By Dr. Derick Pasternak, Malaria Science & Research Coordinator, MPI

Over the last ten days, news broke about two different malaria vaccines; The lay press referred to an interim report of the R21/Matrix-M vaccine trial in Burkina Faso, claiming “80% efficacy.”  On the same day, GlaxoSmithKline announced that WHO “has awarded prequalification to Mosquirix (also known as RTS,S/AS01).” These two publications and their implications are discussed in the report, which is rather lengthy, because of the large number of relevant articles this month (PubMed lists over 3400 published articles relevant to malaria since January of this year).  

 

Prevention: 

 

Vaccines  

The article by Datoo MS & al., Efficacy and Immunogenicity of R-21/Matrix-M Vaccine Against Clinical Malaria after 2 Years’ Follow-Up in Children in Burkina Faso: A Phase 1/2b Randomised Controlled Trial, Lancet Inf Dis, 2022 Sep 7, doi: 10.1016/S1473-3099(22)0422-X has found echoes in the lay press, including paper and internet publications.  These latter repeat the statement from the paper that “[v]accine efficacy was … 80% … in the high-dose adjuvant group. In the high-dose adjuvant group, vaccine efficacy against multiple episodes of malaria was 78%”  The article reported on the outcome of administering a booster of the vaccine 12 months after the completion of the original three injection series.  Although this reviewer read the entire article, his level of knowledge of biostatistics does not allow him to understand how 80% efficacy can be claimed when the authors also report that “[f]ollowing the booster vaccination, …, 54 (39%) of 137 children who received R21/Matrix-M with high-dose adjuvant, and 121 (86%) of 140 children who received the rabies vaccine {controls} developed clinical malaria by 12 months,” which is only a 42% reduction! 

 

One day before the appearance of the above article on the internet, the GlaxoSmithKline (GSK) Media Department made the following announcement: “the World Health Organization (WHO) has awarded prequalification to Mosquirix (also known as RTS,S/AS01), GSK’s groundbreaking malaria vaccine. This is the first prequalification for a malaria vaccine and is an important step in rolling out the vaccine in countries with moderate to high P. falciparum malaria transmission. (¶) The WHO prequalification decision is a mandatory prerequisite for United Nations (UN) agencies, such as UNICEF, to procure the vaccine in partnership with Gavi, the Vaccine Alliance, and eligible countries. Pre-qualification for Mosquirix is the result of a rigorous regulatory process with the assessment of clinical, safety and technical data ensuring that the vaccine meets standards of quality, safety and efficacy, and is suitable for the target population.”  As of 5 days later, the WHO website does not allude to this event at all, so it is unclear when it occurred. This may simply be a repeat announcement from the time RTS,S/AS01 was first recommended by a working group of WHO for use and is quoted by WHO in April 2022 as follows: “WHO recommends the RTS,S/AS01 malaria vaccine be used for the prevention of P. falciparum malaria in children living in regions with moderate to high transmission as defined by WHO.” In that case, it must have been published in anticipation of the above article, which is about a competing product.  It remains a fact that while the R21 vaccine seems more efficacious, it has not been through Phase 3 trials, which are already behind the GSK product. 

 

Huang WC & al. state in Vaccine Co-Display of CSP and Pfs230 on Liposomes Targeting Two Plasmodium falciparum Differentiation Stages, Commun Biol. 2022 Aug 1; 5(1):773. doi: 10.1038/s42003-022-03688-z that a “vaccine targeting multiple stages of the Plasmodium falciparum parasite life cycle is desirable.”  They allude to the above two vaccines which are aimed at the sporozoite surface Circumsporozoite Protein (CSP) and propose to combine a similar product in a liposome with “Pfs230, a sexual-stage P. falciparum surface protein, … currently in trials as the basis for a transmission-blocking vaccine, which inhibits parasite development in the mosquito vector.”  The product would then produce antibodies against the infective agent in humans and when ingested by a biting mosquito, it would work against it in the body of the vector as well. 

 

Relevant to the efficacy of CSP-based vaccines are the findings reported by He Z-Q & al. in Genetic Polymorphism of Circumsporozoite Protein of Plasmodium falciparum Among Chinese Migrant Workers Returning from Africa to Henan Province, Malaria J, 2022 Aug 27, vol 21 art 248, doi: 10.1186/s12936-022-04275-7.  They conclude that “gene polymorphism pattern among Chinese migrant workers returning from Africa … was consistent with that in Africa. The geographical pattern of population differentiation and the evidence of natural selection and gene recombination suggested that the effect of polymorphism on the efficacy of PfCSP-based vaccines should be considered.” 

 

An announcement in Yale Medicine (2022, issue 169) by Hirschman R, An End to Malaria? (https://medicine.yale.edu/news/yale-medicine-magazine/article/an-end-to-malaria/) describes work by Richard Bucala MD PhD on “self-amplifying RNA” vaccine against malaria, being developed and patented by Yale. No further information is available about this work at this time. 

 

Vector control and protection from vectors 

Mponzi WP & al. state that “[u]nderstanding mosquito biting behaviours is important for designing and evaluating protection methods against nuisance biting and mosquito-borne diseases.” In studies reported as Observing the Distribution of Mosquito Bites on Humans to Inform Personal Protection Measures Against Malaria and Dengue Vectors, PLoS One, 2022 Jul 25; 17(7):e0271833. doi: 10.1371/journal.pone.0271833, they conclude that Anopheles mosquitoes tend to bite upright adults in the lower extremities, but for recumbent ones, the biting patterns are more broadly spread.  They recommend appropriate clothing to prevent biting.  

 

Human volunteers were set up in six experimental huts equipped with a variety of preventive approaches, as described in the title of Yewhalaw D & al., An Experimental Hut Study Evaluating the Impact of Pyrethroid-Only and PBO Nets Alone and in Combination with Pirimiphos-Methyl-Based IRS In Ethiopia, Malaria J, 2022 Aug 20, vol 21 art 238, doi: 10.1186/s12936-022-04263-x. The conclusion was that “[m]osquito mortality rates from the huts with IRS alone were similar to mosquito mortality rates from the huts with the combination of … tools (IRS + ITNs) and mosquito mortality rates from huts with PBO nets alone were significantly higher than huts with pyrethroid-only nets.” 

 

Nolden M & al., Sequential Phase I Metabolism of Pyrethroids by Duplicated CYP6P9 Variants Results in the Loss of the Terminal Benzene Moiety and Determines Resistance in the Malaria Mosquito Anopheles funestus, Insect Biochem Mol Biol, 2022 Jul 20: 103813, doi: 10.1016/j.ibmb.2022.103813 is a basic science article, but is included here because it speaks to a problem that is being encountered in the field of vector control. 

 

“Long-lasting insecticidal nets (LLINs) and indoor residual spraying (IRS) target night-time indoor biting mosquitoes and effectively reduce malaria transmission in rural settings across Africa, but additional vector control tools are needed to interrupt transmission,” according to the Attractive Targeted Sugar Bait Phase III Trial Group.  In Attractive Targeted Sugar Bait Phase III Trials in Kenya, Mali, and Zambia, Trials, 2022 Aug 9; 23(1):640, doi: 10.1186/s13063-022-06555-8, they announce that a trial is under way in 3 sub-Saharan countries and go into detail on how it will be conducted.  

 

Chemoprophylaxis 

Chotsiri P & al., Pharmacokinetic Considerations in Seasonal Malaria Chemoprevention, Trends Parasitol, 2022 Aug; 38(8):673-682, doi: 10.1016/j.pt.2022.05.003 is an apparently all encompassing review of chemoprevention for children with sulfadoxine/pyrimethamine (SP) plus amodiaquine (AQ).  It also refers to a different regimen (dihydroartemisinin and piperaquine) for pregnant women. 

 

Three papers refer to seasonal chemoprevention in Mali. Cissoko M & al. assert that seasonal chemo-preventive regimens should be tailored region by region to the timing of the rainy seasons.  Their paper is Sub-National Tailoring of Seasonal Malaria Chemoprevention in Mali Based on Malaria Surveillance and Rainfall Data, Parasit Vectors, 2022 Aug 4; 15(1):278, doi: 86/s13071-022-05379-4. Diawara SI & al. report on the results of chemoprevention.  They document in Effect of Seasonal Malaria Chemo-prevention in Children Between 5 and 9 Years Old in Kita and Bafoulabe Districts, Mali, Parasite Epidemiol Control,  2022 Jun 22; 18:e00258, doi: 10.1016/j.parepi.2022.e00258 that “significant reduction in the prevalence of parasitemia in children 60 to 120 months was observed in the intervention district, but the prevalence of clinical malaria remained relatively constant.” Nonetheless they conclude that these results are “encouraging.” Maiga H & al. applied two different chemo-prevention regimens to schoolchildren and report in Overall and Gender-Specific Effects of Intermittent Preventive Treatment of Malaria with Artemisinin-Based Combination Therapies Among Schoolchildren in Mali: A Three-Group Open Label Randomized Controlled Trial, Am J Trop Med Hyg, 2022 Aug 22: tpmd211218, doi: 10.4269/ajtmh.21-1218 that both SP plus artesunate and AQ plus artesunate reduced the odds of P. falciparum infection. Additional findings included the improvement in grade point averages in children who received the regimens, with girls improving slight more than boys.  

     

Coming on the heels of Wu & al.’s article on an injectable monoclonal antibody reported last month, is van der Boor SC & al., Safety, Tolerability, and Plasmodium falciparum Transmission-Reducing Activity of Monoclonal Antibody TB31F: A Single-Centre, Open-Label, First-In-Human, Dose-Escalation, Phase 1 Trial in Healthy Malaria-Naive Adults, Lancet Infect Dis, 2022 Aug 10, doi: 10.1016/S1473-3099(22)00428-5. This product “binds the gamete surface protein Pfs48/45 and inhibits fertilisation, thereby preventing further parasite development in the mosquito midgut and onward transmission.  The study involved 25 participants who received various doses of the antibody and were monitored for persistence for 84 days.  Transmission-reducing activity (TRA) of participant sera was assessed… The authors conclude that at the largest dose administered, which caused no “serious or severe adverse effects,” the substance is “a well-tolerated and highly potent monoclonal antibody capable of completely blocking transmission of P. falciparum parasites from humans to mosquitoes. In areas of seasonal transmission, a single dose might cover an entire malaria season.” In a related Comment in Lancet Infect Dis, 2022 Aug 10, doi: 10.1016/S1473-3099(22)00428-5, Monoclonal Antibodies for Reducing Malaria Transmission,  Daubenberger CA and Gupta R comment on the development of this modality of malaria control. The event was also reported in a news release from Radboud University in the Netherlands, where the study was conducted (Eek A, New Drug Blocks Transmission of Malaria Parasites, 2022 Aug 10).  

 

Other prevention 

Uushona SI & al., Sociocultural Factors that Influence the Prevention of Malaria in Ohangwena Region, Namibia, Afr J Prim Health Care Fam Med, 2022 Aug 30; 14(1):E1-E10, doi: 10.4102/phcfm.V14i1.3524 concludes thet “traditional preventive practices” are more prevalent in the geographic area studied than modern, evidence-based ones.  Barriers to these later are explored in the paper, which also concludes that the effectiveness of the more traditional practices should be studied.  

 

Diagnosis: 

 

General diagnostics 

The title of Badiane A & al., Sensitivity and Specificity for Malaria Classification of Febrile Persons by Rapid Diagnostic Test, Microscopy, Parasite DNA, Histidine-Rich Protein 2, and IgG: Dakar, Senegal 2015, Int J Infect Dis, 2022 Aug; 121:92-97, doi: 10.1016/j.ijid.2022.04.060 describes thrust of this study. Using polymerase chain reaction (PCR) as the gold standard, they found in close to 500 hospitalized patients, both rapid diagnostic tests (RDTs) and microscopy yielded high sensitivity and specificity, while laboratory determination of anti-histidine rich protein (HRP) IgG was sensitive, but not highly  specific.  

 

Gebresenbet RF & al. plan to evaluate the impact of enhanced case detection using molecular testing called loop-mediated isothermal amplification (LAMP) on birth outcomes in a prospective study design. They describe the details of the study in Active Case Detection and Treatment of Malaria in Pregnancy Using LAMP Technology (LAMPREG): A Pragmatic Randomised Diagnostic Outcomes Trial-Study Protocol, BMJ Open, 2022 Jul 18; 12(7):e058397, doi: 10.1136/bmjopen-2021-058397. 

 

Samuels AM & al. conducted a diagnostic accuracy study to evaluate new point-of-care tests to screen pregnant women for malaria at their first antenatal visit in western Kenya. In Diagnostic Performance of Loop-Mediated Isothermal Amplification and Ultrasensitive Rapid Diagnostic Tests for Malaria Screening Among Pregnant Women in Kenya, J Infect Dis, 2022 Sep 4; 226(4):696-707, doi: 10.1093/infdis/jiac289, they report that compared to the PCR gold standard, LAMP performed the best with “ultrasensitive RDT” next,  “conventional RDT” less so, and microscopy least sensitive.  This hierarchy was maintained among women with asymptomatic parasitemia. 

 

Field diagnostics 

In view of changes in HRP increasingly reported and resulting in the reduced reliability of HRP-based RDTs, Feleke SM & al. review the use of a different RDT in Field Performance of Plasmodium falciparum Lactate Dehydrogenase Rapid Diagnostic Tests During a Large Histidine-Rich Protein 2 Deletion Survey in Ethiopia, Malaria J, 2022 Aug 15, vol 21 art 236, doi: 10.1186/s12936-022-04257-9. In this large study, the lactate dehydrogenase (LDH) based RDTs detected more cases of parasitemia than the HRP based tests. However, they raise a concern, because the specificity of the LDH-based assay was relatively low, possibly resulting in false positives. 

 

Puri M & al., Rapid Diagnosis of Plasmodium falciparum Malaria Using a Point-Of-Care Loop-Mediated Isothermal Amplification Device, Front Cell Infect Microbiol, 2022 Aug 19; 12:961832,  doi: 10.3389/fcimb.2022.961832 asserts that “LAMP diagnosis of malaria is simple and cost-effective with acceptable sensitivity and specificity … thus its deployment for onsite screening of malaria in resource-limited regions is under consideration. However, the requirement of an electricity-operated dry bath and bulky read-out unit is still a major concern.” They “have developed a point-of-care diagnostic LAMP device that is easy to operate by a mobile application, and the results can be quantified with a fluorescent readout unit” and claim that this method is reliable. 

 

On the other hand, Mangeni JN & al. assume that RDTs are indeed reliable and in Experience And Confidence in Health Technologies: Evidence from Malaria Testing and Treatment in Western Kenya, BMC Public Health, 2022 Sep 6; 22(1):1689, doi: 10.1186/S12889-022-14102-Y they conclude that greater experience with RDTs can not only increase people’s confidence in their accuracy but also improve adherence to the test result. 

 

New diagnostic methods 

RDTs “have become the cornerstone for the management of malaria in many endemic settings, but their use is constrained for several reasons: (i) persistent malaria antigen (histidine-rich protein 2; HRP2) leading to false positive test results; (ii) hrp2 deletions leading to false negative PfHRP2 results; and (iii) limited sensitivity with a detection threshold of around 100 parasites/μl blood (pLDH- and HRP2-based) leading to false negative tests.” Based on this background, Kiemde F & al., Phase 3 Evaluation of an Innovative Simple Molecular Test for the Diagnosis of Malaria in Different Endemic and Health Settings in Sub-Saharan Africa (DIAGMAL), PLoS One, 2022 Sep 1; 17(9):e0272847, doi: 10.1371/journal.pone.0272847 describe the proposed to study to be conducted in 5 sub-Saharan countries. The test is described as a “direct on blood mini PCR-NALFIA test that combines the benefits of molecular biology with low infrastructural requirements and extensive training.” 

 

Arias-Alpízar K & al. advocate the use of a point-of-care (POC) device “for highly sensitive and selective detection of Plasmodium falciparum lactate dehydrogenase (Pf-LDH)” in Malaria Quantitative POC Testing Using Magnetic Particles, a Paper Microfluidic Device and a Hand-Held Fluorescence Reader, Biosens Bioelectron, 2022 Nov 1; 215:114513, doi: 10.1016/j.bios.2022.114513. Epub 2022 Jun 28. It is evident from the abstract that while there is evidence that the test is reliable, perhaps more so than current RDTs, there are yet obstacles for widespread use.  No mention of cost of the test is made. 

 

Kagaya W & al. also start with the premise of reduced reliability of RDTs and present Potential Application of the Haematology Analyser XN-31 Prototype for Field Malaria Surveillance in Kenya, Malaria J, 2022 Sep 1, vol 21 art 531, doi: 10.1186/s12936-022-04259-7.  Even though the title implies field testing, it is evident that these tests have to be performed in institutions.  

 

Treatment: 

 

Treatment results 

Open-label, non-randomized controlled trials of artemisinin-piperaquine (AP) and artemether-lumefantrine (AL) were conducted by Li G & al. in Grande Comore Island.  As reported in Artemisinin-Piperaquine Versus Artemether-Lumefantrine for Treatment of Uncomplicated Plasmodium falciparum Malaria in Grande Comore Island: an Open-Label, Non-Randomized Controlled Trial, Int J Antimicrob Agents, 2022 Aug 18: 106658, doi: 10.1016/j.ijantimicag.2022.106658, both combinations effectively treated malaria, but AL was quicker to clear parasites from patients’ bloodstreams.  

 

Groger M, & al. provide a post-hoc analysis on a “random subset of samples from two sites (in the Democratic Republic of the Congo and in Gabon) of the CANTAM-Pyramax trial assessing pyronaridine-artesunate therapy.” Their report, Effectiveness of Pyronaridine-Artesunate Against Plasmodium malariae, Plasmodium ovale spp, and Mixed-Plasmodium Infections: A Post-Hoc Analysis of the CANTAM-Pyramax Trial, Lancet Microbe, 2022 Aug; 3(8):e598-e605, doi: 10.1016/s2666-5247(22)00092-1, asserts the “high efficacy of pyronaridine-artesunate against mono-infections with P malariae, P ovale curtisi, or P ovale wallikeri and mixed-Plasmodium infections in a real-world setting.” 

 

One of the most dreaded complication of malaria is cerebral malaria (CM). “The currently available anti-malarial drugs lack lipophilicity and are thus not able to reach the brain tissues. Therefore, safe, cost-effective agents with … potential to target brain tissues are needed to be searched in order to fight CM worldwide,” argue Purohit D & al. in An Update on Recent Advances for the Treatment of Cerebral Malaria, Mini Rev Med Chem, 2022; 22(12):1607-1618, doi: 10.2174/1389557521666211124143117. The article reviews research work in this aspect of malaria treatment.  

 

“[T]here are inconsistent data relating to the effect of haemoglobinopathies on disposition of artemisinin antimalarial combination therapy, and none in sickle cell trait (SCT) or sickle cell disease (SCD), the aim of this study was to characterize the pharmacokinetic properties of artemether-lumefantrine (ARM-LUM) in children with SCD/SCT. According to Sugiarto SR & al., The Effect of Sickle Cell Genotype on the Pharmacokinetic Properties of Artemether-Lumefantrine in Tanzanian Children, Int J Parasitol Drugs Drug Resist, 2022 Aug; 19:31-39, doi: 10.1016/j.ijpddr.2022.05.002, both the pharmacokinetic data and the clinical results indicate that the regimen is effective in this population.  

 

Hakizayezu F & al., Treatment Outcome and Factors Associated with Mortality Due to Malaria in Munini District Hospital, Rwanda in 2016-2017: Retrospective Cross-Sectional Study, Front Public Health, 2022 Aug 9; 10:898528, doi: 10.3389/fpubh.2022.898528 is actually a mortality study, not focused on treatment. Over 56% of deaths were women. “Socio-economic and clinical determinants are important predictors of death among patients with severe malaria. … The possibility of mortality increased by almost four times in patients who delayed consultation by a day.”  Not really related to treatment results but akin in conclusions is the report by Abiodun MT & Ilori OR, Caregivers’ Perception and Determinants of Delayed Presentation of Children with Severe Malaria in an Emergency Room in Benin City, Nigeria, Niger Postgrad Med J, 2022 Jul-Sep; 29(3):198-205, doi: 10.4103/npmj.npmj_80_22.  

 

Side effects and complications 

The “2021 WHO Guidelines for Malaria reaffirmed their position that there is not adequate clinical safety data on artemisinins to support that usage.” Clark RL, Safety of Treating Malaria with Artemisinin-Based Combination Therapy in the First Trimester of Pregnancy, Reprod Toxicol, 2022 Aug; 111:204-210, doi: 10.1016/j.reprotox.2022.05.016 confirms that “WHO’s position is consistent with several issues with the existing clinical data” and enumerates them. 

 

Primaquine is essential for the radical cure of vivax malaria, but as described in Liu H & al., Risk of Hemolysis in Plasmodium vivax Malaria Patients Receiving Standard Primaquine Treatment in a Population with High Prevalence of G6PD Deficiency, Infection, 2022 Aug 17, doi: 10.1007/s15010-022-01905-9, almost a third of the patients with G6PD deficiency studied in Myanmar “experienced clinically concerning declines in hemoglobin, with five {of 152} requiring blood transfusion.” 

 

Drug resistance 

In a very brief abstract Tandoh KZ & al. explain Malaria Artemisinin Resistance: An Extracellular Vesicles Export Hypothesis, Trends Parasitol, 2022 Aug; 38(8):614-617, doi: 10.1016/j.pt.2022.05.004. “ART resistance (ARTr) is driven by increased tolerance to oxidative stress and reduced haemoglobin trafficking to the food vacuole. … extracellular vesicles (EVs) may play a role in developing ARTr.” 

 

New drug research 

“A central challenge of antimalarial therapy is the emergence of resistance to the component ts of artemisinin-based combination therapies (ACTs) and the urgent need for new drugs acting through novel mechanism of action. … compounds identified in phenotypic high throughput screens (HTS) have provided the starting point for six candidate drugs currently in the Medicines for Malaria Venture (MMV) clinical development portfolio. Dechering KJ & al., Replenishing the Malaria Drug Discovery Pipeline: Screening and Hit Evaluation of the MMV Hit Generation Library 1 (HGL1) Against Asexual Blood Stage Plasmodium falciparum, Using a Nano Luciferase Reporter Read-Out, SLAS Discov, 2022 Jul 21: S2472-5552(22)13684-1. https://doi.org/10.1016/j.slasd.2022.07.002 describes how 33 further compounds “were identified that meet the MMV Confirmed Active profile and are high quality starting points for new antimalarial drug discovery projects.” 

 

Mughal H & al. also conducted searches for new agents, both those against falciparum malaria and agents that may be effective against liver stage parasites. They claim in  Random Forest Model Predictions Afford Dual-Stage Antimalarial Agents, ACS Infect Dis, 2022 Aug 12; 8(8):1553-1562, doi: 10.1021/acsinfecdis.2c00189 that their modeling identified 18 promising compounds. 

 

“In continuation of the search for new anti-malarial agents,” Ibezim & al. screened “new pyrazole-hydrazine coupled Schiff-base derivatives previously synthesized … for anti-malarial property.” They published their results as Evaluation of Anti-Malarial Potency of New Pyrazole-Hydrazine Coupled to Schiff Base Derivatives, Malaria J, 2022 Aug 22, vol 21 art 243, doi: 10.1186/s12936-022-04266-8. Two compounds were reported to significantly reduce parasitemia after 3 days’ treatment.   

 

Another approach to new antimalarials is to modify already existing drugs that are no longer optimally effective Poje G & al., Design and Synthesis of Harmiquins, Harmine and Chloroquine Hybrids as Potent Antiplasmodial Agents, Eur J Med Chem, 2022 Aug 5; 238:114408, doi: 10.1016/j.ejmech.2022.114408 is an article that describes harmiquins, which “represent hybrids that combine two moieties with different mechanisms of antiplasmodial activity in one molecule, i.e., a chloroquine (CQ) scaffold, known to inhibit heme polymerization and a β-carboline ring capable of binding to P. falciparum heat shock protein 90 (PfHsp90). {The authors} present their synthesis, evaluation of biological activity and potential mechanism of action.” 

Swale C & al. studied a drug originally developed to treat an aggressive brain tumor (glioblastoma), which has been found to act against a family of unicellular parasites. In  Altiratinib Blocks Toxoplasma gondii and Plasmodium falciparum Development by Selectively Targeting a Spliceosome Kinase, Sci Transl Med, 2022 Aug 3; 14(656):eabn3231, https://doi.org/10.1126/scitranslmed.abn3231 they elucidate the mechanism by which this drug works against the two human parasites mentioned. 

 

From a Commentary in Science: “Molecules that derail translation can be useful tools and drugs, but they are also likely to be toxic unless they are highly specific for a desired target. Xie SC et al. (Reaction Hijacking of Tyrosine tRNA Synthetase as a New Whole-Of-Life-Cycle Antimalarial Strategy, Science, 2022 Aug 26, 10-74-79, doi: 10.1126/science.abn0611) found that adenosine sulfamate can react to form mimics of adenylates, which are common biosynthetic intermediates in condensation reactions … Screening a panel of sulfamates, they found a molecule with a modified base, ML901, that inhibited the growth of the malaria parasite Plasmodium falciparum in vitro and in animals but was not toxic to human cells. …”  

 

Traditional treatments 

Okello D & al. investigated conditions under which the medicinal plant Aspilia africana, also known as wild sunflower or hemorrhage plant, may thrive and reported their results in Influence of Various Temperatures, Seed Priming Treatments and Durations on Germination and Growth of the Medicinal Plant Aspilia africana, Sci Rep, 2022 Aug 19; 12(1):14180, doi: 10.1038/s41598-022-18236-2. 

 

Campaigns: 

 

Cohee LM & al. “screened 704 students in 4 Malawian primary schools for P. falciparum infection using rapid diagnostic tests (RDTs), and treated students who tested positive with artemether-lumefantrine. We determined P. falciparum infection by microscopy and quantitative polymerase chain reaction (qPCR), and hemoglobin concentrations over 6 weeks in all students.” As reported in School-Based Malaria Screening and Treatment Reduces Plasmodium falciparum Infection and Anemia Prevalence in Two Transmission Settings in Malawi, J Infect Dis, 2022 Aug 12; 226(1):138-146. doi: 10.1093/infdis/jiac097, “[p]revalence of infection by RDT screening was 37% (9%-64% among schools). An additional 9% of students had infections detected by qPCR. Treatment was instituted as needed. 

 

“To contribute to the mission of the National Malaria Control Programme (NMCP) and guide future interventions in Cameroon in general, and in Makenene in particular,” Djoufounna J & al., Population Knowledge, Attitudes and Practices Towards Malaria Prevention in the Locality of Makenene, Centre-Cameroon, Malar J, 2022 Aug 5; vol 21, art 234, doi: 10.1186/s12936-022-04253-z, assessed the knowledge, attitudes and practices of the population of Makenene towards the fight against malaria. “Out of the 413 households surveyed, all …claimed to have heard of malaria with over 94% … associating disease transmission with mosquito bites. The main mosquito control tools used in the area were mosquito nets … The majority of participants had good knowledge … good practices … but moderate attitudes … towards malaria control and fight.” 

 

Recognizing the temporally limited effectiveness of ITNs, Koenker H & al. modeled the results of a different distribution schedule, in order to maintain at least 80% effectiveness at all times.  The report is Annual Distributions of Insecticide-Treated Nets to Schoolchildren and Other Key Populations to Maintain Higher ITN Access than with Mass Campaigns: A Modelling Study for Mainland Tanzania, Malaria J, 2022 Aug 26, vol 21 art 247, doi: 10.1186/s12936-022-04272-w. They claim that the proposed schedule reduces the ITNs needed to maintain efficacy, compared to triennial mass campaigns.  

 

The Democratic Republic of the Congo (DRC) organized a first mass distribution campaign of long-lasting insecticidal nets (LLINs) with digitalized data management with coordinated support from the Ministry of Health (MOH) and Santé Pour Tous En Milieu Rural {an NGO}, in the context of the Covid-19 pandemic in Kongo Central province. Likwela JL & al., Digitalized Long-Lasting Insecticidal Nets Mass Distribution Campaign in the Context of Covid-19 Pandemic in Kongo Central, Democratic Republic of Congo: Challenges and Lessons Learned, Malaria J, 2022 Sep 1, vol 21 art 253, doi: 10.1186/s12936-022-04258-8 describes the planning and implementation process of this campaign as well as the challenges and lessons learned. Over 5 million people were registered and over 2.8 million LLINs were distributed (94% of supplies). “Out of 11,070 villages and 3,947 teams planned, 91.7% of villages were reached and 93% of teams were established.” 

 

Epidemiology: 

 

Climate change and malaria 

“With greenhouse gas emissions, temperatures continue to rise. Based on diverse shared socioeconomic pathways (SSPs), future temperatures can be estimated.  However, the impacts of climate change on malaria infection rates in all epidemic regions are unknown.” Li C & Managi S “estimate the differences in global malaria infection rates predicted under different SSPs during several periods as well as malaria infection case changes (MICCs) resulting from those differences” and report in Global Malaria Infection Risk from Climate Change, Environ Res, 2022 Aug 5: 114028. doi: 10.1016/j.envres.2022.114028 that “[t]emperature increases will adversely affect malaria the most in Africa during the 2021-2040 period. … Climate change will increase the danger and risks associated with malaria in the most vulnerable regions in the near term, thus aggravating the difficulty of eliminating malaria.” 

 

Mafwele BJ & Lee JW, Relationships Between Transmission of Malaria in Africa and Climate Factors, Sci Rep, 2022 Aug 23; 12(1):14392, doi: 10.1038/s41598-022-18782-9 is retrospective, encompassing rainfall from 1901 to 2015. “Malaria networks show a positive correlation with temperature and rainfall networks, except for the 1981-2015 period, in which the malaria network shows a negative correlation with rainfall.” 

 

“Temperature is an especially important constraint on the fitness of a wide variety of ectothermic insects.  A mechanistic understanding of how temperature impacts traits of ectotherms, and thus the distribution of ectotherms and vector-borne infections, is key to predicting the consequences of climate change on transmission of VBDs like malaria.” Villena OC & al., Temperature Impacts the Environmental Suitability for Malaria Transmission by Anopheles gambiae and Anopheles stephensi, Ecology, 2022 Aug; 103(8):e3685, doi: 10.1002/ecy.3685 reviews in detail how temperature changes influence the rate that these two species of mosquitoes transmit the malaria parasite. 

 

Population dynamics 

As reported in Akinnawo A & al., Assessing the Relationship Between Gravidity and Placental Malaria {PM} Among Pregnant Women in a High Transmission Area in Ghana, Malaria J, 2022 Aug 20, vol 21 art 240, doi: 10.1186/s12936-022-04252-0, “primigravidae were shown to have over three times the odds of PM compared to multigravidae, defined as women with 2 or more previous pregnancies,” especially in rural areas and among women with lower socio-economic status. The authors advocate focusing preventive efforts on young rural women who have never been pregnant. 

 

As reported by Duval L & al., “[h]igh malaria treatment costs are incurred by pregnant women in Burkina Faso and The Gambia. Beyond the medical costs of fees and drugs, costs in terms of transport, food and time are significant drivers.” Their article, Household Costs Associated with Seeking Malaria Treatment During Pregnancy: Evidence from Burkina Faso and The Gambia, Cost Eff Resour Alloc, 2022 Aug 20; 20(1):42, doi: 10.1186/s12962-022-00376-x documents these costs, which seem very low in US context, but not in these communities. 

 

Yeda R & al. investigated the Burden of Malaria Infection Among Individuals of Varied Blood Groups in Kenya, Malaria J, 2022 Sep 1, vol 21 art 251, doi: 10.1186/s12936-022-04251-1.  Although the data cited in the abstract are somewhat difficult to interpret, the authors conclude that “[i]ndividuals of blood group B harbour high parasitaemia compared with the blood group O. Additionally, blood group A and B present with symptoms at lower parasitaemia than blood group O. …, individuals from endemic zones showed up with high parasitaemia and among them were more individuals of blood groups A and B than individuals of blood group O” even though blood group O was the most prevalent in the population. 

 

A potentially important and interesting article is Mkombachepa M & al.,  High Incidence of Malaria in Patients with Sickle Cell Disease, Am J Hematol, 2022 Oct; 97(10):E380-E381, doi: 10.1002/ajh.26676. Epub 2022 Aug 17. Unfortunately no abstract is available and access to the article is restricted. 

 

Spatiotemporal studies 

As begun last month, studies that simply report incidence or prevalence of malaria or its complications in restricted geographic areas are mentioned without comments: 

Sangaré I & al.,  Spatial-Temporal Pattern of Malaria in Burkina Faso from 2013 to 2020, Parasite Epidemiol Control. 2022 Jul 2;18:e00261. doi: 10.1016/j.parepi.2022.e00261 

Bayisa G, Dufera M, Malaria Infection, Parasitemia, and Hemoglobin Levels in Febrile Patients Attending Sibu Sire Health Facilities, Western Ethiopia, Biomed Res Int, 2022 Aug 12; 2022:6161410, doi: 10.1155/2022/6161410.  

Goshu EM &al., Occurrence of Asymptomatic Malaria Infection and Living Conditions in the Lowlands of Ethiopia: A Community-Based Cross-Sectional Study, Infect Dis Poverty, 2022 Sep 5; 11(1):94, doi: 10.1186/S40249-022-01018-3. 

Olapeju B & al., Psychosocial Factors Associated with Malaria Care-Seeking in Rural Ethiopia, BMC Public Health, 2022 Aug 1; 22(1):1460, doi: 10.1186/S12889-022-13862-X. 

Elagali A & al., Spatiotemporal Mapping of Malaria Incidence in Sudan Using Routine Surveillance Data, Sci Rep, 2022 Aug 18; 12(1):14114, doi: 10.1038/s41598-022-16706-1. 

 

Global distribution of Plasmodium vivax prevalence during 2020. Map modeled using reported patient infections, with permission of the Malaria Atlas Project (https://malariaatlas.org/trends/region/MAP/GLOBAL). 

Plasmodium falciparum Parasite Rate In Two To Ten Year Olds In 2020. Map modeled using reported patient infections, with permission of the Malaria Atlas Project. https://malariaatlas.org/trends/region/MAP/GLOBAL 

 

Other 

WHO Report: Technical Consultation on the Malaria Rebound Phenomenon, https://media.malariaworld.org/9789240055582_eng_b0324aaa24.pdf,  On 22 and 23 March 2022, a WHO technical consultation was convened by the Global Malaria Programme to discuss the malaria rebound phenomenon. The aims of the technical consultation were to: 1) define what is meant by the rebound phenomenon and understand its determinants; 2) understand the potential public health significance of the rebound phenomenon; and 3) clarify expectations (e.g. study design, duration of follow-up) for evaluation of the rebound phenomenon during product development. 

 

Most attention is focused on Plasmodium falciparum infections in Africa, rather than other malaria parasites that also cause disease. Baird JK, African Plasmodium vivax Malaria Improbably Rare or Benign, Trends Parasitol, 2022 Aug; 38(8):683-696, doi: 10.1016/j.pt.2022.05.006 includes a discussion why vivax malaria may be of lesser import.