver age, and home visits to caregivers delivered by the Lead Mothers intervention in Nigeria …, were significantly associated with caregiver adherence to Day 2 and Day 3 AQ administration. The paper is Predictors of Caregiver Adherence to Administration of Amodiaquine During Delivery of Seasonal Malaria Chemoprevention in Nigeria, Burkina Faso, Chad, and Togo, Malar J, 2023 May 5, 22:148, https://doi.org/10.1186/s12936-023-04576-5.
Manga IA & al. report on a case control study of sick children aged 3 months to 10 years with positive RDT in Effectiveness of Seasonal Malaria Chemoprevention Administered in a Mass Campaign in the Kedougou Region of Senegal in 2016: A Case-Control Study, Wellcome Open Res, 2023 Apr 12; 7:216, https://doi.org/10.12688/wellcomeopenres.18057.3. “Each case was matched with two controls. Exposure to SMC was assessed by interviewing the mothers/caretakers and by checking the SMC administration card.” Net ownership was equivalent between the two groups. The authors state that the “protective effectiveness of SMC was 89%.”
“Three months of postdischarge malaria chemoprevention (PDMC) reduces malaria-related mortality and morbidity in pre-school children recently discharged from hospital following recovery from severe anemia.” Kühl MJ & al., Predicting Adherence to Postdischarge Malaria Chemoprevention in Malawian Pre-School Children: A Prognostic Multivariable Analysis, PLoS Glob Public Health. 2023 Apr 17; 3(4):e0001779, https://doi.org/10.1371/journal.pgph.0001779 reports on follow up on 354 children. While the abstract does not cite the extent of full compliance, the authors state that they could not establish a pattern of what factors enhance such compliance, other than the fact that in families that experienced four or more episodes of malaria in a year, compliance was diminished.
WHO recommends perennial chemoprevention (PMC) in very young children in high transmission areas. Runge M & al. report on modeling it in various transmission zones with and without vaccination with the RTS,S vaccine. They report in Perennial Malaria Chemoprevention with and Without Malaria Vaccination to Reduce Malaria Burden in Young Children: A Modelling Analysis, Malar J, 2023 Apr 24, 22:133, https://doi.org/10.1186/s12936-023-04564-9 that “PMC can substantially reduce clinical and severe cases in the first two years of life in areas with high malaria burden and perennial transmission” and that the combination of both intervention “was more impactful than either intervention alone.”
Other
Last month’s report included an article on “Lethal House Lures.” Another article on the subject, Cook J & al., Housing Modification for Malaria Control: Impact of a “Lethal House Lure” Intervention on Malaria Infection Prevalence in a Cluster Randomised Control Trial in Côte D’Ivoire, BMC Med. 2023 May 4; 21(1):168, https://doi.org/10.1186/s12916-023-02871-1 “evaluated the impact of [combining screening with ‘Eave Tubes’ on malaria infection prevalence in Côte d’Ivoire” and compared the result in the primary outcome, malaria case incidence. The drop in incidence as measured by rapid diagnostic test (50.4% to 36.7%) was statistically significant, though not dramatic.
Genetic engineering of mosquitoes is another way of controlling the vector population. Wyse AP & al., Mathematical Modeling of the Performance of Wild and Transgenic Mosquitoes in Malaria Transmission, PLoS One. 2023 Apr 28; 18(4):e0285000, https://doi.org/10.1371/journal.pone.0285000 is about fostering a group of mosquitoes that are themselves resistant to hosting the parasite and breeding them with a wild population.
“Recently, a highly potent Plasmodium falciparum transmission-blocking monoclonal antibody (TB31F) was demonstrated to be safe and efficacious in malaria-naive volunteers.” In Modelling the Impact of a Highly Potent Plasmodium falciparum Transmission-Blocking Monoclonal Antibody in Areas of Seasonal Malaria Transmission, J Infect Dis. 2023 Apr 12: jiad101, https://doi.org/10.1093/infdis/ jiad101 Challenger JD & al. “predict the potential public health impact of large-scale implementation of TB31F alongside existing interventions… Community-wide annual administration (at 80% coverage) of TB31F over a three-year period was predicted to reduce clinical incidence by 54% (381 cases averted per 1000 people per year) in a high-transmission seasonal setting, and 74% (157 cases averted per 1000 people per year) in a low-transmission seasonal setting. Targeting school-aged children gave the largest reduction in terms of cases averted per dose.”
“Plasmodium vivax is the most geographically widespread malaria-causing parasite resulting in significant associated global morbidity and mortality. One of the factors driving this widespread phenomenon is the ability of the parasites to remain dormant in the liver. Known as ‘hypnozoites’, they reside in the liver following an initial exposure, before activating later to cause further infections, referred to as ‘relapses’. As around 79-96% of infections are attributed to relapses from activating hypnozoites, … it will be highly impactful to apply treatment to target the hypnozoite reservoir … to eliminate P. vivax. Treatment with radical cure, for example tafenoquine or primaquine, to target the hypnozoite reservoir is a potential tool to control and/or eliminate P. vivax. [Anwar MN & al.] developed a … mathematical model … to study the anticipated effect of radical cure treatment administered via a mass drug administration (MDA) program.” The article is Optimal Interruption of P. vivax Malaria Transmission Using Mass Drug Administration, Bull Math Biol. 2023 Apr 19; 85(6):43, https://doi.org/10.1007/s11538-023-01153-4
Diagnosis
General diagnostics
Savonius O & al. describe a study of 345 children aged 30 days–15 years old, admitted to a hospital. They used PCR tests to confirm whether malaria was the cause of the illness and found that 46.7% of them. Children with diminished consciousness caused by malaria had shorter courses and were less prone to seizures than other children with the same presenting symptom. PCR-Confirmed Malaria Among Children Presenting with a Decreased Level of Consciousness in Angola: A Prospective, Observational Study, Malar J, 2023 Apr 22, 22:130, https://doi.org/10.1186/s12936-023-04556-9#Sec1 describes the study.
Preißinger K & al. claim to demonstrate that their automated method of microscopic diagnosis “is applicable to images recorded by various microscopy techniques and available as a software package.•Identifying individual RBCs in multi-cell microscopy images.•Extracting characteristic one-dimensional cross-sections from individual RBC images. These cross-sections are selected by a simple algorithm to contain key information about the status of the RBCs and are used to.•Classify the malaria blood stages. Their paper is An Automated Neural Network-Based Stage-Specific Malaria Detection Software Using Dimension Reduction: The Malaria Microscopy Classifier, Methodsx, 2023 Apr 20; 10:102189, https://doi.org/10.1016/J.Mex.2023.102189.
Field diagnostics
See below, Malpartida-Cardenas & al. on LAMP and also Oduma & al. (in Epidemiology) on comparison on sensitivity of qPCR versus microscopy.
New diagnostic methods
The loop mediated isothermal amplification (LAMP) method of diagnosing Plasmodium falciparum infections has been shown to effective. Malpartida-Cardenas K & al. state in their paper, Sensitive Detection of Asymptomatic and Symptomatic Malaria with Seven Novel Parasite-Specific LAMP Assays and Translation for Use at Point-of-Care, Microbiol Spectr, 2023 May 9; e0522222, https://doi.org/10.1128/spectrum.05222-22 that “seven species-specific loop-mediated isothermal amplification (LAMP) assays were designed and evaluated against TaqMan quantitative PCR (qPCR), microscopy, and enzyme-linked immunosorbent assays (ELISAs). Their clinical performance was assessed with a cohort of 164 samples of symptomatic and asymptomatic patients from Ghana.” They state that their method is translatable to point-of-care situations.
Other
A very unusual situation is described by Reifler K &al., Delayed Malaria Recrudescence and Relapse in the Setting of COVID-19, Ann Int Med Clin Cases, 2023 May 2, 2:e221034, https://doi.org/10.7326/ aimcc.2022.1034. The infective agents in this case were P. falciparum and P. ovale, yet the patient denied having been in an area where malaria was prevalent for over five years. Whereas P. ovale may hide in the liver (the “hypnozoite”) for a long time, P. falciparum does not have this stage. So it must have been sequestered in some other way. Also, reactivation in the setting of COVID-19 for any malaria is rare, but apparently unreported so far with P. falciparum.
Treatment
Treatment results
Following up on WHO’s endorsement of atovaquone-proguanil as first line treatment for malaria in some settings, Blanchard A & Hine P reviewed the reports of use of this combination. In Atovaquone-Proguanil for Treating Uncomplicated Plasmodium falciparum Malaria, Emergencias. 2023 Apr; 35(2):139-141, https://doi.org/10.1002/14651858.cd004529.pub3 they state that “[a]tovaquone-proguanil was effective against uncomplicated P. falciparum malaria, although in some instances treatment failure rates were between 5% and 10%. The addition of artesunate to atovaquone-proguanil may reduce treatment failure rates.”
Falade CO & al. report in Efficacy and Safety of Pyronaridine–Artesunate {PA} Versus Artemether–Lumefantrine {AL} in the Treatment of Acute Uncomplicated Malaria in Children in South-West Nigeria: An Open-Labelled Randomized Controlled Trial, Malar J, 2023 May 13 22:154, https://doi.org/10.1186/s12936-023-04574-7 that PA and AL were well-tolerated. PA was significantly more efficacious than AL in both the PCR-uncorrected and PCR-corrected per-protocol populations during this study. The results of this study support the inclusion of PA in the anti-malarial treatment guidelines in Nigeria.
Mekonnen DA & al. followed 102 patients in the study, Treatment of Uncomplicated Plasmodium vivax with Chloroquine Plus Radical Cure with Primaquine Without G6PDD Testing Is Safe in Arba Minch, Ethiopia: Assessment of Clinical and Parasitological Response, Malar J, 2023 Apr 25, 22:135, https://doi.org/10.1186/s12936-023-04562-x and observed that all “patients had adequate clinical and parasitological responses within the 28 days of follow up. … The cumulative incidence of failure was 10.9% (95% confidence interval, 5.8–19.9%) on day 42.” They state that despite no testing for G6PD deficiency, there were no adverse reactions to the low dose of primaquine.
Adherence to guidelines
Azizi H & AL., Availability of Malaria Diagnostic Tests, Anti-Malarial Drugs, and the Correctness of Treatment: A Systematic Review and Meta-Analysis, Malar J, 2023 Apr 18, 22:127, https://doi.org/ 10.1186/s12936-023-04555-w is a study that goes beyond the treatment issue, but an interesting finding in their review of 18 studies encompassing 15,398 malaria patients is the following: “A pooled meta-analysis using random effects indicates the overall proportion of the correctness of malaria treatment 62% (95% CI 54–69). The appropriate malaria treatment was improved over time from 2009 to 2023. In the sub-group analysis, the correctness of treatment proportion was 53% (95% CI 50–63) for non-physician health workers and 69% (95% CI 55–84) for physicians.”
Structured questionnaires submitted to at-home caregivers of children were used as research instruments, as reported in Bamikole OJ & al., Drug Use Practices and Self-treatment for Suspected Malaria in Ibadan, Nigeria, Am J Trop Med Hyg. 2023 Apr 17:tpmd220489, https://doi.org/ 10.4269/ajtmh.22-0489. The results indicated that … “69% of caregivers self-prescribed and self-managed malaria for children under 5 years old without immediate hospital visits, and 76.4% of the caregivers believed most recommended and available antimalarial drugs were ineffective. Generally, 44.2% of respondents preferred and used antibiotics as a treatment strategy for malaria, 13.2% used agbo (a locally made liquid extract of plants and roots), 12.5% used prayers, and 19.6% used antimalarial drugs.” This report is problematic, since it seems to show that while over ¾ of caregivers think that recommended treatment is ineffective, “57.1% of respondents stated that they always complete the standard antimalarial dosage regimen.”
Demarta-Gatsi C & al. propose a method of predicting the extent to which new antimalarial drugs and combinations may be optimally effective in humans in Predicting Optimal Antimalarial Drug Combinations from a Standardized Plasmodium falciparum Humanized Mouse Model, Antimicrob Agents Chemother. 2023 May 3: e0157422, https://doi.org/10.1128/aac.01574-22.
Side effects and complications
See the Mekonnen article above.
Drug resistance
Moss S & al. sequenced “[a]mplified DNA from P. falciparum isolates sourced from dried blood spot samples of 15 asymptomatic malaria cases. In Population Dynamics and Drug Resistance Mutations in Plasmodium falciparum on the Bijagós Archipelago, Guinea-Bissau, Sci Rep. 2023 Apr 18; 13(1):6311, https://doi.org/10.1038/s41598-023-33176-1 they report “mutations … associated with resistance to sulphadoxine-pyrimethamine, and [another mutation] associated with chloroquine resistance.
“Artemisinin-based combination therapy (ACT) is the most effective treatment for malaria and has significantly reduced morbimortality. Polymorphisms associated with the Plasmodium falciparum Kelch gene (Pfkelch13) have been associated with delayed parasite clearance even with ACT treatment.” Arzika II & al., Plasmodium falciparum kelch13 polymorphisms identified after treatment failure with artemisinin-based combination therapy in Niger, Malar J, 2023 May 1, 22:142, https://doi.org/ 10.1186/s12936-023-04571-w. The authors demonstrate that during treatment with artemether/ lumefantrine, several resistant mutations are selected to survive.
Balta VA & al. claim to show in a laboratory study “that clinically relevant atovaquone-resistant malaria parasites survive poorly, if at all, in mosquitoes, and that mosquitoes do not transmit drug-resistant parasites to humanized mice.” The paper is Transmissibility of Clinically Relevant Atovaquone-Resistant Plasmodium falciparum by Anopheline Mosquitoes, bioRxiv. 2023 Feb 9: 2023.02.07.527535, https:// doi.org/10.1101/2023.02.07.527535.
New drug research
Lopes EA & al., Antimalarial Drugs: What’s New in the Patents, Expert Opin Ther Pat. 2023 Apr 15, https://doi.org/10.1080/13543776.2023.2203814 is a review that “covers patents that protect antimalarial small molecules bearing the artemisinin or other chemical scaffolds, as well as vaccines, that have been published in the period 2015-2022. … Most of these candidates have been tested in standardized strains, with the use of Plasmodium clinical isolates for testing still underdeveloped. Several compounds have been profiled in in vivo mouse models of malaria, including humanised mice.”
Much like the afore mentioned article, M Dhameliya T & al., A Quinquennial Review on Recent Advancements and Developments in Search of Anti-Malarial Agents, Curr Top Med Chem. 2023 Apr 27, https://doi.org/10.2174/1568026623666230427115241 is a review of the potential new drugs that were investigated between 2016 and 2020, specifically naming at least some of them.
“Cladosporium cladosporioides is a darkly pigmented mold that occurs world-wide on a wide range of materials both outdoors and indoors.” (Wikipedia). Hou A & al., Cladosporin, A Highly Potent Antimalaria Drug, Chembiochem. 2023 May 9: e202300154, https://tinyurl.com/9kmnz24s states that “[c]ladosporin, a unique natural product from [the fungus] … exhibits nanomolar inhibitory activity against Plasmodium falciparum …[and] has become a very promising lead compound for developing antiparasitic drugs to treat drug-resistant malaria.”
Kreutzfeld O & al. report on testing 19 potential new antimalarials. Susceptibility of Ugandan Plasmodium falciparum Isolates to the Antimalarial Drug Pipeline, Microbiol Spectr. 2023 May 9: e0523622, https://doi.org/10.1128/spectrum.05236-22 states that “African isolates were generally highly susceptible to the 19 studied lead antimalarials. … These results offer confidence that the activities of the tested antimalarial compounds now under development will not be limited by preexisting resistance-mediating mutations in African malaria parasites.”
Ravindar L & al., Recent Developments in Antimalarial Activities of 4-Aminoquinoline Derivatives, Eur J Med Chem, 2023 May 5; 256:115458, https://doi.org/10.1016/j.ejmech.2023.115458 is a “review focused on the antimalarial efficacy of the 4-aminoquinoline moiety hybridised with various heterocyclic scaffolds developed by scientists since 2018 against diverse Plasmodium clones.”
Plant extracts and traditional treatments
“Curcumin, one of the major ingredients of turmeric (Curcuma longa), has been widely reported for its diverse bioactivities, including against malaria and inflammatory-related diseases.” Jamil SNH, & al., Curcumin and Its Derivatives as Potential Antimalarial and Anti-Inflammatory Agents: A Review on Structure-Activity Relationship and Mechanism of Action, Pharmaceuticals (Basel). 2023 Apr 18; 16(4):609, https://doi.org/10.3390/ph16040609 “discusses the antimalarial and anti-inflammatory activities and the structure-activity relationship (SAR), as well as the mechanisms of action of curcumin and its derivatives in malarial treatment.”
Faloye KO & al. studied the effects of ginger in malaria infected mice and report in Antimalarial Potential, LC-MS Secondary Metabolite Profiling and Computational Studies of Zingiber officinale, J Biomol Struct Dyn. 2023 Apr 28: 1-16, https://doi.org/10.1080/07391102.2023.2205949 that one of the common food additive’s components, gingerenone A has significant antimalarial potential. The abstract is silent on where, if anywhere, the plant is used in communities against malaria.
Alcea glabrata, also known as Alcea tabrisiana is a flowering plant in Turkey and Iran. From the latter country, Pirmohammadi Y & al., Bioactivity Assays and Phytochemical Analysis upon Alcea glabrata; Focusing on Xanthine Oxidase Inhibitory and Antimalarial Properties, Toxicon. 2023 Apr 27: 107140, https://doi.org/10.1016/j.toxicon.2023.107140 report on investigating its potential as a source of antimalarials.
Kevin TDA & al. investigated the Antiplasmodial, Antioxidant, and Cytotoxic Activity of Bridelia micrantha a Cameroonian Medicinal Plant Used for the Treatment of Malaria, (Biomed Res Int. 2023 Apr 11; 2023:1219432, https://doi.org/10.1155/2023/1219432) “for antiplasmodial activity on strains of Plasmodium falciparum sensitive to chloroquine (3D7) and resistant (Dd2).” They publish data that lead them to conclude that B. micrantha or its extract was non-toxic and “can serve as an antimalarial agent.”
Other
Posadina AM & al., Medicinal and Mechanistic Overview of Artemisinin in the Treatment of Human Diseases, Biomed Pharmacother, 2023 May 12; 163:114866, https://doi.org/10.1016/j.biopha.2023. 114866 is a comprehensive review that “aims to update the biomedical potential of [artemisinin] and its derivatives for treating human diseases highlighting its pharmacokinetic and pharmacological properties based on the results of experimental pharmacological studies in vitro and in vivo. Cellular and molecular mechanisms of action, tested doses and toxic effects of artemisinin [are] also described.”
According to Lendongo Wombo JB & al., Knowledge, Attitudes, and Practices of Mothers Regarding Childhood Malaria in Southeastern Gabon, Malar J, 2023 May 15, 22:155, https://doi.org/10.1186/ s12936-023-04584-5, [w]omen identified fever as the main symptom of malaria, which could be beneficial for a quicker and more efficient management of the disease in children. … Gabonese mothers react quickly when their children have fever. However, several external factors lead them to practice self-medication as a first resort. In this survey population, the practice of self-medication did not depend on social status, marital status, level of education, on the young age or inexperience of mothers.”
Judging from its abstract, Tripathi H & al., Malaria Therapeutics: Are We Close Enough, Parasit Vectors. 2023 Apr 14; 16(1):130, https://doi.org/10.1186/s13071-023-05755-8 claims to be a thorough review of “basic malaria biology, the parasite’s life cycle, approved drugs, vaccine candidates, and available diagnostic approaches.”
Campaigns and Policies
It will be no surprise that Ilboudo PG & Siri A conclude in Effects of the Free Healthcare Policy on Maternal and Child Health in Burkina Faso: A Nationwide Evaluation Using Interrupted Time-Series Analysis, Health Econ Rev, 2023 May 5; 13(1):27, https://doi.org/10.1186/s13561-023-00443-w that the recent decision to “institute a free healthcare policy for women and children under five…significantly increased the use of healthcare facilities for child consultations and reduced mortality from severe malaria in children under the age of five years.” Effects on maternal care are also mentioned.
Ozodiegwu ID & al., Application of Mathematical Modelling to Inform National Malaria Intervention Planning in Nigeria, Malar J, 2023 Apr 26, 22:137, hrrps://doi.org/10.1186/s12936-023-04563-w describes the method used in modeling various scenarios of “business as usual” versus partial of more extensive implementation of campaigns. “The greatest intervention impact was associated with the NMSP scenario with 80% or greater coverage of standard interventions coupled with intermittent preventive treatment in infants and extension of SMC to 404 [local government areas] (LGAs), compared to 80 LGAs in 2019.”
Followers of the work of MPI and MPI Zambia are aware of the multiple malaria control efforts exerted in Zambia. Katowa B & al. document immunologic evidence that the country is making significant progress and has been making it for some time now. The article is Declining Age-Specific Seroprevalence and Seroconversion Rates in Plasmodium falciparum from 2009 to 2018 Documents Progress Toward Malaria Elimination in Southern Zambia, Am J Trop Med Hyg. 2023 May 1: ajtmh.22-0401, https://doi.org/10.4269/ajtmh.22-0401.
See also the article by Manga & al. above, in Prevention.
Epidemiology
Climate change, biodiversity and environment
Beloconi A & al. state in Malaria, Climate Variability, and Interventions: Modelling Transmission Dynamics, Sci Rep. 2023 May 5; 13(1):7367, https://doi.org/10.1038/s41598-023-33868-8 that “in the lowlands of malaria endemic western Kenya, variations in climatic factors played a key role in driving malaria incidence during 2008-2019, despite high bed net coverage and use among the population. The model captures some of the main mechanisms of human, parasite, and vector dynamics, and opens the possibility to forecast malaria in endemic regions, taking into account the interaction between future climatic conditions and intervention scenarios.”
Oduma C & al. collected finger-prick blood samples from 3061 individuals irrespective of clinical symptoms in 20 clusters … in western Kenya and screened for Plasmodium falciparum parasites using qPCR and microscopy. As reported in, Altitude, Not Potential Larval Habitat Availability, Explains Pronounced Variation in Plasmodium falciparum Infection Prevalence in the Western Kenya Highlands, PLoS Glob Public Health. 2023 Apr 17; 3(4):e0001505, https://doi.org/10.1371/ journal.pgph.0001505 Across all clusters, P. falciparum parasites were detected in 49.8% (1524/3061) of individuals by qPCR and 19.5% (596/3061) by microscopy. … Using a generalized linear mixed effect model (GLMM), a 5% decrease in the odds of getting infected per each 10m increase in altitude was observed, while the number of larval habitats and their proximity to households were not statistically significant predictors for prevalence.”
“Knowledge of insect dispersal is relevant to the control of agricultural pests, vector-borne transmission of human and veterinary pathogens, and insect biodiversity.” Atieli HE & al. report in Wind-Assisted High-Altitude Dispersal of Mosquitoes and Other Insects in East Africa, Journal of Medical Entomology, 2023 Apr 24, tjad 033, https://doi.org/10.1093/jme/tjad033 that in the Western Region of Kenya, Anopheles species were among the least encountered mosquitoes at high altitudes. “The survival rate of mosquitoes experimentally exposed to high-altitude overnight was significantly lower than controls maintained in the laboratory (19% vs. 85%).” The article is echoed in Ricciutti E, Mosquito Migration: Study Finds More High-Altitude Dispersal of Disease Vectors in Africa, Entomology Today, 2023 May 5, https://entomologytoday.org/2023/05/05/mosquito-migration-more-high-altitude-dispersal-disease-vectors-africa-malaria/
Nzioki I & al.’s study, Current Observations on Shifts in Malaria Vector Biting Behavior and Changing Vulnerability to Malaria Transmission in Contrasting Ecosystems in Western Kenya, Res Sq. 2023 Apr 10: rs.3.rs-2772202, https://doi.org/10.21203/rs.3.rs-2772202/v1 study shows heterogeneity of Anophelines distribution, high outdoor malaria transmission, and peak biting activity by An. funestus (early morning) when humans are not protected by bed nets in the lowland sites.” The abstract includes specific data on species of Anopheles in the region and their temporal activities.
An Archetypes Approach to Malaria Intervention Impact Mapping: A New Framework and Example Application, Malar J, 2023 Apr 26, 22:138, https://doi.org/10.1186/s12936-023-04535-0 Bertozzi-Villa A & al. introduce “a novel methodology which combines the richness of spatiotemporal mapping with the rigor of mechanistic modeling to create a multi-purpose infrastructure for answering a broad range of important questions in the malaria policy space. It … can be adapted to the modelers’ setting of choice.”
The “recent establishment and expansion of the invasive urban Asian vector Anopheles stephensi will likely drastically change Africa’s disease risk landscape.” According to Lehmann T & al., Urban Malaria May Be Spreading Via the Wind-Here’s Why That’s Important, Proc Natl Acad Sci U S A. 2023 May 2; 120(18):e2301666120, https://doi.org/10.1073/pnas.2301666120, [u]rban malaria will become a bigger threat. Unlike all other African malaria vectors, An. stephensi larvae thrive in container habitats (e.g., abandoned tires or cisterns) near human dwellings …”
General epidemiology
Gametocytes are the only Plasmodium parasite life stage that can infect mosquitoes. Andolina C & al. studied how long it takes to have this stage develop in an infected person. Plasmodium falciparum Gametocyte Carriage in Longitudinally Monitored Incident Infections Is Associated with Duration of Infection and Human Host Factors, Sci Rep. 2023 May 1; 13(1):7072, https://doi.org/10.1038/s41598-023-33657-3 reports that in case of “infections that lasted ≥ 3 months, gametocyte appearance was near-universal” (96%) while gametocyte detection on every 28-day sampling was much less frequent in infections of lesser duration. Also, “individuals with sickle-cell trait (HbAS) were more likely to have gametocytes detected” than those with normal hemoglobin (HbAA).
Ngou CM & al. also found that “Plasmodium transmission stages were more prevalent in [sickle cell trait] individuals. This may reflect the parasite’s enhanced investment in the sexual stage to increase their survival rate when asexual replication is impeded.” Their paper is Influence of the Sickle Cell Trait on Plasmodium falciparum Infectivity from Naturally Infected Gametocyte Carriers, BMC Infect Dis, 2023 May 10; 23(1):317, https://doi.org/10.1186/s12879-023-08134-x.
Cardona-Arias JA, Synthesis of Qualitative Evidence on Malaria in Pregnancy {MiP}, 2005-2022: A Systematic Review, Trop Med Infect Dis. 2023 Apr 20; 8(4):235, https://doi.org/10.3390/ tropicalmed8040235 “systematizes the qualitative research on MiP, … through a meta-synthesis in 10 databases…[and conclude that] socioeconomic and cultural determinants were poverty and low educational level of pregnant women, distance to the hospital, patriarchal-sexist gender roles, and predominance of local conceptions on maternal-fetal-neonatal health.”
Das AM & al. present a “model of malaria transmission that distinguishes between imported, introduced and indigenous cases, and can be used to test the impact of new interventions in a setting with low transmission and ongoing case importation.” In Modelling the Impact of Interventions on Imported, Introduced and Indigenous Malaria Infections in Zanzibar, Tanzania, Nat Commun, 2023 May 12; 14(1):2750, https://doi.org/10.1038/s41467-023-38379-8 they “use human movement and malaria prevalence data from Zanzibar … [and conclude] that the majority of new cases on both major islands of Zanzibar are indigenous cases, despite high case importation rates. (It is uncertain if this is a peer reviewed publication).
Two studies highlight the problem of trans-border spread of malaria. Munsense IM & Tsoka-Gwegweni JM, Perceived Health System Challenges of Implementing Cross-Border Malaria Preventive Measures at Ports of Entry in KwaZulu-Natal, Ann Glob Health. 2023 Apr 27; 89(1):29, https://doi.org/10.5334/ aogh.3992 focuses on cases imported from Mozambique. The prevention challenges included lack of novelty in the existing cross-border preventive measures, insecurity and illegal migration. … travellers [often refuse to disclose] their health-related information to health border officers. They were more eager to cross and attend to their business. Because of the porous borders and the shortage of staff to cover all the uncontrolled entries, travellers constantly crossed without any hindrances. Similarly, Kollipara A & al., Mobilizing Resources with an Investment Case to Mitigate Cross-Border Malaria Transmission and Achieve Malaria Elimination in South Africa, Glob Health Action, 2023 Dec 31(!!); 16(1):2205700, https://doi.org/10.1080/ 16549716.2023.2205700 reports that malaria control in southern Mozambique is a prerequisite to eliminate malaria in South Africa. Based on this, the South African government … allocated funding towards a co-financing mechanism to support malaria control efforts in southern Mozambique.”
Further to the North in South Africa, Patrick SM & al. describe Household Living Conditions and Individual Behaviours Associated with Malaria Risk: A Community-Based Survey in the Limpopo River Valley, 2020, South Africa, Malar J, 2023 May 15, 22:156, https://doi.org/10.1186/s12936-023-04585-4. The article concludes that “the influence of contextual factors, particularly those defined by the type of habitat, was significant. Housing conditions and poor living environments were factors of malaria exposure and history, regardless of site of investigation, individual preventive behaviours and personal characteristics of inhabitants.”
Schaffner SF & al., Malaria Surveillance Reveals Parasite Relatedness, Signatures of Selection, and Correlates of Transmission Across Senegal, medRxiv. 2023 Apr 17: 2023.04.11.23288401, https://doi.org/10.1101/2023.04.11.23288401 describes “an analysis of data from the first year of an ongoing, nationwide program of genetic surveillance of Plasmodium falciparum parasites in Senegal, intended to provide actionable information for malaria control efforts… Throughout the country, most related parasites proved to belong to a single network of relatives, within which parasites were enriched for shared haplotypes at known and suspected drug resistance loci as well as at one novel locus, reflective of ongoing selection pressure.”
The relationship of malaria to the so-called Duffy groups has been cited before. As a result of a study of 44 patients infected by Plasmodium vivax, Abate A & al., Differential Transmissibility to Anopheles arabiensis of Plasmodium vivax Gametocytes in Patients with Diverse Duffy Blood Group Genotypes, Malar J, 2023 Apr 25, 22:136, https://doi.org/10.1186/s12936-023-04570-x concludes that “Duffy antigen polymorphisms appears to contribute to transmissibility difference of P. vivax gametocytes to Anopheles mosquitoes…”
Spatiotemporal studies
Millogo AA & al., Spatial Modelling of Malaria Prevalence Associated with Geographical Factors in Houet Province of Burkina Faso, West Africa, GeoJournal, 2023; 88(2):1769-1783. https://doi.org/10.1007/s10708-022-10692-7.
El Mustapha I & al., Malaria Prevalence in Mauritania: a Systematic Review and Meta-Analysis, Malar J, 2023 May 2, 22:146, hrttps://doi.org/10.1186/s12936-023-04569-4.
Katale RN & Gemechu DB, Spatio-Temporal Analysis of Malaria Incidence and Its Risk Factors in North Namibia, Malar J, 2023 May 6, 22:149, https://doi.org/10.1186/s12936-023-04577-4.
Tetteh JA &al. , Prevalence, Trends and Associated Factors of Malaria in the Shai-Osudoku District Hospital, Ghana, Malar J, 2023 Apr 22, 22:131, https://doi.org/10.1186/s12936-023-04561-y