By Dr. Derick Pasternak, Ambassador, Malaria Science & Research Coordinator, MPI
In August 2024, the WHO published is pamphlet reporting on the Fourth Annual Global Forum of Malaria-Eliminating Countries, which took place in South Africa in 2023. The 89-page pamphlet is available at https://www.who.int/publications/i/item/9789240097438 or from this reviewer.
PEER REVIEWED ARTICLES (see notes after citations from non-peer-reviewed publications)
Prevention
Vaccines
In our August report, two articles touched on the role of adjuvants in enhancing the effectiveness of vaccines. Roman F & al., Adjuvant System AS01: from Mode of Action to Effective Vaccines, Expert Rev Vaccines. 2024 Jul 23, https://doi.org/10.1080/14760584.2024.2382725 is specifically focused on the role of the adjuvant that replaced the original AS02 adjuvant in the currently used RTS,S AS01 vaccine.
PfRH5 is a protein component of the parasite wall that facilitates the invasion of the infected person’s red blood cells. Harrison TE & al., Rational Structure-Guided Design of a Blood Stage Malaria Vaccine Immunogen Presenting a Single Epitope from PfRH5, EMBO Mol Med. 2024 Sep 2, https://doi.org/10.1038/s44321-024-00123-0 designed a protein that induces the development of antibodies to PfRH5. When this new protein was used to immunize rats, it induced “PfRH5-targeting antibodies that inhibit parasite growth.” While this is a long way from the creation of a new antimalaria vaccine, it is promising approach for future vaccine research.
Lissom A & al., Specific Antibody Responses to Qbeta-Displayed Plasmodium falciparum-Derived UB05 and MSP3 Proteins in Mother-Neonate Couples, Scand J Immunol. 2024 Aug 19: e13404, https://doi.org/10.1111/sji.13404 is a report on the transfer of immune substances from pregnant women to their offspring, when the mothers are exposed to MSP3, an experimental anti-malaria vaccine or UB05, an antigen derived from Plasmodium falciparum. The authors discuss the implication of possible transfer of immunity induced in the mother to the newborn.
Focusing mostly on P. vivax, Moita D & Prudêncio M, Whole-Sporozoite Malaria Vaccines: Where We Are, Where We Are Going, EMBO Mol Med, 2024 Sep 16, https://doi.org/10.1038/s44321-024-00131-0, explores the notion of using whole sporozoites in vaccine development.
Vectors
Ajonina MU & al. report that among 411 pregnant women seen in a prenatal clinic in Cameroon, 65.1% stated that they regularly used long-lasting insecticide nets (LLINs). Among the same women, 35.4% were found to have malaria. As they report in their article, Long-Lasting Insecticidal Nets Use and the Prevalence of Plasmodium falciparum Infection Among Pregnant Women Attending Antenatal Care at the Bonassama District Hospital, Littoral Region of Cameroon: A Cross-Sectional Study, BMC Pregnancy Childbirth. 2024 Aug 28; 24(1):560, https://doi.org/10.1186/s12884-024-06769-5, the “risk of malaria infection was 2.7 times higher … among women who did not consistently use LLINs compared to those who did. Pregnant women in their first trimester … and second trimester … were more likely to sleep under net when compared to those in the third trimester. Younger women 20-29 years …, those in the first trimester …, and those who had the nets before pregnancy … were amongst those who frequently used use the nets. Among the reasons reported for not frequently using LLINs were heat …, suffocation …, and the smell of nets ...”
“Indoor residual spraying (IRS) is one of the most effective malaria control tools. However, its application has become limited to specific contexts due to the increased costs of IRS products and implementation programmes. Selective spraying—selective spray targeted to particular areas/surfaces of dwellings—has been proposed to maintain the malaria control and resistance-management benefits of IRS while decreasing the costs of the intervention.” Irish SR & al., A Review of Selective Indoor Residual Spraying for Malaria Control, Malaria J, 2024 Aug 23, 23:252, https://doi.org/10.1186/s12936-024-05053-3 is the result of extensive literature search on the subject, not uniquely focusing on the malaria vector. The authors conclude that while there are reports of savings in the program, the determination of how to select sites to spray is inexact and there need to be better data on whether the application of IRS in this manner remains effective.
Using WHO endorsed methods, Kweka EJ & al. tested an IRS product that contains broflanilide as the insecticide, as opposed to clothianidin, contained by the usual products used. As they reveal in The Bioefficacy of a Novel VECTRON™ T500 Indoor Residual Spray Formulation in an Experimental Huts Trial Against Anopheles gambiae s.l. Populations, Acta Trop. 2024 Aug 30, 107376, https://doi.org/10.1016/j.actatropica.2024.107376, the new product caused 97+% mortality among over 3000 mosquitoes tested. Since the control substance (which also caused high, but somewhat lesser mortality) contained clothianidin, the mosquito populations used in the tests were not resistant.
Asingizwe D & al. conducted a study of public knowledge and attitude toward malaria prevention among 382 heads of households. As expected, Why Becoming a Positive Deviant for Malaria Prevention and Control: A Sequential Explanatory Mixed Methods Study in Bugesera District, Rwanda, Malaria J, 2024 Sep 19; 23:284, https://doi.org/10.1186/s12936-024-05108-5 showed that “knowledge about malaria, family support, and community mobilization are the top motivating factors to practice positive behaviours while, lack of bet nets, poverty, and lack of time were reported as main barriers.”
A case study of a single village, Perugini E & al., Longitudinal Survey of Insecticide Resistance in a Village of Central Region of Burkina Faso Reveals Co-Occurrence of 1014F, 1014S and 402L Mutations in Anopheles coluzzii and Anopheles arabiensis, Malaria J, 2024 Aug 20, 23:250, https://doi.org/10.1186/s12936-024-05069-9, reveals that the three different genetic mutations present in at least some of the mosquitoes collected from both species changed over time. “Overall, an increasing level of target-site resistance was observed among the populations…”
In another article on the same subject from Burkina Faso, Kientega M & al., Whole-Genome Sequencing of Major Malaria Vectors Reveals the Evolution of New Insecticide Resistance Variants in a Longitudinal Study in Burkina Faso, Malaria J, 2024 Sep 17, 23:280, https://doi.org/10.1186/s12936-024-05106-7. Once again, the emergence of resistance is tied to the mutations discovered in gene sequencing.
Just as with IRS insecticides, resistance is building in mosquitoes against pyrethroids used in insecticide-treated nets (ITNs). Syme T & al., Laboratory Evaluation of the Regeneration Time, Efficacy and Wash-Resistance of Permanet Dual (a Deltamethrin-Chlorfenapyr Net) Against Susceptible and Pyrethroid-Resistant Strains of Anopheles gambiae sensu lato, PLoS One, 2024 Aug 29; 19(8):e0298513, https://doi.org/10.1371/journal.pone.0298513 also reports on using WHO guidelines to test the net mentioned in the article’s title. “Tests were performed with susceptible and pyrethroid-resistant strains of Anopheles gambiae to assess the pyrethroid and chlorfenapyr components separately. Net pieces were also analysed to determine insecticide content. In regeneration time studies, the biological activity of the deltamethrin and chlorfenapyr components of PermaNet® Dual regenerated within one day after washing…[In] tests against the pyrethroid-resistant strain, PermaNet® Dual washed 20 times induced high mortality (91%) and blood-feeding inhibition (73%)…” much higher than the product that contained pyrethroid alone.
Dennis TPW & al. reports somewhat surprising findings from three regions in Cryptic Population Structure and Insecticide Resistance in Anopheles gambiae from the Southern Democratic Republic of Congo Sci Rep, 2024 Sep 18; 14(1):21782, https://doi.org/10.1038/s41598-024-70885-7. After testing for resistance, which was present upwards of 8% of the total mosquitoes collected, genetic analysis revealed similar mechanisms some 800 km apart, while in other regions populations less than 10 km apart were widely divergent. The paper contains details of the genetic mechanisms found.
“Eave spaces are major entry points through which malaria vectors enter houses. Interventions that target mosquitoes at the eaves have recently been developed. However, most of these interventions are based on insecticides for which resistance has been reported. [Shirima RS & al.] evaluated the efficacy of mosquito electrocuting eave tubes (MEETs)” against two Anopheles species and report in Semi-Field Evaluation of Electrocuting Eave Tubes for the Control of Endophagic Mosquitoes in South-East Tanzania, Parasit Vectors. 2024 Aug 20; 17(1):349, https://doi.org/10.1186/s13071-024-06407-1 that the [placement of MEETs significantly reduced the nightly An. gambiae s.s. indoor and outdoor biting, by 21.1% and 37.4%, respectively. Indoor-biting An. funestus s.s. were reduced by 87.5% while outdoor-biting numbers of An. funestus s.s. declined by 10.4%.” The article suggests that these tubes can be used with solar panels in homes that are not wired for electricity.
“Attractive Targeted Sugar Baits (ATSBs) are a proposed new vector control tool for malaria that contain sugar and an ingestion toxicant, and are designed to attract and kill sugar-feeding mosquitoes. During a … Phase III trial … ATSB stations deployed on eligible household structures within intervention clusters were routinely monitored to ensure their good physical condition and high coverage.” Kyomuhangi I & al., Evaluating Trends in Damage to Attractive Targeted Sugar Baits (ATSBs) Deployed During the Second Year of a Two-Year Phase III Trial in Western Zambia, Malaria J, 2024 Aug 29, 23:264, https://doi.org/10.1186/s12936-024-05089-5 reports that of over 68,000 of these traps constructed, over 18,000 suffered damage during year 2. Most of the damage reported were “tears” and mold. “Both structure characteristics and environmental factors significantly impacted the odds and rate of damage to ATSB stations on structures, including: ATSB stations’ level of protection from rainfall and sunshine; roof and wall material of the structure; night-time temperature; rainfall; enhanced vegetation index, and land cover.”
Chemoprophylaxis
“Intermittent preventive treatment with sulfadoxine-pyrimethamine (IPTp-SP) during pregnancy can prevent malaria but uptake is suboptimal.” Adeojo OS & Fayehun O, Determinants of the Optimal Uptake of Sulfadoxine-Pyrimethamine Doses for Intermittent Treatment of Malaria in Pregnancy in Urban Nigeria, Sci Rep. 2024 Aug 17; 14(1):19097, https://doi.org/10.1038/s41598-024-52927-2 analyzes data from a 2015 survey and reports that only 39% of surveyed pregnant women received the recommended three doses. “Region and wealth index significantly predicted optimal IPTp-SP uptake while education did not. Women from lower-income regions in the urban areas were less likely to receive optimal IPTp-SP.” Whether data from 2015 are currently relevant is an unanswered question.
Asem L & al., The Demand for Intermittent Preventive Treatment of Malaria in Pregnancy Using Sulfadoxine-Pyrimethamine in the Volta Region of Ghana, PLoS One. 2024 Sep 5; 19(9): e0308321, https://doi.org/10.1371/journal.pone.0308321 and Asem L & al., Knowledge, and Attitude of Service User of Intermittent Preventive Treatment of Malaria in Pregnancy Using Sulfadoxine Pyrimethamine in the Volta Region of Ghana, PLoS One. 2024 Sep 6; 19(9):e0309340, https://doi.org/10.1371/journal.pone.0309340 are companion articles, yet again concluding that the “uptake of 3+ doses of IPTp-SP is still lower than the global target of 80%” (it was about 60%) and that the “number of antenatal visits that affect both knowledge of services and attitude to use IPTp-SP.” Also, 10.4% of mothers queried didn’t receive a single dose. “Respondents who attended antenatal clinics 4-7 times had 7 … times higher uptake of 3+ doses of IPTp-SP as compared to others who attended less than 4 visits. Similarly, women who had 8 or more visits had a 16.1 … times higher chance of getting more than 2 doses of IPTp-SP compared with others who had fewer than 4 attendances.” But it is unclear whether the mothers who didn’t receive a single dose received antenatal care at all.
Koita K &al., Community-Based Strategies to Increase Coverage of Intermittent Preventive Treatment of Malaria in Pregnancy with Sulfadoxine-Pyrimethamine in Sub-Saharan Africa: A Systematic Review, Meta-Analysis, Meta-Ethnography, and Economic Assessment, Lancet Glob Health. 2024 Sep;12(9):e1456-e1469. https://doi.org/10.1016/s2214-109x(24)00228-6 is a meta-analysis of several publications dealing with the effect of involving community health workers (CHWs) in IPTp-SP education and sometimes delivery of the medication. Although the authors emphasize that findings were somewhat diverse, they found statistically significant improvement in the number of IPTp-SP doses delivered to pregnant women if CHWs were involved in their care. The authors also state that this involvement did not reduce the number of antenatal visits the pregnant women made. “Community sensitisation, engagement of husbands, pre-established community health worker networks, and trained and supported community health workers facilitated IPTp-SP delivery by community health workers. Incremental cost-effectiveness ratios ranged from $1·1 to $543 per disability-adjusted life-year averted.” This article could also be cited under Campaigns.
“Post-discharge malaria chemoprevention (PDMC) is an intervention aimed at reducing morbidity and mortality in patients hospitalized with severe anaemia, with its effectiveness established in several clinical trials.” Audibert C & Rietveld H conducted 46 individual interviews “in five sub-Saharan countries amongst malaria key opinion leaders and national decision makers” and report in, Perceived Barriers and Opportunities for the Introduction of Post-Discharge Malaria Chemoprevention (PDMC) in Five Sub-Saharan Countries: A Qualitative Survey Amongst Malaria Key Stakeholders, Malaria J, 2024 Sep 6, 23:270, https://doi.org/10.1186/s12936-024-05100-z that “although PDMC was perceived as a relevant tool to prevent malaria, further clarification was needed in terms of the relevant patient population, delivery mechanisms, and {that] more evidence should be generated from implementation research to ensure policy adoption and funding.”
Other
Munyakanage D & al. report on an unusual application of biologic control of mosquito larvae by means of drone delivery. “A non-randomized larviciding trial was carried out in irrigated rice fields in sub-urban Kigali, Rwanda. Potential mosquito larval habitats in study sites were mapped and subsequently sprayed using multirotor drones. Application of Bacillus thuringiensis var. israelensis (Bti) (Vectobac® WDG) was followed by entomological surveys that were performed every two weeks over a ten-month period … The abundance of all-species mosquito larvae, Anopheles larvae and all-species pupae declined by 68.1%, 74.6% and 99.6%, respectively… Malaria incidence also declined significantly between intervention and control sites…” The article is The Impact of Bacillus thuringiensis var. israelensis (Vectobac® WDG) Larvicide Sprayed with Drones on the Bio-Control of Malaria Vectors in Rice Fields of Sub-Urban Kigali, Rwanda, Malaria J, 2024 Sep 17, 23:281, https://doi.org/10.1186/s12936-024-05104-9.
The abstract of Zhan Q & al., Hyper-Diverse Antigenic Variation and Resilience to Transmission-Reducing Intervention in Falciparum Malaria, Nat Commun. 2024 Aug 26; 15(1):7343, https://doi.org/10.1038/s41467-024-51468-6 is quoted in its entirety: “Intervention efforts against falciparum malaria in high-transmission regions remain challenging, with rapid resurgence typically following their relaxation. Such resilience co-occurs with incomplete immunity and a large transmission reservoir from high asymptomatic prevalence. Incomplete immunity relates to the large antigenic variation of the parasite, with the major surface antigen of the blood stage of infection encoded by the multigene and recombinant family known as var. With a stochastic agent-based model, we investigate the existence of a sharp transition in resurgence ability with intervention intensity and identify molecular indicators informative of its proximity. Their application to survey data with deep sampling of var sequences from individual isolates in northern Ghana suggests that the transmission system was brought close to transition by intervention with indoor residual spraying. These results indicate that sustaining and intensifying intervention would have pushed malaria dynamics to a slow-rebound regime with an increased probability of local parasite extinction.”
”When malaria vectors consume ivermectin in a blood meal, their survival probability decreases, potentially reducing malaria transmission during mass drug administrations (MDA). However, questions remain regarding the optimal dosing. [Kamau Y & al. tested] the mosquitocidal effect and pharmacokinetics of two dose regimens of ivermectin for malaria vector control” and report in Mosquitocidal Efficacy and Pharmacokinetics of Single-Dose Ivermectin Versus Three-Day Dose Regimen for Malaria Vector Control in Comparison with Albendazole and No Treatment: an Open-Label Randomized Controlled Trial, Int J Infect Dis. 2024 Sep 6: 107236, https://doi.org/10.1016/j.ijid.2024.107236 that the results were unexpected. A single dose to volunteers was more effective even after ten days than three daily doses at somewhat lower dosage levels. While from point of view of ease of adminstratrion and cost, the single dose approach seems more advantageous, the authors caution that explanation for the phenomenon is lacking.
Wang LT & al. cite experimental evidence from the literature in Monoclonal Antibodies to the Circumsporozoite Proteins as an Emerging Tool for Malaria Prevention, Nat Immunol. 2024 Sep; 25(9):1530-1545, https://doi.org/10.1038/s41590-024-01938-2 to argue that monoclonal antibodies may play a role in the future in preventing malaria infection. {This substance may turn out to be similar in terms of population-wide prevention efforts to a vaccine, since it will have to be administered by injection, although its mechanism of action is different from that of a vaccine.}
Diagnosis
General diagnostics
In a massive study encompassing 35 sub-Saharan countries, “approximately 3.9 million child-year observations and approximately 260 000 febrile illness episodes in children younger than 5 years of age between 2000 and 2019, Zhang H & al., Malaria Rapid Tests, Febrile Illness Management, and Child Mortality Across Sub-Saharan African Countries, J Am Med Assn, 2024 Sep 18. https://doi.org/10.1001/jama.2024.12589 reports the analysis of “the association between variation in malaria RDTs distributed per child younger than 5 years of age (by country per year) and blood testing, antimalarial drug use, antibiotic use, use of symptomatic treatments, and mortality rates… Each additional malaria RDT distributed per child younger than 5 years of age was associated with an increase of 3.5 percentage points … in blood testing, an increase of 1.5 percentage points … in the use of antimalarial drugs, an increase of 0.4 percentage points … in antibiotic use, and a decrease of 0.4 percentage points … in the use of treatments for symptoms. Each additional malaria RDT distributed per child younger than 5 years of age was associated with a reduction in child mortality of 0.34 deaths per 1000 child-years…” Ogbuoji O & O’Meara WP, The Crucial Role of Rapid Point-of-Care Tests for Malaria in Improving Fever Management, J Am Med Assn, 2024 Sep 18, https://doi.org/10.1001/jama.2024.13544 is the associated editorial that appears to strongly endorse the use of rapid diagnostic tests (RDTs). Unfortunately, the Journal’s firewall prevents reading more than the first few sentences of the editorial.
In a paper that highlights the distinction between asymptomatic malaria and “subpatent” infection, Sagna AB & al. reports that using three diagnostic tests (RDT, microscopy, and quantitative polymerase chain reaction [qPCR]), in an urban environment asymptomatic infections were very prevalent, but mostly so in school-age children. In contrast, subpatent infections (symptomatic but negative on RDT and/or microscopy) were more prevalent in tnose ove age 15. The paper, High Prevalence of Asymptomatic and Subpatent Plasmodium falciparum Infections but No Histidine-Rich Protein 2 Gene Deletion in Bouake, Cote d'Ivoire, Sci Rep. 2024 Aug 17; 14(1):19060, https://doi.org/10.1038/s41598-024-70215-x also reveals that testing revealed no histidine-rich protein 2 (HRP2) deletions at all, signifying that the false negative RDT results were likely related to low parasite density even in symptomatic individuals.
Mandefro A & al. report in Novel Plasmodium falciparum Histidine-Rich Protein 2/3 Repeat Type in Ethiopian Malaria Infection: Does This Affect Performance of HRP2-Based Malaria RDT, Malaria J. 2024 Aug 29; 23:262, https://doi.org/10.1186/s12936-024-05093-9 that there is a great deal of variability in the genetics of P. falciparum at the loci controlling HRP2 and 3, which potentially influence the reliability to RDT testing. However, the article focuses on the genetics, not the accuracy of the diagnostic tests.
Lateral Flow Amplification for Malaria Parasites (LAMP) assays have long been used for malaria diagnosis, but Higgins M & al. state that “their implementation in resource-constrained settings poses significant challenges.” Their article, A Pan Plasmodium Lateral Flow Recombinase Polymerase Amplification Assay for Monitoring Malaria Parasites in Vectors and Human Populations, Sci Rep. 2024 Aug 30; 14(1):20165, https://doi.org/10.1038/s41598-024-71129-4, presents a “Pan Plasmodium recombinase polymerase amplification lateral flow (RPA-LF) assay, capable of detecting all six human infecting Plasmodium species in low resource settings.” In addition, they assert that when combined “with crude nucleic acid extraction, the assay can serve as a point-of-need tool for molecular monitoring the major Anopheles vector species as well.
It is now apparent that what used to be thought to be a single species (Plasmodium ovale) are two distinct ones. They tend to occur in Central Africa, extending to the Atlantic coast. He W & al. describe the development of PCR tests for these two species in Development of New Real-Time PCR Assays for Detection and Species Differentiation of Plasmodium ovale, PLoS Negl Trop Dis. 2024 Sep 10; 18(9):e0011759, https://doi.org/10.1371/journal.pntd.0011759. The authors conclude after thorough testing that while P. ovalecurtisi is reliably diagnosed with the assay developed for it, “the P. ovalewallikeri assay did not reliably detect low-density infections…”
Field diagnostics
Adebusuyi SA & al. “assessed the effectiveness of a Plasmodium falciparum-specific RDT compared with microscopy and polymerase chain reaction (PCR) in diagnosing asymptomatic malaria in pregnant women in southwest Nigeria.” Among 406 asymptomatic pregnant women seeking antenatal care, they found that using qPCR as controls, RDTs had “sensitivity of 51.4% and specificity of 69.5%, whereas microscopy had a sensitivity of 65.3% and specificity of 98.2%. The combined testing of microscopy and RDT had a sensitivity and specificity of 100%.” Their paper, Performance of Rapid Diagnostic Test, Light Microscopy, and Polymerase Chain Reaction in Pregnant Women with Asymptomatic Malaria in Nigeria, IJID Reg. 2024 Aug 2; 12:100416, https://doi.org/10.1016/j.ijregi.2024.100416 concludes that “[d]espite the RDT's low sensitivity, its high negative predictive value suggests it could be useful in combination with microscopy in ruling out asymptomatic malaria in pregnancy.”
Aninagyei & al. studied 347 patients “initially diagnosed with asymptomatic malaria” in Ghana, applying the WHO laboratory criteria for the diagnosis of severe malaria. They found that 13.8% of them met the criteria for severe malaria. “… patients diagnosed with severe malaria presented with pallor, vomiting, diarrhea, chills, fever and nausea, concurrently … Irrespective of the etiology, patients diagnosed with severe malaria presented with pallor, vomiting, diarrhea, chills, fever and nausea, concurrently.” In their paper, The Use of the WHO Criteria to Detect Severe Malaria Among Patients Clinically Diagnosed with Uncomplicated Malaria, PLOS Glob Public Health. 2024 Aug 15; 4(8):e0003158, https://doi.org/10.1371/journal.pgph.0003158, they state that “healthcare facilities need adequate human and logistical resources to be able to diagnose severe malaria for appropriate management to avert any untoward outcomes.”
Also in Ghana, Kayode TA & al., Comparison of Three Rapid Diagnostic Tests for Plasmodium falciparum Diagnosis in Ghana, Malaria J, 2024 Aug 30, 23:265, https://doi.org/10.1186/s12936-024-05073-z reports that when measured against qPCR, all three RDTs had sensitivities below 40% and that of microscopy was even lower. When individuals with low parasite counts (<20/μL) noted on qPCR were excluded, two of the RDTs had comparable sensitivities of 88.8% with >95% specificity. Again, all three RDTs had higher sensitivity than microscopy in this delineated group.
In contrast with the above two countries, Teou DC & al. found the reliability of a particular brand of HRP2-based RDT to be exceptional (sensitivity and selectivity of “97.9% and 90.7%, respectively, when compared with PCR”) among a sample of 278 patient-derived specimens in Togo. Their paper, Performance of ParaHIT® HRP2-Based Rapid Diagnostic Test and Proportions of Plasmodium falciparum Histidine-Rich Protein 2/3 Gene Deletions in Togo, Am J Trop Med Hyg, 2024 Sep 17: tpmd240197, https://doi.org/10.4269/ajtmh.24-0197 also informs us that among the positive samples, 138 were analyzed for pfhrp2 and pfhrp3 gene deletions; none were found.
Rapigen RDTs apparently come in two versions, one that detects P. falciparum through dual detection of HRP2 and species-specific lactic dehydrogenase (LDH) and another that detects LDH of both P. falciparum and P. vivax. Golden A & al., Analytical Sensitivity Analysis and Clinical Impact Modeling of Rapigen Rapid Diagnostic Tests for Malaria, Am J Trop Med Hyg. 2024 Sep 3:tpmd240003, https://doi.org/10.4269/ajtmh.24-0003 compares their performance against “two best-in-class WHO-prequalified comparator RDTs, generated using standardized panels containing recombinant antigen, in vitro cultured parasites, international standards, and clinical samples.” They state that the performance of this new product is “incremental” over standard RDTs.
“Reactive case detection (RCD) aims to reduce malaria transmission stemming from asymptomatic carriers. Symptomatic individuals diagnosed with malaria at a health centre are followed to their households, where members of the index case and neighbouring households are tested and treated for malaria.” In a test of RCD, Reynders M & al. tested contacts of 264 infected individuals in a community with RDTs, comparing the results to both field and expert microscopy and qPCR as controls. They report in Challenges in Diagnosis of Clinical and Subclinical Plasmodium falciparum Infections in Ghana and Feasibility of Reactive Interventions to Shrink the Subclinical Reservoir, Malaria J, 2024 Sep 10, 23:272, https://doi.org/10.1186/s12936-024-05096-6 that not only was the outcome of the diagnostic testing disappointing (50 RDT positive, while 83 positive on qPCR), but the authors report that there was very low acceptance of the research staff’s recommendations in the community. Most of the asymptomatic individuals tested declined to participate in follow up or refused treatment.
New diagnostic methods
None this month
Treatment
Treatment results
“The emergence of Plasmodium falciparum drug resistance against artemisinin-based combination therapy has threatened malaria control efforts. … [Woldesenbet D & al.] aimed to assess the therapeutic efficacy and safety of artemether-lumefantrine for the treatment of uncomplicated P. falciparum malaria” and report in Therapeutic Efficacy and Safety of Artemether-Lumefantrine Combination Therapy for the Treatment of Uncomplicated Plasmodium falciparum Malaria at Teda Health Centre, Northwest Ethiopia, 2022/23, Malaria J, 2024 Aug 30, 23:266, httpas://doi.org/10.1186/s12936-024-05082-y that of over 900 patients with P. falciparum malaria in the center, only 88 were found to be eligible to be studied. Among these, 69 followed the follow-up protocol and 65 of them were free of parasites after 28 days (but one had pneumonia and two of the ones with parasitemia had P. vivax on day 28). Adverse drug effects were tabulated; they were mild and transient. Based on these results the authors concluded that “[a]rtemether-lumefantrine continued to be an efficacious and safe drug for the treatment of uncomplicated Plasmodium falciparum malaria” at the center studied.
Another report of the efficacy of the same combination of drugs is Daka D & al., Therapeutic Efficacy of Artemether–Lumefantrine in the Treatment of Uncomplicated Plasmodium falciparum Malaria in Arba Minch Zuria District, Gamo Zone, Southwest Ethiopia, Malaria J, 2024 Sep 17, 23:282, https://doi.org/10.1186/s12936-024-05087-7. Of 89 patients reviewed, fever resolved in two days for all of them, most were free of parasites by day three and all by day 14. Of five recurrences, two were demonstrated to be reinfections with a different strain of parasite.
Guidelines
In Nigeria, Olisakwe SC & al. found in a “nationally-representative, weighted sample of 22,802 children aged 6–59 months, [that] fever prevalence remained stable over time, while confirmed malaria prevalence decreased from 51.2% in 2010 to 44.3% in 2015 and 38.5% in 2021 … Anti-malarial use among these children decreased from 19% in 2010 to 10% in 2021, accompanied by an increase in ACT use…” Yet a disturbing finding reported in Receipt of Antimalarials Among Children Aged 6–59 Months in Nigeria from 2010 to 2021, Malaria J, 2024 Aug 20, 23:249, https://doi.org/10.1186/s12936-024-05075-x was that among “children who had fever in the prior 2 weeks, anti-malarial receipt was similar between children with either positive or negative survey RDT results, indicative of persistent challenges in reducing inappropriate anti-malarials uptake.”
Although Oceane Minka S & al.’s article, New Guidelines Reduce the Risk of Hospitalization for Adult Patients with Uncomplicated Plasmodium falciparum Malaria: An Observational, Multicenter, Retrospective French Study, Infect Dis Now. 2024 Aug 20: 104963, https://doi.org/10.1016/j.idnow.2024.104963 reports on malaria in metropolitan France, it reflects the importance of studying the effects of introducing new guidelines for treatment. In the case trhey report, the guidelines resulted in reduced hospitalizations.
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Side effects and complications
“Cardiovascular events following anti-malarial treatment are reported infrequently; only a few studies have reported adverse outcomes… [Amir M & al. present a] life-threatening arrhythmia during anti-malarial treatment” in Brugada Syndrome Precipitated by Uncomplicated Malaria Treated with Dihydroartemisinin Piperaquine: A Case Report, Malaria J, 2024 Sep 17, 23:283, https://doi.org/10.1186/s12936-024-05099-3. The report is from Indonesia; the patient in question had taken the drugs before, without symptomatic side effects; this time he was found to have a potentially fatal heart rhythm problem that is rare but when it occurs, it is usually in young men. He survived after being taken off the drug combination. Of the two drugs, piperaquine has propensity to cause heart rhythm abnormalities, although usually not as severe as in the reported case.
Drug resistance
“Increasing sulfadoxine-pyrimethamine (SP) resistance in the Democratic Republic of the Congo (DRC) has threatened its use for prevention of malaria in one of the most malarious countries in the world. Using geographic information on mining operations in the DRC and genetic data on SP drug resistance markers from the 2013-2014 Demographic and Health Surveys, [Mitchell CL & al.] evaluated associations between close residence to mining and the presence of mutations conferring resistance to sulfadoxine. As they report in Close Proximity to Mining Is Associated with Increased Prevalence of the Drug Resistance-Associated Mutation dhps540E in Eastern Democratic Republic of the Congo, Am J Trop Med Hyg. 2024 Jun 11; 111(2):361-364, https://doi.org/10.4269/ajtmh.23-0355, they adjusted “for confounding variables and space” and yet the association with geographic proximity remained. The reason for this association is unclear.
Rosenthal PJ & al., The Emergence of Artemisinin Partial Resistance in Africa: How Do We Respond, Lancet Infect Dis. 2024 Sep; 24(9):e591-e600, https://doi.org/10.1016/s1473-3099(24)00141-5 is identified as a “Personal View,” even though it is the collaborative product of ten authors. “…partial resistance to artemisinins (ART-R), the most important class for the treatment of malaria, was until recently confined to southeast Asia. This situation has changed, with the emergence of ART-R in multiple countries in eastern Africa. ART-R is mediated primarily by single point mutations in the P falciparum kelch13 protein, with several mutations present in African parasites that are now validated resistance mediators based on clinical and laboratory criteria. Major priorities at present are the expansion of genomic surveillance for ART-R mutations across the continent, more frequent testing of the efficacies of artemisinin-based regimens against uncomplicated and severe malaria in trials, more regular assessment of ex-vivo antimalarial drug susceptibilities, consideration of changes in treatment policy to deter the spread of ART-R, and accelerated development of new antimalarial regimens to overcome the impacts of ART-R. The emergence of ART-R in Africa is an urgent concern, and it is essential that we increase efforts to characterise its spread and mitigate its impact.”
The complicated genetics of drug resistance is a highlight of Fola AA & al., National Genomic Profiling of Plasmodium falciparum Antimalarial Resistance in Zambian Children Participating in the 2018 Malaria Indicator Survey, medRxiv [Preprint]. 2024 Aug 6: 2024.08.05.24311512, https://doi.org/10.1101/2024.08.05.24311512. Of 29 mutations of the artemisinin-resistance-associated Kelch13 gene found while sequencing the genomes of 282 P. falciparum specimens, only “three were WHO-validated artemisinin partial resistance mutations…” It appears that medRxiv now identifies its articles as “Preprints” in order to highlight the fact that the articles published have not undergone peer review.
New drug research
Ganaplacide is a new antimalarial, currently in Phase 3 clinical research in combination with lumefantrine as an antimalarial. It is the subject of two articles this past month. (1) Kreutzfeld O & al., Ex vivo Susceptibilities to Ganaplacide and Diversity in Potential Resistance Mediators in Ugandan Plasmodium falciparum Isolates, Antimicrob Agents Chemother. 2024 Aug 13: e0046624, https://doi.org/10.1128/aac.00466-24 addresses the issue that some strains of P. falciparum have been found to be resistant to the drug in the laboratory. The authors used specimens of the parasite obtained from patients. While they identified some mutations, “[o]verall, Ugandan P. falciparum isolates were mostly highly susceptible to ganaplacide. Known resistance mediators were polymorphic, but mutations previously selected with in vitro drug pressure were not seen, and mutations identified in the Ugandan isolates were generally not associated with decreased ganaplacide susceptibility.” (2) Manaranche J & al., In vitro Evaluation of Ganaplacide/Lumefantrine Combination Against Plasmodium falciparum in a Context of Artemisinin Resistance, J Antimicrob Chemother. 2024 Aug 29: dkae300, https://doi.org/10.1093/jac/dkae300 deals with its combination with lumefantrine. The combination “could replace the current front-line artemisinin-based combination therapies (ACTs) in case of Plasmodium falciparum resistance to both artemisinins and partner drugs.” The authors tested its efficacy in a triple drug combination (artemisinin included) against artemisinin resistant parasites and found that ganaplacide “alone and in combination with lumefantrine was active against artemisinin-resistant parasites, including when they are quiescent.”
Pyronaridine is an antimalarial that has been in use for over 50 years, yet its use is not widespread even though a combination with artesunate is available. Cabamiquine has a more recent history but has been cited as effective in both treating and preventing clinical malaria. Maiga M & al.’s article, Towards Clinically Relevant Dose Ratios for Cabamiquine and Pyronaridine Combination Using P. falciparum Field Isolate Data, Nat Commun. 2024 Sep 3; 15(1):7659, https://doi.org/10.1038/s41467-024-51994-3 is a modeling study that “demonstrate[s] that the pharmacometrics model of parasite growth and killing provides a detailed description of parasite kinetics against cabamiquine-susceptible and resistant parasites. Pyronaridine monotherapy provides suboptimal killing rates at doses as high as 720 mg. In contrast, the combination of a single dose of 330 mg cabamiquine and 360 mg pyronaridine provides over 90% parasite killing in most of the simulated patients.”
Bagratee T & al., Exploring the Recent Pioneering Developments of Small Molecules in Antimalarial Drug Armamentarium: A Chemistry Prospective Appraisal, Chem Biodivers. 2024 Aug; 21(8):e202400460, https://doi.org/10.1002/cbdv.202400460 “presents a comprehensive overview of the latest advancements in the medicinal chemistry pertaining to small molecules, with a specific focus on their potential as antimalarial agents. As possible antimalarial drugs that might target both the dual stage and multi-stage stages of the parasite life cycle, these small hybrid molecules have been studied. This review explores a variety of physiologically active compounds that have been described in the literature in order to lay a strong foundation for the logical design and eventual identification of antimalarial drugs based on lead frameworks.”
Kabeche S & al. report on a drug so far identified only as “MMV1580853” in A Fast-Acting Inhibitor of Blood-Stage P. falciparum with Mechanism Distinct from Artemisinin and Chloroquine, bioRxiv [Preprint]. 2024 Aug 12:2024.08.12.607553, https://doi.org/10.1101/2024.08.12.607553. They state that in vitro, “[n]ear-complete parasite growth inhibition was observed within 1 hour of treatment with MMV1580853 and dihydroartemisinin, while chloroquine, another fast-acting antimalarial, showed partial growth inhibition after 1h ... [and compared to artemisinin and chloroquine] MMV1580853 has a distinct mechanism-of-action leading to a very fast killing rate.” It appears that bioRxiv also identifies its articles as “Preprints” in order to highlight the fact that the articles published have not undergone peer review.
Plant extracts and traditional treatments
Ganoderma colossus is a non-edible wood inhabiting mushroom prevalent in the tropics, including sub-Saharan Africa. Its extracts have been promising in the search for anticancer drugs. Chanphen R & al., Ganopyrone A, a Highly Rearranged Lanostane Triterpenoid with Antimalarial Activity from Artificially Cultivated Fruiting Bodies of Ganoderma colossus, Phytochemistry. 2024 Aug; 224:114168, https://doi.org/10.1016/j.phytochem.2024.114168 extends the potential therapeutic application of some of these extracts by demonstrating anti plasmodial effects in the laboratory.
Other
When this reviewer lived in the Middle East some 15 years ago, there was a great deal of anxiety about drugs that were imported from manufacturers of suspect quality as well as about counterfeit drugs. Ahmed F & al., Quality Assessment of Common Anti-Malarial Medicines Marketed in Gambella, National Regional State, South Western-Ethiopia, Malaria J, 2024 Sep 13, 23:278, https://doi.org/10.1186/s12936-024-05091-x#Sec22 verifies that the problem continues to exist. According to the authors, the WHO “has received about 1500 reports that mentions instances of substandard and falsified products since 2013. The majority of the reports concerned antibiotics and anti-malarials. The majority of reports (42%) originate from the WHO African region.” The authors acquired and tested a limited supply of antimalarials from retail drug outlets. Applying techniques recommended by WHO they found that “[o]nly 25% of the samples were registered on the Ethiopian Food and Drug Authority (EFDA’s) electronic regulatory/ registration system … and 38% of the unregistered products failed the quality tests,” resulting in a percentage of 58.5% of substandard products.
Campaigns and Policies
Mwebesa E & al. explored “the influence of audiovisual messages on the knowledge of malaria prevention measures among pregnant women in Uganda.” They report on a survey of 8868 women of whom 721 were pregnant at the time in Impact of Mass Media Campaigns on Knowledge of Malaria Prevention Measures Among Pregnant Mothers in Uganda: A Propensity Score-Matched Analysis, Malaria J, 2024 Aug 24, 23:256, https://doi.org/10.1186/s12936-024-05083-x. “The study revealed that 39% … of pregnant women were exposed to malaria messages before the survey. Those exposed had a 17.2% higher knowledge … of using mosquito nets for prevention compared to those unexposed. Among women exposed, radios accounted for most form of access to mass media campaigns …, followed by interpersonal communication …, community health workers …, community events …, and social mobilization …”
Lequechane JD & al. state that “community involvement and the people's knowledge allow detailed information about the distribution, location, and identification of mosquito breeding-sites.” Their paper, Community Participatory Mapping of Malaria Mosquito Breeding Sites in Mozambique, Malaria J. 2024 Aug 29; 23:264, https://doi.org/10.1186/s12936-024-05084-w, describes the application of “the methodology to identify and map potential mosquito breeding-sites” in a particular community in Mozambique… A total of 125 potential breeding-sites (36 permanent and 89 temporary) were mapped. [The authors conclude that] [c]ommunity participatory mapping could be used to identify potential mosquito breeding-sites by the national malaria control programmes to establish an efficient larval surveillance system, while improving community engagement and control strategies.”
Legendre E & al. conducted interviews, called together focus groups, and distributed questionnaires to leaders, healthcare workers, and close to 300 members of the general population of the area they studied for the acceptability of mass drug administration (MDA). Per Prospective Acceptability of Mass Drug Administration for Malaria in Kedougou Region in Senegal: A Mixed Method Study, Malaria J, 2024 Sep 16, 23:279, https://doi.org/10.1186/s12936-024-05078-8, MDA may be an acceptable approach to a community in which malaria rates are high but there is also a likely reservoir of asymptomatic infection. “Two potential barriers were identified: the contradiction of taking a medication without feeling sick and the occurrence of side effects; and four facilitators: the perception of malaria as a burden, a good understanding of MDA, a good perceived effectiveness, and the resulting economic benefits.” In addition, young men tended to demonstrate lower acceptability.
Please see Koita K &al., Community-Based Strategies to Increase Coverage of Intermittent Preventive Treatment of Malaria in Pregnancy with Sulfadoxine-Pyrimethamine in Sub-Saharan Africa: A Systematic Review, Meta-Analysis, Meta-Ethnography, and Economic Assessment, Lancet Glob Health. 2024 Sep;12(9):e1456-e1469. https://doi.org/10.1016/s2214-109x(24)00228-6 above, under Prevention/Chemoprevention.
Epidemiology
Climate change, biodiversity and environment
Rubuga FK & al. “analysed the potential impact of temperature and cumulative rainfall on malaria incidence in Rwanda from 2012 to 2021 using meteorological data … and malaria case records…” They report thet “[a]verage temperature of 18.5 °C was associated with higher malaria risk, while temperature above 23.9 °C reduced the risk. Rainfall demonstrated a dual effect on malaria risk: conditions of low (below 73 mm per month) and high (above 223 mm per month) precipitation correlated with lower risk, while moderate rainfall (87 to 223 mm per month) correlated with higher risk. Seasonal patterns showed increased malaria risk during the major rainy season, while the short dry season presented lower risk. The article is Impact of Climatic Factors on Malaria in Rwanda Between 2012 and 2021: A Time-Series Analysis, Malaria J, 2024 Sep 10, 23:274, https://doi.org/10.1186/s12936-024-05097-5.
“Mosquito vectors of pathogens … are geographically shifting under climate and other anthropogenic changes. As small-bodied ectotherms, mosquitoes are strongly affected by temperature, which causes unimodal responses in mosquito life history traits (e.g., biting rate, adult mortality rate, mosquito development rate, and probability of egg-to-adult survival) that exhibit upper and lower thermal limits and intermediate thermal optima in laboratory studies.” Athni TS & al. used “thousands of global mosquito occurrences and geospatial satellite data at high spatial resolution to construct machine-learning based species distribution models, from which vector thermal responses [were] estimated.” As reported in Temperature Dependence of Mosquitoes: Comparing Mechanistic and Machine Learning Approaches, PLoS Negl Trop Dis, 2024 Sep 16; 18(9):e0012488, https://doi.org/10.1371/journal.pntd.0012488, the authors “found that thermal minima estimated from laboratory studies were highly correlated with those from the species distributions (r = 0.87).”
Risk factors
Analyzing data over nine years ending in 2022, Sambe BS & al. describe the risk of “subpatent” (defined as symptomatic but negative on RDT and/or microscopy) malaria in Senegal in their article, Persistent Carriage of Subpatent Plasmodium falciparum Parasites Associated with Clinical Malaria in a Low Transmission Area in Senegal, Int J Infect Dis. 2024 Aug 14: 107211, https://doi.org/10.1016/j.ijid.2024.107211. The risk is defined by the authors as primarily related to geographic proximity to an individual with malaria. “The relative risk of P. falciparum infection or clinical malaria calculated with a 95% confidence interval significantly increased in the vicinity of infected individuals and was 1.44 … and 2.64 … when at least one individual in the direct (household) or indirect (block of households) vicinity is infected, respectively. The risk increased to 3.64 … if at least 1/5 of individuals in the indirect vicinity were P. falciparum-infected.”
Molina-de la Fuente I & al., Malaria Diagnosis Challenges and pfhrp2 and pfhrp3 Gene Deletions Using Pregnant Women as Sentinel Population in Nanoro Region, Burkina Faso, Pathog Glob Health. 2024 Aug 14: 1-11, https://doi.org/10.1080/20477724.2024.2388489 reaches a similar conclusion to Sambe & al. above, as to the dependence of RDT sensitivity on parasite density. However, in the region that these authors studied, 21+% of RDT negative but infected patients studied also had gene deletions for HDT2.
General epidemiology
Satapathy P & al. report the results of a world-wide literature search in, Adverse Pregnancy Outcomes in Maternal Malarial Infection: A Systematic Review and Meta-Analysis, New Microbes New Infect, 2024 Aug 30: 62:101474, https://doi.org/10.1016/j.nmni.2024.101474. Thirty-one studies were included, “showing high prevalence of low birth weight (LBW; 17.4 %), preterm birth (17.9 %), and small for gestational age (SGA; 16.1 %) in malaria-affected pregnancies. Infected mothers were significantly more likely to have LBW infants (RR [risk ratio] = 1.755), preterm births (RR = 1.484), and SGA infants (RR = 1.554). The risk of stillbirth was not significantly increased (RR = 1.238).”
“More than 17% of all infectious diseases are caused by vector-borne diseases resulting in more than 1 billion cases and over 1 million deaths each year. Of this malaria continues to be a global burden in over eighty countries.” Bladford J examines “how geographic information, geospatial technologies and spatial data science are being used to reduce the burden of vector-borne diseases such as malaria and explore the opportunities that lie ahead with GeoAI and other geospatial technology advancements. Malaria is a dynamic and complex system and as such a range of data and approaches are needed to tackle different parts of the malaria cycle at different local and global scales. Geospatial technologies provide an integrated framework vital for monitoring, analysing, managing” malaria and other vector-borne diseases. The paper is Managing Vector-Borne Diseases in a geoAI-Enabled Society. Malaria as an Example, Acta Trop, 2024 Sep 17: 107406, https://doi.org/10.1016/j.actatropica.2024.107406.
Spatiotemporal studies:
Demsash AW & al., Pooled Prevalence of Malaria and Associated Factors Among Vulnerable Populations in Ethiopia: A Systematic Review and Meta-Analysis, BMC Infect Dis. 2024 Aug 15; 24(1):828, https://doi.org/10.1186/s12879-024-09736-9
Bassinga H & al., Prevalence of Asymptomatic Malaria at the Communal Level in Burkina Faso: An Application of The Small Area Estimation Approach, Popul Health Metr. 2024 Aug 18; 22(1):21, https://doi.org/10.1186/s12963-024-00341-1
Aninagyei E & al., Epidemiology and Likelihood of Asymptomatic Malaria Among Community Dwellers in the Fanteakwa South District of Ghana, Parasite Epidemiol Control, 2024 Sep 5: 27:e00378, https://doi.org/10.1016/j.parepi.2024.e00378