By Dr. Derick Pasternak, Ambassador, Malaria Science & Research Coordinator, MPI
NEWS RELEASE FROM WHO ON 2 OCTOBER 2023:
“The World Health Organization (WHO) has recommended a new vaccine, R21/Matrix-M, for the prevention of malaria in children. The recommendation follows advice from the WHO: Strategic Advisory Group of Experts on Immunization (SAGE) and the Malaria Policy Advisory Group (MPAG) and was endorsed by the WHO Director-General following its regular biannual meeting held on 25-29 September. …
The R21 vaccine is the second malaria vaccine recommended by WHO, following the RTS,S/AS01 vaccine, which received a WHO recommendation in 2021. Both vaccines are shown to be safe and effective in preventing malaria in children and, when implemented broadly, are expected to have high public health impact. Malaria, a mosquito-borne disease, places a particularly high burden on children in the African Region, where nearly half a million children die from the disease each year.
Demand for malaria vaccines is unprecedented; however, available supply of RTS,S is limited. The addition of R21 to the list of WHO-recommended malaria vaccines is expected to result in sufficient vaccine supply to benefit all children living in areas where malaria is a public health risk.
“As a malaria researcher, I used to dream of the day we would have a safe and effective vaccine against malaria. Now we have two,” said Dr Tedros Adhanom Ghebreyesus, WHO Director-General. “Demand for the RTS,S vaccine far exceeds supply, so this second vaccine is a vital additional tool to protect more children faster, and to bring us closer to our vision of a malaria-free future.” …
Key features of the R21 malaria vaccine:
The updated WHO malaria vaccine recommendation is informed by evidence from an ongoing R21 vaccine clinical trial and other studies, which showed:
- High efficacy when given just before the high transmission season: In areas with highly seasonal malaria transmission (where malaria transmission is largely limited to 4 or 5 months per year), the R21 vaccine was shown to reduce symptomatic cases of malaria by 75% during the 12 months following a 3-dose series. A fourth dose given a year after the third maintained efficacy. This high efficacy is similar to the efficacy demonstrated when RTS,S is given seasonally.
- Good efficacy when given in an age-based schedule: The vaccine showed good efficacy (66%) during the 12 months following the first 3 doses. A fourth dose a year after the third maintained efficacy.
- High impact: Mathematical modelling estimates indicate the public health impact of the R21 vaccine is expected to be high in a wide range of malaria transmission settings, including low transmission settings.
- Cost effectiveness: At prices of US$ 2 – US$ 4 per dose, the cost-effectiveness of the R21 vaccine would be comparable with other recommended malaria interventions and other childhood vaccines.
- Similarity of R21 and RTS,S vaccines: The two WHO-recommended vaccines, R21 and RTS,S, have not been tested in a head-to-head trial. There is no evidence to date showing one vaccine performs better than the other. The choice of product to be used in a country should be based on programmatic characteristics, vaccine supply, and vaccine affordability
- Safety: The R21 vaccine was shown to be safe in clinical trials. As with other new vaccines, safety monitoring will continue.
Next steps for the second recommended malaria vaccine, R21/Matrix-M, include completing the ongoing WHO prequalification which would enable international procurement of the vaccine for broader rollout.
At least 28 countries in Africa plan to introduce a WHO-recommended malaria vaccine as part of their national immunization programmes. Gavi, the Vaccine Alliance has approved providing technical and financial support to roll out malaria vaccines to 18 countries. The RTS,S vaccine will be rolled out in some African countries in early 2024, and the R21 malaria vaccine is expected to become available to countries mid-2024…”
Dzi KTJ, Issues Related to the Approval of the R21/Matrix-M Malaria Vaccine for Use in Nigeria and Ghana, Front Public Health, 2023 Oct 4: 11:1237011. https://doi.org/10.3389/fpubh.2023.1237011 is a relevant article as judged by the title, but neither the abstract nor the article is available to judge.
¶ “The NIH has awarded a multi-disciplinary team led by Ross Boyce, MD, MSc, [of the U. of North Carolina] a $4.4 million, five-year (R01) grant to evaluate the effectiveness of a chemoprevention effort designed to prevent malaria outbreaks after flooding, using a combination of interventions. … The project builds on findings from a “proof-of-concept” pilot study, one aspect of which was recently published in the Journal of Infectious Diseases…. Disease outbreaks and climate-related health emergencies have reportedly reached their highest levels ever in … western Uganda where an increase in the frequency of extreme precipitation events, likely exacerbated by changes in land use, is believed to have resulted in seasonal surges of malaria transmission. ….” Mbarara University of Science and Technology scientists will collaborate in the study.
¶ Philip Low of Purdue U. received a grant from Open Philanthropy “to further validate a drug therapy that he and his colleagues have previously shown to successfully treat [malaria]… While studying how malaria propagates in human blood, Low and his research team discovered that the cancer drug therapy imatinib is effective in the treatment of drug-resistant malaria. Trials in Southeast Asia showed that imatinib, when combined with the customary malaria therapy, clears all malaria parasites from 90% of patients within 48 hours and 100% of patients within three days. The patients receiving imatinib were also relieved of their fevers in less than half of the time experienced by similar patients treated with the standard therapy… Open Philanthropy … awarded Low $780,000 to determine whether the usual three-day therapy can be reduced to two days or even one. This work will be focused in … Kenya and Tanzania…”
¶ https://www.news-medical.net/health/The-Science-Behind-Why-Mosquitoes-Prefer-to-Bite-Certain-People.aspx?utm_source=news_medical_newsletter&utm_medium=email&utm_campaign=malaria_ newsletter_16_october_2023 carries an article by L. Thomas MD about a variety of mosquito vectors and their reactions to odors. Among other statements are the following: “Mosquito-human attractions change with age, body size, and physiological changes, as well as the distance from the host. Bananas and perhaps alcohol may enhance mosquito attractiveness, but not garlic or vitamin B supplements.
Pregnant women attract more mosquitoes, due to the greater body heat and metabolic rate, and perhaps a distinctive scent.
Malaria also attracts mosquitoes due to a distinct “malaria smell” enriched for aldehydes and thioethers, during the gametocyte stage of Plasmodium which can develop further only in the mosquito host.
These are parasite-induced changes in the individual’s breath and scent composition, assisted by malaria-associated changes in skin bacteria. Plasmodium also stimulates the release of a volatile attractant called (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate (HMBPP) from infected red cells.”
The author cites 14 references, mostly from peer-reviewed literature.
PEER REVIEWED ARTICLES
Prevention
Vaccines
Written and published ahead of the WHO announcement quoted above, Stanisic DI & Good MF, Malaria Vaccines: Progress to Date, BioDrugs. 2023 Sep 20, https://doi.org/10.1007/s40259-023-00623-4 also references work being done on “Sanaria’s irradiated sporozoite vaccine (PfSPZ Vaccine) [and] the chemoattenuated sporozoite vaccine (PfSPZ-CVac).” {See also Richie TL & al., Sporozoite Immunization: Innovative Translational Science to Support the Fight Against Malaria, Expert Rev Vaccines, 2023 Aug 11, https://doi.org/10.1080/14760584.2023.2245890, reported in August of this year.}
Moturi AK & al. estimated “the coverage of the RTS,S/AS01 vaccine during the first 36 months of the Kenyan pilot implementation” and report in Malaria Vaccine Coverage Estimation Using Age-Eligible Populations and Service User Denominators in Kenya, Malaria J, 2023 Sep 27, 22:287, https://doi.org/10.1186/s12936-023-04721-0 that over “36 months, 818,648 RTSS/AS01 doses were administered. Facilities managed by the Ministry of Health and faith-based organizations accounted for over 88% of all vaccines delivered. Overall, service-based malaria vaccine coverage was 96%, 87%, 78%, and 39% for doses 1–4 respectively… Consistent with vaccines delivered over the age of 1 year, coverage of the fourth malaria dose was low. Vaccine uptake, service access and dropout rates for malaria vaccines require constant monitoring and intervention to ensure maximum protection is conferred.”
Gelband H & al., Could Vaccinating Adults Against Malaria Materially Reduce Adult Mortality in High-Transmission Areas? Malaria J, 20232 Sep 19, 22:278, https://doi.org/10.1186/s12936-023-04714-z considers the possibility that malaria in adults is underestimated and propose a study in Sierra Leone to ascertain whether vaccinating adults would make a difference in general adult mortality. {It may be difficult to justify expanding the ambit of the currently available vaccines, since they have already been shown to be inadequate just to reach all vulnerable children in highly endemic areas.}
Ohene-Adjei K & al., Malaria Vaccine-Related Adverse Events Among Children Under 5 in Sub-Saharan Africa: Systematic Review and Meta-Analysis Protocol, BMJ Open. 2023 Oct 4; 13(10):e076985, https://doi.org/10.1136/bmjopen-2023-076985 is an announcement on how side effects and complications will be searched for and analyzed.
A different approach to vaccine development is the subject of Patel PN & al., Structure-Based Design of a Strain Transcending AMA1-RON2L Malaria Vaccine, Nat Commun. 2023 Sep 2; 14(1):5345, https://doi.org/10.1038/s41467-023-40878-7. “Apical membrane antigen 1 (AMA1) is a key malaria vaccine candidate and target of neutralizing antibodies. AMA1 binds to a loop in rhoptry neck protein 2 (RON2L) to form the moving junction during parasite invasion of host cells, and this complex is conserved among apicomplexan parasites.” The paper describes a structure-based design of vaccine that appears to be efficacious against multiple Plasmodium species under laboratory conditions.
The abstract of the article by Rajneesh & al., Advancements and Challenges in Developing Malaria Vaccines: Targeting Multiple Stages of the Parasite Life Cycle, ACS Infect Dis. 2023 Sep 14, https://doi.org/10.1021/acsinfecdis.3c00332 is quite opaque. Its conclusion is stated as “[a] cost-effective and multistage vaccine could hold the key to controlling and eradicating malaria.”
Tsoumani ME & al., Malaria Vaccines: From the Past Towards the mRNA Vaccine Era, Vaccines (Basel). 2023 Sep 4; 11(9):1452, https://doi.org/10.3390/vaccines11091452 hints at the possibility of the development of an mRNA vaccine for malaria, but nothing in the abstract indicates that they have special insight as to how that may come about.
When testing a hypothesis, negative results may be just as important as ones supporting it. Nyandele JP & al. followed up on the proposition that pre-vaccination monocyte-to-lymphocyte ratio is a marker for malaria vaccine effectiveness. In Pre-Vaccination Monocyte-To-Lymphocyte Ratio as a Biomarker for the Efficacy of Malaria Candidate Vaccines: A Subgroup Analysis of Pooled Clinical Trial Data, PLoS One. 2023 Sep 14; 18(9):e0291244, https://doi.org/10.1371/journal.pone.0291244 they report that no correlation could be found between the ratio proposed and RTS,S vaccine effectiveness.
Varijakshi G & al., Transcriptomic Approaches for Identifying Potential Transmission Blocking Vaccine Candidates in Plasmodium falciparum: A Review of Current Knowledge and Future Directions, 3 Biotech. 2023 Oct; 13(10):344, https://doi.org/10.1007/s13205-023-03752-3 is a summary of meticulous search of Plasmodium falciparum gametocyte genes that may be targeted in the development of a transmission blocking vaccine.
Vector control and protection from vectors
There has been much attention paid recently to the spread of Anopheles stephensi in Africa and its implication in fostering malaria in urban environments. Diop A & al., Urban Malaria Vector Bionomics and Human Sleeping Behavior in Three Cities in Senegal, Parasit Vectors. 2023 Sep 19; 16(1):331, https://doi.org/10.1186/s13071-023-05932-9 points out that 99% of malaria vectors collected in the three cities mentioned was found to be Anopheles arabiensis. Even though this species has a slight tendency to bit outdoors in preference to indoors, outdoor activities in the evenings and night by the populace make them at high risk of malaria.
In Tanzania, the “National Malaria Strategic Plan (NMSP) includes long-lasting insecticidal nets (LLINs) delivery through the commercial sector as a complementary mechanism.” Kamala B & al., Trends in Retail Sales of Insecticide-Treated Nets and Untreated Nets in Tanzania: Cross-Section Surveys, Malaria J, 2023 Oct 4, 22:296, https://doi.org/10.1186/s12936-023-04726-9 is a report on two surveys conducted in 2021-22 of close to 400 outlets selling nets. The overwhelming majority of nets available for sale were untreated nates. They even uncovered a small number of nets fabricated in China that were advertised as LLINs but turned out to have been untreated.
Multiple articles have reported on a long-term study of multiple impregnated nets in Tanzania. Mosha JF, & al., Effectiveness of Long-Lasting Insecticidal Nets with Pyriproxyfen–Pyrethroid, Chlorfenapyr–Pyrethroid, or Piperonyl Butoxide–Pyrethroid Versus Pyrethroid Only Against Malaria in Tanzania: Final-Year Results of a Four-Arm, Single-Blind, Cluster-Randomised Trial, Lancet Infect Dis, 2023 Sep 27, https://doi.org/10.1016/S1473-3099(23)00420-6 report a statistically significant reduction of malaria infection for individuals using chlorphenapyr-pyrethroid nets as compared to those with pyrethroid only nets. The apparent benefit of the other two substances added to pyrethroid was less impressive. Of greatest concern, however, is that overall usage of study nets was less than 25% after 36 months.
Bajunirwe F & Nantongo F, Effectiveness and Durability of Insecticide Mixtures for Pyrethroid Resistance in Sub-Saharan Africa, Lancet Infect Dis, 2023 Sep 27, https://doi.org/10.1016/S1437-3099(23)00437-1 is an editorial commenting on the above. Likewise, Protopopoff N & al., Effectiveness of Piperonyl Butoxide and Pyrethroid-Treated Long-Lasting Insecticidal Nets (LLINs) Versus Pyrethroid-Only LLINs with and Without Indoor Residual Spray Against Malaria Infection: Third Year Results of a Cluster, Randomised Controlled, Two-By-Two Factorial Design Trial in Tanzania, Malaria J, 2023 Oct 3, 22:294, https://doi.org/10.1186/s12936-023-04727-8 is a report of a massive trial in its third year. “During the third year follow-up, malaria infection prevalence in 80 children per cluster, aged 6 months to 14 years, was measured at 28- and 33-months post-intervention and analysed…” The dishearteningly low rate of utilization of the nets at 33 months (33%) notwithstanding, data supported a slight benefit for those utilizing the nets impregnated by both agents.
Madgwick PG & al. state that “pyrethroid resistance is now widespread. Going forward, new insecticides have been and continue to be developed for use on bed nets, but it is unclear how to best deploy them for maximum impact.” In Optimization of Long-Lasting Insecticidal Bed Nets for Resistance Management: A Modelling Study and User-Friendly App, Malaria J, 2023 Sep 29, 22:290, https://doi.org/10.1186/s12936-023-04724-x they claim to have developed an “app” that “allows for the quantitative exploration of trade-offs and constraints under different conditions. … results for the deployment of a new insecticide are explored under default parameter values across public health budgets for the purchase of bed nets. Optimization can lead to substantial gains in the average control of the mosquito population, and these gains are comparatively greater with lower budgets.” They state that “a pyrethroid is shown to be an effective partner for a new insecticide in this model because of its contribution to resistance management in delaying the onset of resistance to the new insecticide.”
Reporting on a set of elegant laboratory experiments using a stock of pyrethroid-resistant Anopheles, Kweyamba PA & al., Sub-Lethal Exposure to Chlorfenapyr Reduces the Probability of Developing Plasmodium Falciparum Parasites in Surviving Anopheles Mosquitoes, Parasit Vectors. 2023 Oct 3; 16(1):342, https://doi.org/10.1186/s13071-023-05963-2 concludes that “sub-lethal exposure of pyrethroid-resistant mosquitoes to chlorfenapyr substantially reduces the proportion of infected mosquitoes and the intensity of the P. falciparum infection. This will likely also contribute to the reduction of malaria in communities beyond the direct killing of mosquitoes.”
Mbare O & al. tested mosquito traps made in South Africa and report in Evaluation of the Solar-Powered Silver Bullet 2.1 (Lumin 8) Light Trap for Sampling Malaria Vectors in Western Kenya, Malaria J, 2023 Sep 16, 22:277, https://doi.org/10.1186/s12936-023-04707-y that they “compared well with the CDC trap in the field and presents a promising new surveillance device especially when charging on mains electricity is challenging in remote settings” because they are solar powered.
Kunambi HJ & al. report that when female mosquitoes are exposed to a sterilizing agent for sufficient amount of time, the eggs they deposit tend not to hatch. In their conclusion they also assert that “sterilized An. funestus can transfer [pyriproxyfen — the sterilizing agent] to prevent adult emergence at breeding habitats. The paper is Sterilized Anopheles funestus Can Autodisseminate Sufficient Pyriproxyfen to the Breeding Habitat Under Semi-Field Settings, Malaria J, 2023 Sep 21, 22:280, https://doi.org/10.1186/s12936-023-04699-9.
Tondossama N & al. “present the results of an entomological survey conducted in a coastal and in an inland village with the aim to estimate Anopheles gambiae sensu lato (s.l.) female’s abundance indoor/outdoor and Plasmodium falciparum infection rate and analyze the occurrence of blood-feeding in relation to LLINs {long-lasting-insecticide-impregnated nets} use.” As they report in their paper, A High Proportion of Malaria Vector Biting and Resting Indoors Despite Extensive LLIN Coverage in Côte d’Ivoire, Insects, 2023 Sep 12; 14(9):758, https://doi.org/10.3390/insects14090758, their “results show a high proportion of mosquito biting and resting indoors despite extensive LLINs.” According to the authors, “under LLINs the probability for a mosquito to bite decreases of 48% and 95% in the coastal and inland village, respectively.”
“Larval Source Management (LSM) is an important tool for malaria vector control and is recommended by WHO as a supplementary vector control measure… However, this approach is typically labour-intensive, largely due to the difficulties in locating and mapping potential malarial mosquito breeding sites.” Hardy A & al., Cost and Quality of Operational Larviciding Using Drones and Smartphone Technology, Malaria J, 2023 Sep 27, 22:286, https://doi.org/10.1186/s12936-023-04713-0 presents a system [“SIS”] that employs drones and smartphones in locating larval beds. While the costs of this method are similar to the conventional location of larval beds, the success rate in locating the beds using the SIS system was greatly increased from seeking these beds manually. On the other hand, malaria infection rates in the areas using SIS did not differ from the control area.
“The rise of insecticide resistance against malaria vectors in sub-Saharan Africa has resulted in the need to consider other methods of vector control. The potential use of biological methods, including larvivorous fish, Bacillus thuringiensis israelensis (Bti) and plant shading, is sustainable and environmentally friendly options. [Orondo PW & al.] examined the survivorship of Anopheles arabiensis and Anopheles funestus larvae and habitat productivity in four permanent habitat types in Homa Bay county, western Kenya.” As reported in Effect of Predators on Anopheles arabiensis and Anopheles funestus Larval Survivorship in Homa Bay County Western Kenya, Malaria J, 2023 Oct 5, 22:298, https://doi.org/10.1186/s12936-023-04741-w, “[f]ish were … the most efficient predator (75.8% larval reduction rate) followed by water boatman (69%), and dragonfly nymph (69.5%) in predation rates.”
Chemoprophylaxis
Traore K & al. explored the use of artemisinin instead of sulfadoxine-pyrimethamine in seasonal chemoprevention and report in Randomized Field Trial to Assess the Safety and Efficacy of Dihydroartemisinin-Piperaquine for Seasonal Malaria Chemoprevention in School-Aged Children in Bandiagara, Mali, J Infect Dis. 2023 Sep 8: jiad387, https://doi.org/10.1093/infdis/jiad387 that the two regimens were equally effective in reducing the incidence of malaria, but that the artemisinin combination caused fewer side effects.
Benjamin-Chung J & al. studied the effect of chemoprevention plus indoor residual spraying on persons in the environment of those receiving the interventions. Incidence, infection prevalence, and seroprevalence were determined “between study arms among intervention recipients (direct effects) and non-recipients (spillover effects) up to 3 km away from index cases.” In Targeted Malaria Elimination Interventions Reduce Plasmodium falciparum Infections up to 3 Kilometers Away, medRxiv. 2023 Sep 20: 2023.09.19.23295806, https://doi.org/10.1101/2023.09.19.23295806 they found that among non-recipients within 1 km from index cases, the combined intervention reduced malaria incidence by 43%… In secondary analyses among non-recipients 500m-3 km from interventions, the combined intervention reduced infection by 79% and seroprevalence by 43%.
Based on screening of children in a community of Burkina Faso, in which prevalence of asymptomatic Plasmodium prevalence was 21.4% in children under age five and 44.2% in school age children, Ouattara SM & al. Malariometric Indices in the Context of Seasonal Malaria Chemoprevention in Children Aged 1.5 to 12 Years During the Period of High Malaria Transmission in the Suburban Area of Banfora, Burkina Faso, Trop Med Infect Dis. 2023 Sep 9; 8(9):442, https://doi.org/10.3390/tropicalmed8090442 recommends the implementation of seasonal chemoprevention in the area.
“Despite scale-up of seasonal malaria chemoprevention (SMC) with sulfadoxine-pyrimethamine and amodiaquine (SP-AQ) in children 3-59 months of age in Burkina Faso, malaria incidence remains high, raising concerns regarding SMC effectiveness and selection of drug resistance.” Roh ME & al. “determined associations between SMC drug levels, drug resistance markers, and presentation with malaria” and report in 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 Oct 3; 228(7):926-935, https://doi.org/10.1093/infdis/jiad172 that “compared to SMC-eligible controls, children with malaria were less likely to have any detectable SP or AQ … and have lower drug levels (P < .05). Prevalences of mutations mediating high-level SP resistance were rare (0%-1%)” and conclude that “Incident malaria among SMC-eligible children was likely due to suboptimal levels of SP-AQ, resulting from missed cycles rather than increased antimalarial resistance to SP-AQ.”
Sondo P & al. hypothesized that undernutrition had a role in the severity of malaria in children and conducted a study of under five children treated with SMC only or with three different kind of supplements. They report that administering one of the supplements (“PlumpyDoz™ plus Vitamin A) significantly reduced both the incidence of uncomplicated malaria and severe malaria in comparison to the control group, while the other two supplements (Vitamin A only or Vit A plus zinc) didn’t. The paper is Enhanced Effect of Seasonal Malaria Chemoprevention when Coupled with Nutrients Supplementation for Preventing Malaria in Children Under 5 Years Old in Burkina Faso: A Randomized Open Label Trial, Malaria J, 2023 Oct 18, 22:315, https://doi.org/10.1186/s12936-023-04745-6.
In a study of malaria of pregnancy, Ampofo GD & al. focused on the preventive aspects of treating pregnant women for malaria. They report in Interventions for Malaria Prevention in Pregnancy; Factors Influencing Uptake and Their Effect on Pregnancy Outcomes Among Post-Natal Women in a Tertiary Facility in the Volta Region of Ghana, SAGE Open Med. 2023 Sep 14; 11:205031 21231199653, https://doi.org/10.1177/20503121231199653 that “[r]eceiving ⩾3 doses of sulphadoxine-pyrimethamine was associated with having normal-weight babies … while ITN use was associated with having term babies … and normal maternal haemoglobin concentration at term…”
Studying maternal blood at delivery, placental blood, and neonatal cord blood, Onoja H & al., Effects of Sulphadoxine-Pyrimethamine on Maternal, Neonatal and Placental Malaria in Port Harcourt, Rivers State, Nigeria, J Vector Borne Dis, 2023 Jul-Sep; 60(3):285-291, https://doi/.org/10.4103/0972-9062.374243 reports similar conclusion to the above: The prevalence of parasitemia in all three types of blood collected was markedly reduced if the mother had undergone intermittent preventive treatment of malaria in pregnancy (IPTp).
Figueroa-Romero A & al. explored whether IPTp might predispose to emergence of resistance to the agents used. In Prevalence of Molecular Markers of Resistance to Sulfadoxine-Pyrimethamine Before and After Community Delivery of Intermittent Preventive Treatment of Malaria in Pregnancy in Sub-Saharan Africa: A Multi-Country Evaluation, Lancet Glob Health, 2023 Nov; 11(11):e1765-e1774, https://doi.org/10.1016/S2214-109X(23)00414-X they cite evidence from multiple sub-Saharan countries that “IPTp did not increase the prevalence of molecular markers associated with sulfadoxine-pyrimethamine resistance after three years of programme implementation.”
Sawadogo H & al. come to a different conclusion in Plasmodium falciparum Genetic Diversity and Resistance Genotype Profile in Infected Placental Samples Collected After Delivery in Ouagadougou, Infect Drug Resist, 2023 Oct 12: 16:6673-6680, https://doi.org/10.2147/IDR.S420004. They suggest that “mutant genotypes are potential early warning factors in the increase in the sulfadoxine-pyrimethamine resistance.” Incidentally, Burkina Faso was not one of the locations of Figueroa-Romero & al.’s study.
Other
Zarenezhad E & al. created a “nanogel” from a weed, commonly known as “Russian knapweed.” In Repellent Efficacy of the Nanogel Containing Acroptilon repens Essential Oil in Comparison with DEET Against Anopheles stephensi, BMC Res Notes. 2023 Oct 9; 16(1):261, https://doi.org/10.1186/s13104-023-06538-1 they state the following: “protection time and repellent activity of nanogel compared to DEET (N, N-diethyl-meta-toluamide) were investigated against Anopheles stephensi. Interestingly, the nanogel with a protection time of 310 ± 45 min was significantly more potent than DEET (160 ± 17 min).
Diagnosis
General diagnostics
Stauning MA & al. present a new diagnostic method of the most prevalent malaria parasite in Detection and Quantification of Plasmodium falciparum in Human Blood by Matrix-Assisted Laser Desorption/ Ionization Time-Of-Flight Mass Spectrometry: A Proof of Concept Study, Malaria J, 2023 Sep 26, 22:285, https://doi.org/10.1186/s12936-023-04719-8. MALDI-TOF, as the complex name of the method is abbreviated, was shown in the laboratory to identify three unrelated strains of P. falciparum. The authors recommend further study of the method as it applies to other malaria parasites.
The variable reliability of rapid diagnostic tests has been noted in many reports. Kojom Foko LP & al. try to shed some light on the reasons for it in Global Polymorphism of Plasmodium falciparum Histidine Rich Proteins 2/3 and Impact on Malaria Rapid Diagnostic Test Detection: A Systematic Review and Meta-Analysis, Expert Rev Mol Diagn, 2023 Sep 12, https://doi.org/10.1080/14737159.2023.2255136. However, their conclusion after reviewing the literature is the following: “PfHRP2/3 are highly polymorphic and current findings are insufficient, conflicting and not convincing enough to conclude on the role of PfHRP2/3 sequence polymorphism in PfHRP2-based RDT detection.”
Antwi-Baffour S & al., Haematological Parameters and Their Correlation with the Degree of Malaria Parasitaemia Among Outpatients Attending a Polyclinic, Malaria J, 2023 Sep 25, 22:281, https://doi.org/10.1186/s12936-023-04710-3 reports that there are significant correlations between lowered red blood cell count, elevated white blood cell count and other hematologic parameters and the severity of parasitemia in patients with malaria. The conclusion is somewhat compromised by the wide diversity in ages of patients (9 months to 78 years) and preponderance of females (61%) in the relatively small sample of patients studied (89).
“Malaria and schistosomiasis persist as major public health challenge in sub-Saharan Africa. These infections have independently and also in polyparasitic infection been implicated in anaemia and nutritional deficiencies.” Dassah SD & al. studied malaria, intestinal Schistosoma infections and the risk of anaemia among school children in a region of Ghana. They report in Co-Infection of Plasmodium falciparum and Schistosoma mansoni Is Associated with Anaemia, Malaria J, 2023 Sep 14, 22:273, https://doi.org/10.1186/s12936-023-04709-w that among 326 school children studied, 104 had asymptomatic malaria, 82 had schistosomiasis, and 25 had both. “There was no statistically significant difference in the odds of being anaemic in mono-infection with malaria … or S. mansoni … compared to those with no infection. However, the odds of being anaemic was 3.03 times higher” among those co-infected with malaria parasite species and S. mansoni, compared to those with no infection.
Field diagnostics
In countries such as Ethiopia, where P. falciparum and P. vivax are co-endemic [but] with different proportion in different settings, “the accuracy of species identification is critical, in view of the different treatments recommended for the two types of malaria.” In Malaria Misdiagnosis in the Routine Health System in Arba Minch Area District in Southwest Ethiopia: An Implication for Malaria Control and Elimination, Malaria J, 2023 Sep 14, 22:274, https://doi.org/10.1186/s12936-023-04711-2, Yigezu E & al. report that compared to polymerase chain reaction (PCR) as the standard, microscopic diagnosis in 193 microscopically positive cases reviewed misidentification of the species in up to 11% of cases, mostly in missing the existence of mixed species infections. Also, about 20% of febrile patients who were negative on microscopy were proven to have malaria, missing falciparum or vivax in about equal proportion. The authors recommend regular monitoring of “the comp etency of malaria microscopists in the study area to improve species identification and diagnosis accuracy.”
While malaria is the leading cause of acute febrile illness in sub-Saharan Africa, Tagoe JNA & al., Coinfection of Malaria and Bacterial Pathogens among Acute Febrile Patients in Selected Clinics in Ghana, Am J Trop Med Hyg. 2023 Sep 25: tpmd230099, https://doi.org/10.4269/ajtmh.23-0099 calls attention to the possibility of co-infections with bacterial pathogens. In their study of 399 febrile patients, of whom 275 were proven to have malaria, 41 of the latter were found also to be infected with leptospirosis, Q fever, or other bacterial pathogens. Thay state that therefore, “even in the case of a positive malaria test, other pathogens contributing to febrile illness should be considered.”
“Diagnosis of malaria still depends on microscopic examination of thin and thick blood smears and rapid diagnostic tests (RDTs), which often lack analytical and clinical sensitivity.” Febrer-Sendra B & al. report on the use of loop-mediated isothermal amplification (LAMP) First Field and Laboratory Evaluation of LAMP Assay for Malaria Diagnosis in Cubal, Angola, Parasit Vectors. 2023 Oct 3; 16(1):343, https://doi.org/10.1186/s13071-023-05942-7. The test was more sensitive than either microscopy or RDT and underwent external quality control with acceptable (but not ideal) results. The authors state that the “possibility to use LAMP in a real-time format in a portable device reinforces the reliability of the assay for molecular diagnosis of malaria in resource-poor laboratories in endemic areas.”
Likewise, Biruksew A & al., who aimed to determine the level of asymptomatic malaria in schoolchildren, report in Schoolchildren with Asymptomatic Malaria Are Potential Hotspot for Malaria Reservoir in Ethiopia: Implications for Malaria Control and Elimination Efforts, Malaria J, 2023 Oct 17, 22:311, https://doi.org/10.1186/s12936-023-04736-7 that “both RDT and microscopy underestimated the prevalence of asymptomatic malaria in schoolchildren. However, qPCR was able to detect even low levels of parasitaemia and revealed a higher prevalence of asymptomatic submicroscopic malaria infections. The findings imply that schoolchildren with asymptomatic malaria infection are potential hotspot for malaria reservoir that fuels ongoing transmission.”
According to Zeno EE & al., Risk of Malaria Following Untreated Sub-Patent Plasmodium falciparum Infections: Results over 4 Years from a Cohort in a High Transmission Area in Western Kenya, J Infect Dis. 2023 Sep 15: jiad398, https://doi.org/10.1093/infdis/jiad398, “symptomatic” individuals who are negative on RDT but positive on PCR testing (“sub-patent infection”) do not have a high risk of developing clinical malaria. They arrived at this conclusion based on following 400 such patients in a high-transmission area. The follow up period was 60 days.
Uyaiabasi GN & al. “assessed the comparative diagnostic performance of Malaria Rapid Diagnostic Test (mRDT), microscopy and PCR for malaria diagnosis in pregnant women for early detection of asymptomatic malaria in pregnant women.” They report that among 520 pregnant women at visit 1 (V1) “parasite positivity rates were 4.3%, 8.8% and 25.0% for microscopy, mRDT and PCR … and was 2.4%, 3.4% and 43.4% at delivery, respectively… [The] study demonstrated a high rate of subpatent parasitaemia amongst pregnant women [as well as the low sensitivity of mRDT and microscopy]. This finding therefore raises the question of the effect of subpatent parasitaemia on the health of the mother and foetus.” The paper is The Question of the Early Diagnosis of Asymptomatic and Subpatent Malaria in Pregnancy: Implications for Diagnostic Tools in a Malaria Endemic Area, Eur J Obstet Gynecol Reprod Biol X. 2023 Sep 2; 19:100233, https://doi.org/10.1016/j.eurox.2023.100233
New diagnostic methods
Although Chaianantakul N & al. do not propose a new diagnostic approach, their paper, A Novel Nested Multiplex Polymerase Chain Reaction Assay for Malaria Diagnosis Using the Hydroxymethyl Dihydropterin Pyrophosphokinase-Dihydropteroate Synthase (hppk-dhps) Gene, Am J Trop Med Hyg. 2023 Sep 11: tpmd230130, https://doi.org/10.4269/ajtmh.23-0130 describes using a gene as a target of the assay, rather than ribosomal RNA (rRNA). However, while describing the rRNA method as “time-consuming, laborious, and costly,” the abstract is silent of the effort and cost required to complete this novel approach to PCR testing.
Treatment
Treatment results
Ansah F & al. determined the prevalence rate and the dynamics of Plasmodium species among asymptomatic children (n = 1697) under 5 years from 30 communities within the Hohoe municipality in Ghana… 571 (33.7%) of the children were fond to be infected, over 99% with P. falciparum. After treatment with “artesunate-amodiaquine … of a sub-population of the participants (n = 184), there was a substantial reduction in Plasmodium parasite prevalence …. However, there was an increase in parasite prevalence from day 14 to day 42…” The authors emphasize “the importance of routine surveillance of asymptomatic malaria using sensitive nucleic acid-based amplification techniques.” The paper is The Temporal Dynamics of Plasmodium Species Infection After Artemisinin-Based Combination Therapy (ACT) Among Asymptomatic Children in the Hohoe Municipality, Ghana, Malaria J, 2023 Sep 14, 22:271, https://doi.org/10.1186/s12936-023-04712-1.
Mefloquine has rarely been cited as a first line drug against malaria infection. Yet de Freitas BS & al., Artesunate-Mefloquine Therapy for Uncomplicated Plasmodium falciparum Malaria: An Updated Systematic Review and Meta-Analysis of Efficacy and Safety, Trans R Soc Trop Med Hyg. 2023 Sep 29: trad069, https://doi.org/10.1093/trstmh/trad069 reports on several papers that analyzed the use of the drug in combination with artesunate as first line therapy (ASMQ). “Thirty-two studies were included…[and] the body of evidence gathered indicates that ASMQ continues to be safe and effective for the treatment of uncomplicated infections caused by P. falciparum compared with other ACTs. However, the inclusion of two new studies, which identified failure rates exceeding 10%, suggests a possible reduction in the efficacy of ASMQ in the analysed locations.”
Two African countries, Sudan and Somalia, are represented in the analysis of Adam M & al., Antimalarial Drug Efficacy and Resistance in Malaria-Endemic Countries in HANMAT-PIAM_net Countries of the Eastern Mediterranean Region 2016-2020: Clinical and Genetic Studies, Trop Med Int Health. 2023 Sep 13, https://doi.org/10.1111/tmi.13929. In Sudan, the cure rate of uncomplicated falciparum malaria with artemether-lumefantrine (AL) was 100% in all but four sites, where “cure rates ranged from 92.1% to 98.8%.” This, despite that mutations in the P. falciparum kelch 13 (Pfk13) gene, associated with artemisinin resistance, was found repeatedly in Sudan. The efficacy of AL for the treatment of P. vivax was evaluated in Somalia, with 100% cure rates in the areas studied.
Based on analyzing the results from 23 studies covering over 6800 patients, Commons RJ & al., Effect of Primaquine Dose on the Risk of Recurrence in Patients with Uncomplicated Plasmodium vivax: A Systematic Review and Individual Patient Data Meta-Analysis, Lancet Infect Dis, 2023 Sep 22, https://doi.org/10.1016/S1437-3099(23)00430-9 concludes that at day 180 after treatment, the risk of recurrence in patients who received no primaquine was slightly over 50%, whereas increasing does of primaquine were increasingly efficacious in reducing this rate significantly, to as low as 8.1% with the highest doses reported. This high dose also caused significant gastrointestinal side effects in about 10% of patients who took it.
Recognizing the problem of coinfections by two Plasmodium species, Walker CR & al., A Model for Malaria Treatment Evaluation in the Presence of Multiple Species, Epidemics. 2023 Sep; 44:100687, https://doi.org/10.1016/j.epidem.2023.100687 present an approach to the situation of suspected coinfections by P. falciparum and P. vivax. The abstract also refers to mass drug administration aimed only at P. falciparum, seemingly endorsing it even in situations where coinfection may exist.
In the case of monoinfection with P. vivax, WHO recommends weekly primaquine in what is considered a large dose, according to Taylor WRJ & al. In Weekly Primaquine for Radical Cure of Patients with Plasmodium vivax Malaria and Glucose-6-Phosphate Dehydrogenase Deficiency, PLoS Negl Trop Dis. 2023 Sep 6; 17(9):e0011522, https://doi.org/10.1371/journal.pntd.0011522 they report a study of this regimen for patients with known G6PD deficiency and report that all study subjects did well with it, although some experienced a reduction of hemoglobin after the first dose. Also, a small number of patients had recurrent vivax malaria, presumably not by means of reinfection.
“Tafenoquine, co-administered with chloroquine, is approved for the radical cure (prevention of relapse) of Plasmodium vivax malaria. In areas of chloroquine resistance, artemisinin-based combination therapies are used to treat malaria.” Sutanto I & al. evaluated tafenoquine plus dihydroartemisinin-piperaquine for the radical cure of P vivax malaria. In Tafenoquine Co-Administered with Dihydroartemisinin-Piperaquine for the Radical Cure of Plasmodium vivax Malaria (INSPECTOR): A Randomised, Placebo-Controlled, Efficacy and Safety Study, Lancet Infect Dis. 2023 Oct; 23(10):1153-1163, https://doi.org/10.1016/s1473-3099(23)00213-x they state that “[a]lthough tafenoquine plus dihydroartemisinin-piperaquine was statistically superior to dihydroartemisinin-piperaquine alone for the radical cure of P vivax malaria, the benefit was not clinically meaningful. This contrasts with previous studies in which tafenoquine plus chloroquine was clinically superior to chloroquine alone for radical cure of P vivax malaria.” {Based on reading the abstract, this conclusion seems to hinge primarily on the virtually equal incidence of side effects, which makes sense, since the subjects were not followed long enough to ascertain whether radical cure was achieved or not.}
Adherence to guidelines
Two articles from Kenya addressed adherence to guidelines, with similar conclusions. Osoro CB & al. explored knowledge of and adherence to guidelines by both practitioners and drug outlets with reference to treatment of malaria in pregnancy. In Perceptions and Drivers of Healthcare Provider and Drug Dispenser Practices for the Treatment of Malaria in Pregnancy in the Context of Multiple First-Line Therapies in Western Kenya: A Qualitative Study, Malaria J, 2023 Sep 14, 22:274, https://doi.org/10.1186/s12936-023-04698-w they report that healthcare “providers had not been trained in malaria case management in the previous twelve months. [Drug outlet staff] were unfamiliar with national treatment guidelines in pregnancy and reported having no pregnancy tests. Health managers were unable to supervise [drug outlets] due to resource limitations.” Likewise, Odhiambo FO & al., Adherence to National Malaria Treatment Guidelines in Private Drug Outlets: A Cross-Sectional Survey in the Malaria-Endemic Kisumu County, Kenya, Malaria J, 2023 Oct 11, 22:307, https://doi.org/10.1186/s12936-023-04744-7 contains no surprises. Drug outlets are frequently the only place where parents of febrile children seek care in the region studied. “Of 70 drug outlets studied, 20% adhered to treatment guidelines, though none actually had a copy of those on the premises. “The odds of adherence were higher among staff who had a bachelor’s degree …, those trained on malaria rapid diagnostic test …, and those who asked about patient’s symptoms …. DOs that had higher odds of adherence included those with functional thermometers … Recent PPB inspection … and malaria RDT-trained staff … were independently associated with adherence.” The authors surmise that “[r]egular interaction with regulatory bodies could improve adherence [and recommend that] Ministry of Health should enhance private sector engagement and train DOs on RDT use.”
“Integration of vertical programs for the control of malaria, schistosomiasis, and soil-transmitted helminthiasis has been recommended to achieve elimination of malaria and neglected tropical diseases (NTD) by 2030.” Afolabi MO & al., Provider and User Acceptability of Integrated Treatment for the Control of Malaria and Helminths in Saraya, South-Eastern Senegal, Am J Trop Med Hyg. 2023 Sep 18, tpmd230113, https://doi.org/10.4269/ajtmh.23-0113 reports that there are barriers to such combination of therapies, especially among the children who are the intended recipients, mostly because of the taste of some of the preparations administered.
Side effects and complications
“Primaquine radical cure is used to treat dormant liver-stage parasites and prevent relapsing Plasmodium vivax malaria but is limited by concerns of haemolysis. [Rajasekhar M & al.] undertook a systematic review and individual patient data meta-analysis to investigate the haematological safety of different primaquine regimens for P vivax radical cure.” Using the same database as Commons RJ & al. (see above), conclude that “[t]reatment of patients with G6PD activity of 30% or higher with 0·25–0·5 mg/kg per day primaquine regimens and patients with G6PD activity of 70% or higher with 0·25–1 mg/kg per day regimens were associated with similar risks of haemolysis to those in patients treated without primaquine, supporting the safe use of primaquine radical cure at these doses.” The paper is Primaquine Dose and the Risk of Haemolysis in Patients with Uncomplicated Plasmodium vivax Malaria: A Systematic Review and Individual Patient Data Meta-Analysis, Lancet Infect Dis, 2023 Sep 22, https://doi.org/10.1016/S1437-3099(23)00431-0. Millat-Martínez P & Bassat Q, Primaquine Dose and the Risk of Haemolysis and Plasmodium vivax Recurrence: Pooling the Available Data to Reassure the Unconvinced, Lancet Infect Dis, 2023 Sep 22, https://doi.org/10.1016/S1437-3099(23)00480-2 is an editorial supporting the paper and also commenting on the difference between the uses of primaquine and tafenoquine.
Kosasih A & al., Case Series of Primaquine-Induced Haemolytic Events in Controlled Trials with G6PD Screening, Pathogens. 2023 Sep 19; 12(9):1176, https://doi.org/10.3390/pathogens12091176 reports moderate to severe hemolysis in patients who were treated with primaquine after a G6PD assay that was reported to be normal. They point out the pitfalls of G6PD deficiency testing.
Drug resistance
“A policy response to currently circulating artemisinin-resistant genotypes in Africa is urgently needed to prevent a population-wide rise in treatment failures.” state Zupko RJ & al. in Modeling Policy Interventions for Slowing the Spread of Artemisinin-Resistant Pfkelch R561H Mutations in Rwanda, Nat Med. 2023 Sep 21, https://doi.org/10.1038/s41591-023-02551-w. They explored current options for treating patients with resistant malaria in Rwanda. The “best among these options [a policy of multiple first-line therapies (MFTs)] resulted in median treatment failure counts that were 49% lower … than under baseline. They also propose new approaches to resistance management, “such as triple ACTs or sequential courses of two different ACTs, [which were projected in their modeling research] to have a larger impact than longer ACT courses or MFTs, … associated with median treatment failure counts in 5 years that were 81-92% lower than the current approach, There is also a companion piece without author, under the heading of “Research Briefing,” Modeling to Guide Drug Policy Response to Artemisinin-Resistant Malaria in Rwanda, Nat Med, 2023 Oct 11, https://doi.org/ s41591-023-02619-7.
“Artemisinin-combined treatments are the recommended first-line treatment of Plasmodium falciparum malaria, but they are being threatened by emerging artemisinin resistance. Mutations in pfk13 are the principal molecular marker for artemisinin resistance.” Molina-de la Fuente I & al., Screening for K13-Propeller Mutations Associated with Artemisinin Resistance in Plasmodium falciparum in Yambio County (Western Equatoria State, South Sudan), Am J Trop Med Hyg. 2023 Sep 25: tpmd230382, https://doi.org/10.4269/ajtmh.23-0382 is a report of finding 15 mutations of the Pfk13 gene on screening 468 patients with symptomatic malaria. While each “mutation appeared only once, and none were validated or candidate markers of artemisinin resistance,” the authors recommend routine surveillance for detecting emergence of artemisinin resistance.
While Coonahan E & al., Whole-Genome Surveillance Identifies Markers of Plasmodium falciparum Drug Resistance and Novel Genomic Regions Under Selection in Mozambique, mBio. 2023 Sep 26: e0176823, https://doi.org/10.1128/mbio.01768-23 reports no instance of mutations that cause artemisinin or even chloroquine resistance among 120 samples from 120 Mozambican patients with severe malaria, they call attention to the fact that some mutations of the circumsporozoite protein were found, which may have implications as to the efficacy of the RTS,S vaccine.
Mihreteab S & al. found in Eritrea that the frequency of resistance to ACT has increased greatly between 2016 and 2019, virtually all due to Pfkelch 13 mutation of P. falciparum. What is also troublesome is that many of these same parasites are negative for hrp2 and hrp3, making them invisible to rapid diagnostic testing. The paper is Increasing Prevalence of Artemisinin-Resistant HRP2-Negative Malaria in Eritrea, N Engl J Med. 2023 Sep 28;389(13):1191-1202, https://doi.org/10.1056/nejmoa2210956.
New drug research
“Plasmodium carbonic anhydrases (CAs) have recently been proposed as potential targets for malaria prevention.” As reported in D’Agostino I & al., Antimalarial Agents Targeting Plasmodium falciparum Carbonic Anhydrase: Towards Dual Acting Artesunate Hybrid Compounds, ChemMedChem. 2023 Sep 12: e202300267, https://doi.org/10.1002/cmdc.202300267, “a series of eight hybrid compounds combining the Artesunate core with a sulfonamide moiety were synthesized and evaluated for their inhibition potency against … P. falciparum (PfCA). All derivatives demonstrated high inhibition potency against PfCA… Two Compounds showed a selectivity index of 4.1 and 3.1, respectively, against this protozoan isoform compared to hCA II. Three Derivatives showed no cytotoxic effects on human gingival fibroblasts at 50 µM with a high killing rate against both P. falciparum and P. knowlesi strains with IC50 in the sub-nanomolar range, providing a wide therapeutic window.”
Not for the first time, the idea of forming metal-quinoline complexes is reported in the literature. Colina-Vegas L & al. conclude in Antimalarial Agents Derived from Metal-Amodiaquine Complexes with Activity in Multiple Stages of the Plasmodium Life Cycle, Chemistry. 2023 Oct 2; 29(55):e202301642, https://doi.org/10.1002/chem.202301642 that “metal coordination with antimalarial quinolines is a potential chemical tool for drug design and discovery in malaria and other infectious diseases susceptible to quinoline treatment.”
Plant extracts and traditional treatments
Gumisiriza H & al. report on a survey that yielded information about popular use of plants in the treatment of malaria. Ethnomedicinal Plants Used for Malaria Treatment in Rukungiri District, Western Uganda, Trop Med Health. 2023 Aug 30; 51(1):49, https://doi.org/10.1186/s41182-023-00541-9 reports “48 medicinal plants belonging to 47 genera and 23 families used in the treatment of malaria and its symptoms in the study area. The most frequently cited species were Vernonia amygdalina, Aloe vera and Azadirachta indica. Leaves … were the most used plant organ, mostly for preparation of decoctions … and infusions … which are administered orally … or used for bathing ….”
In a similar study, Evbuomwan IO & al. report 62 “indigenous medicinal plants, including 13 new plants, used for malaria treatment in Indigenous Medicinal Plants Used in Folk Medicine for Malaria Treatment in Kwara State, Nigeria: An Ethnobotanical Study, BMC Complement Med Ther. 2023 Sep 16; 23(1):324, https://doi.org/10.1186/s12906-023-04131-4. “Mangifera indica …, Enantia chlorantha …, Alstonia boonei … followed by Cymbopogon citratus … were the most used plants. … antimalarial activities of many of the plants recorded and their isolated phytocompounds have been demonstrated.”
“Clausena anisata is commonly used in traditional medicine throughout tropical Africa. A decoction of the aromatic leaves or roots is widely drunk to treat” multiple illnesses but not malaria {https://uses.plantnet-project.org/en/Clausena_anisata_(PROTA)}. Why Kumatia EK & al. chose to investigate two of its alkaloids is not clear from the abstract of Anti-Malarial Activity of the Alkaloid, Heptaphylline, and the Furanocoumarin, Imperatorin, from Clausena anisata Against Human Plasmodium falciparum Malaria Parasites: Ex Vivo Trophozoitocidal, Schizonticidal and Gameto-cytocidal Approach, Malaria J, 2023 Sep 9; 22:264, https://doi.org/10.1186/s12936-023-04678-0, nonetheless they found both substances to hold promise as bases of future antimalarial drugs.
Annickia affinis, also known as the African yellow wood, is widely used in Central Africa and parts of West Africa in the treatment of various diseases, including malaria. Erhunse N & al., Annickia affinis (Exell) Versteegh & Sosef Methanol Stembark Extract, Potent Fractions and Isolated Berberine Alkaloid Target Both Blood and Liver Stages of Plasmodium falciparum, J Ethnopharmacol. 2023 Oct 7: 117269, https://doi.org/10.1016/j.jep.2023.117269 is a report of testing its methanol extract, which was found to have “excellent antiplasmodial activity with good selectivity against blood-stage malaria parasite.” In addition, the authors report that “the crude extract and the alkaloid enriched fractions showed promising activity against the liver-stage” of P falciparum. Apparently the substances were not tested against other species of Plasmodium.
Campaigns and Policies
Aguma HB & al. report on Uganda’s “third mass campaign to distribute long-lasting insecticidal nets (LLINs) in 2020 during the COVID-19 pandemic… The 2020/2021 campaign design was modified to follow COVID-19 Standard Operating Procedures (SOPs). These included using Personal Protective Equipment (PPE), e-platforms for training and briefing meetings, electronic data management systems and door-to-door household registration and distribution of LLINs.” Aiming at giving access to LLINs to 85% of the targeted population, they report in Mass Distribution Campaign of Long-Lasting Insecticidal Nets (LLINs) During the COVID-19 Pandemic in Uganda: Lessons Learned, Malaria J, 2023 Oct 16, 22:310, https://doi.org/10.1186/s12936-023-04753-6 that 91.4% household coverage was achieved.
Based on interviews of parents of children whose children had recently experienced a febrile illness,
Hutchinson P & al. Interpersonal Communication, Cultural Norms, and Community Perceptions Associated with Care-Seeking for Fever Among Children Under Age Five in Magoé District, Mozambique, Malaria J, 2023 Sep 21, 22:279, https://doi.org/10.1186/s12936-023-04689-x recommends “social and behaviour change interventions that focus on encouraging families and community members to talk about malaria and the need to promptly seek treatment for fevers in children may be particularly effective at increasing this behaviour in this and similar settings. Such messaging and [interpersonal communication] should consider grandmothers as a target audience, as they appear to be perceived as highly influential in care-seeking decision-making in this community.”
“The World Health Organization (WHO) has recommended that endemic countries stratify malaria to guide interventions.” In response, Djaskano MI & al. stratified health districts in Chad, based on data collected from National health statistics in Chad. The abstract of their report, Stratification and Adaptation of Malaria Control Interventions in Chad, Trop Med Infect Dis. 2023 Sep 15; 8(9):450, https://doi.org/10.3390/tropicalmed8090450 mentions the strata identified from very low to high malaria incidence; however it does not specify the decisions made based on stratification.
“Despite developing a national malaria strategy and monitoring and evaluation strategies, Kenya has not been able to meet the incidence reduction targets set by the World Health Organisation, underscoring the need for more work in identifying the barriers to implementing strategies and optimising the distribution of public health interventions.” Lacey H & al., Combating Malaria in Kenya Through Collaborative Population Health Education: A Systematic Review and Pilot Case Study, Infect Dis (Lond). 2023 Oct; 55(10):664-683, https://doi.org/10.1080/23744235.2023.2231082 reports on a pilot program of strategizing community education, but the abstract is unable to cite any real results.
“The Southern African Development Community Malaria Elimination Eight (E8) established 39 border health facilities on 5 key international borders between high and low-burden countries. These clinics aimed to improve access to prevention, diagnosis, and treatment of malaria for residents in border areas and for mobile and migrant populations who frequently cross borders.” Chisenga M & al., The Provision of Malaria Services in Border Districts of Four Countries in Southern Africa: Results from a Cross-Sectional Community Assessment of Malaria Border Health Posts, Malaria J, 2023 Oct 20, 22:318, https://doi.org/10.1186/s12936-023-04687-z reports on the basis of questionnaires administered in four of the countries that “most providers followed appropriate guidelines performing blood tests when individuals presented with fever, and that nearly all those who reported a positive blood test received medication. …. [A few] respondents reported not receiving timely diagnosis either because they did not seek help, or because they were not offered a blood test when presenting with fever. There was a high level of correct knowledge of causes, symptoms, and prevention of malaria.”
Epidemiology
Climate change, biodiversity and environment
“Global climate change is affecting the incidence and geographic spread of many” vector-borne diseases (VBDs), state Oberlin AM & Wylie BJ in Vector-Borne Disease, Climate Change and Perinatal Health, Semin Perinatol, 2023 Oct 11: 151841. https://doi.org/10.1016/j.semperi.2023.151841. The authors present “the incidence, clinical presentation, implications during pregnancy and intersection with climate change for four of the most important VBDs in pregnancy: malaria, Zika, dengue and Chagas disease.”
Concluding an epidemiological study of rural and urban environments, Beke OA-H & al., Implication of Agricultural Practices in The Micro-Geographic Heterogeneity of Malaria Transmission in Bouna, Côte d’Ivoire, Malaria J, 2023 Oct 17, 22:313, https://doi.org/10.1186/s12936-023-04748-3 state: “The presence of wetlands in urban areas and irrigated agriculture in rural areas resulted in heterogeneity in malaria transmission on a micro-geographical scale. These specific households present particular risk of malaria transmission and could fuel malaria transmission in surrounding households. The identification of micro-geographical areas using heat maps combining several epidemiological parameters can help to identify hotspots of malaria transmission.”
Risk factors
Liheluka EA & al. explored risk factors of persistent high malaria infection rates in two regions of Tanzania and report in Community Knowledge, Attitude, Practices and Beliefs Associated with Persistence of Malaria Transmission in North-Western and Southern Regions of Tanzania, Malaria J, 2023 Oct 10, 22:304, https://doi.org/10.1186/s12936-023-04738-5 based on interviews that “[d]espite good knowledge of malaria, several risk factors, such as socio-economic and behavioural issues, and misconceptions related to the use of bed nets and IRS were reported. Other key factors included unavailability or limited access to health services, poor health financing and economic activities that potentially contributed to persistence of malaria burden in these regions.” They recommend implementation of “[r]elevant policies and targeted malaria interventions, focusing on understanding socio-cultural factors….”
Also in Tanzania, “there is an increasing epidemiological shift in the burden [of malaria] on school-age children. The underlying causes for such an epidemiological shift remain unknown … [Kihwele F & al.] explored activities and behaviours that could increase the vulnerability of school-age children to transmission risk” and report in Exploring Activities and Behaviours Potentially Increases School-Age Children’s Vulnerability to Malaria Infections in South-Eastern Tanzania, Malaria J, 2023 Oct 3, 22:293, https://doi.org/10.1186/s12936-023-04703-2 that “domestic activities such as fetching water, washing kitchen utensils, cooking, and recreational activities … and studying were the reported activities that kept school-age children outdoors early evening to night hours …. Likewise, the social and cultural events including initiation ceremonies and livelihood activities also kept this age group outdoors from late evening to early night and sometimes past midnight hours. Parents migrating to farms from December to June, leaving behind school-age children unsupervised affecting their net use behaviour plus spending more time outdoors at night, and the behaviour of children sprawling legs and hands while sleeping inside treated bed nets were identified as potential risks to infectious mosquito bites.”
Natama HM & al. “investigated how different categories of prenatal malaria exposure (PME) influence levels of maternal antibodies in cord blood samples and the subsequent risk of malaria in early childhood in a birth cohort study…” They report in Associations Between Prenatal Malaria Exposure, Maternal Antibodies at Birth, and Malaria Susceptibility During the First Year of Life in Burkina Faso, Infect Immun. 2023 Sep 27 :e0026823, https://doi.org/10.1128/iai.00268-23 that “[h]igh levels of antibodies to certain erythrocytic antigens … were independent predictors of protection from clinical malaria during the first year of life. By contrast, high levels of [other antigens] were significantly associated with an increased risk of clinical malaria. These findings indicate that PME categories have different effects on the levels of maternal-derived antibodies to malaria antigens in children at birth, and this might drive heterogeneity to clinical malaria susceptibility in early childhood.
As reported in Semakula HM & al., Bayesian Belief Network Modelling Approach for Predicting and Ranking Risk Factors for Malaria Infections Among Children Under 5 Years in Refugee Settlements in Uganda, Malaria J. 2023 Oct 4; 22:297, https://doi.org/10.1186/s12936-023-04735-8, the top ranked malaria risk factors based on “sensitivity analysis included: (1) age of child; (2) roof materials (i.e., thatch roofs); (3) wall materials (i.e., poles with mud and thatch walls); (4) whether children sleep under insecticide-treated nets; 5) type of toilet facility used (i.e., no toilet facility, and pit latrines with slabs); (6) walk time distance to water sources (between 0 and 10 min); (7) drinking water sources (i.e., open water sources, and piped water on premises).”
With the increased arrival of Chinese construction crews in Africa, Zou L & al. explored The Perception and Interpretation of Malaria Among Chinese Construction Workers in Sub-Saharan Africa: A Qualitative Study, (Malaria J, 2023 Oct 10, 22:305, https://doi.org/10.1186/s12936-023-04739-4.) Their conclusions, based on interviewing a small sample of such workers, is that “[m]alaria poses major health issues to Chinese construction workers in sub-Saharan Africa who lack immunity and live in an environment of high transmission. Their dearth of awareness and misunderstanding of malaria impacts their prevention and treatment behaviors and health outcomes.”
General epidemiology
Two articles touch on co-infection of malaria and dengue. In Increasing Prevalence of Malaria and Acute Dengue Virus Coinfection in Africa: A Meta-Analysis and Meta-Regression of Cross-Sectional Studies, Malaria J, 2023 Oct 6, 22:300, https://doi.org/10.1186/s12936-023-04723-y Gebremariam TT & al. “estimate the prevalence of dengue and malaria coinfection among acute … febrile diseases in Africa” through a systematic review of the literature. The results of reviewing 22 studies “revealed a pooled prevalence of malaria and dengue coinfection of 4.2%, with Central Africa having the highest rate (4.7%), followed by East Africa (2.7%) and West Africa (1.6%). Continent-wide, P. falciparum and acute dengue virus coinfection prevalence increased significantly from 0.9% during 2008–2013 to 3.8% during 2014–2017 and to 5.5% during 2018–2021. Alsedig K & al. studied 395 febrile patients in a Sudanese hospital and report in Prevalence of Malaria and Dengue Co-Infections Among Febrile Patients During Dengue Transmission Season in Kassala, Eastern Sudan, PLoS Negl Trop Dis. 2023 Oct 4; 17(10): e0011660, https://doi.org/10.1371/journal.pntd.0011660 that 26 of them (6.6%) were proven to have both infections simultaneously. Co-infections were more frequent among people under the age of 41.
Natuhamya C & al. undertook a study to “determine the complete sources of cluster variation on the risk of under-five malaria and risk factors associated with under-five malaria in Uganda.” They report in Sources of Cluster Variation on the Risk of Under-Five Malaria in Uganda: A Multilevel-Weighted Mixed Effects Logistic Regression Model Approach, Malaria J, 2023 Oct 19, 22:317, https://doi.org/10.1186/s12936-023-04756-3 that “[e]very additional year in a child’s age was positively associated with malaria infection …. Children whose mothers had at least a secondary school education were less likely to suffer from malaria infection … as well as those who dwelled in households in the two highest wealth quintiles …. An increase in altitude by 1 m was negatively associated with malaria infection …. About 77% of the total variation in the positive testing for malaria was attributable to differences between enumeration areas.”
“Until recently, little or no endemic transmission of Plasmodium vivax has been reported in sub-Saharan Africa outside of the Horn of Africa. P. vivax was presumed to be largely absent because the Duffy blood group antigen was rare in persons living in the region.” However, O’Meara WP & al., Plasmodium vivax Prevalence in Semiarid Region of Northern Kenya, 2019, Emerg Infect Dis. 2023 Oct 1; 29(11), https://tinyurl.com/4bzpudvk found in Turkana County, Kenya, “that 2% of household members of patients with Plasmodium falciparum infections were also infected with P. vivax.”
“Blood group O is associated with protection against severe malaria and reduced size and stability of P. falciparum-host red blood cell (RBC) rosettes compared to non-O blood groups.” Opi DH & al. set out to determine whether “the non-O blood groups encoded by the specific ABO genotypes AO, BO, AA, BB and AB differ in their associations with severe malaria.” They conclude in Non-O ABO Blood Group Genotypes Differ in Their Associations with Plasmodium falciparum Rosetting and Severe Malaria, PLoS Genet. 2023 Sep 14; 19(9):e1010910, https://doi.org/10.1371/journal.pgen.1010910, a study conducted in Kenya, that “ genotype influences P. falciparum rosetting and support the hypothesis that double dose non-O genotypes confer a greater risk of severe malaria than AO/BO heterozygosity.”
Spatiotemporal studies
Three studies relate to the epidemiology of non-falciparum malaria. While Dao F & al., The Prevalence of Human Plasmodium Species during Peak Transmission Seasons from 2016 to 2021 in the Rural Commune of Ntjiba, Mali, Trop Med Infect Dis, 2023 Sep 7; 8(9):438, https://doi.org/10.3390/ tropicalmed8090438 is a spatiotemporal study, it is of particular importance because of the frequency of non-falciparum parasites reported in blood specimens collected. “Children aged 5-9 presented the highest frequency of P. falciparum infections (41.91%). Non-falciparum species were primarily detected in adolescents (10-14 years) with frequencies above 50%… [The] data highlight that P. falciparum represented the first burden, but other non-falciparum species were also important. Increasing attention to P. malariae and P. ovale is essential if malaria elimination is to be achieved.” Essentially the same points are made in Popkin Hall ZR & al., Malaria Species Positivity Rates Among Symptomatic Individuals Across Regions of Differing Transmission Intensities in Mainland Tanzania, medRxiv, 2023 Sep 20: 2023.09.19.23295562, https://doi.org/10.1101/2023.09.19.23295562. In that study, all Plasmodium species known to infect humans were found, quite a few in mono-infections. Likewise, Sendor R & al. emphasize in Epidemiology of Plasmodium malariae and Plasmodium ovale spp. in Kinshasa Province, Democratic Republic of Congo, Nat Commun, 2023 Oct 19; 14(1):6618.
https://doi.org/10.1038/s41467-023-42190-w that even though the two species mentioned in the title amount to less than 10% of cases found at a survey, that is not an insignificant prevalence.
Dabaro D & al., Prevalence and Predictors of Asymptomatic Malaria Infection in Boricha District, Sidama Region, Ethiopia: Implications for Elimination Strategies, Malaria J, 2023 Sep 26, 22:284, https://doi.org/10.1186/s12936-023-04722-z.
Samake JN & al., Population Genomic Analyses Reveal Population Structure and Major Hubs of Invasive Anopheles stephensi in the Horn of Africa, Mol Ecol, 2023 Oct 5, https://doi.org/10.1111/mec.17136
Kitawa YS & Asfaw ZG, Space-Time Modelling of Monthly Malaria Incidence for Seasonal Associated Drivers and Early Epidemic Detection in Southern Ethiopia, Malaria J, 2023 Oct 9, 22:301, https://doi.org/10.1186/s12936-023-04742-9.