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

On April 11 Michael MacDonald published an opinion piece entitled Regaining the Path to Malaria Elimination: Lessons from the Pandemic, Malaria World J, 2024, Apr 11, 15:6, https://www.malariaworld.org/malariaworld-journal/regaining-the-path-to-malaria-elimination-lessons-from-the-pandemic. In it, he decries what he describes as formulaic approaches to the guideline-driven efforts at vector control, chemoprophylaxis and treatment. He claims that these are driven by commercial interests and researchers in search of funding. He highlights what he identifies as a new menace, namely the huge refugee populations in parts of the world where malaria is endemic and where he states that new approaches are needed. To quote him: “There is a gap where new tools in development could play a life-saving role if WHO would provide ‘emergency use listing’, as it did in response to COVID-19, that would enable donor funding for large-scale pilot deployment. We will not reach global malaria targets unless we address these ever-expanding challenges, especially during the acute phase of humanitarian emergencies. Vector control in the acute aftermath of an emergency or disaster is NOT traditional vector control. …. We need to fast-track development and deployment, learning by doing, providing emergency-use authorisation for emerging vector control tools including spatial repellents, IRS adapted for temporary shelters, etofenprox treated materials, improved targeting and delivery of larvicides – all at an advanced stage of development, just waiting for word from Geneva.”

Chaphalkhar SR, Innovative Approaches Needed to Overcome Health System Barriers in Malaria Vaccination, https://www.news-medical.net/news/20240315/Innovative-approaches-needed-to-overcome-health-system-barriers-in-malaria-vaccination.aspx is a much more revealing summary than the abstract of the Amimo article reported last month on these pages.  The following is a short list of the barriers mentioned:

  • Limited public health financing
  • Some countries ineligible at this time
  • Delivery costs
  • Vaccine wastage by lack of proper cold chain
  • Suboptimal prioritization based on outdated data
  • Geographical barriers

 

The work of Dr. Stefan Koppe of Seattle Children’s hospital, who visited the MPI fundraiser last year, is the subject of a news release from Sanaria Inc. on April 2 that refers to an article in EMBO Molecular Medicine (“A Replication Competent Plasmodium falciparum Completely Attenuated by Dual Gene Deletions”) which refers to the first paper quoted under Vaccines below. ” ‘These weakened parasite strains can check in but they can’t check out,’ says Kappe… Sanaria founder and CEO, Stephen L. Hoffman, MD said, ‘Sanaria’s PfSPZ-LARC2 Vaccine has the potential to save millions of lives and eliminate malaria from defined geographic areas when administered in mass vaccination programs. We are planning to assess PfSPZ-LARC2 Vaccine in clinical trials in 2024 in the US, Germany, and Burkina Faso. Previous generations of PfSPZ vaccines either do not meet WHO requirements for 90% protection against infection or have potential for breakthrough infections into the blood stream. We are therefore eagerly anticipating taking this novel, genetically engineered vaccine strain into clinical studies.’”

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

Prevention

Vaccines

Goswami D & al., A Replication Competent Plasmodium falciparum Parasite Completely Attenuated by Dual Gene Deletion, EMBO Mol Med. 2024 Mar 21, https://doi.org/10.1038/s44321-024-00057-7 describes a strain of P. falciparum that holds promise as a vaccine. The strain is called “LARC2 (Late liver-stage Arresting, Replication Competent).”  LARC2 parasites stimulate a very strong immune response in the liver, which protects against future malaria infections. By assessing aseptic, purified, cryopreserved PfSPZ-LARC2 produced at Sanaria in humanized mice with human liver cells and human red blood cells, the study team was able to show that the mature, late liver stages of the malaria parasite life cycle were completely compromised.

“Malaria eradication efforts prioritize safe and efficient vaccination strategies, although none with high-level efficacy against malaria infection are yet available. Among several vaccine candidates, Sanaria® PfSPZ Vaccine and Sanaria PfSPZ-CVac are, respectively, live radiation- and chemo-attenuated sporozoite vaccines designed to prevent infection with Plasmodium falciparum …” Indrihutami K & al., Implementation of a Randomized, Placebo-Controlled Trial of Live Attenuated Malaria Sporozoite Vaccines in an Indonesian Military Study Population, Am J Trop Med Hyg. 2024 Mar 26, tpmd230597, https://doi.org/10.4269/ajtmh.23-0597 describes the study but it is ongoing, and results are not quoted.

 

“Three months after the first shipment of RTS,S1/AS01 vaccines, Cameroon started, on 22 January 2024, to roll out malaria vaccines in 42 districts among the most at risk for malaria. Cameroon adopted and implemented the World Health Organization (WHO) malaria vaccine readiness assessment tool to monitor the implementation of preintroduction activities at the district and national levels.” Mboussou F & al., Setting up a Data System for Monitoring Malaria Vaccine Introduction Readiness and Uptake in 42 Health Districts in Cameroon, BMJ Glob Health. 2024 Apr 4; 9(4):e015312, https://doi.org/10.1136/bmjgh-2024-015312 describes the status in the country according to seven parameters (vaccine, cold chain, logistics, training, planning, monitoring and supervision, and advocacy, social mobilization and communication).

Amani A & al. published Introduction and Rollout of Malaria Vaccines in Cameroon and Burkina Faso: Early Lessons Learned in the Correspondence section of Lancet Glob Health, 2024 May, https://doi.org/10.1016/S2214-109X(24)00101-3. In it, they emphasize the following: “First, a commitment from national authorities at all levels, extending from the central to peripheral tiers, in addition to adherence to WHO’s recommendation of fully integrating malaria vaccines into routine immunisation, is key… Second, early monitoring of readiness for malaria vaccine introduction is crucial, ideally commencing 12–18 months before the planned launch. The WHO African Region provided support, deploying 61staff members for field grid mapping, and making strategic investments in data systems by developing a toolkit for readiness assessments, which was deployed in Cameroon. Burkina Faso received its initial malaria vaccine shipment … just 39 days before the official launch, posing constraints on the setup time for the WHO monitoring readiness tool… Third, partnership is key to new vaccine introduction. The launch of the malaria vaccines in Cameroon and Burkina Faso had technical and financial support from partners, including Gavi and additional technical assistance providers…”

Although, as seen above, the first WHO approved vaccine has been officially launched, Asante KP & al., Feasibility, Safety, and Impact of the RTS,S/AS01E Malaria Vaccine When Implemented Through National Immunisation Programmes: Evaluation of Cluster-Randomised Introduction of the Vaccine in Ghana, Kenya, and Malawi, Lancet, 2024 Apr 4: S0140-6736(24)00004-7, https://doi.org/10.1016/S0140-6736(24)00004-7 now recounts experience with the three countries where it was pilot tested in 2019-21. The experience with over 490,000 children who received three doses showed a 32% reduction of hospital admissions for severe malaria and a 9% reduction of all-cause mortality (excluding accidents). Safety concerns raised in earlier studies were allayed. Tha authors conclude that “the three primary doses were effectively deployed through national immunisation programmes.” Follow up study of a four-dose regimen is ongoing.

The study reported in Cummings JF & al., A Phase IIa, Randomized, Double-Blind, Safety, Immunogenicity and Efficacy Trial of Plasmodium falciparum Vaccine Antigens Merozoite Surface Protein 1 and RTS,S Formulated With AS02 Adjuvant in Healthy, Malaria-Naïve Adults, Vaccine, 2024 Apr 6: S0264-410X(24)00389-X, https://doi.org/10.1016/j.vaccine.2024.03.072 disclosed that the combination used in healthy volunteers who were then subjected to controlled malaria showed some activity, but no better than the formulation in current use.

 

As described in the title, Tiono AB & al., A Randomized First-In-Human Phase I Trial of Differentially Adjuvanted Pfs48/45 Malaria Vaccines in Burkinabe Adults, J Clin Invest. 2024 Apr 1; 134(7):e175707, https://doi.org/10.1172/jci175707 reports on the safety of administering the described transmission blocking vaccine to adults.  After three injections, the vaccine resulted in suitable antibody levels in the subjects and the authors describe side effects to be “mild to moderate” in 7 of 125 adults. There were apparently no “vaccine-related serious adverse events.”

According to Palacpac NMQ & al. “Plasmodium parasites have evolved a range of strategies to manipulate the host immune system to guarantee survival and establish parasitism. These immune evasion strategies hamper efforts to develop effective malaria vaccines.” In their paper, Immune Tolerance Caused by Repeated P. falciparum Infection Against SE36 Malaria Vaccine Candidate Antigen and the Resulting Limited Polymorphism, Parasitol Int. 2024 Apr; 99:102845, https://doi.org/10.1016/j.parint.2023.102845, they describe “reduced responsiveness (lowered immunogenicity) which may be attributed to immune tolerance/immune suppression” and summarize relevant “insights into … immune responses … from epidemiological studies and clinical trials.”

Vectors

Once again, we can read that despite the availability of insecticide treated nets, they are not being used by a large proportion of the public, this time in Southern Ethiopia. Endriyas M & al. relate in Low Long-Lasting Insecticidal Net Use in Malaria Elimination Areas in Southern Ethiopia: Results from Community Based Cross-Sectional Study, Malaria J, 2024 Apr 4, 23:94, https://doi.org/10.1186/s12936-024-04909-y that of 2466 households surveyed, fewer than 50% possessed long-lasting insecticidal nets (LLINs) and of those fewer than two thirds used them regularly, giving the population usage rate as 22.9%. “Malaria endemicity, educational status, wealth status, and knowledge about malaria were associated with LLINs utilization. In addition, reasons for non-use included perceived absence of malaria, side effects of LLIN, conditions of LLINs, inconvenient space and low awareness.” The abstract does not mention why households fail to possess the nets.

The question of durability of nets has been vexing for many years. The issue of their proper use likewise. Alafo C & al., An Evaluation of LLIN Physical Integrity and Population Attitudes Towards Net Use, Care and Handling During the Magude Project in Southern Mozambique, Malaria J, 2024 Mar 27, 23:87, https://doi.org/10.1186/s12936-024-04910-5 addresses these issues, finding that while the nets were properly used during two years, “[t]wo thirds of the nets had only been washed once or twice since distribution. Most nets (80.9%) were holed and 18% were torn… None of the six nets that were tested for bio-efficacy passed the WHO threshold of 80% mosquito mortality.”

The efficacy of indoor residual spraying (IRS) in Côte d’Ivoire is addressed in Hilton ER & al., Reduction of Malaria Case Incidence Following the Introduction of Clothianidin-Based Indoor Residual Spraying in Previously Unsprayed Districts: An Observational Analysis Using Health Facility Register Data from Cote D’Ivoire, 2018-2022, BMJ Glob Health. 2024 Mar 22; 9(3):e013324, https://doi.org/10.1136/bmjgh-2023-013324. By comparing districts in which IRS was used with control districts, they conclude that the application of the insecticides averted over 10,000 malaria infections.

In a comprehensive study within a defined geographic area, Alves G & al. report on the various malaria vectors as well as their infection rates by P. falciparum and their resistance to insecticides. Their paper, Molecular and Entomological Surveillance of Malaria Vectors in Urban and Rural Communities of Benguela Province, Angola, Parasit Vectors. 2024 Mar 6; 17(1):112, https://doi.org/10.1186/s13071-024-06214-8 demonstrates a wide diversity of species without any trends in any of the aspects that they studied.

Causes of insecticide resistance are the subjects of Saizonou H & al., Transcriptomic Analysis of Anopheles gambiae from Benin Reveals Overexpression of Salivary and Cuticular Proteins Associated with Cross-Resistance to Pyrethroids and Organophosphates, BMC Genomics. 2024 Apr 6; 25(1):348, https://doi.org/10.1186/s12864-024-10261-x. The results of their laboratory studies “suggest that in addition to metabolic enzymes, cuticular and salivary gland proteins could play an important role in cross-resistance to multiple classes of insecticides in Benin. These genes warrant further investigation to validate their functional role in An. gambiae resistance to insecticides.”

Ibrahim EA & al., Insights and Challenges of Insecticide Resistance Modelling in Malaria Vectors: A Review, Parasit Vectors. 2024 Apr 3; 17(1):174, https://doi.org/10.1186/s13071-024-06237-1 is a review of 33 articles on the subject. The authors conclude “that incorporating pest-biology parameters, and ecological principles into IR [insecticide resistance] models, in tandem with fundamental ecological concepts, potentially offers crucial insights into the evolution of IR. The results extend our knowledge of IR models that provide potentially accurate results, which can be translated into policy recommendations to combat the challenge of IR in malaria control.”

The spread of Anopheles stephensi in Africa raises several concerns. Ashine T & al.’s paper, Spatiotemporal Distribution and Bionomics of Anopheles stephensi in Different Eco-Epidemiological Settings in Ethiopia, Parasit Vectors, 2024 Mar 31; 17(1):166, https://doi.org/10.1186/s13071-024-06243-3 describes the extension of the vector’s territory in western Ethiopia. At this point none of the mosquitoes of the species captured harbored Plasmodium parasites, possibly because they appeared to have fed mostly on animals.  However, almost a quarter of them had human blood in them as well, so it is probably a matter of time before this population becomes a major vector in the area studied as well.

In Attributes of Anopheles gambiae Swarms in South Central Uganda, Parasit Vectors, 2024 Mar 21; 17(1):149, https://doi.org/10.1186/s13071-024-06132-9, Birungi K & al., demonstrate “that An. gambiae s.l. swarms could be effectively located and sampled in South Central Uganda and [provide] in-depth descriptions of hitherto poorly understood aspects of An. gambiae local swarm characteristics” “Swarms were found close to inhabited households and were greater in size and number during the rainy season. Anopheles gambiae s.s swarms were significantly associated with bare ground markers and were sometimes at heights over 4 m above the ground, showing a necessity to develop tools suitable for swarm sampling at these heights.”

As a result of computer-based modeling, Davis EL, & al. found that larval control measures are less efficacious than ITNs and IRS.  Nonetheless, they conclude in An Analytically Tractable, Age-Structured Model of the Impact of Vector Control on Mosquito-Transmitted Infections, PLoS Comput Biol. 2024 Mar 14; 20(3):e1011440, https://doi.org/10.1371/journal.pcbi.1011440 that larval control added to the other modalities of vector control provides additional benefit.

 

Chemoprophylaxis

Guidance for seasonal malaria chemoprevention (SMC) is specific in terms of children who should receive it. Ibinaiye T & al. investigated to what extent the age cutoff of five years is being observed in nine states of Nigeria. They report in Receipt of Seasonal Malaria Chemoprevention by Age-Ineligible Children and Associated Factors in Nine Implementation States in Nigeria, Malaria J, 2024 Mar 30, 23:91, https://doi.org/10.1186/s12936-024-04916-z that 30.30%  “of ineligible children sampled received at least one dose of SMC medicines in 2022, the majority (60.60%) of whom were aged 5–6 years while the rest were aged 7–10 years.” The findings reflect many caregivers’ desire to protect their children from malaria even if they are older than the guidelines call for. On the other hand, using up medications, of which supplies may be limited, for ineligible recipients is not optimal for public health.  This tension is reflected in the article, though not in the abstract.

While Hill J & al., Implementation of Post-Discharge Malaria Chemoprevention (PDMC) in Benin, Kenya, Malawi, and Uganda: Stakeholder Engagement Meeting Report, Malaria J, 2024 Mar 37, 23:89, https://doi.org/10.1186/s12936-023-04810-0 is a report on the meeting to which the title refers, the article contains some results of PDMC conducted with at least three different regimens in four sub-Saharan countries. These indicate “a significant reduction in all-cause mortality by 77% (95% CI 30–98) and a 55% (95% CI 44–64) reduction in all-cause hospital readmissions 6 months post-discharge. The recommendation has not yet been implemented in sub-Saharan Africa. There is no established platform for PDMC delivery. … The meeting served as the beginning of stakeholder engagement within the PDMC Saves Lives project and will be followed by formative and implementation research to evaluate alternative delivery strategies in selected countries.”

Guimsop DK & al. allude to the fact that pregnant women in Cameroon generally do not receive the full recommended preventive treatment during their pregnancy (IPTp-SP) and investigate why that might be the case. As they report in Factors Associated with the Uptake of Intermittent Preventive Treatment for Malaria During Pregnancy in Cameroon: An Analysis of Data from the 2018 Cameroon Demographic and Health Survey, PLoS Glob Public Health. 2024 Mar 27; 4(3):e0001245, https://doi.org/10.1371/journal.pgph.0001245, they questioned over 5500 women who met their selection criteria and found that 15.3% had no antenatal visit at all and another 20% had three of fewer visits. Interestingly, they “did not find a significant association between a higher level of education and the uptake of IPTp-SP.” Overall only 38.5% received the recommended three doses. It appears that increasing the number of prenatal visits may improve this situation.

Mutoro J & al. also “determined the level of and factors associated with uptake Intermittent preventive treatment of malaria for pregnant women (IPTp) at private-not-for-profit (PNFP) health facilities in Kasese District, Uganda.”  Their paper. Level of and Factors Associated with Optimal Uptake of Intermittent Preventive Treatment for Malaria in Pregnancy at Private-Not-For-Profit Health Facilities in Kasese District, PLoS Glob Public Health. 2024 Apr 3; 4(4):e0002622, https://doi.org/10.1371/journal.pgph.0002622 reports on “a cross-sectional study involving 396 postpartum mothers in the postnatal wards of 8 PNFP health facilities in Kasese district was conducted in September 2022…[The] level of optimal uptake of IPTp was 51.5% .. Being married …, attending ANC more than 4 Visits … positively influence optimal uptake while not taking IPTp at recommended time intervals … and mothers paying for IPTp drugs themselves … negatively influence optimal uptake.”

“Drug resistance to sulfadoxine-pyrimethamine and amodiaquine threatens the efficacy of malaria chemoprevention interventions in children and pregnant women. Combining pyronaridine (PYR) and piperaquine (PQP), both components of approved antimalarial therapies, has the potential to protect vulnerable populations from severe malaria.” Kuemmerle A & al. conducted a Randomized, Placebo-Controlled, Double-Blind Phase I Trial of Co-Administered Pyronaridine and Piperaquine in Healthy Adults of Sub-Saharan Origin, and report in Clin Transl Sci, 2024 Apr; 17(4):e13738, https://doi.org/10.1111/cts.13738 that 67% of study subjects experienced side effects of mild to moderate severity. Notwithstanding, the authors suggest that the regimen they employed “may have potential in chemoprevention strategies. Further studies are needed in the target populations to assess chemoprotective efficacy and define the benefit-risk profile, with special considerations regarding hepatic and cardiac safety.”

Other

Friedman-Klabanoff DJ & al., Malaria Prevention in Children: An Update, Curr Opin Pediatr. 2024 Apr 1; 36(2):164-170, https://doi.org/10.1097/mop.0000000000001332 summarizes current status as follows: “Fifteen countries have now rolled out seasonal malaria chemoprophylaxis (SMC) in children at highest risk for severe malaria, and new WHO recommendations provide more flexibility for SMC implementation in terms of target age groups, geographic region, and number of cycles. Recent studies confirm that malaria burden in school aged children, and their contribution to transmission, is high. New guidelines permit expanded chemoprevention options for these children. Two vaccines have been approved for use in malaria endemic countries, RTS,S/AS01E and R21/Matrix-M. Additionally, pyrethroid-chlorfenapyr bed nets are being deployed to combat resistant mosquitoes.”

Brokhattingen N & al., Genomic Malaria Surveillance of Antenatal Care Users Detects Reduced Transmission Following Elimination Interventions in Mozambique, Nat Commun. 2024 Mar 16; 15(1):2402, https://doi.org/10.1038/s41467-024-46535-x is a report on a method by which the effectiveness of elimination efforts can be measured in a very specific population.

Knowledge about malaria prevention and application of the knowledge in communities in conflict are the subjects of Tanue EA & al., A Formative Cross-Sectional Study to Assess Caregiver’s Health-Seeking Behaviour and Knowledge Surrounding Malaria, and Understand the Burden of Malaria Among Children Under-Five in Conflict-Affected Communities of Cameroon, Malaria J, 2024 Apr 8, 23:99, https://doi.org/10.1186/s12936-024-04902-5. As deduced from answers to questionnaires administered to close to 2400 persons in conflict-ridden areas of the country and performance of close to 1500 rapid diagnostic tests (RDTs), the authors conclude that “[o]ver half of the population have correct knowledge and attitudes towards malaria prevention but gaps in complete knowledge remained. Some of the caregivers know the correct malaria preventive practices coupled with largely unsatisfactory treatment approaches and reflected by the high prevalence of malaria among their children.”

“… malaria control programmes rely on only two insecticidal methods: indoor residual spraying and insecticidal-treated nets. House improvement (HI) can complement these interventions by reducing human-mosquito contact, thereby reinforcing the gains in disease reduction.” Tizifa TA & al., Assessing the Implementation Fidelity, Feasibility, and Sustainability of Community-Based House Improvement for Malaria Control in Southern Malawi: A Mixed-Methods Study, BMC Public Health. 2024 Apr 2; 24(1):951, https://doi.org/10.1186/s12889-024-18401-4 assessed the implementation fidelity, which is the assessment of how closely an intervention aligns with its intended design, feasibility, and sustainability of community-led HI in southern Malawi” They studied 22 villages (2730 households), and found “good adherence to the intended community-led HI design; however, the adherence could have been higher [and] gradually declined over time. The authors recommend a ”combination of rigorous community education, consistent training, information, education and communication, and intervention modifications…”

“Anopheles gambiae, the major malaria mosquito in sub-Saharan Africa, feed largely indoors at night. Raising a house off the ground with no barriers underneath reduces mosquito-house entry.” Carrasco-Tenezaca M & al. conducted an experiment that “tested whether walling off the space under an elevated hut affects mosquito-hut entry.” Their result showed that while the walled off hut facilitated fewer mosquito entries than unraised huts, it was less effective in this regard than huts that were raised but with air entry below. The mitigating effect was noted with An. gambiae and Mansonia mosquitoes, but not with Culex mosquitoes. The article is The Effect of Physical Barriers Under a Raised House on Mosquito Entry: An Experimental Study in Rural Gambia, Malaria J, 2024 Apr 8, 23:100, https://doi.org/10.1186/s12936-024-04889-z.

Diagnosis

General diagnostics

Working in the laboratory with P. falciparum cultures and mice infected by P. berghei, Sikulu-Lord MT & al. found that “using blood [containing P. falciparum] spotted on slides and non-invasively, by simply scanning various body areas …” they could accurately detect parasites using near-infrared spectroscopy (NIRS). “The spectra were analysed using machine learning to develop predictive models for infection.” This work is awaiting field confirmation. The paper is Rapid and Non-Invasive Detection of Malaria Parasites Using Near-Infrared Spectroscopy and Machine Learning, PLoS One. 2024 Mar 25; 19(3):e0289232, https://doi.org/10.1371/journal.pone.0289232.

Microscopy continues to be referred to as the “Gold Standard” of malaria diagnosis. Patel P & al., Confirmatory Assay for Laboratory Diagnosis of Malaria Using Molecular Approach, Acta Parasitol. 2024 Mar 18, https://doi.org/10.1007/s11686-024-00831-0 is yet another paper that challenges the concept.  Although the abstract of their paper is not specific as to the outcome of microscopy in the case of 50 samples from “clinically diagnosed” patients with malaria, they state That “nested PCR not only detected all microscopic positive samples, but also detected submicroscopic infections that were missed or misread by microscopy. Hence, the sensitivity of molecular based detection technique is proved to be more compared to microscopic examination.”

Field diagnostics

Ikegbunam M & al. found gene deletion of Histidine Rich Protein (HRP) 2 or 3 in only one of 207 samples tested from patients hospitalized for malaria. It is not surprising therefore that they found Rapid Diagnostic Tests (RDTs) highly predictive in this population. More surprising, perhaps, was the finding reported in their paper, Evaluating Malaria Rapid Diagnostic Tests and Microscopy for Detecting Plasmodium Infection and Status of Plasmodium falciparum Histidine-Rich Protein 2/3 Gene Deletions in Southeastern Nigeria, Am J Trop Med Hyg. 2024 Mar 26: tpmd230690, https://doi.org/10.4269/ajtmh.23-0690, that microscopy yielded less diagnostic accuracy when compared to species-specific quantitative polymerase chain reaction (SS-qPCR). One may question the training effectiveness of personnel involved in microscopy, perhaps? 

Rogier E & al. also looked for the same gene deletions in Tanzania. As reported in their paper, Plasmodium falciparum pfhrp2 and pfhrp3 Gene Deletions Among Patients Enrolled at 100 Health Facilities Throughout Tanzania: February to July 2021, Sci Rep. 2024 Apr 8; 14(1):8158, https://doi.org/10.1038/s41598-024-58455-3, “parasites with these gene deletions are rare in Tanzania,.. [they] estimated that 0.24% (95% confidence interval: 0.08% to 0.39%) of false-negative HRP2-RDTs for symptomatic persons were due to pfhrp2 deletions in this 2021 Tanzania survey. These data provide evidence for HRP2-based diagnostics as currently accurate for P. falciparum diagnosis in Tanzania.”

 

“HealthPulse, a smartphone mRDT reader application, was developed by Audere {a Seattle-based NGO that received partial funding from the Gates Foundation} to aid health workers in mRDT administration and interpretation.” Skjefte M & al. studied the training and performance of community health workers in the use of this application. They found that diagnostic performance improved so that about 90% of the time it was correctly used. As reported in Use of a Health Worker-Targeted Smartphone App to Support Quality Malaria RDT Implementation in Busia County, Kenya: A Feasibility and Acceptability Study, PLoS One. 2024 Mar 26; 19(3):e0295049, https://doi.org/10.1371/journal.pone.0295049, over 99% of the workers in the study found the application useful.

“While Plasmodium falciparum and Plasmodium vivax cause the majority of malaria cases and deaths, infection by Plasmodium malariae and other Plasmodium species also causes morbidity and mortality.” Assefa A & al.’s paper, Detection of P. malariae Using a New Rapid Isothermal Amplification Lateral Flow Assay, Malaria J, 2024 Apr 12, 23:104, https://doi.org/10.1186/s12936-024-04928-9 is particularly relevant in countries like Angola and DRC, but also to a lesser extent in Ethiopia and Tanzania. “…the assay demonstrates a detection limit of 10 copies/µL (~ 1.7 genome equivalents) and 100% analytical specificity. Testing in field samples showed 95% clinical sensitivity and 88% specificity compared to qPCR. Total assay time was less than 40 min…  Combined with simplified DNA extraction methods, the assay has potential for future field-deployable, point-of-care use to detect P. malariae infection.”

New diagnostic methods

Fatema T & al. “propose a surface plasmon resonance (SPR) sensor based on photonic crystal fibers (PCFs) using three hexagonal ring lattices” in Numerical Analysis and Early Detection of Plasmodium falciparum Using a High Performance Plasmonic Biosensor with an External Sensing Approach, Appl Opt. 2024 Apr 1; 63(10):2552-2560, https://doi.org/10.1364/ao.521186. “The sensor can detect biomolecules with maximum wavelength and amplitude sensitivities [that are specific for the characteristics of] infected red blood cells with Plasmodium falciparum… With these impressive results and identification capacity, the proposed sensor would benefit the biomaterial field and be appropriate for the early identification of malaria disease.”

Hoyos K & Hoyos W propose a model using “deep learning-based approach in Supporting Malaria Diagnosis Using Deep Learning and Data Augmentation, Diagnostics (Basel), 2024 Mar 25; 14(7):690, https://doi.org/10.3390/diagnostics14070690. They assert that the method they propose “showed the ability of the model to detect parasites and leukocytes with 95% and 98% accuracy, respectively. The time spent by the model to report parasitemia is significantly less than the time spent by malaria experts.”

Other

While not strictly a paper about diagnosing malaria, Johnson AE & al.’s article, Subclinical Inflammation in Asymptomatic Schoolchildren with Plasmodium falciparum Parasitemia Correlates with Impaired Cognition, J Pediatric Infect Dis Soc. 2024 Mar 21: piae025, https://doi.org/10.1093/jpids/piae025 is important because it highlights the association of asymptomatic P. falciparum infection in schoolchildren with demonstrated impairment in cognition. That, in turn, may lead to diminished benefit from schooling and impaired functioning in society as adults.  Therefore, diagnosing subclinical infections is critically important.

Treatment                                                                                           

Treatment results

Three articles by the same author group headed by Ngasala BE were published this month in Malaria Journal: In Efficacy of Artesunate-Amodiaquine for Treatment of Uncomplicated Plasmodium falciparum Malaria in Mainland Tanzania, Malaria J, 2024 Mar 29, 23:90, https://doi.org/10.1186/s12936-024-04923-0 they report that a “total of 264 children, … were enrolled and treated with ASAQ. The ASAQ PCR-corrected cure rate was 100% at all the three study sites. None of the participants had early treatment failure or late clinical failure. Furthermore, none of the participants had a serious adverse event.” Two others, Efficacy and Safety of Artemether-Lumefantrine for the Treatment of Uncomplicated Falciparum Malaria in Mainland Tanzania, 2018, Malaria J, 2024 Apr 6, 23:95, https://doi.org/10.1186/s12936-024-04926-x and Efficacy and Safety of Artemether-Lumefantrine for the Treatment of Uncomplicated Falciparum Malaria in Mainland Tanzania, 2019, Malaria J, 2024 Apr 9, 23:101, https://doi.org/10.1186/s12936-024-04931-0, follow up on the WHO recommendation of “regular assessment and monitoring of the efficacy of the first-line treatment… Children aged six months to 10 years with microscopy confirmed uncomplicated P. falciparum malaria who met the inclusion criteria were recruited based on the WHO protocol. The children received AL (a 6-dose regimen of AL twice daily for three days) … There were no early treatment failures; recurrent infections during follow-up were common at two sites” of four. These were shown to be reinfections.  The authors mention in the conclusion that post- treatment prophylaxis may be indicated.

In Togo, Dorkenoo AM & al. found similar results, using two alternative artemisinin combinaton regimens. In Efficacy of Artemether-Lumefantrine and Dihydroartemisinin-Piperaquine and Prevalence of Molecular Markers of Anti-Malarial Drug Resistance in Children in Togo in 2021, Malaria J, 2024 Apr 4, 23:92, https://doi.org/10.1186/s12936-024-04922-1 they report 28-day cure rates in excess of 96% with both regimens.  Of concern is that a significant number of children still had parasites detected in their blood, especially with AL. At the same time, they genetically screened 357 parasites obtained from the children and none carried the mutation associated with artemisinin resistance.

Guidelines

Ruwanpura VSH & al. queried “36 international malaria stakeholders to gain insights on the processes involved in the World Health Organization’s Global Malaria Programme’s recommendations for their treatment guidelines of P. vivax malaria.” They conclude in, Evidence Uptake is Only Part of the Process: Stakeholders’ Insights on WHO Treatment Guideline Recommendation Processes for Radical Cure of P. vivax Malaria, PLoS Glob Public Health. 2024 Mar 14; 4(3):e0002990, https://doi.org/10.1371/journal.pgph.0002990 that “more clarity is needed on what triggers global malaria policy change processes, a clearer justification of evidence types used to inform policymaking, better understanding of the impact of the WHO’s funding model on policymaking and further transparency and improved communication of these processes to external stakeholders is also needed.”

Treatment guidelines are carefully crafted by WHO expert panels in order to optimize treatment and to reduce the development of drug resistance. Hossain MS & al. studied one barrier to compliance with guidelines, the procurement of medications from what the authors call “unqualified sources.” They classified “government hospitals, private hospitals, clinics, NGOs, and public health sectors” as qualified sources and, using Malaria Indicator Survey (MIS) datasets (n = 106265), report very high utilization of unqualified sources (over 60%) in data obtained from several sub-Saharan countries in  Prevalence of Unqualified Sources of Antimalarial Drug Prescription for Children Under the Age of Five: A Study in 19 Low- and Middle-Income Countries, PLoS One. 2024 Mar 21; 19(3):e0300347, https://doi.org/10.1371/journal.pone.0300347.

WWARN ACT Malaria and Malnutrition Study Group, Does Acute Malnutrition in Young Children Increase the Risk of Treatment Failure Following Artemisinin-Based Combination Therapy? A WWARN Individual Patient Data Meta-Analysis, Lancet Glob Health. 2024 Apr; 12(4):e631-e640, https://doi.org/10.1016/s2214-109x(24)00003-2 is an analysis of 15 papers on the subject, 11 from Africa.  “Of 11 301 eligible children in 75 study sites, 11·5% were wasted …, and 31·8% were stunted … [Wasting] was associated with increased risk of day 2 positivity …, treatment failure …, and reinfection after therapy …. Children with milder wasting … also had a higher risk of recrudescence …. Stunting was not associated with reduced ACT efficacy.”

Side effects and complications

None this month

Drug resistance

Zida A & al. studied 150 parasite samples from a health care facility for six genetic markers of antimalarial drug resistance. {The abstract does not specify which drugs are the subject of resistance.} They report in Characterization of Plasmodium falciparum Resistance Genes to Common Antimalarial Drugs in Semi-urban Areas of Burkina Faso, Acta Parasitol. 2024 Mar 13, https://doi.org/10.1007/s11686-024-00826-x that the frequency of these markers is variable from less than 1% to 82%, with two markers being present in over 40% of specimens examined.  They comment of the implications of the high frequency of resistant genes but do not connect the finding to actual clinical results in the patients who supplied the samples.

Rosenthal PJ & al., The Emergence of Artemisinin Partial Resistance in Africa; How Do We Respond? Lancet Infect Dis, 2024 Mar 26, https://doi.org/10.1016/S1473-3099(24)00141-5 is largely a recapitulation of the history and geography of the emergence of resistance.  While the abstract is silent of the “how do we respond” issues, there are commentson the subject in the article itself, such as: “based on experience in southeast Asia and some recent efficacy trials from Africa, decreasing efficacy of artemisinin-based regimens can be anticipated, and so it is prudent to discuss new potential treatment strategies. First, before considering new treatment regimens, it is important to assure access to high-quality and appropriate drugs, both in the public and private sectors. The use of monotherapies must be eliminated, including the use of intravenous artesunate to treat uncomplicated malaria, which is often administered in the private sector as a partial course of therapy…”

New drug research

None this month

Plant extracts and traditional treatments

“Records of malaria in TCM date back thousands of years, and the same is true for the usage of Artemisia (Qinghao) plants as medicinal herbs. First mentioned as a specific remedy for malarial symptoms in Ge Hong’s Zhouhou Beiji Fang (Handbook of Prescriptions for Emergency) dating back to the Eastern Jin Dynasty (317–420 AD), the application of Qinghao and other techniques for malarial relief was subsequently noted in a series of historical Chinese medical writings that included the influential Bencao Gangmu (Compendium of Materia Medica) by Li Shizhen (Ming Dynasty, 1368–1644 AD). This wealth of ancient knowledge would later prove to be instrumental in the discovery and development of artemisinin” (quoted from Wang J & al., Artemisinin, the Magic Drug Discovered from Traditional Chinese Medicine, Engineering, 2019 Feb, 5(1):32-39, https://doi.org/10.1016/j.eng.2018.11.011). Cai TY & al. returned to the original plant to investigate what else may have been present in its extracts to improve effectiveness. They report the finding of two additional compounds, which, when added to artemisinin, enhanced its effect in the mouse model, but not when used in vitro against P. falciparum. In the conclusion of their paper, Targeted Screening of the Synergistic Components in Artemisia annua L. Leading to Enhanced Antiplasmodial Potency of Artemisinin Based on a “Top Down” PD-PK Approach, J Ethno-pharmacol. 2024 Mar 25; 322:117612, https://doi.org/10.1016/j.jep.2023.117612, they consider the possibility that these compounds enhance absorption of artemisinin from the intestine.

Amekyeh H & al., Evaluation of Packaging, Labels, and Some Physicochemical Properties of Herbal Antimalarial Products on the Ghanaian Market, Heliyon. 2024 Feb 28; 10(5):e27032, https://doi.org/10.1016/j.heliyon.2024.e27032 starts from the premise that “[m]any Ghanaians depend on herbal products for malaria treatment. [Therefore the authors] aimed to survey and evaluate commercial herbal antimalarials in the Volta Region of Ghana.” On evaluating 34 liquids, each containing between 1 and 9 active ingredients, they found serious deficiencies in either formulation, packaging, or direction on the labeling in virtually all of them. In addition, 10 of the products were deemed erosive (pH <4.0). The authors conclude by urging Ghanaian authorities to exercise oversight over these products.

In the search for new compounds to treat malaria if artemisinin resistance becomes widespread, Chaniad P & al. mention that the “potent antiplasmodial activity of 1-hydroxy-5,6,7-trimethoxyxanthone (HTX), isolated from Mammea siamensis … flowers, has previously been demonstrated in vitro. However, its in vivo activity has not been reported.” In their paper, In vivo Antimalarial Effect of 1-Hydroxy-5,6,7-Trimethoxyxanthone Isolated from Mammea siamensis T. Anders. Flowers: Pharmacokinetic and Acute Toxicity Studies, BMC Complement Med Ther. 2024 Mar 23; 24(1):129, https://doi.org/10.1186/s12906-024-04427-z, they report that the substance was effective in suppressing, but not eliminating parasitemia in at various doses administered to Plasmodium infected mice. Toxicity studies for liver and kidney were negative and the median mortality was at five times the maximum therapeutic dose administered.  Whether this compound will yield useful antiplasmodial medication is dependent of further studies.

Lagnika HO & al. state in Beninese Plant Extracts with Antiplasmodial Activity Select New Allele Variants Msp1 and Msp2 in Plasmodium falciparum, J Parasitol Res. 2024 Mar 20; 2024:9980715, https://doi.org/10.1155/2024/9980715 that extracts of six plants used in folk medicine to treat malaria in Benin “select” new genetic variants of P. falciparum when tested in vitro. Although the implication of new variants emerging as a result of treatment not recommended by WHO is of concern, neither the abstract nor the article demonstrate that these variants are resistant to the recommended administration of ART.

Elmaidomy AH & al. cite several authors reporting on the folk medicine uses of key lime (Citrus aurantifola). Presumably that led the group to investigate the potential of six substances extracted from the peel of the fruit for activity against P. falciparum in vitro. As Antiplasmodial Potential of Phytochemicals from Citrus aurantifolia Peels: A Comprehensive in vitro And in silico Study, BMC Chem. 2024 Mar 30; 18(1):60, https://doi.org/10.1186/s13065-024-01162-x reports, three of the substances tested had considerable antiplasmoidal activity, so the authors suggest continuing to explore them as bases for future antimalarials.

“The whole extract of Maytenus senegalensis has been scientifically investigated for potential biological activities both in vitro and in vivo, demonstrating strong antimalarial activity.” Published articles on the subject date back to the 2000s.  Kassimu KR & al., The Effect of an Anti-Malarial Herbal Remedy, Maytenus senegalensis, on Electrocardiograms of Healthy Tanzanian Volunteers, Malaria J, 2024 Apr 12, 23:103, https://doi.org/10.1186/s12936-024-04935-w focuses exclusively on the potential ECG effects of the substance and conclude that the “results of this study support both the traditional use and the modern therapeutic potential of M. senegalensis. They also set the stage for future research involving larger and more diverse populations to explore the safety profile of M. senegalensis in different demographic groups. This is especially important considering the potential use of M. senegalensis as a therapeutic agent and its widespread utilization as traditional medicine.”

Other

“… prompt treatment-seeking for malaria is necessary to reduce the progression of the disease to its severe forms and the associated mortality.” Alga A & al., Factors Influencing Delay in Malaria Treatment Seeking at Selected Public Health Facilities in South Gonder, Ethiopia, Sci Rep. 2024 Mar 20; 14(1):6648, https://doi.org/10.1038/s41598-024-56413-7 identifies the following barriers to early treatment: “Patients who were unable to read and write … fear of side effects of malaria treatment drugs …, lack of access to health education malaria disease and its treatment …, lack of transportation access …, [lack of] membership of community-based health insurance … and lack of confidence on malaria care health facility providing [the care].”

Yet another barrier is the price of drugs. Ocan M & al., Copayment Mechanism in Selected Districts of Uganda: Availability, Market Share and Price of Quality Assured Artemisinin-Based Combination Therapies in Private Drug Outlets, PLoS One,  2024 Mar 27; 19(3):e0295198, https://doi.org/10.1371/journal.pone.0295198 highlights the poor affordability of ACT in private pharmacies, which is worsened by the even higher price of the higher quality, Quality Assured ACT. Further, “[t]here was a statistically significant difference between the dispensing price of ‘Green leaf’ ACTs (QAACT) and the recommended price,” the dispensing price being uniformly higher.

Campaigns and Policies

Mekonen ZT & al., Global Health Commodities Supply Chain in the Era of COVID-19 Pandemic: Challenges, Impacts, and Prospects: A Systematic Review, J Multidiscip Healthc, 2024 Apr 11: 17:1523-1539, https://doi.org/10.2147/JMDH.S448654 is a review of data from 13 relevant articles dealing with the subject mentioned in the title. “Almost 38.5% of the studies targeted the supply chain of health commodities used to treat HIV, TB, and malaria. Lockdown policies, travel restrictions, lack of transportation, low manufacturing capacity, and rising costs were the significant challenges indicated for the supply interruption of essential health commodities and COVID-19 vaccines. Findings indicated that the supply interruption of essential health commodities leads to a devastating impact on global health.”

Epidemiology

Climate change, biodiversity and environment

Using machine learning, Abdelkrim O & al. “developed model predictions, under current and future (2050) climate, for the prospective distribution of Anopheles claviger, Anopheles labranchiae, Anopheles multicolor, and Anopheles sergentii, [all of them] implicated or incriminated in malaria transmission.” Their results show that all “modelled species are expected to find suitable habitats and have the potential to become established in the northern and central parts of the country, under present-day conditions. Distinct changes in the distributions of the four mosquitoes are to be expected under climate change. Even under the most optimistic scenario, all investigated species are likely to acquire new habitats that are now unsuitable, placing further populations in danger. [The authors] also observed a northward and altitudinal shift in their distribution towards higher altitudes. The paper is Anopheles Mosquitoes in Morocco: Implication for Public Health and Underlined Challenges for Malaria Re-Establishment Prevention Under Current and Future Climate Conditions, Pest Manag Sci. 2024 Apr; 80(4):2085-2095, https://doi.org/10.1002/ps.7943.

 

Liu Q & al. state in Possible Potential Spread of Anopheles stephensi, the Asian Malaria Vector, BMC Infect Dis. 2024 Mar 20; 24(1):333, https://doi.org/10.1186/s12879-024-09213-3 that their modeling of the future extent of An. stephensi distribution indicates that it will be more widespread in the future, partly as a result of global climate change. They used the current distribution of the vector along with various climate change predictions and anticipate a resurgence of malaria in previously controlled areas, “as has been the case in Djibouti.”

“Hydrogeomorphic changes, encompassing erosion, waterlogging, and siltation, disproportionately threaten impoverished rural communities.” Huijser L & al. “explore the complex relationships between hydrogeomorphic hazards, malaria incidence, and poverty in Nigeria. Through spatial analyses we expand traditional boundaries, incorporating factors such as healthcare access, migration patterns, dam locations, demographics, and wealth disparities into a unified framework. Our findings reveal a stark reality: most residents in hydrogeomorphic hotspots live in poverty (earnings per person ≤$1.25/day), face elevated malaria risks (80 % in malaria hotspots), reside near dams (59 %), and struggle with limited healthcare access. Moreover, exposure to hydrogeomorphic hotspots could double by 2080, affecting an estimated 5.8 million Nigerians.” The paper is From Erosion to Epidemics: Understanding the Overlapping Vulnerability of Hydrogeomorphic Hotspots, Malaria Affliction, and Poverty in Nigeria, Sci Total Environ, 2024 Apr 9: 172245, https://doi.org/10.1016/j.scitotenv.2024.172245.

Risk factors

Yu Q & al. quantified “the associations between violent conflict, climate variability, and malaria risk in sub-Saharan Africa using health surveys from 128,326 individuals, historical climate data, and 17,429 recorded violent conflicts from 2006 to 2017” in Spatial Spillovers of Violent Conflict Amplify the Impacts of Climate Variability on Malaria Risk in Sub-Saharan Africa, Proc Natl Acad Sci U S A. 2024 Apr 9; 121(15):e2309087121, https://doi.org/10.1073/pnas.2309087121. “… spatial spillovers of violent conflict (SSVCs) have spatially distant effects on malaria risk. Malaria risk induced by SSVCs within 50 to 100 km from the households gradually increases from 0.1% (not significant, P>0.05) to 6.5% (95% CI: 0 to 13.0%). SSVCs significantly promote malaria risk within the average 20.1 to 26.9 °C range. At the 12-mo mean temperature of 22.5 °C, conflict deaths have the largest impact on malaria risk, with an approximately 5.8% increase (95% CI: 1.0 to 11.0%). Additionally, a pronounced association between SSVCs and malaria risk exists in the regions with 9.2 wet days per month.”

Based in the review of the literature, Kotepui M & al., Malaria Is Associated with Diminished Levels of Ascorbic Acid: A Systematic Review and Meta-Analysis, Antioxid Redox Signal. 2024 Mar; 40(7-9):460-469, https://doi.org/10.1089/ars.2023.0306 conclude that the association of low levels of ascorbic acid and either falciparum or vivax malaria is valid.  While the analysis does not prove cause and effect, the authors conclude that ascorbic acid supplementation in areas where malaria is prevalent may be appropriate.

Meredith HR & al. studied the relationship between mobile and sedentary lifestyles in the Turkana region of Kenya and report in Characterizing Mobility Patterns and Malaria Risk Factors in Semi-Nomadic Populations of Northern Kenya, PLoS Glob Public Health. 2024 Mar 13; 4(3):e0002750, https://doi.org/10.1371/journal.pgph.0002750 that “travelers had a higher prevalence of malaria than those who remained at the household (9.2% vs 4.4%), regardless of gender and age. These findings highlight the need to develop intervention strategies amenable to mobile lifestyles that can ultimately help prevent the transmission of malaria.”

Mobile lifestyle was also partly the focus of Moukénet A & al., Malaria Infection and Predictor Factors Among Chadian Nomads’ Children, BMC Public Health. 2024 Mar 28; 24(1):918, https://doi.org/10.1186/s12889-024-18454-5. “Blood samples were collected and tested from 187 Arab, Fulani and Dazagada nomadic children aged 3-59 months using [RDT]. A structured electronic questionnaire was administered to their parents to collect information about the socio‑economic data…The overall malaria prevalence in nomadic children was 24.60%, with 65.20% being Plasmodium falciparum species and 34.8% mixed species. Boys were twice as likely … to have malaria than girls. Children whose parents used to seek traditional drugs were five times more likely … to have malaria than children whose parents used to seek health facilities. Children whose parents reported spending the last night under a mosquito net were one-fifth as likely … to have malaria compared to children whose parents did not use a mosquito net.” There were significant differences based on ethnicities as well.

General epidemiology

Hailemeskel E & al. addressed the question whether patients harboring asymptomatic infection may transmit the parasite to mosquitoes. Their study, Dynamics of Asymptomatic Plasmodium falciparum and Plasmodium vivax Infections and Their Infectiousness to Mosquitoes in a Low Transmission Setting of Ethiopia: A Longitudinal Observational Study, Int J Infect Dis. 2024 Mar 13: 107010, https://doi.org/10.1016/j.ijid.2024.107010 reveals that transmissibility was very low, which is apparently in contrast with other studies of similar nature.  The authors consider whether the low transmission setting may be influencing the results.

 

Popkin-Hall ZR & al., Prevalence of Non-Falciparum Malaria Infections Among Asymptomatic Individuals in Four Regions of Mainland Tanzania, Parasit Vectors. 2024 Mar 23; 17(1):153, https://doi.org/10.1186/s13071-024-06242-4 points out that whereas the percentage of P. falciparum is about 95% of all malaria species found in asymptomatic patients in the areas studied, the possibility of the other species causing infection cannot be ignored, given the different treatment regimens required for radical cure.

Spatiotemporal studies

Inoue J & al., Dynamics of Plasmodium Species and Genotype Diversity in Adults with Asymptomatic Infection in Gabon, Int J Infect Dis. 2024 Mar 16: 107013, https://doi.org/10.1016/j.ijid.2024.107013

Aheto JMK & al., Modelling Spatiotemporal Variation in Under-Five Malaria Risk in Ghana in 2016–2021, Malaria J, 2024 Apr 9, 23:102, https://doi.org/10.1186/s12936-024-04918-x

 

 

 

 

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