December 2024 Science & Research Report

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

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The 320-page 2024 World Malaria Report; Addressing Inequity in the Global Malaria Response was published by WHO on 11 December. According to it, there were an estimated 263 million cases and 597 000 malaria deaths worldwide in 2023. This represents about 11 million more cases in 2023 compared to 2022, and nearly the same number of deaths. Approximately 95% of the deaths occurred in the WHO African Region. The report is available from the reviewer or at https://www.who.int/teams/global-malaria-programme/reports/world-malaria-report-2024. The current WHO Guidelines for Malaria (462 pages) was published the day before and can be found at https://media.malariaworld.org/B09146_eng_e61c150520.pdf.

News release from MMV (Medicines for Malaria Venture), 15 November 2024:
“The West African Network for Clinical Trials of Antimalarial drugs (WANECAM2) consortium has announced positive results from KALUMI, a Phase 2 study of a novel, non-artemisinin malaria drug combination in development with Novartis and MMV. … The KALUMI study evaluated the efficacy and safety of a combination of ganaplacide, a novel agent, and lumefantrine, reformulated for once-daily dosing. Conducted in Burkina Faso, Mali, Gabon, the Democratic Republic of Congo and Côte d’Ivoire, the study … targeted children between 6 months and 12 years of age with acute, uncomplicated malaria, who were given the ganaplacide/lumefantrine solid dispersion formulation once daily with food for 3 days. The trial data revealed that this combination was as effective as artemether-lumefantrine in children as young as 6 months, with a 99% adequate clinical and parasitological rate observed on Day 29 of treatment, achieving the study’s primary objective of demonstrating non-inferiority. The same dosing schedule and regimen are currently being studied in a Phase 3 trial, KALUMA, with results expected in 2025.” https://www.mmv.org/newsroom/news-resources-search/new-non-artemisinin-malaria-treatment-shows-promise-young-children

As part of the President’s Malaria Initiative, USAID announced on 12 November a USD 2.3 million commitment to purchase 4.8 million doses of sulfadoxine-pyrimethamine tablets. The medication is manufactured by Swiss Pharma, a Nigerian firm that has achieved WHO prequalification for this product, a rarity in sub-Saharan African pharmaceutical products. https://www.usaid.gov/nigeria/press-release/nov-12-2024-usaid-announces-23-million-commitment-procure-life-saving-malaria-tablets-nigerian-pharmaceutical-leader-swiss-pharma

On 4 December, the BBC announced that Nigeria has begun to distribute the R21/Matrix-M vaccine developed in the UK and approved by the WHO as the second effective malaria vaccine, with approximately 75% efficacy if administered according to the recommended schedule. “The roll-out started in two of the worst-affected states – Bayelsa and Kebbi – and the plan is to expand it to the rest of the country by next year.” https://www.bbc.com/news/articles/crk0mpz47jjo

Also on 4 December, GSK … and Medicines for Malaria Venture (MMV) announced “that the World Health Organization (WHO) has awarded prequalification to tafenoquine, the first single-dose medicine for the prevention of relapse of Plasmodium vivax (P. vivax) malaria. Tafenoquine, co-administered with chloroquine, is now also included in WHO’s updated Guidelines for malaria…”

Some Countries Have Eliminated Malaria, but Cases Are Growing Elsewhere is the title of an article in Science News, published on 11 December. The unsigned article states that “[b]etween 2000 and 2023, an estimated 2.2 billion cases of malaria and 12.7 million deaths from the mosquito-borne disease were averted, according to a report from the World Health Organization issued December 11. But challenges including climate change, conflict and biological threats have eroded some recent gains, with 11 million more malaria cases in 2023 than in 2022. Most of those cases occurred in Africa. Globally 597,000 people died of malaria in 2023, the majority of them young children in Africa.” The article then goes on to enumerate newer malaria control measures in effect, such as vaccines and gene drive as well as the well-established ones such as nets and chemoprevention. (https://www.sciencenews.org/article/malaria-report-card?utm_medium=email&utm_term=N%2FA&utm_source=D365&utm_content=SN%20Headlines%202024%2012%2012&utm_campaign=Final%20SN%20Headlines%20Newsletter%202024%2012%2012#msdynmkt_trackingcontext=0991f9b2-53db-464c-906f-295d3da6de58)

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PEER REVIEWED ARTICLES (see notes after citations from non-peer-reviewed publications)
Prevention

Vaccines
As the two WHO-endorsed malaria vaccines are rolled out, information is being gathered about their acceptability and efficacy beyond what was gathered during Phase III studies. Zacharia MM & al., RTS,S Malaria Vaccination Among Children Aged 24-59 Months in the Sunyani Municipality, Ghana; 2023, Vaccine. 2024 Oct 31; 42(26):126490, https://doi.org/10.1016/j.vaccine.2024.126490 is one such study, reporting that completion rate of all four vaccines remains around 45%. Over 90% of the children received two injections, but only 54% received three. “Children aged 48-59 months, … those with caregivers who believed that children were being used for experiment … or doubted the safety of the vaccine … were less likely to complete the four doses. On the other hand, children of caregivers who … travelled long distances to access immunization services …, and those with adequate knowledge on the malaria vaccine … were more likely to complete the vaccination schedule.” The authors opine that “[s]trengthening caregiver education and access to immunization services could improve uptake of the subsequent doses and coverage of the fourth dose.”

One of the many articles on the rate of acceptance of vaccines is Bugase E & Tindana P, Influence of Trust on the Acceptance of the RTS,S Malaria Vaccine in the Kassena-Nankana Districts of Ghana, Malaria J, 2024 Nov 29, 23:365, https://doi.org/10.1186/s12936-024-05180-x. In the area they studied with questionnaires, they found that 91.4% of mothers queried trusted that the vaccines were beneficial. “… educational status (P = 0.013), ethnicity (P = 0.008), marital status (P = 0.041), education on the vaccine and perceived ineffectiveness P < 0.05, and trust for the malaria vaccine (P < 0.05) were found to be statistically associated with vaccine acceptance. Compared with participants who agree that vaccines are harmless to children, those who disagree were significantly less likely to accept vaccines (OR = 0.25, 95%CI [0.08, 0.83], p = 0.017). The qualitative data correspondingly revealed that mothers trusted vaccines which thus accounted for the high uptake of the malaria vaccine in the districts.”

“Two pre-erythrocytic vaccines (R21/Matrix-M and RTS,S/AS01) are now approved for Plasmodium falciparum malaria. However, neither induces blood-stage immunity against parasites that break through from the liver. RH5.1/Matrix-M, a blood-stage P. falciparum malaria vaccine candidate, was highly immunogenic in Tanzanian adults and children. [Natama HM & al.] assessed the safety and efficacy of RH5.1/Matrix-M in Burkinabe children.” Their article, Safety and Efficacy of the Blood-Stage Malaria Vaccine RH5.1/Matrix-M in Burkina Faso: Interim Results of a Double-Blind Randomized, Controlled Phase 2b Trial in Children, Lancet Infect Dis, 2024 Dec 10, https://doi.org/10.1016/S1473-3099(24)00752-7, reveals results after one-year of follow-up. The vaccines were effective in generating an immune response and were found to be safe. In terms of clinical effectiveness of three vaccinations, the vaccine was 40% effective if the third dose was given a month after the second dose, and 55% effective if the third dose was delayed four months after the second. Palacpac NMQ & Horii T, RH5.1/Matrix-M: Highlighting Blood-Stage Malaria Vaccines, Lancet Infect Dis, 2024 Dec 10, https://doi.org/10.1016/S1437-3099(24)00800-4 is commentary on the above article by two researchers who are working on a different blood-stage vaccine.

According to Lamers OAC & al., “[c]urrently licensed and approved malaria subunit vaccines provide modest, short-lived protection against malaria. Immunization with live-attenuated Plasmodium falciparum malaria parasites is an alternative vaccination strategy that has potential to improve protection. [They] conducted a double-blind, controlled clinical trial to evaluate the safety, side-effect profile, and efficacy of immunization, by means of mosquito bites, with a second-generation genetically attenuated parasite (GA2)” and report in Safety and Efficacy of Immunization with a Late-Liver-Stage Attenuated Malaria Parasite, N Engl J Med. 2024 Nov 21; 391(20):1913-1923, https://doi.org/10.1056/nejmoa2313892, that “[p]rotective efficacy against subsequent controlled human malaria infection was observed in 8 of 9 participants (89%) in the GA2 group,” whereas two control groups showed 1/8 and 0/3 protection. Unspecified “[a]dverse events were similar across the trial groups.”

Vectors
“Insecticide-treated bed nets [ITNs] are cost-effective vector control methods for malaria prevention… [Getnet Y & al.] aimed to assess insecticide-treated nets utilization and associated factors among pregnant women.” As many other authors have done in sub-Saharan Africa, their paper, Long Lasting Insecticide-Treated Nets Utilization and Associated Factors Among Pregnant Women in Shebel Berenta District, Northwest Ethiopia, Environ Health Insights. 2024 Oct 21; 18:11786302241291957, https://doi.org/10.1177/11786302241291957, reports utilization to be suboptimal (around 45%), based on questionnaires and observation. While more than half of the women interviewed displayed adequate knowledge of the principles of malaria prevention, only 58% of those displaying good knowledge used ITNs consistently. Illiterate women were less likely to utilize the nets than educated ones (evident from reading the article).

Andrianantoandro VTA & al. also found ITNs to be cost effective in their study, Cost of the National Malaria Control Program and Cost-Effectiveness of Indoor Residual Spraying and Insecticide-Treated Bed Net Interventions in Two Districts of Madagascar, Cost Eff Resour Alloc. 2024 Dec 3; 22(1):89, https://doi.org/10.1186/s12962-024-00598-1. However, their data were not consistent when it came to cost effectiveness of indoor residual spraying (IRS). Implementation costs of IRS were four times those of ITNs, and the cost effectiveness ratio per lives protected was also unfavorable to IRS. Based on these findings, the authors state that “[w]illingness to pay for IRS is questioned.” {Caution about these conclusions is warranted because the data collected were for the years 2009–2013.}

Sovi A & al. report on a study of two-ingredient ITNs in The Effect of Next-Generation, Dual-Active-Ingredient, Long-Lasting Insecticidal Net Deployment on Insecticide Resistance in Malaria Vectors in Benin: Results of a 3-Year, Three-Arm, Cluster-Randomised, Controlled Trial, Lancet Planet Health. 2024 Nov; 8(11):e894-e905, https://doi.org/10.1016/s2542-5196(24)00232-8. They conclude that “[a]fter 24 months of use, chlorfenapyr-pyrethroid [ITNs] no longer mitigated pyrethroid resistance selection in this area of southern Benin, which has high malaria transmission dominated by highly resistant An. gambiae sensu lato. This finding raises issues for current net-procurement schedules, which are based on an operational net lifespan of 3 years.”

Parallel to the above study, Agbevo A & al. measured the efficacy of multi-agent ITNs after use up to three years. They conclude in The Experimental Hut Efficacy of Next-Generation Insecticide-Treated Nets Against Pyrethroid-Resistant Malaria Vectors After 12, 24 and 36 Months of Household Use in Benin, Malaria J, 2024 Dec 18, 23:388, https://doi.org/10.1186/s12936-024-05199-0, that “Interceptor® G2 outperformed the other ITNs, confirming the superiority of pyrethroid-chlorfenapyr nets over other net types. When new, all next-generation ITNs showed superior bioefficacy compared to Interceptor®; however, the size of this improvement fell after field-ageing due to poor durability of the non-pyrethroid compound. These findings emphasize the need to enhance the insecticidal durability of next-generation ITNs.”

Djoko Tagne CS & al., A Single Mutation G454A in the P450 CYP9K1 Drives Pyrethroid Resistance in the Major Malaria Vector Anopheles funestus Reducing Bed Net Efficacy, Genetics. 2024 Nov 7: iyae181, https://doi.org/10.1093/genetics/iyae181, is a genetic analysis of what drives pyrethroid resistance in Anopheles funestus. This mutation is now present in mosquitoes in Uganda and Cameroon, but so far not found in Ghana or Malawi.

During 25 collection days over the course of 28 months, Abel L & al. collected mosquitoes indoors in 75 ITN-using households. They then tested the 712 Anopheles specimens obtained for survival and for carrying Plasmodium parasites. As reported in Relationship Between Malaria Vector Survival, Infectivity, and Insecticide-Treated Net Use in Western Kenya, Parasit Vectors. 2024 Nov 12; 17(1):464, https://doi.org/10.1186/s13071-024-06550-9, the mortality of mosquitoes after collection was for the most part unrelated to the frequency of ITN usage by household members, as was the case with the presence of parasites in the mosquitoes’ bodies upon dissection. {Two items of interest: the paper is silent on the possibility that some of the mosquitoes incubating parasites may have already had Plasmodium in their bodies when they entered the homes. Also, the 712 Anopheles were fewer than 10% of all mosquitoes collected!}

Hien AS & al. “tested VECTRON™ T500, a new indoor residual spraying (IRS) formulation using broflanilide, … in a Phase III community trial.” They report in Long-Lasting Residual Efficacy of a New Indoor Residual Spraying Product, VECTRONTM T500 (Broflanilide), Against Pyrethroid-Resistant Malaria Vectors and its Acceptance in a Community Trial in Burkina Faso, Parasit Vectors. 2024 Nov 23; 17(1):484, https://doi.org/10.1186/s13071-024-06577-y, that “VECTRON™ T500 consistently achieved 100% mortality across all wall types for both susceptible and resistant mosquito strains over the 12-month period.” In comparison, a currently used insecticide achieved only an 80% kill rate. Also, “no adverse events were reported in households sprayed with VECTRON™ T500.”

In contrast to the study from Madagascar (see above), Nsekuye O & al., Indoor Residual Spraying Uptake and Its Effect on Malaria Morbidity in Ngoma District, Eastern Province of Rwanda, 2018–2021, Malaria J. 2024 Dec 18; 23:381, https://doi.org/10.1186/s12936-024-05194-5, reports on data from two IRS campaigns in 2019 and 2020 and estimates the number of malaria cases reduced by each intervention. The article also states that “[h]ouseholds receiving IRS information through media channels … were less likely to participate compared to those informed by community health workers.”

Correa M & al. state that despite elimination efforts, malaria is increasing from its very low prevalence on the islands of São Tomé e Príncipe. They explored the possibility that the vectors have become resistant to the insecticides used. As they describe in The Status of Insecticide Resistance of Anopheles coluzzii on the Islands of São Tomé and Príncipe, After 20 Years of Malaria Vector Control, Malaria J. 2024 Dec 18; 23:390, https://doi.org/10.1186/s12936-024-05212-6, there are high levels of resistance to pyrethroids and DDT in the specimens they collected on the two main islands. Therefore, they recommend “the use of non-pyrethroid insecticides or combination with synergists to overcome the high levels of pyrethroid resistance.”

Using the biolarvicide Bacillus thuringiensis var israelensis, Mapua SA & al. trained rural residents in the safety and efficacy of this method of reducing the population of An. funestus, the main malaria vector in Tanzania. They report in Empowering Rural Communities for Effective Larval Source Management: A Small-Scale Field Evaluation of a Community-Led Larviciding Approach to Control Malaria in South-Eastern Tanzania, Parasite Epidemiol Control. 2024 Oct 4; 27:e00382, https://doi.org/10.1016/j.parepi.2024.e00382, that “training community members to identify, characterize, and target larval habitats of the dominant malaria vectors can be effective for larval source management in rural Tanzania.” In terms of efficacy, “[a]pplication of biolarvicides reduced the abundance of adult An. funestus and Culex spp. species inside human houses in the same villages, by 46.3% and 35.4%, respectively. Abundance of late-stage instar larvae of the same taxa was also reduced by 74% and 42%, respectively.”

Ayana GM & al. “describe the evaluation of a larval source management (LSM) strategy implemented in response to An. stephensi” in two towns, compared to a third, where LSM was not implemented. They used a statistical technique called “interrupted time series model with a cyclic second-order random walk structure periodic seasonal term … to assess the impact of LSM on malaria incidence rate in the intervention and control settings” and conclude in Larval Source Management in Ethiopia: Modelling to Assess Its Effectiveness in Curbing Malaria Surge in Dire Dawa and Batu Towns, Malaria J. 2024 Dec 3; 23:366, https://doi.org/10.1186/s12936-024-05189-2, that no beneficial effect of LSM could be demonstrated. However, their study was conducted in 2020 against the backdrop of COVID-19.

Zembere K expresses his concern that with the proliferation of the outdoor-biting An. arabiensis, ITNs and IRS will become less effective as malaria control tools. In his article, The Potential for Attractive Toxic Sugar Baits to Complement Core Malaria Interventions Strategies: The Need for More Evidence, Malaria J. 2024 Nov 23; 23:356, https://doi.org/10.1186/s12936-024-05161-0, he expresses hope that by 2025, “attractive sugar baits (ATSBs) “would be considered for the World Health Organization prequalification listing as a complementary tool for mosquito control. This article highlights evidence that ATSBs can advance malaria elimination by complementing indoor-based tools. However, for effective control programmes and elimination campaigns, the use of ATSBs alone might not be adequate, and this article recommends the combined use of ATSBs with either IRS or ITNs.”

Based on its abstract, Ravishankaran S & al., Influence of Household Roof Types on the Development of Plasmodium vivax in Anopheles stephensi Mosquitoes, Am J Trop Med Hyg. 2024 Dec 3; tpmd240243, https://doi.org/10.4269/ajtmh.24-0243, is also about the survival of infected mosquitoes in addition to the development of the parasite. The authors found that development of oocysts and sporozoites of P. vivax was optimal, and survival of An. stephensi was longest under thatched roofs, as opposed to asbestos or tiled roofs.

Chemoprophylaxis
The effectiveness of seasonal malaria chemoprevention (SMC) is dependent on children completing the three-day course prescribed. Gao C & al., Examination of Factors Impacting Spitting or Vomiting Among Children Under 5 Years of Age During Seasonal Malaria Chemoprevention: A Quantitative Study in Burkina Faso, Chad, Nigeria and Togo, Trop Med Health. 2024 Nov 12; 52(1):82, https://doi.org/10.1186/s41182-024-00642-z, reports that children in the four countries studied either spit or vomit out the doses given in variable proportions up to 4.36% of the time. Although these percentages are low, the authors are concerned that the doses are not readministered in over half of these cases.

“Seasonal malaria chemoprevention (SMC) refers to monthly administration of full treatment courses of anti-malarial medicine to children … during high malaria transmission seasons.” Kwiringira A & al., Effect of Seasonal Malaria Chemoprevention on Incidence of Malaria Among Children Under Five Years in Kotido and Moroto Districts, Uganda, 2021: Time Series Analysis, Malaria J. 2024 Dec 18; 23:389, https://doi.org/10.1186/s12936-024-05220-6, is a report comparing data from years in which SMC was implemented against previous years when it had not. The authors found malaria incidence to be “693/1000 during SMC implementation period, compared to an expected 1216/1000 if SMC had not been implemented. The mean monthly malaria incidence was 87/1000, compared to an expected mean of 152/1000 if SMC had not been implemented.” They recommend implementing SMC for children under 5 in other districts as well.

The main conclusion of Ali IM & al.’s article, Asymptomatic Plasmodium falciparum Infections and Determinants of Carriage in a Seasonal Malaria Chemoprevention Setting in Northern Cameroon and South Senegal (Kedougou), Malaria J. 2024 Dec 18; 23:386, https://doi.org/10.1186/s12936-024-05150-3, is that the peak years in which asymptomatic malaria manifests itself in children in Cameroon is between 5 and 10 years. Therefore, the authors recommend extending SMC in Cameroon to 10 years of age, as it is done in Senegal.

“Implemented in 17 countries to date, seasonal malaria chemoprevention (SMC) is a recommended strategy to prevent childhood malaria in areas with seasonal transmission of P. falciparum through monthly administration of antimalarial medicines.” Ruisch A & al. reviewed six studies of the cost of the program, covering nine sub-Saharan countries between 2012 and 2024 (some of these studies have been reported on these pages). They report in Systematic Review on the Cost of Seasonal Malaria Chemoprevention (SMC), Malaria J. 2024 Dec 18; 23:384, https://doi.org/10.1186/s12936-024-05217-1, that there is too much variability in the studies and that most of them study the scale-up phase. Therefore, firm conclusions cannot be drawn about them. “Adopting a standardized costing approach for mature SMC programmes could provide a better understanding of resource requirements and costs while enhancing study comparability across settings, better informing future resource allocation and improving efficiency.”

Nakalega R & al. state that suboptimal uptake of intermittent preventive treatment of pregnancy (IPTp) “is primarily due to inadequate knowledge among women.” They assessed “the feasibility and acceptability of an educational video.” They describe the results in Video-Based Education Messaging to Enhance Optimal Uptake of Malaria Preventive Therapy in Pregnant Women: A Mixed Methods Study Involving Pregnant Women and Midwives in Uganda, Malaria J. 2024 Dec 18; 23:391, https://doi.org/10.1186/s12936-024-05223-3. The authors conclude that the “video-based intervention … was found acceptable among women and midwives and was feasible and appropriate to a public health facility. Future studies would test the effectiveness of the intervention in improving knowledge and uptake of” IPTp.

Djontu JC & al. conducted extensive genetic and biochemical research and report in Profile of Molecular Markers of Sulfadoxine-Pyrimethamine-Resistant Plasmodium falciparum in Individuals Living in Southern Area of Brazzaville, Republic of Congo, Int J Parasitol Drugs Drug Resist. 2024 Oct 26; 26:100569, https://doi.org/10.1016/j.ijpddr.2024.100569, that the prevalence of various markers of resistance in parasites obtained from asymptomatic individuals calls into question the efficacy of intermittent treatment with sulfadoxine-pyrimethamine (IPTp-SP) in the area studied.

Diagnosis

General diagnostics
Polymerase Chain Reaction (PCR) is generally regarded as the most sensitive diagnostic test for the malaria parasite. Tegegn G & al. conform this conclusion in their study, Comparative Assessment of Microscopy, Malaria Rapid Diagnostic Test and Polymerase Chain Reaction as Malaria Diagnostic Tools in Adama Woreda, East Shoa Zone of Ethiopia: A Cross-Sectional Study, BMC Infect Dis. 2024 Nov 28; 24(1):1363, https://doi.org/10.1186/s12879-024-10173-x. However, they note the financial and logistical barriers to implementing PCR in the field and recommend the simultaneous use of rapid diagnostic testing of a particular proprietary origin and microscopy.

Field diagnostics
“Rapid diagnostic tests (RDTs) targeting pfhistidine-rich protein 2 (Pfhrp2) are widely used for diagnosis of Plasmodium falciparum infections in resource-limited malaria endemic countries. However, test results are affected by deletions of the Pfhrp2, Pfhrp3, and flanking genes…” The findings reported in Getie S & al.’s paper, High Prevalence of Pfhrp2/3 Gene Deletions and Major Threat to Malaria Control Programs in Ethiopia, J Trop Med. 2024 Nov 2; 2024:8848997, https://doi.org/10.1155/2024/8848997, lead the authors to conclude that there are “widespread deletions in the Pfhrp2 and Pfhrp3 genes in Ethiopia, thereby confirming anecdotal reports of diagnostic failure with Pfhrp2-based RDTs in the region. The implications of [the authors’] finding for the current diagnostic paradigm, which relies on the detection of P. falciparum by Pfhrp2-based RDTs in remote areas, are that they “may need rethinking.”

Kambou SAE & al. compared two kinds of rapid diagnostic tests (RDTs and ultrasensitive RDTs or usRDTs) for the detection of asymptomatic individuals. While usRDT was significantly more sensitive than RDT in detecting asymptomatic individuals who carry Plasmodium, it was also significantly less specific, when compared to microscopy. Nonetheless, the authors of the paper, Prevalence of Asymptomatic Parasitaemia Among Household Members of Children Under Seasonal Malaria Chemoprevention Coverage and Comparison of the Performance of Standard Rapid Diagnostic Tests Versus Ultrasensitive RDT for the Detection of Asymptomatic Parasitaemia in Nanoro District, Burkina Faso, Parasitol Res. 2024 Nov 15; 123(11):383, https://doi.org/10.1007/s00436-024-08380-1, conclude that “usRDT seems more appropriate for strategies based on detection and treatment of parasite carriers within the community.”

New diagnostic methods
None this month.

Other
The importance of diagnosing patients with malaria is highlighted in the infective species in Diagne A & al.’s article, Variable Effects of Non-Falciparum Species Infections on Malaria Disease Severity in High Transmission Regions in Senegal, Trop Med Health. 2024 Dec 4; 52:93, https://doi.org/10.1186/s41182-024-00655-8. Studying 617 blood samples obtained over six years in three areas of high transmission, they found that while “94.8% of samples contained P. falciparum,” P. ovale was present alone or in combination in 60.1%, P. vivax in 13.6%, and P. malariae in 1.62%. The importance of these coinfections is brought out by the fact that coinfection with P. vivax was associated with a higher incidence of severe malaria, while P. ovale showed a protective effect against severe malaria, though not in statistically significant strength. Furthermore, though not the focus of this article, the three non-falciparum species require so-called “radical cure” in order to prevent recurrences even without repeated exposure, so establishing their presence or absence is important in diagnosis.

Treatment

Treatment results
Mouline K & Costantini C argue in Is Ivermectin Surviving Expectations in Residual Malaria Control? Lancet Infect Dis. 2024 Nov 14: S1473-3099(24)00652-2, https://doi.org/10.1016/s1473-3099(24)00652-2, that in fact, once ingested by people or animals, “ivermectin makes vertebrate blood toxic to blood-feeding arthropods, including resistant vectors of Plasmodium, acting in this way as a systemic insecticide. The effectiveness of ivermectin in such an application, therefore, relies on vectors feeding on treated hosts. This approach holds the potential to serve in malaria control when facing resistances. The focus is on mosquitoes that elude existing indoor interventions because of diurnal and outdoor feeding, or are otherwise resistant to mainstay insecticides.”

Side effects and complications
None this month.

Drug resistance
Studying genetic markers for drug resistance in parasite samples collected between 2013 and 2018, Fola AA & al. report in Temporal Genomics in Southern Zambia Shows Rising Prevalence of Plasmodium falciparum Mutations Linked to Delayed Clearance After Artemisinin-Lumefantrine Treatment, Sci Rep. 2024 Nov 5; 14(1):26789, https://doi.org/10.1038/s41598-024-76442-6, that markers that are associated with martial lumefantrine resistance and delayed clearing of parasites in clinical settings were increasing in frequency in samples collected in the latter years. The authors conclude that while artemisinin combination therapy partial resistance “mutations are rare, a mutation associated with slow parasite clearance in Africa appears to be under selection in southern Zambia.”

New drug research
Chloroquine and primaquine are antimalarials of the 4-aminoquinoline (4-AQ) family of compounds. Ferreira LT & al., A Novel 4-Aminoquinoline Chemotype with Multistage Antimalarial Activity and Lack of Cross-Resistance with PfCRT and PfMDR1 Mutants, PLoS Pathog. 2024 Oct 29; 20(10):e1012627, https://doi.org/10.1371/journal.ppat.1012627, describes a similar compound, now denoted as LDT-623, which possesses “activity against multiple stages (liver schizonts, stage IV-V gametocytes, and ookinetes) of Plasmodium‘s life cycle, a feature unlike” the 4-AQs mentioned above. They noted that some of the strains of Plasmodium that have mutations rendering them resistant to chloroquine were sensitive to LDT-623. The authors conclude that their “findings support further exploration of this promising 4-AQ.”

Upadhyay C & al. report on two specific compounds among 21 synthesized, which demonstrated significant activity against laboratory strains of P. falciparum, including a chloroquine-resistant strain. As reported in Synthesis and Evaluation of Fluorinated Piperazine-Hydroxyethylamine Analogues as Potential Antiplasmodial Candidates, ChemMedChem. 2024 Nov 8: e202400616, https://doi.org/10.1002/cmdc.202400616, the two compounds were also tested for cellular toxicity and for efficacy in infected mice, with promising results.

Artefenomel was a promising synthetic antimalarial, which was shown in Phase II trials to have suboptimal efficacy against P. falciparum. Abd-Rahman AN & al., Characterizing the Pharmacological Interaction of the Antimalarial Combination Artefenomel-Piperaquine in Healthy Volunteers with Induced Blood-Stage Plasmodium falciparum to Predict Efficacy in Patients with Malaria, BMC Med. 2024 Nov 28; 22(1):563, https://doi.org/10.1186/s12916-024-03787-0, reports a small volunteer-infection-study (VIS) with the aim of determining whether such a study might have predicted the outcome and thereby saved the time and expense of a full-blown Phase 2b trial. In their outcomes, they achieved virtually the same results as the reported Phase 2b trial, thus the authors conclude that “VIS offer an efficient means for informing antimalarial combination trials conducted in the field, potentially expediting clinical development.” {This seems to be a hasty conclusion to this reviewer, given that this was only one small study.}

Xie SC & al. studied a derivative of a previously identified potential inhibitor of P. falciparum. The new compound is designated ML471 and was found to be “fast-acting and exhibit[ing] a long in vivo half-life [in the mouse model]. ML471 is well-tolerated and shows single dose oral efficacy in the SCID mouse model of P. falciparum malaria.” The paper is A Potent and Selective Reaction Hijacking Inhibitor of Plasmodium falciparum Tyrosine tRNA Synthetase Exhibits Single Dose Oral Efficacy in vivo, PLoS Pathog. 2024 Dec 9, https://doi.org/10.1371/journal.ppat.1012429.

Plant extracts and traditional treatments
Tinospora sinensis bark and stem are used as herbal remedies “to treat malaria and it is also traditionally employed for conditions such as dyspepsia, inflammation, fever, ulcers, jaundice, diabetes and various urinary, skin, and liver diseases.” Although these uses are primarily in Asia, the plant is found in all the tropics and its extracts are available in the United States. Gogoi N & al. studied five extracts for their effects on P. falciparum in the laboratory and report in Identification of Antimalarial Phytoconstituents from Tinospora Sinensis (Lour.) Merr. Stem by in vitro Whole Cell Assay and Multiple Targets Directed in silico Screening Against Plasmodium falciparum, J Ethnopharmacol. 2024 Nov 18: 119134, https://doi.org/10.1016/j.jep.2024.119134, that two of them showed activity against both chloroquine-sensitive and chloroquine-resistant strains.

Ziziphus mucronata (Buffalo thorn) has been the subject of a number of articles describing antimalarial effects of its extracts. Masia KJ & al., Antiplasmodial Potential of Compounds Isolated from Ziziphus mucronata and Their Binding to Plasmodium falciparum HGXPRT Using Biophysical and Molecular Docking Studies, Naunyn Schmiedebergs Arch Pharmacol. 2024 Nov 19, https://doi.org/10.1007/s00210-024-03611-9, explores the extracts’ mechanism of action and claims to “prove that Z. mucronata could serve as a reservoir of effective agents for treating malaria, while also scientifically validating its use in traditional medicine.”

Oleuropein is a substance extracted from olives and is readily available in multiple over-the-counter preparations and supplements. Devi S & al. state the following about the drug’s effect on malaria: “Monotherapy with [oleuropein (OLP)] could not completely eliminate P. falciparum from a routine culture of asexual BS infection or achieve parasite clearance in a rodent model of P. berghei infection. Instead, OLP was observed to activate an autophagy-like self-defense mechanism, enabling the parasite to survive under drug pressure. However, when combined with artesunate, OLP was seen to significantly enhance the antimalarial activity of artesunate…” The article is Oleuropein: A Viable Therapeutic Option for Malaria and Cancer, Drug Discov Today. 2024 Nov 27: 104254, https://doi.org/10.1016/j.drudis.2024.104254.

Kacholi DS, A Comprehensive Review of Antimalarial Medicinal Plants Used by Tanzanians, Pharm Biol. 2024 Dec; 62(1):133-152, https://doi.org/10.1080/13880209.2024.2305453, identifies 227 medicinal plants that have appeared in the literature. Of these, “25.9% have been scientifically investigated for antimalarial activities with positive results.” The author advocates follow-up on these as well as studying those among the others that have not yet been evaluated for antimalarial effect.

Other
The controversy about the benefits of ivermectin in the fight against malaria continues. Parth & al., Antiplasmodial and Insecticidal Activities of Third-Generation Ivermectin Hybrids, J Med Chem. 2024 Nov 6, https://doi.org/10.1021/acs.jmedchem.4c01606, describes a process by which the authors appended molecular moieties to the ivermectin molecule and tested the resultant compounds for antiplasmodial activity in the laboratory. They assert that the new compounds enhance the effectiveness of ivermectin against the two species of Plasmodium tested.

WHO emphasizes the importance of early diagnosis and prompt treatment within 24 hours after the onset of symptoms. Delays in seeking treatment for malaria can lead to disease progression, an increased risk of complications, and even ongoing transmission of the malaria parasite. In this context, Melese YA & al., Magnitude and Associated Factors of Delayed Treatment Seeking Among Patients with Malaria in Andabet District, Northwest Ethiopia, 2022: A Multicentre Institution-Based Cross-Sectional Study, BMJ Open. 2024 Nov 28; 14(11):e087888, https://doi.org/10.1136/bmjopen-2024-087888, is an investigation into the causes of delay among 403 patients of all ages in the geographic area studied. “The prevalence of delayed malaria treatment seeking was 78.41% … [Not knowing] the cause of malaria …, [not knowing malaria signs and symptoms …, distance greater than 5 km traveled … and fear of treatment cost … were the statistically significant factors associated with delayed treatment seeking among malaria patients.”

Campaigns and Policies
Vey T & al. explored the efficacy of providing e-vouchers for ITNs to pregnant women who undergo prenatal examinations. They report in Implementation of a Mobile Health Approach to a Long-Lasting Insecticidal Net Uptake Intervention for Malaria Prevention Among Pregnant Women in Tanzania: Process Evaluation of the Hati Salama (HASA) Randomized Controlled Trial Study, J Med Internet Res. 2024 Nov 5; 26:e51527, https://doi.org/10.2196/51527Abstract, that there was no difference in accessing ITNs among women who received e-vouchers and those who did not. The authors surmise about the barriers that resulted in failure of the initiative.

Das S & al. used “data quality audit data collected at health facilities reporting into the monthly health management information system (HMIS) and weekly malaria rapid reporting system (MRRS) … to measure data reporting accuracy trends from 2015 to 2022 and potential influencing factors, and report in Documenting Trends in Malaria Data Reporting Accuracy Using Routine Data Quality Audits in Zambia, 2015–2022, Am J Trop Med Hyg. 2024 Nov 26: tpmd240429, https://doi.org/10.4269/ajtmh.24-0429, that with each successive data quality audit visit, “the proportion of facilities with high accuracy increased from visits 1 to 8: 23% to 56% (HMIS) and 42% to 85% (MRRS)…[and] starting in 2017, about 40-50% of health facilities appeared to be over-reporting incidence in comparison with their register-based incidence.” The significance of this last finding is unclear.

Obeagu EI & Obeagu GU summarize the developments in malaria control for a readership that is apparently not routinely exposed to this information in Emerging Public Health Strategies in Malaria Control: Innovations and Implications, Ann Med Surg (Lond). 2024 Sep 20; 86(11):6576-6584, https://doi.org/10.1097/ms9.0000000000002578.

Epidemiology

Climate change, biodiversity, and environment
“Malaria is a climate-sensitive and season-dependent disease that mainly affects the populations of tropical and subtropical regions of the world. Climatic variables such as rainfall, temperature, and humidity are identified as the driving factors affecting the epidemiology of malaria. In Ethiopia, recently unexpectedly high malaria burden accompanied by substantial morbidity and mortality is observed. The incidence rate of vector-borne diseases such as malaria is largely influenced by fluctuation of seasonal variables due to the proceeding global warming.” Tefera S, & al. assessed “the impact of seasonal and climate variability on the burden of malaria in one of the drought-prone areas of north central Ethiopia” and found that “three to four months of lagged rainfall is associated with high malaria positivity … However, monthly minimum temperature positivity influenced the rate of malaria positivity” most significantly. The paper is Effect of Seasonal Variability on the Increased Malaria Positivity Rate in Drought-Prone Malaria Endemic Areas of Ethiopia, J Parasit Dis. 2024 Dec; 48(4):860-871, https://doi.org/10.1007/s12639-024-01720-z.

Risk Factors
Using a statistical technique called multilevel logistic regression, Ayele DG & al. report in Assessment of Malaria Transmission in Kenya Using Multilevel Logistic Regression, Heliyon. 2024 Oct 24; 10(21):e39835, https://doi.org/10.1016/j.heliyon.2024.e39835, that “findings reveal that factors such as region, place of residence, mosquito bed net use, water source location, wealth index, age, household size, and altitude are significantly associated with malaria’s prevalence.”

It is no surprise that Haberman T & al. report in The Mediating Role of Behavioural and Socio-Structural Factors on the Association Between Household Wealth and Childhood Malaria in Ghana, Malaria J. 2024 Dec 13; 23:370, https://doi.org/10.1186/s12936-024-05204-6, that “the link between socioeconomic position (SEP) and malaria is well established…” However, the authors state that “the causal pathways remain poorly understood.” They studied data on 3884 children from the Ghana Health and Demographic Survey of 2022. Of them, 19.4% had malaria (presumably that year). Analyzing the families “through housing quality, educational attainment (EA), long-lasting insecticidal net (LLIN) use, indoor residual spraying (IRS), and healthcare-seeking behaviour (HSB),” the results showed that maternal EA of secondary school or higher …, improved housing … [and ITN use] partially mediated the association between SEP and malaria, stronger if all three factors were present. Analyzing IRS and HSB did not yield statistically significant association.

Another risk factor analysis is Gobe DE & al., Determinants of Malaria Infection Among Under Five Children in Gursum District of Somali Region, Eastern Ethiopia, Malaria J. 2024 Dec 19; 23:393, https://doi.org/10.1186/s12936-024-05206-4. These authors found “five exposures significantly associated with malaria positivity among children: living near a source of water …, residing in rural areas …, living in houses with openings or holes in the walls that facilitate mosquito entry …, not receiving malaria health information [and] proximity to malaria vector breeding habitats…”

A risk factor for malaria not often commented on is blood transfusion in communities where blood donors or donated blood are not routinely tested for Plasmodium parasites. Loua OO & al. report in Risk of Transfusion-Associated Malaria in Sub-Saharan Africa: The Case of Mali, Transfus Med. 2024 Nov 4, https://doi.org/10.1111/tme.13101, that among 348 blood bags transfused into 108 patients over 8 months, 22% were found to have Plasmodium present. Among 54 initially negative patients, 20 received blood containing Plasmodium. All of the latter developed clinical malaria, and some died of it.

Placental malaria was rare (4.4%) among women who delivered their babies in a referral hospital, reported in Epuitai J & al., Prevalence and Factors Associated with Placental Malaria in Lira District, Northern Uganda: A Cross-Sectional Study, Malaria J. 2024 Nov 27; 23:360, https://doi.org/10.1186/s12936-024-05187-4. “Women aged less than 20 years …, and those not taking iron supplements during pregnancy … were associated with an increased likelihood of having placental malaria.”

General Epidemiology
Satapathy P & al. abstracted data from 31 studies encompassing 15 countries (12 in Africa) and tens of thousands of pregnant women to prepare their paper, 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. Their data confirm what is already generally held, namely that pregnant women with malaria are 48.4% more likely to have preterm delivery and 75.5% more likely to have low birthweight infants. The excess of stillbirth deliveries of women with malaria fell short of statistical significance.

While Alhassan A, & al.’s paper Call for Elimination Program of Malaria Among Children Under 5 Years Old Living in Refugee Camps in Eastern Democratic Republic of Congo, New Microbes New Infect. 2024 Oct 11, 62:101508, https://doi.org/10.1016/j.nmni.2024.101508, is not a paper based on data collected or analyzed by the authors, it is an important one because it draws attention to the prevalence of malaria in the high-risk environments of refugee camps, which frequently also suffer from lack of resources even more severe than the surrounding areas.

Ademoyegun JK & Aremu SO report that malaria prevalence in the medical center they studied was over 50% of 248 “randomly selected” patients, who “attended” the medical center, presumably these were outpatients. Males had higher prevalence than females. “Malaria was most common in the 26-40 age group (35.4%).” However, the criteria for selection required that patients presenting have symptoms that could be caused by malaria or hepatitis, so it was not a true random sample even among the health-care-seeking population. The article is Socioeconomic Determinants of Malaria and Hepatitis Infections: Insights from the Federal Medical Center, Makurdi, North Central, Nigeria, BMC Public Health. 2024 Nov 16; 24(1):3187, https://doi.org/10.1186/s12889-024-20666-8.

Grimée M & al., Heterogeneous Mosquito Exposure Increases Plasmodium vivax and Plasmodium falciparum Co-Infections: A Modelling Study, Proc Biol Sci. 2024 Dec; 291(2036):20242061, https://doi.org/10.1098/rspb.2024.2061, addresses the issue of coinfections by two Plasmodium species with its implications of treatment. The modeling performed by the authors leads to the conclusion that coinfections are more likely caused by near-simultaneous exposure to the two parasites by different mosquito bites, rather than P. falciparum infection reactivating P. vivax from the previously infected liver of the patient.

Another paper on a similar topic is Souleiman Y & al., Modeling and Investigating Malaria P. falciparum and P. vivax Infections: Application to Djibouti Data, Infect Dis Model. 2024 Jun 16; 9(4):1095-1116, https://doi.org/10.1016/j.idm.2024.06.003. The authors state in the abstract that their focus is on coinfections of the two Plasmodium species in Djibouti.

Spatiotemporal Studies
“Malaria transmission in Tanzania has declined significantly over the last 2 decades due to scaled-up control interventions. However, recent confirmation of artemisinin partial resistance (ART-R) in Kagera region in northwest Tanzania threatens the ongoing efforts to eliminate malaria in the country.” Petro DA & al., Geospatial Analysis of Malaria Burden in Kagera Region, Northwestern Tanzania Using Health Facility and Community Survey Data, Open Forum Infect Dis. 2024 Oct 11; 11(11):ofae609, https://doi.org/10.1093/ofid/ofae609, “was conducted according to the World Health Organization recommendation to generate evidence of malaria burden in areas with confirmed ART-R as the first step before developing a response strategy to the resistance.”

Soyekwo D & al., Assessing the Malaria Burden and Community Response to the Malaria Control and Management Programs in Omoro District, Northern Uganda, J Parasitol Res. 2024 Oct 28; 2024:8009447, https://doi.org/10.1155/2024/8009447.

Afriyie SO & al., Socio-Demographic Factors, Housing Characteristics, and Clinical Symptoms Associated with Falciparum Malaria in Two Rapidly Urbanizing Areas in the Ashanti region of Ghana, Malaria J, 2024 Nov 21, 23:354, https://doi.org/10.1186/s12936-024-05185-6.

Whyte M & al., Nigeria’s Malaria Prevalence In 2015: A Geospatial, Exploratory District-Level Approach, Geospat Health. 2024 Nov 25; 19(2), https://doi.org/10.4081/gh.2024.1243.

Aboisse A & al., Profiling Vivax Malaria Incidence, Residual Transmission, and Risk Factors Using Reactive Case Detection in Low Transmission Settings of Ethiopia, Malaria J, 2024 Nov 29, 23:363, https://doi.org/10.1186/s12936-024-05171-y.