June 2023 Science & Research Report

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

[On June 8] the World Health Organization (WHO) and the Global Fund to Fight AIDS, Tuberculosis and Malaria (the Global Fund) signed a new and revised Strategic Framework for Collaboration, designed to build stronger and more resilient health systems and maximize collaboration and impact in support of country, regional and global responses to major communicable diseases. 

The new five-year framework builds on the previous agreement signed in 2018. It aligns with the 2023-2028 Global Fund Strategy and the WHO General Programme of Work, which put communities at the centre of the health response and also address pandemic preparedness and challenges posed by climate change. The framework fits with broader collaboration platforms to accelerate support to countries to achieve the health-related Sustainable Development Goals … including Universal Health Coverage …

‘As health budgets globally are strained and under pressure, it is imperative for our two organizations to continue to work together to support countries to expand access to services for the three diseases as part of their journey towards universal health coverage,’ said Dr Tedros Adhanom Ghebreyesus, WHO Director-General. ‘In light of slowing progress towards ending the AIDS, TB, and malaria epidemics, coupled with emerging health challenges, stronger collaboration between WHO and the Global Fund is needed more than ever.’

With WHO and the Global Fund’s common mission and commitment to serve countries, the new Strategic Framework for Collaboration will further strengthen and extend collaboration.

‘At a time when the world is beset by interlocking and intersecting crises, from conflict to climate change, the partnership between the Global Fund and WHO is more critical than ever,’ said Peter Sands, Executive Director of the Global Fund. ‘Crises shock global systems and roll back gains, with the world’s most vulnerable people bearing the brunt. Organizations like ours are most effective when we collaborate closely with national governments and other trusted partners to strengthen local, community-driven systems for health.’

… much work remains to be done in countries to accelerate progress towards ending AIDS, TB and malaria epidemics and to build strong health systems that are also capable of responding to the next emergency.

Through this new framework, WHO and the Global Fund will be leveraging their comparative strengths across 35 areas for collaboration divided into 4 categories:

1. Health policies and normative guidance
2. Advocacy and health governance
3. Health products and innovations
4. Technical support and capacity building”

‘Malaria is a highly climate sensitive disease’

Farmer B, How Climate Change is Giving the World’s Worst Diseases a Deadly Boost, The Telegraph (UK website news), 2023 May 26, https://www.telegraph.co.uk/global-health/science-and-disease/climate-change-malaria-diseases-pandemic/ recounts that “malaria’s normal seasonal cycle has been disrupted as a result of catastrophic flooding earlier in the year caused by Cyclone Freddy, the latest example of the extreme weather events predicted to become more common due to climate change.

Now should be the dry season with few mosquitoes, but there are pools of standing water everywhere attracting the insects…

Cases of the mosquito-borne sickness have risen, and Mozambican health officials are worried the uptick will start to eat into decades of gains against the ancient disease.

But it’s not just experts in Mozambique who are concerned about a reversal in progress. Set against a backdrop of increasingly unpredictable and extreme weather events, other countries are starting to report an untimely rise in malaria infections.”

PEER REVIEWED PUBLICATIONS:

Prevention

Vaccines

Oyong DA & al., Distinct Immune Responses Associated with Vaccination Status and Protection Outcomes After Malaria Challenge, PLoS Pathog. 2023 May 17; 19(5):e1011051. https://doi.org/10.1371/journal.ppat.1011051 is a report on investigation of immune responses to whole attenuated Plasmodium falciparum circumsporozoite (PfRAS) vaccine in health individuals and in volunteers subjected to controlled malaria infections (CHMI).  They state that their “data provide key insights in understanding immune mechanistic pathways of PfRAS-induced protection and infective CHMI…”

Gbedande K & al. report on laboratory work on using “[c]ytomegalovirus (CMV) chronic vaccine vectors” as adjuvants to an experimental vaccine against zoonotic malaria. They conclude in Boosting Live Malaria Vaccine with Cytomegalovirus Vector Can Prolong Immunity Through Innate and Adaptive Mechanisms, bioRxiv. 2023 May 2: 2023.05.02.539025, https://doi.org/10.1101/2023.05.02.539025 that the effectiveness of the vaccine they used was prolonged by using the adjuvant under study and describe the purported mechanism.

El-Moamly AA & El-Sweify MA, Malaria Vaccines: The 60-Year Journey of Hope and Final Success-Lessons Learned and Future Prospects, Trop Med Health. 2023 May 17; 51(1):29. https://doi.org/10.1186/s41182-023-00516-w is a review of the experience with currently used vaccines and those under investigation.

Vector control and protection from vectors

Afagbedzi SK & al. studied the use of LLINs in a setting where they were provided to households free of charge. They report in Universal Coverage and Utilization of Free Long-Lasting Insecticidal Nets for Malaria Prevention in Ghana: A Cross-Sectional Study, Front Public Health, 2023 May 25; 11:1140604, https://doi.org/10.3389/fpubh.2023.1140604 that of close to 10,000 households studied, 88.0% “owned at least one LLIN, … while utilization was 65.6% among households with at least one LLIN… Households with under-five children were 40% more likely to utilize LLIN… there was about 4-fold increase in household utilization of LLINs in rural areas compared to urban areas … Household size of more than 2 has high odds of LLINs utilization and awareness of the benefit of LLINs.”

The species of Anopheles that potentially transmit malaria include several within what is described as Anopheles gambiae sensu lato (in the wide sense).  Within that spectrum are several species, including An. gambiae sensu stricto (strict sense) and others.  In a locally based study, Sy O & al. report on finding two of these “others” that potentially transmit malaria in the area, but not a third one. The paper is Residual Malaria Transmission and the Role of Anopheles arabiensis and Anopheles melas in Central Senegal, J Med Entomol. 2023 May 12; 60(3):546-553. https://doi.org/10.1093/jme/tjad020

According to Yalla N & al., A Comparison of the Attractiveness of Flowering Plant Blossoms Versus Attractive Targeted Sugar Baits (ATSBs) In Western Kenya, PLoS One. 2023 Jun 6; 18(6):e0286679. https://doi.org/10.1371/journal.pone.0286679, “[a]ttractive Targeted Sugar Baits (ATSB) have been demonstrated to result in significant reductions in malaria vector numbers in areas of scarce vegetation cover such as in Mali and Israel, but it is not clear whether such an effect can be replicated in environments where mosquitoes have a wide range of options for sugar resources.” They compared two versions of commercial ATSBs to local plants in attractiveness and found that the newer “ATSB 1.2” was more attractive to malaria vector species of mosquitoes than the local flora.

Studying the biting behavior of mosquitoes, Giraldo D & al. developed a large-scale multi-choice preference assay in Zambia with infrared motion vision under semi-field conditions.” They report in Human Scent Guides Mosquito Thermotaxis and Host Selection Under Naturalistic Conditions. Current Biology. https://doi.org/10.1016/j.cub.2023.04.050 that certain compounds emitted from sleeping humans greatly influence the choice of mosquitoes in choosing whom to approach for a blood meal.

Orondo PW & al. assessed “the effects of bacterial composition and habitat metabolites on malaria vector larval availability in irrigated and non-irrigated potential larval sources. Water samples were collected from larval positive and negative habitats in … irrigated and non- irrigated areas.” Their paper, Effects of Bacterial Composition and Aquatic Habitat Metabolites on Malaria Vector Larval Availability in Irrigated and Non-Irrigated Sites of Homa Bay County, Western Kenya, PLoS One. 2023 Jun 2; 18(6):e0286509, https://doi.org/10.1371/journal.pone.0286509, reports that more diversity of bacteria were found in the water from irrigated areas certain nutritionally important metals were equally present in both types of areas.  The abstract avers that their results should guide the development of larvicides.

Chemoprophylaxis

Anabire NG & al. “evaluated the impact of adherence to malaria control measures [number of antenatal clinics (ANC) attended, supervised intake of sulphadoxine pyrimethamine (SP), and use of insecticide treated bed nets (ITNs)] on asymptomatic malaria and anaemia outcomes among pregnant women on ANC in hospitals in the Central region of Ghana” Despite up to 80% adherence to ANC visits and to SP chemoprophylaxis in this population, their paper, High Burden of Asymptomatic Malaria and Anaemia Despite High Adherence to Malaria Control Measures: A Cross-Sectional Study Among Pregnant Women Across Two Seasons in a Malaria-Endemic Setting in Ghana, Infection, 2023 Jun 10, https://doi.org/10.1007/s15010-023-02058-z reports that ‘[a]symptomatic P. falciparum carriage was high for both seasons (44.4% for the dry season; 46.9% for the rainy season),” as was anemia. In their conclusion, they infer that the WHO recommended measures may be inadequate to prevent asymptomatic Plasmodium infestation and consequent anemia.

“Despite scale-up of seasonal malaria chemoprevention (SMC) with sulfadoxine-pyrimethamine and amodiaquine (SP-AQ) in children <5 years old in Burkina Faso, malaria incidence remains high, raising concerns regarding SMC effectiveness and selection of drug resistance.” The case control study by Roh ME & al., Seasonal Malaria Chemoprevention Drug Levels and Drug Resistance Markers in Children with or Without Malaria in Burkina Faso: A Case Control Study, J Infect Dis. 2023 May 23: jiad172, https://doi.org/10.1093/infdis/jiad172 concludes that ineffective chemoprophylaxis in this population is likely due to poor adherence to the regimen rather than to development of resistance to the drugs.

Keita MS & al. “conducted a pilot study to assess whether nutrition assessments could be integrated into existing SMC programming in two districts in Guinea.” While Integrating Nutrition Assessments and Seasonal Malaria Chemoprevention: Results from a Mixed-Methods Feasibility Study in Guinea, Trop Med Int Health. 2023 May 31. https://doi.org/10.1111/tmi.13897 acknowledges that the integration of two health interventions created extra work for the health community workers initially charged with SMC alone, they report that there was no drop in SMC coverage, while referrals for malnutrition increased.

The use of ivermectin to reduce the transmissibility of malaria from individuals potentially already infected is another form of chemoprophylaxis.  Based on laboratory studies, Kobylinski KC & al., Ivermectin Metabolites Reduce Anopheles Survival, Sci Rep. 2023 May 19; 13(1):8131, https://doi.org/10.1038/s41598-023-34719-2 concludes that mosquitoes that bit individuals treated by ivermectin die not only from the drug administered, but from its circulating metabolites as well.

Other

None this month

Diagnosis

General diagnostics

“The World Health Organization (WHO) recommends that when peripheral malarial parasitaemia is quantified by thick film microscopy, an actual white blood cell (WBC) count from a concurrently collected blood sample is used in calculations. However, in resource-limited settings an assumed WBC count is often used instead.” The aim of WorldWide Antimalarial Resistance Network White Blood Cell Count in Malaria Study Group, Variability in White Blood Cell Count During Uncomplicated Malaria and Implications for Parasite Density Estimation: A WorldWide Antimalarial Resistance Network Individual Patient Data Meta-Analysis, Malaria J, 2023 Jun 6, 22:174, https://doi.org/10.1186/s12936-023-04583-6 “was to describe the variability in WBC count during acute uncomplicated malaria and estimate the impact of using an assumed value of WBC on estimates of parasite density and clearance.” After analyzing the data from over 27,000 patients, they conclude that “[u]sing an assumed WBC value for parasite density estimation from a thick smear may lead to underdiagnosis of hyperparasitaemia and could adversely affect clinical management; but does not result in clinically consequential inaccuracies in the estimation of the prevalence of prolonged parasite clearance and artemisinin resistance.”

Field diagnostics

Natama HM & al. “evaluated the performance of a P. falciparum Histidine Rich Protein 2 (PfHRP2)-based rapid diagnostic test (RDT) used for malaria case detection (SD-Bioline malaria RDT P.f®) along with light microscopy (LM) against qPCR among children during the first year of life in a high and seasonal malaria transmission area in Burkina Faso… A total of 723 suspected malaria cases that occurred among 414 children participating in a birth-cohort study were included…” They report in Performance of PfHRP2-RDT for Malaria Diagnosis During the First Year of Life in a High Malaria Transmission Area in Burkina Faso, J Parasit Dis. 2023 Jun; 47(2):280-289. https://doi.org/10.1007/s12639-023-01566-x that “malaria cases as detected by RDT, LM and qPCR were 63.8%, 41.5% and 49.8%, respectively. Compared with qPCR, RDT had a false-positive results rate of 26.7%, resulting in an overall accuracy of 79.9% with a sensitivity of 93%, a specificity of 66.1%, a Positive Predictive Value of 73.3% and a Negative Predictive Value of 91.6%. Its specificity differed significantly between high and low transmission seasons (53.7% vs 79.8%…) and decreased with increasing age (80.6-62%…).”

New diagnostic methods

Alluding to well-known “challenges to the use of reliable diagnostic tests in non-clinical settings at the point-of-need (PON),” Diaz J & al. turned to a “new saliva-based malaria asymptomatic and asexual rapid test (SMAART-1) [that] shows increased detection sensitivity and precision potential by identifying a new P. falciparum protein marker (PSSP17)…” They used three survey methods “to provide an overarching acceptability evaluation of the SMAART-1 at PON field sites: observation checklists of SMAART-1 implementation, focus group discussions, and surveys with local health care practitioners—particularly teachers and community health workers.” Their paper, A Mixed Methods Study Assessing the Adoption Potential of a Saliva-Based Malaria Rapid Test in the Democratic Republic of Congo, Malaria J, 2023 Jun 8, 22:180, https://doi.org/10.1186/s12936-023-04599-y concludes the following: “The SMAART-1 protocol’s clinically reliable results demonstrate a promising new level of sensitivity and precision for detecting parasite biomarkers. This study’s mixed-methods assessment of the protocol’s utility and adoption potential in the field, with a target user audience, advances its development and points to opportunities to formalize and expand evaluation efforts.”

Malpartida-Cardenas K & al., A Dual Paper-Based Nucleic Acid Extraction Method from Blood in Under Ten Minutes for Point-Of-Care Diagnostics, Analyst. 2023 Jun 2, https://doi.org/10.1039/d3an00296a is a study of a diagnostic test that is also claimed to take little time and to be feasible at the point of care.  The abstract seems to assert the method’s applicability to malaria field diagnosis but does not contain validation data. 

Other

None this month

Treatment

Treatment results

Tafenoquine is promoted as an important new drug to use to effect radical cure of vivax malaria. To the contrary Sutanto I & al., Tafenoquine Co-Administered with Dihydroartemisinin-Piperaquine {DP} for the Radical Cure of Plasmodium vivax Malaria (INSPECTOR); A Randomized, Placebo-Controlled Efficacy and Safety Study, Lancet Infx Dis, 2023 May 23; https://doi.org/10.1016/S1473-3099(23)00249-X report a study in which tafenoquine plus DP was superior to DP alone, but only to the extent of 21% radical cure versus 11%, while adding primaquine to DP achieved superior results (52%).  The paper also comments on the high rate of adverse effects in all three groups of patients studied.  

Adherence to guidelines

Focusing on non-adherence to treatment guidelines, Aryeetey GC & al., Cost of Inappropriate Prescriptions for Uncomplicated Malaria in Ghana, Malaria J, 2023 May 18, 22:157, https://doi.org/10.1186/s12936-023-04581-8 reports the results of analyzing outpatient records of 1625 patients with malaria in three regions of the country… about 55% of malaria prescriptions were evaluated as inappropriate during the review period, which translates into economic cost of approximately US$4.52 million for the entire country in 2016.  

Side effects and complications

Awuah A & al., Delayed Hemolysis with Parenteral Artesunate, Hosp Pharm. 2023 Jun; 58(3):259-262, https://doi.org/10.1177/00185787221142471 is a case report of a patient who suffered hemolysis seven days after parenteral artesunate. (The complication was thoroughly described in an article that somehow eluded this reviewer’s attention:  Jaita S & al., Post-Artesunate Delayed Hemolysis: A Revie of Current Evidence, Trop Med Inf Dis, 2023 Jan 7, 8(1):49, https://doi.org/10.3390/tropicalmed8010049)

Drug resistance

The objective of Azmi WA & al. is “to provide current molecular insights into artemisinin resistance in Plasmodium falciparum.” Molecular Insights into Artemisinin Resistance in Plasmodium falciparum: An Updated Review, Infect Genet Evol. 2023 Jun 1: 105460, https://doi.org/10.1016/j.meegid.2023.105460 states that “artemisinin resistance is mostly related to the mutations in the propeller domain of the kelch13 (k13) gene that encodes protein Kelch13 (K13). The K13 protein has an important role in parasite reaction to oxidative stress. The most widely spread mutation in K13, with the highest degree of resistance, is a C580Y mutation. Other mutations, which are already identified as markers of artemisinin resistance, are R539T, I543T, and Y493H.”

Simmons C & al. argue in their paper, A Novel Modulator of Ring Stage Translation (MRST) Gene Alters Artemisinin Sensitivity in Plasmodium falciparum, mSphere. 2023 May 23: e0015223, https://doi.org/10.1128/msphere.00152-23, that a significant number of possible mutations may cause artemisinin resistance and cite as an example the gene identified in the title of the paper.

da Silva C & al. looked for the genetic mutation responsible for most reported instances of artemisinin resistance in “450 participants with malaria infection detected by Rapid Diagnostic Tests, from three different study sites,”  Their paper, Anti-Malarial Resistance in Mozambique: Absence of Plasmodium falciparum Kelch 13 (K13) Propeller Domain Polymorphisms Associated with Resistance to Artemisinins, Malaria J, 2023 May 19, 22:160, https://doi.org/10.1186/s12936-023-04589-0 avers that none were detected in this group, even though other mutations of the parasite were found.

In a subsequent paper with different co-authors, da Silva C & al., Targeted and Whole-Genome Sequencing Reveal a North-South Divide in P. falciparum Drug Resistance Markers and Genetic Structure in Mozambique, Commun Biol, 2023 Jun 8; 6(1):619, https://doi.org/10.1038/s42003-023-04997-7 report on resistance to sulfadoxine-pyrimethamine (SP).  The findings indicate genetic markers of resistance in the country, but on a gradient from widespread (72%) in the North to virtually universal (95%) in the South.

Ndiaye YD & al. also investigated resistance to SP that is used in seasonal chemoprevention. They observed “a rapid increase in [the marker for SP resistance] and decline in [the marker for chloroquine {CQ}] resistance starting in 2014, which [they] hypothesize may reflect changes in resistance or fitness caused by seasonal malaria chemoprevention (SMC).” They conclude that “[p]arasite populations evolve rapidly in response to drug use, and SMC preventive efficacy should be closely monitored.” The paper is Two Decades of Molecular Surveillance in Senegal Reveal Changes in Known Drug Resistance Mutations Associated with Historical Drug Use and Seasonal Malaria Chemoprevention, medRxiv. 2023 Apr 26: 2023.04.24.23288820. https://doi.org/10.1101/2023.04.24.23288820.

Senegal is also the country in which Yade MS & al., Ex Vivo RSA and pfkelch13 Targeted-Amplicon Deep Sequencing Reveal Parasites Susceptibility to Artemisinin in Senegal, 2017, Malaria J, 2023 May 26, 22:167, https://doi.org/10.1186/s12936-023-04588-1 reports that among 38 samples of P. falciparum collected in a specific region in 2017, there was no resistance to artemisinin found.

“Pfcrt gene has been associated with chloroquine resistance and the pfmdr1 gene can alter malaria parasite susceptibility to lumefantrine, mefloquine, and chloroquine. In the absence of chloroquine (CQ) and extensive use of artemether–lumefantrine (AL) from 2004 to 2020 to treat uncomplicated falciparum malaria, pfcrt haplotype, and pfmdr1 single nucleotide polymorphisms (SNPs) were determined in two sites of West Ethiopia with a gradient of malaria transmission” by Tadele G & al. Clinical Isolates of Uncomplicated Falciparum Malaria from High and Low Malaria Transmission Areas Show Distinct pfcrt and pfmdr1 Polymorphisms in Western Ethiopia, Malaria J, 2023 Jun 4, 22:171, https://doi.org/10.1186/s12936-023-04602-6 concludes that “Plasmodium falciparum with the pfcrt wild-type haplotype was prevalent in high malaria transmission site than in low transmission area. … continuous investigation is needed to closely monitor the changes in the pfmdr1 SNPs, which are associated with the selection of parasite populations by ACT.”

Genetic markers of lumefantrine resistance are the subject of Gachie B & al., Prevalence of Mutations in the Cysteine Desulfurase iscs (Pfnfs1) Gene in Recurrent Plasmodium falciparum Infections Following Artemether-Lumefantrine (AL) and Dihydroartemisinin-Piperaquine (DP) Treatment in Matayos, Western Kenya, Malaria J, 2023 May 19, 22:158, https://doi.org/10.1186/s12936-023-04587-2. They tested the infective agents from patients with recurrent infections after AL and DP treatments and found what while they were more frequently found after AL, a significant number of specimens from patients who had been treated with DP also had the resistant gene.

New drug research

The drug described in Basilico N & al., Favorable Preclinical Pharmacological Profile of a Novel Antimalarial Pyrrolizidinylmethyl Derivative of 4-amino-7-chloroquinoline with Potent in vitro and in vivo Activities, Biomolecules. 2023 May 14; 13(5):836, https://doi.org/10.3390/biom13050836 is currently designated as MG3. It is “active against a panel of P. vivax and P. falciparum field isolates, either alone or in combination with artemisinin derivatives. …[t]he in vivo and in vitro ADME-Tox studies indicate that MG3 possesses a very good pre-clinical developability profile associated with an excellent oral bioavailability, and low toxicity in … preclinical studies” on a variety of animals and will presumably be soon ready for human trials.

“Drug-resistant parasites have emerged to each introduced small-molecule therapy, highlighting the need for novel treatment approaches for the future eradication of malaria.” Palombi IR & al. report in Development of Antiplasmodial Peptide-Drug Conjugates Using a Human Protein-Derived Cell-Penetrating Peptide with Selectivity for Infected Cells, Bioconjug Chem. 2023 May 26, https://doi.org/10.1021/acs.bioconjchem.3c00147 the investigation of “targeted drug delivery with peptide-drug conjugates (PDCs) … as an alternative antimalarial therapy, inspired by the success of emerging antibody-drug conjugates utilized in cancer treatment. A synthetic peptide derived from an innate human defense molecule was conjugated to the antimalarial drug primaquine (PQ) to produce PDCs…” while the in vitro potency of the conjugate was low, the authors recommend continuing development of PDCs. 

Plant extracts and traditional treatments

“Several regions of the world frequently use the species Moringa oleifera Lam. (Moringaceae) in traditional medicine. This situation is even more common in African countries. Many literature reports point to the antimalarial potential of this species, …” Bezerra JJL & al., Antimalarial Potential of Moringa oleifera Lam. (Moringaceae): A Review of the Ethnomedicinal, Pharmacological, Toxicological, and Phytochemical Evidence, J Venom Anim Toxins Incl Trop Dis. 2023 May 26; 29:e20220079, https://doi.org/10.1590/1678-9199-jvatitd-2022-0079 reports on a review of 72 articles that deal with this plant. They state that “antimalarial activity of M. oleifera was confirmed through several studies using polar and nonpolar extracts, fractions obtained from the extracts, infusion, pellets, and oils obtained from this plant and tested in rodents infected by … parasites of the genus Plasmodium” including P. falciparum. They also state that no toxicity was observed in any reports.

Ejigu YW & Endalifer BL studied possible antimalarial effects of three substances used in folk medicine. They report in In Vitro Anti-Plasmodial Activity of Three Selected Medicinal Plants That Are Used in Local Traditional Medicine in Amhara Region of Ethiopia, BMC Pharmacol Toxicol. 2023 May 11; 24(1):30, https://doi.org/10.1186/s40360-023-00672-z that the methanolic extract of the roots of one of them, Lobelia gibberoa, showed a promising in vitro anti-plasmodial activity against the CQ-sensitive (D10) and CQ-resistant (W2) strains of P. falciparum.  They were unable to show any anti-plasmodial activity of various extracts of the other two plants.

Tabuti JRS A & al. studied “45 plant species belonging to 26 families and 44 genera [that] were used in the preparation of herbal medicines for management of malaria and its symptoms” in Eastern Uganda. . … “Leaves (67.3%) were the most used plant part while maceration (56%) was the major method of herbal remedy preparation.” In Medicinal Plants Used for Treatment of Malaria by Indigenous Communities of Tororo District, Eastern Uganda, Trop Med Health, 2023 Jun 12; 51(1):34,

https://doi.org/10.1186/s41182-023-00526-8, they conclude that “the identified medicinal plants … are potential sources of new antimalarial drugs. This provides a basis for investigating the antimalarial efficacy, phytochemistry and toxicity of the unstudied species with high percentage use values to validate their use in the management of malaria.”

Other

The world-wide problem of counterfeit or ineffective drugs has shown itself in the field of malaria therapy as well. Ocan M & al., Pharmacopeial Quality of Artemether–Lumefantrine Anti-Malarial Agents in Uganda, Malaria J, 2023 May 26, 22:165, https://doi.org/10.1186/s12936-023-04600-8#Sec2 highlights the problem by reporting that of a total of 74 AL purchases made in various regions of the country, “prevalence of substandard quality artemether–lumefantrine was 18.9% … Substandard quality AL was significantly associated with [high-transmission] setting … A total of 10 samples (13.5%) failed artemether content assay test while, 4 samples (5.4%) failed the lumefantrine assay test.” While these percentages are not catastrophic, they indicate the need for testing of imported drug supplies.

Kalantari N & al. state that “[v]itamin D supplementation is recommended as an effective adjunct to counteract malaria pathogenesis, but the evidence on this point is limited and controversial.”  They surveyed the literature and found only six papers that merited inclusion in their analysis, Does Vitamin D Reduce the Mortality Rate of Plasmodium Infection?: A Systematic Review and Meta-Analysis, Malaria J, 2023 Jun 5, 22:173, https://doi.org/10.1186/s12936-023-04612-4. Based on the six papers they conclude that “vitamin D administration positively affects the survival rate in Plasmodium-infected mice. Since the mouse model may not accurately reproduce the clinical and pathological features of human malaria, future research should investigate the impact of vitamin D in human malaria.”

Armstrong JF & al., Advances in Malaria Pharmacology and the Online Guide to MALARIA PHARMACOLOGY: IUPHAR Review X, Br J Pharmacol. 2023 May 17. https://doi.org/10.1111/bph.16144 highlights “the IUPHAR/MMV Guide to MALARIA PHARMACOLOGY, a web resource developed for the malaria research community that provides open and optimized access to published data on malaria pharmacology.”

Campaigns and Policies

“Controlled human malaria infection (CHMI) studies, i.e. the deliberate infection of healthy volunteers with malaria parasites to study immune response and/or test drug or vaccine efficacy, are increasingly being conducted in malaria endemic countries, including in sub-Saharan Africa. However, there have been few studies on the perceptions and acceptability of CHMI by the local communities.” Dabira ED & al., Perceptions and Acceptability of The Controlled Human Malaria Infection (CHMI) Model in The Gambia: A Qualitative Study, Sci Rep. 2023 May 29; 13(1):8708, https://doi.org/10.1038/s41598-023-35752-x “assessed the perception and acceptability of such studies in The Gambia following the first CHMI study conducted in the country in March-May 2018. … Sixty-seven participants were involved, including volunteers enrolled in the CHMI, community stakeholders and members of the Gambian Ethics Committee. Respondents expressed a positive view about CHMI. Key motivating factors for participation were the financial compensation, comprehensive health checks, and willingness to support malaria research. Risks associated with participation were considered low. Concerns raised included the frequency of bleeding and the blood volume collected.

Epidemiology                                                        

Climate change, biodiversity and environment

While Arisco NJ & al., The Effect of Extreme Temperature and Precipitation on Cause-Specific Deaths in Rural Burkina Faso: A Longitudinal Study, Lancet Planet Health, 2023 Jun; 7(6):e478-e489, https://doi.org/10.1016/S2542-5196(23)00027-X reports on several communicable diseases, “malaria (both across all ages and in children younger than 5 years), was associated with 14-day lagged daily maximum temperatures at or above 41·1°C, the 90th percentile of daily maximum temperatures, compared with 36·4°C…”

“To simulate the various impacts of climate change on malaria infection,” Asadgol Z & al. applied artificial Neural Networks (ANNs) … using daily collected data for 12 years (from 2003 to 2014) in Iran.  The paper, Simulation of The Potential Impact of Climate Change on Malaria Incidence Using Artificial Neural Networks (ANNs), Environ Sci Pollut Res Int. 2023 May 23, https://doi.org/10.1007/s11356-023-27374-7  reports “that there is an intense increasing trend in malaria cases … until 2050, with the highest number of infections occurring in the warmer months. Rainfall and maximum temperature were identified as the most influential input variables.

General epidemiology

Madrid L & al., Causes of Stillbirth and Death Among Children Younger than 5 Years in Eastern Hararghe, Ethiopia: A Population-Based Post-Mortem Study, Lancet Glob Health, 2023 Jun 2, https://doi.org/10.1016/S2214-109X(23)00211-5 is a study conducted in a confined geographic area.  The findings among 166 deaths investigated are mainly of interest in that malaria is not reported as being among the most prominent cause of death either in neonates or children younger than five years.

Duguay C & al. studied the effect of the COVID-19 epidemic on malaria preventive behaviors.  They report in Community-Level Impacts of the Coronavirus Pandemic on Malaria Prevention and Health-Seeking Behaviours in Rural Benin: A Mixed Methods Study, PLOS Glob Public Health. 2023 May 19; 3(5):e0001881. https://doi.org/10.1371/journal.pgph.0001881 that “there were minimal community-level impacts of the coronavirus pandemic on malaria prevention and health seeking behaviours in rural Benin, which highlights the importance of efforts to sustain malaria prevention and control interventions in the context of the COVID-19 pandemic…. An unexpected change and unintended challenge for sustained malaria prevention included families socially distancing in their homes, resulting in a shortage of LLINs.”

Ariff A & al. state that “[s]everal blood phenotypes have been associated with malarial resistance, which suggests a genetic component to immune protection.” In Genetic Variants of TLR4, Including the Novel Variant, rs5030719, and Related Genes Are Associated with Susceptibility to Clinical Malaria in African Children, Malaria J, 2023 Jun 7, 22:177, https://doi.org/10/1186/s12936-023-04549-8 they report that 187 “single nucleotide polymorphisms (SNPs) in 37 candidate genes were genotyped and investigated for associations with clinical malaria in a longitudinal cohort of 349 infants … Malaria candidate genes were selected according to involvement in known malarial haemoglobinopathies, immune, and pathogenesis pathways…” The results indicated “significant evidence … for the association of [the gene] TLR4 and related genes with the incidence of clinical malaria.”

Baina MT & al., Comparative Study of Plasmodium falciparum Msp-1 And Msp-2 Genetic Diversity in Isolates from Rural and Urban Areas in the South of Brazzaville, Republic of Congo, Pathogens, 2023 May 22; 12(5):742, https://doi.org/10.3390/pathogens12050742 “aimed to compare the genetic diversity of circulating parasite strains in rural and urban settings in the Republic of Congo after the introduction of artemisinin-based combination therapy (ACT) in 2006… {The] findings reveal a higher P. falciparum genetic diversity … in the rural setting of the Republic of Congo, which is influenced by the season and the participant clinical status.”

Chilot D & al. “aimed to assess the pooled prevalence of malaria among children aged 6–59 months and identify potential factors associated with malaria by using recent Malaria Indicator Surveys in 13 SSA countries.” According to Pooled Prevalence and Risk Factors of Malaria Among Children Aged 6–59 Months in 13 Sub-Saharan African Countries: A Multilevel Analysis Using Recent Malaria Indicator Surveys, PLoS One, 2023 May 31, https://doi.org/10.1371/journal.pone.0285265, the “pooled prevalence of malaria among children aged 6–59 months was found to be 27.41%… It ranges from 5.04% in Senegal to 62.57% in Sierra Leone… This study revealed that older under-five children living in large families with low incomes in rural areas are most vulnerable to malaria infection. [The] results clearly indicate that ITN utilization and improved housing are promising means to effectively prevent malaria infection among children aged 6–59 months.”

van Eijk AM & al. “aimed to describe the epidemiology of submicroscopic malaria infections in pregnant women in Asia, the Americas, and Africa using aggregated and individual participant data.” Prevalence of and Risk Factors for Microscopic and Submicroscopic Malaria Infections in Pregnancy: A Systematic Review and Meta-Analysis, Lancet Glob Health, 2023 Jun 2, https://doi.org/10.1016/S2214-109X(23)00194-8 covers 68 studies between 1997 and 2021. “During pregnancy, median prevalence estimates were 13·5% … for submicroscopic and 8·0% … for microscopic malaria… In individual patient data analysis, compared with women with no malaria infections, those with submicroscopic infections were more likely to present with fever in Africa … but not in other regions… Risk factors for submicroscopic infections among women with … infections in Africa included older age (age ≥30 years), multigravidity, and no HIV infection.”  Di Santi SMF, The Silent Threat of Submicroscopic Plasmodium Infections During Pregnancy, Lancet Glob Health, 2023 Jun 2, https://doi.org/10.1016/S2214-109X(23)00249-8 is an accompanying editorial that includes further data about malaria in pregnancy.

Oyerogba OP & al. wanted to “determine the prevalence and factors associated with malaria parasitaemia among pregnant women at a booking clinic in Ibadan, Nigeria.” The prevalence of 8.7% was within the range reported by van Eijk & al. above. As to associated factors, Prevalence of Malaria Parasitaemia Among Pregnant Women at Booking in Nigeria, Health Sci Rep, 2023 Jun 9; 6(6):e1337, https://doi.org/10.1002/hsr2.1337 cites “age, religion, level of education, and occupation [as being] significantly related to the prevalence of malaria parasitaemia among pregnant women.” While the directions and degrees of association are not cited in the abstract, the conclusion infers that poorer and less educated women were more likely to test positive. 

In a study of the influence of domestic animal ownership on the prevalence of malaria, Morgan CE & al., Association Between Domesticated Animal Ownership and Plasmodium falciparum Parasite Prevalence in the Democratic Republic of the Congo: A National Cross-Sectional Study, Lancet Microbe. 2023 May 31: S2666-5247(23)00109-X. https://doi.org/10.1016/s2666-5247(23)00109-x report that while chicken ownership was associated with slightly increased malaria, cattle ownership was more pronounced in the other direction.  The authors speculate on possible mechanisms of the apparent protection conferred by cattle ownership and what it may mean in terms of malaria prevention efforts.

“Clinicians in areas where malaria and typhoid fever are co-endemic often treat infected patients irrationally, which may lead to the emergence of drug resistance and extra cost to patients” according to Malaria and Typhoid Fever Among Patients Presenting with Febrile Illnesses in Ga West Municipality, Ghana, PLoS One. 2023 May 25; 18(5):e0267528, https://doi.org/10.1371/journal.pone.0267528 by Rufai T & al.  Among 157 juvenile and adult patients with high fever tested in a hospital, malaria was present 36.3% of the time, while typhoid fever was detected 14.6% of the time.  Coinfections by the two agents were only seen in 1.6% of the febrile cases.  The authors stress the need for laboratory confirmation of the causes of fever in children and adults.

Namayanja C & al. studied 300 children severely ill in a malaria epidemic and report in Unusual Clinical Spectra of Childhood Severe Malaria During Malaria Epidemic in Eastern Uganda: A Prospective Study, Malaria J, 2023 Jun 4, 22:169, https://doi.org/10.1186/s12936-023-04586-3 that their symptoms were at variance with the frequency of reported severe falciparum malaria, in that there were fewer cases of cerebral malaria and respiratory distress, but more jaundice and blackwater fever.

Although Ruiz-Castillo P & al., BOHEMIA, a Cluster Randomized Trial to Assess the Impact of an Endectocide-Based One Health Approach to Malaria in Mozambique: Baseline Demographics and Key Malaria Indicators, Malaria J, 2023 Jun 4, 22:172, https://doi.org/10.1186/s12936-023-04605-3 focuses on the eventual administration of transmission blocking agents, the actual thrust of the paper is to describe the demographics of the population that will form the basis of the study envisioned.

Wafula ST & al. report on “a systematic review [that] provides an overview of the current evidence on the mediators of socioeconomic disparities in malaria” in What Are the Pathways Between Poverty and Malaria in Sub-Saharan Africa? A Systematic Review of Mediation Studies, Infect Dis Poverty, 2023 Jun 8; 12(1):58, https://doi.org/10.1186/s40249-023-01110-2. They found 41 articles in English between January 2000 and May 2022, of which 26 reported “socioeconomic inequalities in malaria risk.” However, when they analyzed the papers, they found firm associations with education, insecticide-treated nets, and nutrition, but these were independent of socioeconomic position.  Three … analyses showed limited evidence of mediation of food security, housing quality, and previous antimalarial use. The authors cite methodological limitation in what they call “generally low or moderate-quality studies.”

Spatiotemporal studies

Jeang B & al., Serological Markers of Exposure to Plasmodium falciparum and Plasmodium vivax Infection in Southwestern Ethiopia, Am J Trop Med Hyg. 2023 Apr 10; 108(5):871-881. https://doi.org/10.4269/ajtmh.22-0645

Epstein A & al., Mapping Malaria Incidence Using Routine Health Facility Surveillance Data in Uganda, BMJ Glob Health. 2023 May; 8(5):e011137, https://doi.org/10.1136/bmjgh-2022-011137

Debash H & al., Symptomatic and Asymptomatic Malaria Prevalence and Its Determinant Factors in Pastoral Communities of Waghemira Zone, Northeast Ethiopia: A Community-Based Cross-Sectional Study, Health Sci Rep, 2023 Jun 7; 6(6):e1336, https://doi.org/10.1002/hsr2.1336.