According to a news release on 5 July by the World Health Organization (WHO):

• In response to high demand for the first-ever malaria vaccine, 12 countries in Africa will be allocated a total of 18 million doses of RTS,S/AS01 for the 2023–2025 period
• Malaria Vaccine Implementation Programme countries Ghana, Kenya and Malawi will receive doses to continue vaccinations in pilot areas
• Allocations were also made for new introductions in Benin, Burkina Faso, Burundi, Cameroon, Democratic Republic of the Congo, Liberia, Niger, Sierra Leone and Uganda”

The full news release can be accessed at https://www.who.int/news/item/05-07-2023-18-million-doses-of-first-ever-malaria-vaccine-allocated-to-12-african-countries-for-2023-2025–gavi–who-and-unicef

In June, the WHO declared Belize free of malaria.  During the same month, the lay press reported several cases of domestically transmitted malaria in Florida and one in Texas.  Given the low suspicion of malaria among physicians and other caregivers, one wonders whether the actual case numbers are significantly higher.

PEER REVIEWED PUBLICATIONS:

 

Prevention

 

Vaccines

Using data from the 2014 Phase III trial of the RTS,S/AS01 vaccine, Bell GJ & al. investigated the previously reported “reduced immune response to vaccination as a potential mechanism behind lower efficacy in high transmission areas… They conclude in Malaria Transmission Intensity and Parasitemia during the Three-Dose RTS,S/AS01 Vaccination Series Do Not Reduce Magnitude of Antibody Response nor Efficacy Against the First Case of Malaria, Res Sq. 2023 May 25: rs.3.rs-2960373, https://doi.org/10.21203/rs.3.rs-2960373/v1 that “vaccine efficacy is unrelated to infections during vaccination. Contributing to a conflicting literature, our results suggest that vaccine efficacy is also unrelated to infections before vaccination, meaning that delayed malaria is likely the main reason for lower efficacy in high transmission settings, not reduced immune responses.”

Another approach to vaccination was chosen by Chuang YM & al., who note that “[a]ctive or passive immunization against a mosquito saliva protein, AgTRIO, contributes to protection against Plasmodium infection of mice.” Using the mouse malaria model, they conclude in their paper, A Mosquito AgTRIO MRNA Vaccine Contributes to Immunity Against Malaria, NPJ Vaccines. 2023 Jun 7; 8(1):88, https://doi.org/10.1038/s41541-023-00679-x that “immunized mice exposed to Plasmodium berghei-infected mosquitoes had markedly reduced … infection levels and increased survival compared to control mice. In addition, as the humoral response … waned over 6 months, additional mosquito bites boosted the AgTRIO IgG titers, … which offers a unique advantage compared to pathogen-based vaccines.

 

Vector control and protection from vectors

Trujillano F & al. used drone images from two malaria-endemic regions in Burkina Faso and Côte d’Ivoire to report inMapping Malaria Vector Habitats in West Africa: Drone Imagery and Deep Learning Analysis for Targeted Vector Surveillance, Remote Sens (Basel). 2023 May 26; 15(11):2775, https://doi.org/10.3390/rs15112775 that they were able to consistently identify the “land cover types associated with the breeding sites…”

Abong’o B & al. conclude in Evaluation of Community-Based Vector Surveillance System for Routine Entomological Monitoring Under Low Malaria Vector Densities and High Bed Net Coverage in Western Kenya, Malaria J, 2023 Jul 3, 22:203, https://doi.org/10.1186/s12936-023-04629-9 that “[u]nsupervised community-based mosquito surveillance collected substantially fewer mosquitoes per trap-night compared to quality-assured collection by experienced field teams, while consistently overestimating the number of Anopheles mosquitoes during identification. … Further studies are needed to evaluate whether adopting low-cost, devolved supervision with spot checks, coupled with remedial training of the [community-based collectors], can improve … to be considered a cost-effective alternative to surveillance conducted by experienced entomological technicians.”

“Resistance to pyrethroid insecticides, the active component of most insecticide-treated nets is now widespread in sub-Saharan Africa, reducing the efficacy of these crucial tools. … it remains unknown how these traits influence Plasmodium falciparum infections in malaria-transmitting Anopheles mosquitoes.” Adams KL & al. established “pyrethroid-resistant and pyrethroid-susceptible population[s] of Anopheles gambiae s.l. derived from the same genetic background and performed experimental infections with P. falciparum. [They] found that the pyrethroid-resistant population was more supportive of malaria parasites compared to the susceptible population.” The paper isSelection for Insecticide Resistance Can Promote Plasmodium falciparum Infection in Anopheles, PLoS Pathogens, 2023 Jun 20, https://doi.org/10.1371/journal.ppat.1011448

Consistent with other reports, Aheto JMK & al., Predictors of Mosquito Bed Net Use Among Children Under-Fives in Ghana: A Multilevel Analysis of the 2019 Malaria Indicator Survey, Malaria J, 2023 Jun 26, 22:196, https://doi.org/10.1186/s12936-023-04634-y confirms the universal impression that insecticide treated bed nets (ITNs) are not used universally, even when they are available without cost, although there are wide variances in utilization. Rural families and families with fewer children had higher utilization than average, while the greater Accra region (the capital) was the geographic area with the lowest utilization.

Kuetche MTC & al., Prevalence and Risk Factors Determinants of the Non-Use of Insecticide-Treated Nets in an Endemic Area for Malaria: Analysis of Data from Cameroon, Malaria J, 2023 Jul 5, 22:205, https://doi.org/10.1186/s12936-023-04510-9 is another paper reporting low usage of ITNs through interviews. Of “7593 households interviewed, 77% had at least one ITN and 59% of the population used ITNs. Only 72% of the population with at least one ITN used it…  The factors that were associated with ITN use were the presence of sufficient nets in the household …, the region of residence …, the level of education of the respondent … [all with extremely low p values] and the standard of living (p = 0.0286). Sex, age, colour preferences, as well as the shape and size of the nets were not associated with ITN use.”

Examining “the utilization and the associated individual and community factors of insecticide-treated nets in Northern Nigeria,” Solanke BL & al. extracted and analyzed data of a sample of over 6800 women from the 2021 Nigeria Malaria Indicator Survey. They report in Utilization of Insecticide-Treated Nets and Associated Factors Among Childbearing Women in Northern Nigeria, Malaria J, 2023 Jun 16, 23:184, https://doi.org/10.1186/s12936-023-04620-4 that 71.8% of childbearing women “utilized insecticide-treated nets. Parity and household size were the significant individual/household characteristics associated with the utilization of insecticide-treated nets.”

Koenker H & al. conclude in How Many Mosquito Nets Are Needed to Maintain Universal Coverage: An Update, Malaria J, 2023 Jun 30, 22:200, https://doi.org/10.1186/s12936-023-04609-z that the “current status quo of conducting mass campaigns every three years using a population/1.8 quantifier is insufficient to achieve or maintain targets of 80% population access to ITNs in most malaria-endemic countries, given [that] most estimated retention times are less than three years… Continuous distribution strategies are likely to offer more efficient ways to maintain ITN coverage, with fewer nets, where ITN retention times are at least two and a half years. National malaria programmes and their funding partners should work to increase the number of ITNs available to those vulnerable to malaria, while at the same time working to extend the useful life of these critical commodities.”

After a change in chemicals used in indoor residual spraying by the Zambia malaria eraditation program, Ferriss E & al. “assessed the impact of transitioning from Actellic 300CS to long-acting Fludora Fusion using active surveillance data from 2014 through 2021.” They conclude that while “each 10% increase in community IRS coverage was associated with a 4% to 5% reduction in parasite prevalence …, suggesting a community-level protective effect,” the change in chemicals did not make a difference. The paper is  The Impact of Household and Community Indoor Residual Spray Coverage with Fludora Fusion in a High Malaria Transmission Setting in Northern Zambia, Am J Trop Med Hyg. 2023 Jun 26: tpmd220440, https://doi.org/10.4269/ajtmh.22-0440.

“Gene drive-modified mosquitoes (GDMMs) are proposed as new tools for control and elimination of malaria and other mosquito-borne diseases, and promising results have been observed from testing conducted in containment. Although still at an early stage of development, it is important to begin now to consider approval procedures and market entry strategies for the eventual implementation of GDMMs in the context of disease control programs.” James SL & al. explore the subject in Requirements for Market Entry of Gene Drive-Modified Mosquitoes for Control of Vector-Borne Diseases: Analogies to Other Biologic and Biotechnology Products, Front Bioeng Biotechnol. 2023 Jun 8; 11:1205865, https://doi.org/10.3389/fbioe.2023.1205865.

The gene drive method of vector control is also the subject of Carballar-Lejarazú R & al.’s Dual Effector Population Modification Gene-Drive Strains of the African Malaria Mosquitoes, Anopheles gambiae and Anopheles coluzzii, Proc Natl Acad Sci USA, 2023 Jul 18; 120(29):E2221118120, https://doi.org/10.1073/pnas.2221118120. Epub 2023 Jul 10. They claim to “demonstrate the potential of Cas9/guide RNA (gRNA)-based gene-drive systems linked to dual antiparasite effector genes to spread rapidly through mosquito populations.” Using modeling based on laboratory results, their “data supported transmission modeling of conceptual field releases in an island setting that shows meaningful epidemiological impacts at different sporozoite threshold levels (2.5 to 10 k) for human infection by reducing malaria incidence in optimal simulations by 50 to 90% within as few as 1 to 2 [months] after a series of releases, and by ≥90% within 3 [months].”

An “understanding of vector distribution and malaria transmission dynamics at a local scale is essential for implementing and evaluating effectiveness of vector control strategies. Through the data gathered in the framework of a cluster randomized controlled trial,” Koffi AA &al. investigated “distribution of the Anopheles vector, their biting behaviour and malaria transmission dynamics [in] central Côte d’Ivoire.” Three Anopheles species are known to transmit malaria in the area; an unprotected person in the region was found to receive on the average close to 300 infected bites (italics added) from one or another in the course of a year. “… the highest biting rate … occurred in the months of heavy rainfall. However, mosquitoes infected with malaria parasites remained present in the dry season, despite the low density of mosquito populations.” The paper is Anopheles Vector Distribution and Malaria Transmission Dynamics in Gbêkê Region, Central Côte d’Ivoire, Malaria J, 2023 Jun 22, 23:192, https://doi.org/10.1186/s12936-023-04623-1

Coleman S & al., estimated malaria transmission risk based on vector-human interactions in northern Ghana, where indoor residual spraying (IRS) and insecticide-treated nets (ITNs) have been deployed. As reported in Estimating Malaria Transmission Risk Through Surveillance of Human-Vector Interactions in Northern Ghana, Parasit Vectors. 2023 Jun 19; 16(1):205, https://doi.org/10.1186/s13071-023-05793-2, “[i]ndoor and outdoor human biting rates (HBRs) were measured using monthly human landing catches (HLCs) from June 2017 to April 2019… Indoor and outdoor HBRs were similar in both the IRS intervention … and control communities… After adjusting for human behavior observations and parity, the combined effect of IRS and ITN utilization (IRS: 37.8%; control: 57.3%) on reducing malaria transmission risk was 58% in IRS + ITN communities and 27% in control communities with ITNs alone…”

“Larvicides, especially in endemic regions, [constitute] an effective approach to the control of mosquito-borne diseases.” As reported in Sanei-Dehkordi A & al., Nanoliposomes Containing Three Essential Oils from the Artemisia Genus as Effective Larvicides Against Aedes aegypti and Anopheles stephensi, Sci Rep, 2023 Jul 7; 13(1):11002, https://doi.org/10.1038/s41598-023-38284-6, “the composition of three essential oil from the Artemisia L. family was analyzed by Gas Chromatography-Mass Spectrometry. Afterward, nanoliposomes containing essential oils of A. annua, A. dracunculus, and A. sieberi … were prepared… The results revealed that nanoliposomes containing A. dracunculus exerted the highest potential larvicidal effect against Ae. aegypti and An. stephensi …”

“Attractive targeted sugar baits (ATSBs) control sugar-feeding mosquitoes with oral toxicants, and may effectively complement core malaria interventions, such as insecticide-treated nets even where pyrethroid-resistance is widespread.” Muyaga LL & al., Effects of Vegetation Densities on the Performance of Attractive Targeted Sugar Baits (ATSBs) for Malaria Vector Control: A Semi-Field Study, Malaria J, 2023 Jun 21, 23:190, https://doi.org/10.1186/s12936-023-04625-z is a laboratory-based study of these baits, coupled with human landing catches.  The study showed modest efficacy in reducing biting frequencies, depending to some extent on vegetation in the bait chambers.

 

Chemoprophylaxis

“Cabamiquine is a novel antimalarial that inhibits Plasmodium falciparum translation elongation factor 2. [van der Plas JL & al.] investigated the causal chemoprophylactic activity and dose–exposure–response relationship of single oral doses of cabamiquine following the direct venous inoculation (DVI) of P falciparum sporozoite.  Their report their Phase 1b study in Causal Chemoprophylactic Activity of Cabamiquine Against Plasmodium falciparum in a Controlled Human Malaria Infection: A Randomized, Double-Blind, Placebo- Controlled Study in the Netherlands, Lancet Infect Dis, 2023 Jul 3, https://doi.org/10.1016/S1473-3099(23)00212-8. Using a small number of volunteers who underwent treatment with the drug followed by controlled infection, they concluded that the drug was well tolerated (adverse events “were of mild severity, transient, and resolved without sequelae”). They propose that “cabamiquine could be developed as a single-dose monthly regimen for malaria prevention.” Olotu A & Möhrle JJ, Moving Seasonal Malaria Chemoprevention out of Its Geographical Isolation, Lancet Infect Dis, 2023 Jul 3, https://doi.org/10.1016/S1473-3099(23)00268-2 is an accompanying editorial.

Seasonal Malaria chemoprevention (SMC) is one of the large-scale life-saving malaria interventions … recommended for the Sahel subregion, including Burkina Faso and recently extended to other parts of Africa. Sondo P & al., Baseline Malarial and Nutritional Profile of Children Under Seasonal Malaria Chemoprevention Coverage in the Health District of Nanoro, Burkina Faso, PLoS One. 2023 Jun 26; 18(6):e0287210, https://doi.org/10.1371/journal.pone.0287210 report on the characteristics of the population, especially older children who receive SMC.  One of their major conclusions is that in the areas studied “children who received [SMC] were mostly undernourished during the period of SMC delivery, suggesting the need for combining the SMC with synergistic interventions against malnutrition to achieve best impact.”

“Young women in sub-Saharan Africa are a group at increased risk for malaria in pregnancy. Early antenatal care (ANC) seeking makes it more likely that women will receive the recommended doses of intermittent preventive treatment of malaria in pregnancy.” The abstract of Olapeju B, & al., Malaria-Related Psychosocial Factors, Past Antenatal Care-Seeking Behaviors, and Future Antenatal Care-Seeking Intentions by Maternal Age in Malawi and Democratic Republic of the Congo, Am J Trop Med Hyg. 2023 Jun 26: tpmd230069. https://doi.org/10.4269/ajtmh.23-0069 focuses primarily on the factors that enhance or impede young pregnant women to seek prenatal care early.

“The efficacy and effectiveness of antimalarial drugs are threatened by increasing levels of resistance and therefore require continuous monitoring. Chemoprevention is increasingly deployed as a malaria control measure, but there are no generally accepted methods of assessment. We propose a simple method of grading the parasitological response to chemoprevention (focusing on seasonal malaria chemoprevention) that is based on pharmacometric assessment” is the entire abstract of White NJ & al., A Proposed Method of Grading Malaria Chemoprevention Efficacy, Trans R Soc Trop Med Hyg, 2023 Jul 10; trad042, https://doi.org/10.1093/trstmh/trad042.

 

Other

“The targets and mechanisms of naturally acquired immune responses to P. falciparum parasites remain obscured, owing in part to the absence of a legible signature of immunity in humans exposed to repeated natural infections. A hallmark of functional protection for malaria and other pathogens is a reduced risk of re-infection with homologous strains. In a community-based, longitudinal cohort in a high transmission setting in Western Kenya, [Markwalter CF & al.] observed that, compared to parasites cleared following an asymptomatic infection, the hazard of reinfection following a symptomatic infection was reduced by 30–40%.” The paper is Symptomatic Malaria Enhances Protection from Reinfection with Homologous Plasmodium falciparum Parasites, PLoS Pathogens, 2023 Jun 12, https://doi.org/10.1371/journal.ppat.1011442

Fikadu M & Ashenafi E, Malaria: An Overview, Infect Drug Resist. 2023 May 29; 16:3339-3347, https://doi.org/10.2147/idr.s405668 is a paper that is difficult to assign to any category in these reports. According to the abstract, it covers prevention, diagnosis, treatment, and epidemiology. The abstract ends thus: “…there is no prophylactic agent that can prevent malaria 100%. Therefore, prophylaxis shall be augmented with the use of personal protective measures.” That is why it is cited here.

 

Diagnosis

 

General diagnostics

Although Mahale P, & al., Design and Validation of Multiplex Polymerase Chain Reaction as a Diagnostic Tool for Plasmodium Species, J Vector Borne Dis, 2023 Apr-Jun; 60(2):200-206, https://doi.org/10.4103/0972-9062.374038 refers to a study in India, its conclusions on the merit of multiplex polymerase chain reaction (mPCR) versus standard PCR to diagnose malaria (whether falciparum or vivax) appears relevant world-wide.  It is unclear from the abstract how to proceed after the diagnosis, since the recommended treatments of the two kinds of malaria are different.

“The most specific and sensitive malaria diagnostic methods are PCR and LAMP [loop-mediated isothermal amplification]. However, both require specific equipment, extraction procedures and a cold chain. Ramírez AM & al., Malaria Diagnosis Using a Combined System of a Simple and Fast Extraction Method with a Lyophilised Dual-LAMP Assay in a Non-Endemic Setting, Pathog Glob Health, 2023 Jul 6; 1-11, https://doi.org/10.1080/20477724.2023.2232595 reports on a modification of the LAMP assay that is simpler to perform and is successfully validated by multiplex PCR.

 

Field diagnostics

Similar to other studies included in these reports, Zeleke MT & al., Diagnostic Performance of PfHRP2/pLDH Malaria Rapid Diagnostic Tests in Elimination Setting, Northwest Ethiopia, PLoS Glob Public Health, 2023 Jul 10; 3(7):E0001879, https://doi.org/10.1371/Journal.Pgph.0001879 documents the limited reliability of RDTs in diagnosing malaria, in comparison with light microscopy and PCR.

Hofer LM & al. promote the use of rapid diagnostic tests (RDTs) to discern which children with asymptomatic falciparum infections transmit the parasite to mosquitoes.  As they report in Malaria Rapid Diagnostic Tests Reliably Detect Asymptomatic Plasmodium falciparum Infections in School-Aged Children that Are Infectious to Mosquitoes, Parasit Vectors. 2023 Jun 30; 16(1):217, https://doi.org/10.1186/s13071-023-05761-w, even though significantly more children were positive on qualitative PCR testing (31.7% vs. 18.1% on RDT), the vast majority of mosquitoes that were infected upon being fed venous blood from the children were positive on RDT.  Where this leaves the other children that are positive on PCR is uncertain.

New diagnostic methods

None this month

 

Treatment

 

Treatment results

Alebachew M & al., Therapeutic Efficacy of Pyronaridine-Artesunate (Pyramax^®) Against Uncomplicated Plasmodium falciparum Infection at Hamusit Health Centre, Northwest Ethiopia, Malaria J, 2023 Jun 17, 23:186, https://doi.org/ 10.1186/s12936-023-04618-y is a straight forward report of experience with 90 patients. Among these, 86/90 (95.6%) completed the 42-day follow-up study period. The overall PCR-corrected cure rate … was very high at 86/87 (98.9%) …with no serious adverse events. The parasite clearance rate was high with fast resolution of clinical symptoms; 86/90 (95.6%) and 100% of the study participants cleared parasitaemia and fever on day 3, respectively.

Andrade AO & al. “evaluated the impact of currently used drugs on the transmission of P. vivax.”  The site of their work is not clear from the abstract.  As reported in Transmission-Blocking Activity of Antimalarials for Plasmodium vivax Malaria in Anopheles darlingi, PLoS Negl Trop Dis. 2023 Jun 16; 17(6):e0011425, https://doi.org/10.1371/journal.pntd.0011425, several standard treatment regimens for vivax malaria were also effective in preventing transmission to the species listed in the title.

“… [G]lobal progress in reducing malaria cases has plateaued since 2015 mostly due to the increased insecticide resistance and behavioral changes in Anopheles vectors. Additional control strategies are thus required to further reduce the burden of malaria and contain the spread of resistant and invasive Anopheles vectors.” Sagna AB & al. “discuss the advantages and disadvantages of using ivermectin for malaria control with a focus on the risk of selecting ivermectin resistance in malaria vectors. [They] also highlight the importance of understanding how ivermectin resistance could develop in mosquitoes.” The paper is Ivermectin as a Novel Malaria Control Tool: Getting Ahead of the Resistance Curse, Acta Trop. 2023 Jun 22; 245:106973. https://doi.org/10.1016/j.actatropica.2023.106973.

 

Adherence to guidelines

“Three-day artemisinin-based combination therapy (ACT) is the current standard of care for the treatment of malaria. However, specific drug resistance associated with reduced efficacy of ACT has been observed, therefore necessitating the clinical development of new anti-malarial drugs and drug combinations. Previously, Single Encounter Radical Cure and Prophylaxis (SERCAP) has been proposed as ideal target-product-profile for any new anti-malarial drug regimen as this would improve treatment adherence besides ensuring complete cure and prevention of early reinfection. Mbassi DE & al., Real-Life Effectiveness of Anti-Malarial Treatment Regimens: What Are We Aiming for? Malaria J, 2023 Jun 19, 23:189, https://doi.org/ 10.1186/s12936-023-04606-2 reviews the pros and cons of SERCAP and notes that “an alternative proposition is—in contrast to the current World Health Organization (WHO) treatment guidelines—to aim for less than three days, but still multiple-dose anti-malarial treatment regimens. This may help to strike the optimal balance between improving treatment adherence, maximizing treatment effectiveness, while keeping attrition of new drugs and drug regimens as low as possible.”

 

Side effects and complications

None this month

 

Drug resistance

L’Episcopia M & al. tested 53 falciparum samples collected at the Saint Jean de Dieu hospital in Tanguiéta, Benin studying them for genetic markers of artemisinin resistance. As they report in their article, Polymorphism Analysis of Drug Resistance Markers in Plasmodium falciparum Isolates from Benin, Acta Trop. 2023 Jun 20: 106975, https://doi.org/10.1016/j.actatropica.2023.106975, “[n]o Pfkelch13 validated or candidate artemisinin partial resistant variants were identified… In addition, the frequency of parasites with dual deletion of the histidine-rich protein 2 and 3 genes (pfhrp2 and pfhrp3), known to be responsible of the performance of HRP-based malaria rapid diagnostic tests (HRP-RDT), was estimated and no evidence of these gene deletions was noted.

Vanheer LN & al., Genome-Wide Genetic Variation and Molecular Surveillance of Drug Resistance in Plasmodium falciparum Isolates from Asymptomatic Individuals in Ouélessébougou, Mali, Sci Rep. 2023 Jun 12; 13(1):9522, https://doi.org/10.1038/s41598-023-36002-w “provides the most recent assessment of P. falciparumgenetic diversity in Mali, a country with the second highest burden of malaria in West Africa, thereby informing malaria control activities.”

New drug research

According to Ogutu B, Yeka A, Kusemererwa S & al., Ganaplacide (KAF156) Plus Lumefantrine Solid Dispersion Formulation Combination for Uncomplicated Plasmodium falciparum malaria: An Open-Label Parallel Group, Randomized, Controlled, Phase 2 Trial, Lancet Infect Dis, 2023 Jun 13, hrrps://doi.org/10.1016/S1473-3099(23)00209-8 and Chen I & Ishengoma DS, Ganaplacide Plus Lumefantrine Solid Dispersion Formulation: Considerations for Development and Rollout, Lancet Infect Dis, 2023 Jun 13, https://doi.org/10.1016/ S1473-3099(23)00231-1 “[c]urrently, 12 new drugs and combinations are undergoing phase 2 exploratory studies, as per the pipeline overseen by Medicines for Malaria Venture updated in May, 2022. The combination furthest along the pipeline is ganaplacide plus lumefantrine, which contains a novel compound and a new solid dispersion formulation (SDF) of lumefantrine that can be given once a day to improve adherence… Given the urgent need for efficacious novel medicines against artemisinin-resistant malaria and ganaplacide plus lumefantrine-SDF’s leading place in the pipeline, [the authors] suggest the prompt initiation of regulatory, manufacturing, and implementation preparations. For regulatory approvals, WHO prequalification will be essential to enable drug availability in endemic countries using major funders, including UNITAID and the Global Fund to Fight AIDS, Tuberculosis, and Malaria. For manufacturing, ample production with backup facilities in case of supply chain disruptions and drug stock-outs will be necessary.”

These pages have previously reported on an experimental antimalarial M5717. Yin X & al., Evaluation of a Multiphasic Parasite Clearance Profile After Treatment of Experimental Human Infection with the Investigational Anti-Malarial M5717 Using Segmented Mixed Effect Models, Malaria J, 2023 Jun 28, 22:199, https://doi.org/10.1186/s12936-023-04627-x reports on “the phase 1b experimental Plasmodium falciparum malaria human infection study.” It is a statistical study.

Ariefta NR & al. tested a drug called Phebestin against mouse malaria. They state in Antiplasmodial Activity Evaluation of a Bestatin-Related Aminopeptidase Inhibitor, Phebestin, Antimicrob Agents Chemother. 2023 Jun 14: e0160622, https://doi.org/10.1128/aac.01606-22 that “Phebestin inhibited the in vitro multiplication of the P. falciparum 3D7 (chloroquine-sensitive) and K1 (chloroquine-resistant) strains…” and had no cytotoxic effects on human fibroblast cells. The drug also showed inhibory effects on mouse malaria.

“A functional, multi-organ, serum-free system was developed” by Rupar MJ & al. for the culture of P. falciparum “to establish innovative platforms for therapeutic drug development. It contains 4 human organ constructs including hepatocytes, splenocytes, endothelial cells, as well as recirculating red blood cells which allow for infection with the parasite.” Development of a Human Malaria-On-A-Chip Disease Model For Drug Efficacy And off-Target Toxicity Evaluation, Sci Rep. 2023 Jun 28; 13(1):10509, https://doi.org/10.1038/s41598-023-35694-4 “establishes a new approach to the evaluation of anti-malarial therapeutics in a realistic human model with recirculating blood cells for 7 days.”

An unusual source of potential antimalarials is the subject of Salimo ZM & al., Toxins from Animal Venoms as a Potential Source of Antimalarials: A Comprehensive Review, Toxins (Basel). 2023 Jun 3; 15(6):375, https://doi.org/10.3390/toxins15060375. From their research, “50 isolated substances, 4 venom fractions and 7 venom extracts from animals such as anurans, spiders, scorpions, snakes, and bees were identified. These toxins act as inhibitors at different key points in the biological cycle of Plasmodium and may be important in the context of the resistance of Plasmodium to currently available antimalarial drugs.”

 

Plant extracts and traditional treatments

Ocen M & al., Efficacy of Antimalarial Herbal Medicines Used by Communities in Malaria Affected Regions Globally: A Protocol for Systematic Review and Evidence and Gap Map, BMJ Open, 2023 Jul 7; 13(7):e069771, https://doi.org/10.1136/bmjopen-2022-069771 is a “systematic review and evidence gap map (EGM) is intended to collate and map the available evidence, identify the gaps and synthesise the efficacy of herbal antimalarial medicines used in malaria affected regions globally.”.

Ribeiro GJG & al. focus “on plant extracts and some of their isolated natural products with at least in vitro antiplasmodial effects reported in the literature comprising the last five years (2018-2022) in Plant Extracts as a Source of Natural Products with Potential Antimalarial Effects: An Update from 2018 to 2022, Pharmaceutics.2023 Jun 1; 15(6):1638, https://doi.org/10.3390/pharmaceutics15061638.

 

Other

“Village Health Workers (VHWs) in Uganda provide treatment for the childhood illness of malaria, pneumonia, and diarrhoea through the integrated community case management (iCCM) strategy. Under the strategy children under five years receive treatment for these illnesses within 24 h of onset of illness.” Mulogo E & al., Promptness in Seeking Treatment from Village Health Workers for Children Under Five Years with Malaria, Diarrhoea and Pneumonia in Rural Southwestern Uganda, Malaria J, 2023 Jun 27, 22:198, https://doi.org/10.1186/s12936-023-04633-z “examined promptness in seeking treatment from VHWs by children under five years with malaria, pneumonia, and diarrhoea in rural southwestern Uganda… 64% of the children included in the study sought treatment promptly. Children with fever had the highest likelihood of seeking prompt treatment.

 

Campaigns and Policies

Hodson R, The Challenges Facing Scientists in the Elimination of Malaria; The World Now Has a Malaria Vaccine, But it Won’t Be Enough to Wipe Out the Parasitic Disease, Nature, 2023 Jun 28, 618:S19, https://doi.org/10.1038/d41586-023-02047-0 is not a peer reviewed research article but an opinion piece that contrasts the financial and other obstacles in place against the eradication of malaria with the major advances including vaccine research and now application, the intense research to overcome drug resistance, and new approaches such as monoclonal antibodies.  The article ends with the acknowledgement of the ethical questions raised by the gene drive efforts of vector control.

“Despite developing a national malaria strategy and monitoring and evaluation strategies, Kenya has not been able to meet the incidence reduction targets set by the World Health Organisation, underscoring the need for more work in identifying the barriers to implementing strategies and optimising the distribution of public health interventions,” concludes Lacey H & al., Combating Malaria in Kenya Through Collaborative Population Health Education: A Systematic Review and Pilot Case Study, Infect Dis (Lond), 2023 Jul 10; 1-20, https://doi.org/10.1080/23744235.2023.2231082. A 6-week online educational pilot conducted with healthcare students from Kenya, Japan, the UK, and Cyprus “proposed innovative solutions, including two-tier malaria control strategies, maternal malaria clinical education, community awareness through schools and NGOs, and a 10-year health system strengthening and immunisation plan.”

Mokoulu OA & al.’s paper “is based on an analysis of policy documents and stakeholders’ perspectives drawn from an empirical study conducted in Nigeria, 2019–2020.” In A Framework for Stakeholder Engagement in the Adoption of New Anti-Malarial Treatments in Africa: A Case Study of Nigeria, Malaria J, 2023 Jun 16, 22:185, https://doi.org/10.1186/s12936-023-04622-2 they noted that “the adoption of artemisinin-based combination therapy (ACT) in Nigeria was swift due to political will, funding and support from global developmental partners. However, the implementation of ACT was met with resistance from suppliers, distributors, prescribers, and end-users, attributed to market dynamics, costs and inadequate stakeholder engagement. Deployment of ACT in Nigeria witnessed increased developmental partner support, robust data generation, ACT case-management strengthening and evidence on anti-malarial use in severe malaria and antenatal care management.”

 

Epidemiology

 

Climate  change, biodiversity and environment

While Yadav CP & al., Climate Zones Are a Key Component of the Heterogeneous Presentation of Malaria and Should Be Added as a Malariometric for the Planning of Malaria Elimination, PLOS Glob Public Health. 2023 Jun 28; 3(6):e0001878, https://doi.org/10.1371/journal.pgph.0001878 is focused strictly on the various climactic zones of India, its method of analysis may well be applicable to sub-Saharan Africa, where climate regions are just as numerous and changing in our era.

Tuno N & al. measured “how the malaria parasite infection in A. stephensi is influenced by environmental factors to predict its expansion in a new environment. Effects of temperature and food conditions during larval periods on larval mortality, larval period, female wing size, egg production, egg size, adult longevity, and malaria infection rate were studied using a laboratory strain. Larval survival and female wing size were generally reduced when reared at higher temperatures and with a low food supply during the larval period…The infection rate of mosquitoes that fed on blood from malaria-infected mice was not affected by rearing temperature or food conditions during the larval period. Higher temperatures may reduce infection.” The paper is Effects of Temperature and Nutrition During the Larval Period on Life History Traits in an Invasive Malaria Vector Anopheles stephensi, Insects. 2023 Jun 10; 14(6):543. https://doi.org/10.3390/insects14060543

While the El Niño phenomenon is known to affect a multitude of human activities, and possibly disease, Woyessa A & al., El Niño and Other Climatic Drivers of Epidemic Malaria in Ethiopia: New Tools for National Health Adaptation Plans, Malaria J, 2023 Jun 24, 22:195, https://doi.org/10.1186/s12936-023-04621-3#Sec1 does not appear to reach any firm conclusions as to its effects on malaria.

 

General epidemiology

Shi D & al., Trends of the Global, Regional and National Incidence, Mortality, and Disability-Adjusted Life Years of Malaria, 1990-2019: An Analysis of the Global Burden of Disease Study 2019, Risk Manag Healthc Policy. 2023 Jun 26; 16:1187-1201, https://doi.org/10.2147/rmhp.s419616 is a global study in the setting of declining malaria incidence over 29 years.  Their conclusions track other reports, namely that “[m]alaria threatens global public health, especially in Central Sub-Saharan Africa and Western Sub-Saharan Africa. Children 1-4 years old continue to bear the most significant burden of malaria.”

fetal sex has been identified to modify the risks of maternal asthma, pre-eclampsia, and gestational diabetes. One study demonstrated increased risk of placental malaria in women carrying a female fetus. We investigated the association between fetal sex and malaria in pregnancy in 11 pregnancy studies

“Panels of informative biallelic single nucleotide polymorphisms (SNPs) have been proposed to be an economical method to fast-track the population genetic analysis of Plasmodium falciparum in malaria-endemic areas. Whilst used successfully in low-transmission areas where infections are monoclonal and highly related,” Argyropoulos DC & al., Performance of SNP Barcodes to Determine Genetic Diversity and Population Structure of Plasmodium falciparum in Africa, Front Genet. 2023 Jun 1; 14:1071896, https://doi.org/10.3389/fgene.2023.1071896 presents “the first study to evaluate the performance of these 24- and 96-SNP molecular barcodes in African countries, characterised by moderate-to-high transmission, where multiclonal infections are prevalent.” They state that their “results demonstrate that these SNP barcodes are vulnerable to ascertainment bias and as such cannot be used as a standardised approach for malaria surveillance in moderate-to-high transmission areas in Africa, where the greatest genomic diversity of P. falciparum exists at local, regional and country levels.”

“[F]etal sex has been identified to modify the risks of maternal asthma, pre-eclampsia, and gestational diabetes. One study demonstrated increased risk of placental malaria in women carrying a female fetus.” Unger HW & al.investigated the association between fetal sex and malaria in pregnancy in 11 pregnancy studies” and report that “[t]here is limited evidence that fetal sex influences the risk of malaria infection in pregnancy.” The paper is Fetal Sex and Risk of Pregnancy-Associated Malaria in Plasmodium falciparum-Endemic Regions: A Meta-Analysis, Sci Rep. 2023 Jun 26; 13(1):10310, https://doi.org/10.1038/s41598-023-37431-3.

“Anopheles stephensi is an efficient vector of both Plasmodium falciparum and Plasmodium vivax in South Asia and the Middle East. The spread of An. stephensi to countries within the Horn of Africa threatens progress in malaria control in this region as well as the rest of sub-Saharan Africa.” Al-Eryani SM & al., Public Health Impact of the Spread of Anopheles stephensi in the WHO Eastern Mediterranean Region Countries in Horn of Africa and Yemen: Need for Integrated Vector Surveillance and Control, Malaria J, 2023 Jun 19, 23:187, https://doi.org/10.1186/s12936-023-04545-y reports that “Djibouti, Somalia, Sudan and Yemen had reported the detection of An. stephensi as of 2021. In Djibouti City, following its detection in 2012, the estimated incidence increased from 2.5 cases per 1000 in 2013 to 97.6 cases per 1000 in 2020. However, its contribution to malaria transmission [elsewhere] is unclear because of other factors, quality of the urban malaria data, human mobility, uncertainty about the actual arrival time of An. stephensi and poor entomological surveillance.”

González-Sanz M & al., Updates on Malaria Epidemiology and Prevention Strategies, Curr Infect Dis Rep. 2023 Jun 8: 1-9, https://doi.org/10.1007/s11908-023-00805-9 is a review of recent events, such as “an increase in the number of total cases and deaths globally during 2020-2021, in part attributed to the COVID-19 pandemic. The emergence of artemisinin-resistant species in new areas and the expanding strategies to curb the burden of this infection, such as vaccination, have been implemented in certain endemic areas and their performance is currently being evaluated.” They conclude that “malaria risk is driven more by the external environment than home construction within the study area, possibly due to transmission regularly occurring outside of the home. Additionally, they suggest that when predicting malaria risk the benefit may not outweigh the high costs of attaining detailed information on household predictors.”

“Malaria risk is not uniform across relatively small geographic areas, such as within a village. This heterogeneity in risk is associated with factors including demographic characteristics, individual behaviours, home construction, and environmental conditions, the importance of which varies by setting, making prediction difficult.” Hollingsworth BD & al., Comparing Field-Collected Versus Remotely-Sensed Variables to Model Malaria Risk in the Highlands of Western Uganda, Malaria J, 2023 Jun 26, 22:197, https://doi.org/10.1186/s12936-023-04628-w “attempted to compare the ability of statistical models to predict malaria risk at the household level using either (i) free easily-obtained remotely-sensed data or (ii) results from a resource-intensive household survey.”

As reported in Increased Peripartum Mortality Associated with Maternal Subclinical Malaria in Mozambique, Malaria J. 2023 Jun 12; 22:182, https://doi.org/10.1186/s12936-023-04613-3, Jaén-Sánchez N & al., “found a significant association between subclinical malaria and a higher peripartum mortality risk, which persisted after controlling for maternal comorbidity and maternal and pregnancy characteristics…”  However, their sample of women studied was very small (40).

Kotepui M & al. searched the literature to explore the association of ascorbic acid levels with malaria infections. In Malaria Is Associated with Diminished Levels of Ascorbic Acid: A Systematic Review and Meta-Analysis,Antioxid Redox Signal. 2023 Jun 19, https://doi.org/10.1089/ars.2023.0306 they report that patients with mild or severe malaria consistently had lower ascorbic acid levels than patients without such infections.  However, they make no claim as to causality.

Olewe PK & al.  made extensive studies of Hemoglobinopathies, Merozoite Surface Protein-2 Gene Polymorphisms, and Acquisition of Epstein Barr Virus Among Infants in Western Kenya, BMC Cancer. 2023 Jun 20; 23(1):566, https://doi.org/10.1186/s12885-023-11063-2.  They report that none of the putative in utero causal agents predispose Kenyan children to acquiring EB virus and therefore Burkitt’s lymphoma.

Oyegoke OO & al. developed a so-called “seasonal auto-regressive integrated moving average (SARIMA) model” and report that the vast majority of cases in the province studied are locally acquired. In Towards Malaria Elimination: Analysis of Travel History and Case Forecasting Using the SARIMA Model in Limpopo Province, Parasitol Res, 2023 Jun 13, https://doi.org/10.1007/s00436-023-07870-y they recommend stringent local control measures.

 

Spatiotemporal studies

Wu S & al., Spatial Dynamics of Malaria Transmission, PLoS Comput Biol. 2023 Jun 12; 19(6):e1010684, https://doi.org/10.1371/journal.pcbi.1010684

Debash H & al., Malaria Surveillance, Outbreak Investigation, Response and Its Determinant Factors in Waghemra Zone, Northeast Ethiopia: Unmatched Case-Control Study, Sci Rep. 2023 Jun 19; 13(1):9938, https://doi.org/10.1038/s41598-023-36918-3

Thawer SG & al., Spatio-Temporal Modelling of Routine Health Facility Data for Malaria Risk Micro-Stratification in Mainland Tanzania, Sci Rep. 2023 Jun 30; 13(1):10600, https://doi.org/10.1038/s41598-023-37669-x

Fola AA & al., Temporal and Spatial Analysis of Plasmodium falciparum Genomics Reveals Patterns of Parasite Connectivity in a Low-Transmission District in Southern Province, Zambia, Malaria J, 2023 Jul 7, 22:208, https://doi.org/10.1186/s12936-023-04637-9.

Dieng S & al., Geo-Epidemiology of Malaria Incidence in the Vhembe District to Guide Targeted Elimination Strategies, South-Africa, 2015-2018: A Local Resurgence, Sci Rep, 2023 Jul 8; 13(1):11049, https://doi.org/10.1038/s41598-023-38147-0.