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

A recent article in the New York Times, At Long Last, Can Malaria Be Eliminated? heralds the use of the RTS,S/AS01E vaccine and the continuing field research on the R-21 vaccine, but contains nothing that readers of these summaries have not already seen. All the same, perhaps because of the prevalent optimism expressed therein, this past month has seen an especially large number of published articles not only about vaccines, but other aspects of malaria prevention, along with the continuing plethora of malaria epidemiology and other relevant subjects. One interesting feature of this month’s compendium is the recent publication of some articles that did not show benefit from established chemoprevention.

Prevention:

Vaccines
Daubenberger C & Moncunill G, Next Generation of Malaria Subunit Vaccines to Reduce Disease Burden in African Children, Lancet Infect Dis, 2022 Sep 7, doi: 10.1016/S1473-3099(22)00523-0 is a commentary on article on R21 vaccine reported in September, Datoo MS & al., Efficacy and Immunogenicity of R-21/Matrix-M Vaccine Against Clinical Malaria after 2 Years’ Follow-Up in Children in Burkina Faso: A Phase 1/2b Randomised Controlled Trial, Lancet Inf Dis, 2022 Sep 7, doi: 10.1016/S1473-3099(22)0422-X.

A recent trial of 5920 children in Burkina Faso and Mali showed that the combination of seasonal vaccination with the RTS,S/AS01E malaria vaccine (primary series and two seasonal boosters) and seasonal malaria chemoprevention (four monthly cycles per year) was markedly more effective than either intervention given alone in preventing clinical malaria, severe malaria, and deaths from malaria.
Cairns M & al. report in The Duration of Protection Against Clinical Malaria Provided by the Combination of Seasonal RTS,S/AS01E Vaccination and Seasonal Malaria Chemoprevention Versus Either Intervention Given Alone, BMC Med. 2022 Oct 7, 20: 352, doi: 10.1186/s12916-022-02536-5 that these results, including the fading of protection from both over time, point to the need to time interventions in view of local seasonality.

On the same topic, Sagara I, & al. report on the anti-circumsporozoite antibody response to seasonal RTS,S/AS01E vaccination in children in the trial referred to above. It is reported in The Anti-Circumsporozoite Antibody Response of Children to Seasonal Vaccination With the RTS,S/AS01E Malaria Vaccine, Clin Infect Dis. 2022 Sep 10;75(4):613-622, doi: 10.1093/cid/ciab1017. “A strong antibody response to an annual, pre-malaria transmission season booster dose was observed, but this was lower than after the primary vaccination series and lower after the second than after the first booster dose … Children whose antibody response was in the upper tercile post-vaccination had a lower incidence of malaria during the following year than children in the lowest tercile.”

Oladipo HJ & al. argue that in view of the huge problems arising from emerging artemisinin resistance and other factors in Sub-Saharan Africa, vaccine production and distribution must be increased in Increasing Challenges of Malaria Control in Sub-Saharan Africa: Priorities for Public Health Research and Policymakers, Ann Med Surg (Lond), 2022 Aug 18; 81:104366, doi: 10.1016/j.amsu.2022.104366

Saveria T & al. opine in Needle-Free, Spirulina-Produced Plasmodium falciparum Circumsporozoite Vaccination Provides Sterile Protection Against Pre-Erythrocytic Malaria in Mice, NPJ Vaccines. 2022 Oct 4; 7:113, doi: 10.1038/s41541-022-00534-5 that a non-injectable form of the vaccines mentioned above may be feasible by using “the edible algae, Arthrospira platensis (commonly called ‘spirulina’) as a malaria vaccine platform.” Using mice as test subjects, intranasal insufflation of this formulation “followed by oral PfCSP-spirulina boosters resulted in a strong, systemic anti-PfCSP immune response that was protective against subcutaneous challenge with a PfCSP-expressing Plasmodium species.

Murphy SC & al. previously reported on a vaccine derived from genetically attenuated parasites (GAPs) “through gene deletions.” In A Genetically Engineered Plasmodium falciparum Parasite Vaccine Provides Protection from Controlled Human Malaria Infection, Sci Transl Med, 2022 Aug 24; 14(659):eabn9709, doi: 10.1126/scitranslmed.abn9709 they now show that when mosquitoes infected by these GAPs (PfGAP3KO) bite human volunteers, they remained Plasmodium negative one month later. “Thus, the PfGAP3KO vaccine was safe and immunogenic and was capable of inducing protection against sporozoite infection. [They recommend evaluation of] PfGAP3KO vaccine efficacy in dose-range finding trials with an injectable formulation.

According to Ko K-T & al., “[o]ne of the most promising candidates for inclusion in a transmission-blocking malaria vaccine is the gamete surface protein Pfs48/45, which is essential for development of the parasite in the mosquito midgut.” As detailed in Structure of the Malaria Vaccine Candidate Pfs48/45 and its Recognition by Transmission Blocking Antibodies, Nat Commun. 2022 Sep 24; 13:5603, doi: 10.1038/s41467-022-33379-6, the authors “reveal where transmission-blocking and non-blocking antibodies bind on Pfs48/45 [and] demonstrate that antibodies which bind across this molecule can be transmission-blocking. These studies will guide the development of future Pfs48/45-based vaccine immunogens.” A related editorial by Sather DN, Freshly Remodeled and Ready to Fight Malaria, Immunity. 2022 Sep 13; 55(9):1588-1590, doi: 10.1016/j.immuni.2022.08.013 refers to the application of “structure-guided vaccine design to transform this protein into a stable, high-producing antigen that elicits exceptional blocking antibodies, renewing its promise as a tool to fight malaria.”

Vector control and protection from vectors
Kamau A & al., Long-Lasting Insecticide-Treated Net Use and Malaria Infections on the Kenyan Coast, Trans R Soc Trop Med Hyg. 2022 Oct 2; 116(10):966-970, doi: 10.1093/trstmh/trac029 examines “the impact of long-lasting insecticide-treated net (LLIN) use on the prevalence of malaria infections across all ages, 25 [years] after a trial of insecticide-treated nets was conducted in the same area along the Kenyan coast… There was a high level of reported LLIN use by the community (72%), notably among children <5 [years] of age (84%).”

“LLINEUP was a cluster-randomised trial conducted in 48 districts in eastern and western Uganda. 104 health subdistricts (clusters) without ongoing or planned indoor residual spraying with pirimiphos-methyl (Actellic, Basel, Switzerland) were eligible for inclusion in the trial” reported in Effect of Long-Lasting Insecticidal Nets with and without Piperonyl Butoxide on Malaria Indicators in Uganda (LLINEUP): Final Results of a Cluster-Randomized Trial Embedded in a National Distribution Campaign, Lancet Infect Dis, 2022 Sep 22, doi: 10.1016/S1437-3099(22)00469-8 by Maiteki-Sebuguzi C & al. While the authors conclude that “PBO LLINs outperformed pyrethroid-only LLINs for 25 months,” the data reported seem to indicate that the difference, while statistically significant, is slight. Zinszer K & Talisuna AO, Fighting Insecticide Resistance in Malaria Control, Lancet Infect Dis, 2022 Sep 22, doi: 10.1016/S1437-3099(22)00518-7 is an Editorial commenting on this study and emphasizing that the Vector Control Action Group of WHO “concluded that in areas of high pyrethroid resistance, PBO-pyrethroid nets are more effective than conventional non-PBO LLINs for malaria protection.”

One of three papers from Western Kenya by the same group of researchers is Omondi CJ & al., Asymptomatic and Submicroscopic Plasmodium Infections in an Area Before and During Integrated Vector Control in Homa Bay, Western Kenya, Malaria J, 2022 Sep 24, vol 21 art 272, doi: 10.1186/s12936-022-04288-2. The diagnostic test in subjects with negative microscopy was qPCR. As compared to tests after use of bednets alone for 12 months, both microscopic and submicroscopic tests became significantly less prevalent after two applications of indoor residual spraying 12 months apart.
Impregnated bednets will help only if they are properly used.

Mwangu LM & al, Factors Associated with Non-Use of Insecticide-Treated Bed Nets Among Pregnant Women in Zambia, Malaria J, 2202 Oct 11, vol 21 art 290, doi: 10.1186/s12936-022-04313-4 reports that “[o]nly 49% of pregnant women reported sleeping under an ITN in 2018 in the country… Factors found to be associated with the non-use of ITNs in the study population are: ITN per household member, parity, education, marital status and malaria prevalence provinces.”

Mbewe NJ & al. follow up on reports elsewhere that partially treated bednets may be just as effective as fully treated ones. After their experiments they report in Efficacy of bednets with dual insecticide-treated netting (Interceptor® G2) on side and roof panels against Anopheles arabiensis in north-eastern Tanzania, Parasit Vectors. 2022 Sep 15; 15(1):326, doi: 10.1186/s13071-022-05454-w that while the partially treated nets were more effective than untreated ones, they did not match the efficacy of nets that had been treated in their entirety.

Ngonghala CN considers multiple mosquito factors in Assessing the Impact of Insecticide-Treated Nets in the Face of Insecticide Resistance on Malaria Control, J Theor Biol. 2022 Sep 22:111281, doi: 10.1016/j.jtbi.2022.111281. Using mathematical modeling, the author concludes “that replacing ITNs before the prescribed useful lifespan or designing ITNs with longer lifespans is important for malaria control and that piperonyl butoxide ITNs (which inhibit or reverse insecticide resistance) outperform regular ITNs in malaria control.”

Iacovidou MA & al. “present survival data on insecticide-resistant Anopheles gambiae s.l. from experiments in Côte d’Ivoire” in Omitting Age-Dependent Mosquito Mortality in Malaria Models Underestimates the Effectiveness of Insecticide-Treated Nets, PLoS Comput Biol, 2022 Sep 19; 18(9):e1009540, doi: 10.1371/journal.pcbi.1009540 and from it, they develop mathematical models predicting that even insecticide resistant mosquitoes will reduce the number of bites they will inflict on humans after being exposed to “standard” insecticide treated bednets. Although the article does not explicitly identify the insecticide, the presumption is that it is a pyrethroid.

Verma V & al. report on a new chemical to treat bednets in Laboratory Evaluation of a New Alphacypermethrin Long-Lasting Insecticidal Net Against Anopheles culicifacies s.l., Parasitol Res, 2022 Sep; 121(9):2725-2731, doi: 10.1007/s00436-022-07604-6. Since these nets were tested using insecticide sensitive vectors, the only conclusion was that the chemical withstood 20 washes.

Nkya TE & al. are the authors of Six Decades of Malaria Vector Control in Southern Africa: A Review of The Entomological Evidence-Base, Malaria J, 2022 Oct 2, vol 21 art 279, doi: 10.1186/s12936-022-04292-6. “The search resulted in 718 publications with 145 eligible and included in this review for the six countries generated over six decades. The majority (139) were from three countries, namely Zambia (59) and Mozambique (48), and Zimbabwe (32) whilst scientific publications were relatively scanty from front-line malaria elimination countries, such as Namibia (2), Botswana (10) and Eswatini (4). Most of the research reported in the publications focused on vector bionomics generated mostly from Mozambique and Zambia, while information on insecticide resistance was mostly available from Mozambique… [The recommend] that malaria vector research capacity and routine entomological monitoring and evaluation [be] strengthened to enhance decision-making, considering changing vector bionomics and insecticide resistance, among other determinants of malaria vector control.”

Fernandez Montoya L & al. argue in Overlaying Human and Mosquito Behavioral Data to Estimate Residual Exposure to Host-Seeking Mosquitoes and the Protection of Bednets in a Malaria Elimination Setting Where Indoor Residual Spraying and Nets Were Deployed Together, PLoS One. 2022 Sep 15; 17(9):e0270882, doi: 10.1371/journal.pone.0270882 that the existence of several species of Anopheles that may be vectors of malaria, and their different diurnal and spatial behaviors bednets and other preventive measures should always supplement the use of indoor residual spraying.

One of the “other preventive measures” referred to above is the topic of Fox T & al., House Modifications for Preventing Malaria, Cochrane Database Syst Rev. 2022 Oct 6; 2022(10): CD013398, doi: 10.1002/14651858.CD013398.pub4. Searching the literature on the subject, the found that “[h]ouse modifications – largely screening, sometimes combined with insecticide and lure and kill devices – were associated with a reduction in malaria parasite prevalence and a reduction in people with anaemia.”

“With more than 40% of the population in Africa living in urban environments, the invasion and spread of Anopheles stephensi could pose a significant threat to the control and elimination of malaria in the region” according to WHO, WHO Launches New Initiative to Stop the Spread of Invasive Malaria Vector in Africa, 2022 Sep 29, https://www.who.int/news/item/29-09-2022-who-launches-new-initiative-to-stop-the-spread-of-invasive-malaria-vector-in-africa. “But large-scale surveillance of the vector is still in its infancy, and more research and data are urgently needed.” This vector, which has a propensity for urban living, has now been spotted not only in the Horn of Africa, but also in Nigeria.

An interesting approach to studying vector control is reported in Lacroux C & al., Repellent Activity Against Anopheles gambiae of the Leaves of Nesting Trees in the Sebitoli Chimpanzee Community of Kibale National Park, Uganda, Malaria J, 2022 Sep 27, vol 21 art 271, doi: 10.1186/s12936-022-04291-7. “To test the hypothesis that chimpanzees choose tree species for their aromatic properties, data related to 1,081 nesting trees built … in the Sebitoli community of Kibale National Park … were analysed. The 10 most used trees were compared to the 10 most common trees in the habitat that were not preferred for nesting… [The 10 most used] species correspond to more than 80% of the nesting trees. Out of the essential oil obtained from the 10 nesting trees, 7 extracts for at least one concentration tested showed spatial repellency, 7 were irritant by contact and none were toxic…[while of] the abundant trees in their habitat not used by chimpanzees, only 3 were repellent and 5 irritants.”

Chemoprophylaxis
Although Intermittent Preventive Treatment for malaria in pregnancy with sulfamethoxide-pyrimeth-amine (IPTp-SP) is a “lifesaving World Health Organization (WHO) recommended preventive intervention for pregnant women in malaria-endemic regions,” Mohammed AG & al. state that “IPTp-SP uptake in the Northern region of Ghana is much lower than the sub-optimal national coverage level.” Therefore they studied healthcare worker compliance with the WHO recommendation in the area. Factors Influencing Health Workers’ Compliance with the WHO Intermittent Preventive Treatment for Malaria in Pregnancy Recommendations in the Northern Region, Ghana, Malaria J, 2022 Sep 24, vol 21 art 273, doi: 10.1186/s12936-022-04286-4 reports that the largest group of workers studied were midwives; interestingly those working in health centers had the lowest level of compliance.

A recently awarded MPI Small Grant in Uganda has as one of its goals to improve pregnancy outcomes. Godwin IO & al., Effectiveness of Antenatal Intermittent Preventive Treatment for Malaria with Sulphadoxine-Pyrimethamine on Peripartum Outcomes, Ther Adv Infect Dis, 2022 Sep 6; 9:20499361221122620, doi: 10.1177/20499361221122620 is one of a number of articles that endorses the use of chemoprevention not just to reduce morbidity of the mother, but to improve the health of the newborn.

Closely related to the above two articles is Ameyaw EK, Uptake of Intermittent Preventive Treatment of Malaria in Pregnancy Using Sulfadoxine-Pyrimethamine (Iptp-SP) in Uganda: A National Survey, Malaria J, 2022 Oct 7, vol 21 art 285, doi: 10.1186/s12936-022-04299-z, which documents that in 2018, fewer than half of all pregnant women received at least three courses of IPTp-SP. The data were particularly troublesome for adolescents and young women 19 years of age and under and for poor women. The author recommends “[c]ontextually responsive behavioural change communication interventions are required to invoke women’s passion to achieve the recommended dosage” without mentioning now that can be accomplished.

Somewhat contrary to the promise of chemoprevention improving children’s development is the article by Bangirana P & al., Effect of Malaria and Malaria Chemoprevention Regimens in Pregnancy and Childhood on Neurodevelopmental and Behavioral Outcomes in Children at 12, 24 And 36 Months: A Randomized Clinical Trial, Clin Infect Dis, 2022 Oct 11; doi: 10.1093/cid/ciac815. They concluded that “[m]alaria in pregnancy was associated with worse cognitive, behavioral and executive function scores in affected children, but more effective malaria chemoprevention measures did not result in better outcomes. Malaria chemoprevention prior to and early in gestation and with even higher efficacy in mothers and children may be required to prevent neurodevelopmental impairment in children.”

Another article that raises questions about the use of current modes of chemoprvenetion is Taylor SM, & al., Monthly Sulfadoxine/Pyrimethamine-Amodiaquine or Dihydroartemisinin-Piperaquine as Malaria Chemoprevention in Young Kenyan Children with Sickle Cell Anemia: A Randomized Controlled Trial, PLoS Med, 2022 Oct 10; 19(10):e1004104. doi: 10.1371/journal.pmed.1004104. The outcome of the trial for clinical malaria was that the regiment offered no protection, though children who received the drugs had fewer episodes of certain complications of their sickle cell disease and there were fewer cases of asymptomatic P. falciparum infestations.

According to Pons-Duran C & al., “[m]alaria is among the top causes of death in adolescent girls (10 to 19 years) globally. Adolescent motherhood is associated with increased risk of adverse maternal and neonatal outcomes. The interaction of malaria, adolescence, and pregnancy is especially relevant in malaria endemic areas, where rates of adolescent pregnancy are high.” In Burden of Malaria in Pregnancy Among Adolescent Girls Compared to Adult Women in 5 Sub-Saharan African Countries: A Secondary Individual Participant Data Meta-Analysis of 2 Clinical Trials, PLoS Med, 2022 Sep 2; 19(9):e1004084. doi: 10.1371/journal.pmed.1004084, they report having “observed that adolescent girls in sub-Saharan Africa (SSA) are more prone to experience clinical malaria episodes during pregnancy and have peripheral malaria and placental infection at delivery than adult women.”

Kühl M-J & al. studied the clinical outcomes of young children who had been hospitalized with severe anemia. They report in Economic Evaluation of Postdischarge Malaria Chemoprevention in Preschool Children Treated for Severe Anaemia in Malawi, Kenya, and Uganda: A Cost-Effectiveness Analysis, eClinical Medicine, 2022 Oct 1, doi: 10.1016/j.eclinm.2022.101669 that in addition to the presumed health benefits to the children, there is evidence that the “strategies were cost-saving …, meaning less costly and more effective in increasing health-adjusted life expectancy than the standard of care.” EurekAlert, New study – Malaria Treatment Is Saving Money While Saving Young Lives, Malaria prophylaxis-treatment for children both saves lives and reduces cost , shows a new study from the University of Bergen (UiB). 2022 Oct 3, https://www.eurekalert.org/news-releases/966670 is a news release referring to the above study.

Baker K & al., Feasibility, Acceptability, and Protective Efficacy of Seasonal Malaria Chemoprevention Implementation in Nampula Province, Mozambique: Protocol for a Hybrid Effectiveness-Implement-ation Study, JMIR Res Protoc. 2022 Sep 23; 11(9):e36403, doi: 10.2196/36403 is a type of article that discloses the protocol of a future or ongoing study but does not quote any results.

Other prevention
Hoermann A & al., “augmented a midgut gene of the malaria mosquito Anopheles gambiae to secrete two exogenous antimicrobial peptides, magainin 2 and melittin.” They report this gene drive project in Gene Drive Mosquitoes Can Aid Malaria Elimination by Retarding Plasmodium Sporogonic Development, Sci Adv. 2022 Sep 23; 8(38):eabo1733, doi: 10.1126/sciadv.abo1733. The “small genetic modification, capable of efficient nonautonomous gene drive, hampers oocyst development in both Plasmodium falciparum and Plasmodium berghei. It delays the release of infectious sporozoites, while it simultaneously reduces the life span of homozygous female transgenic mosquitoes.”

Zerdo Z & al. do not have good things to report in, Implementation of a Malaria Prevention Education Intervention in Southern Ethiopia: A Qualitative Evaluation, BMC Public Health. 2022 Sep 23; 22(1):1811, doi: 10.1186/s12889-022-14200-x. “Low attendance of parents in the training was the major challenge for the success of MPE.” They assert that the [n]ational malaria program should ensure the access to malaria prevention measures; and future studies using increased frequency of the intervention embedded with monitoring adherence to the intervention protocol [should] be conducted to improve the gains from existing malaria interventions.

Diagnosis:

General diagnostics
Seevaratnam D & al., Analysis and Validation of Silica-Immobilised BST Polymerase in Loop-Mediated Isothermal Amplification (LAMP) for Malaria Diagnosis, Anal Bioanal Chem, 2022 Sep; 414(21):6309-6326, doi: 10.1007/s00216-022-04131-2 is a complex explanation of various preparations used in LAMP diagnosis of malaria.

Aninagyei E & al. comment on the increasing prevalence of false negative tests in individuals who nevertheless carry the malaria parasite in their body. Utilization of 18s Ribosomal RNA LAMP for Detecting Plasmodium falciparum in Microscopy and Rapid Diagnostic Test Negative Patients, PLoS One. 2022 Oct 6; 17(10): e0275052, doi: 10.1371/journal.pone.0275052 advocates the use of this test with evidence that it often detects malaria in patients who present with other complaints and are RDT and microscopy negative. The abstract does not address the issues of availability and cost of the test.

Field diagnostics
In view of genetic heterogeneity that may compromise the accuracy of the common histidine rich protein (HRP) based rapid diagnostic tests (RDTs) Lynch E & al. report in Evaluation of HRP2 and pLDH-Based Rapid Diagnostic Tests for Malaria and Prevalence of pfhrp2/3 Deletions in Aweil, South Sudan, Malaria J, 2022 Sep 9, vol 21 art 261, doi: 10.1186/s12936-022-04280-w that they used RDTs based on different proteins and compared the results to microscopy and PCR. While the sensitivities of these tests against both controls were well over 95%, their specificities were low enough to call into question their routine use.

Molina-de la Fuente I & al., Deletion Patterns, Genetic Variability and Protein Structure of pfhrp2 and pfhrp3: Implications for Malaria Rapid Diagnostic Test in Amhara Region, Ethiopia, Malaria J, 2022 Oct 8, vol 21 art 287, doi: 10.1186/s12936-022-04306-3 emphasizes the limitation of rapid diagnostic tests,. Just as the articles above and below. The authors advocate diligent surveillance of these genes in order “to ensure the effectiveness of public health interventions in this region.”

Gene deletions that cause inaccurate RDTs are also common in Djibouti, according to Rogier E & al., Plasmodium falciparum pfhrp2 and pfhrp3 Gene Deletions and Relatedness to Other Global Isolates, Djibouti, 2019-2020, Emerg Infect Dis. 2022 Oct; 28(10):2043-2050, doi: 10.3201/eid2810.220695. These data are similar to those in adjacent regions in Eritrea and Ethiopia.

The main argument of Schmedes SE & al., Predicting Plasmodium falciparum Infection Status in Blood Using a Multiplexed Bead-Based Antigen Detection Assay and Machine Learning Approaches, PLoS One, 2022 Sep 29; 17(9):e0275096, doi: 10.1371/journal.pone.0275096 is that in view of the genetic heterogeneity of P. falciparum proteins, tests based on multiple proteins should be available. It is unclear from the abstract how this relates to machine learning.

Another protocol description is the subject of Tahita MC & al., Impact and Operational Feasibility of Adding Malaria Infection Screening Using an Ultrasensitive RDT for Placental and Fetal Outcomes in an Area of High IPTP-SP Coverage in Burkina Faso: the ASSER MALARIA Pilot Study Protocol, Pilot Feasibility Stud. 2022 Oct 1; 8(1):221, doi: 10.1186/s40814-022-01181-2

New diagnostic methods
No articles this month

Treatment:

Treatment results
Whalen ME & al studied extending the routine three-day treatment of children to five days. Their report, The Impact of Extended Treatment with Artemether-Lumefantrine on Antimalarial Exposure and Reinfection Risks in Ugandan Children with Uncomplicated Malaria: A Randomized Controlled Trial, Clin Infect Dis. 2022 Sep 20, doi: 10.1093/cid/ciac783, states that the extension was safe; however it did not necessarily reduce recurrence risk. As also demonstrated by Marwa & al. below, Lumefantrine levels on day 7 were predictive or recurrence risk.

Based on studies in three countries, Hetzel MW & al. report in Effectiveness of Rectal Artesunate as Pre-Referral Treatment for Severe Malaria in Children Under 5 Years of Age: A Multi-Country Observational Study, BMC Med, 2022 Oct 11; 20(1):343. doi: 10.1186/s12916-022-02541-8 that the benefit of pre-referral rectal artesunate is not observed in environments in which post-referral therapy does not consistently use artesunate combination therapy.

The success of treatment of malaria depends in large part on using the proper dosage of the appropriate medications. Marwa KJ & al. report on studying the effects of dosing in Lumefantrine Plasma Concentrations in Uncontrolled Conditions Among Patients Treated with Artemether-Lumefantrine for Uncomplicated Plasmodium falciparum Malaria in Mwanza, Tanzania, Int J Infect Dis, 2022 Sep 2: S1201-9712(22)00490-8, doi: 10.1016/j.ijid.2022.08.020. The authors used data “from an efficacy study employing the WHO protocol, 2015 for monitoring antimalarial drug efficacy. Lumefantrine plasma concentration was measured…” They concluded that [l]umefantrine plasma concentrations below cut off points (175ng/ml and 200ng/ml) on [treatment] day 3 and 7 did not influence treatment outcomes.” However, the abstract does not relate these findings to the dosages used.

Rogerson SJ & Unger HW, Pregnancy and Malaria: The Perfect Storm, Curr Opin Infect Dis. 2022 Oct 1; 35(5):410-416, doi: 10.1097/qco.0000000000000859 reviews the effects of the IPTp-SP regimen as treatment for malaria in pregnancy rather than as chemoprevention. “The alternative, IPTp with dihydroartemisinin-piperaquine, has greater antimalarial efficacy, but does not appear to improve pregnancy outcomes, because sulfadoxine-pyrimethamine has poorly understood nonmalarial benefits on birthweight.” In any event, artemisinins are not considered safe during the first trimester.

According to Stepniewska K et al., “the World Health Organization (WHO) recommended single low-dose (SLD, 0.25 mg/kg) primaquine to be added as a Plasmodium (P.) falciparum gametocytocide to artemisinin-based combination therapy (ACT) without glucose-6-phosphate dehydrogenase (G6PD) testing, to accelerate malaria elimination efforts and avoid the spread of artemisinin resistance. Uptake of this recommendation has been relatively slow primarily due to safety concerns.” Their report, Safety of Single-Dose Primaquine as a Plasmodium falciparum Gametocytocide: A Systematic Review and Meta-Analysis of Individual Patient Data, BMC Med. 2022 Sep 16; 20(1):350, doi: 10.1186/s12916-022-02504-z includes outcomes from over 6000 participants in 20 studies. Serious hematological events after primaquine were exceedingly rare (0.3%) among 113 children with known G6PD deficiency. Thus the authors conclude that the WHO recommendation ought to be followed.

Side effects and complications
Kalkman LC & al. focus on babies younger than 6 months in Antimalarial Treatment in Infants, Expert Opin Pharmacother. 2022 Sep 29, doi: 10.1080/14656566.2022.2130687. They note that there are reports on frequent side effects of treatment. As they state, “infants with malaria may be at increased risk of treatment failure and drug toxicity.” They recommend further research on the subject.

Drug resistance
Duffy S & Avery VM contribute to the understanding of “parasite evolution and control of artemisinin tolerance.” Their paper , Naturally Acquired Kelch13 Mutations in Plasmodium falciparum Strains Modulate In Vitro Ring-Stage Artemisinin-Based Drug Tolerance and Parasite Survival in Response to Hyperoxia, Microbiol Spectr, 2022 Sep 12: e0128221, doi: 10.1128/spectrum.01282-21, “will provide innovative approaches to mitigate the development of artemisinin tolerance and thereby artemisinin-based drug treatment failure and loss of life globally to malaria infections.”

The “recent independent emergence of artemisinin resistance in Africa is alarming. In response, triple artemisinin-based combination therapies (TACTs) are being developed to mitigate the risks associated with increasing drug resistance. Since ACTs are still effective in Africa, where malaria is mainly a paediatric disease, the potential deployment of TACTs raises important ethical questions.” Tindana P & al., Ethical Considerations in Deploying Triple Artemisinin-Based Combination Therapies for Malaria: An Analysis of Stakeholders’ Perspectives in Burkina Faso and Nigeria, PLoS One. 2022 Sep 9; 17(9):e0273249, doi: 10.1371/journal.pone.0273249 “presents an analysis of stakeholders’ perspectives regarding key ethical considerations to be considered in the deployment of TACTs in Africa provided they are found to be safe, well-tolerated and effective for the treatment of uncomplicated malaria.”

Ward KE & al., Plasmodium falciparum Resistance to Artemisinin-Based Combination Therapies, Curr Opin Microbiol. 2022 Oct;69:102193, doi: 10.1016/j.mib.2022.102193 is a review of the basic mechanisms of drug resistance.

In a study of molecular markers, Zhou Z & al. collected dried blood spot samples in two “community surveys in Asembo, Kenya.. [They] were genotyped by Sanger sequencing for markers associated with resistance to SP (Pfdhfr, Pfdhps), CQ, AQ, lumefantrine (Pfcrt, Pfmdr1) and artemisinin (Pfk13). Their report, Temporal Trends in Molecular Markers of Drug Resistance in Plasmodium falciparum in Human Blood and Profiles of Corresponding Resistant Markers in Mosquito Oocysts in Asembo, Western Kenya, Malaria J, 2022 Sep 13, vol 21 art 265, doi: 10.1186/s12936-022-04284-6, showed an increase over the years in markers od resistance, except for that to chloroquine following the withdrawal of that drug from the treatment of malaria.
Wang X & al. discuss resistance to the sulfadoxine-pyrimethamine (SP) combination in the context of the genetic makeup of P. falciparum in two papers, Molecular Determinants of Sulfadoxine-Pyrimethamine Resistance in Plasmodium falciparum Isolates from Central Africa between 2016 and 2021: Wide Geographic Spread of Highly Mutated Pfdhfr and Pfdhps Alleles, Microbiol Spectr. 2022 Sep 19: e0200522, doi: 10.1128/spectrum.02005-22 and Molecular Epidemiology of Drug Resistance Genes in Plasmodium falciparum Isolates Imported from Nigeria Between 2016 and 2020: Continued Emergence of Fully Resistant Pfdhfr-Pfdhps Alleles, Microbiol Spectr. 2022 Sep 15: e0052822, doi: 10.1128/spectrum.00528-22. The authors claim to have “demonstrated the wide geographic spread and increasing trends in highly SP-resistant … genes and varying spatial patterns of [other] mutants across countries in … Africa,” which alone or in combination may confer partial or total resistance to SP.
Resistance to primaquine can also be a problem, though at this time mainly confined to Southeast Asia.

Wicht KJ & al., Mutant PfCRT Can Mediate Piperaquine Resistance in African Plasmodium falciparum with Reduced Fitness and Increased Susceptibility to Other Antimalarials, J Infect Dis. 2022 Sep 9:jiac365, doi: 10.1093/infdis/jiac365 reviews the cause and implications of this resistance.

Hassen J & al. measured the prevalence of chloroquine-resistant genotypes in a Region of Ethiopia manuy years after chloroquine stopped being the drug of choice for malaria. In High Prevalence of pfcrt 76T and pfmdr1 N86 Genotypes in Malaria Infected Patients Attending Health Facilities in East Shewa Zone, Oromia Regional State, Ethiopia, Malaria J, 2022 Oct 7, vol 21 art 286, doi: 10.1186/s12936-022-04304-5 the explore the reasons for the persistence of these genes.

As the title of their paper, Self-Medication and Anti-Malarial Drug Resistance in the Democratic Republic of the Congo (DRC): A Silent Threat, Trop Med Health. 2022 Oct 4; 50:73, doi: 10.1186/s41182-022-00466-9, indicates Akilimali A & al. consider an additional factor beyond drug resistance in the high prevalence of malaria in the DRC. Unfortunately the abstract does not cite their method of study, nor their results.

Drug resistance is also becoming evident in P. vivax. In their review, Khan N & Daily JP, Update on Pathogenesis, Management, and Control of Plasmodium vivax, Curr Opin Infect Dis. 2022 Oct 1; 35(5):404-409, doi: 10.1097/qco.0000000000000867, highlight “recent developments in understanding the complexity of P. vivax biology and optimization of antimalarial therapy. Studies toward the development of best practices for P. vivax control and elimination programs are ongoing.”

New drug research
According to Hemasa AL & al., Roseoflavin, a Natural Riboflavin Analogue, Possesses In Vitro and In Vivo Antiplasmodial Activity, Antimicrob Agents Chemother, 2022 Sep 12: e0054022, doi: 10.1128/aac.00540-22. They tested the compound in mice and found that it severely inhibited parasitemia after injection with a specific Plasmodium species.

Bassanini I & al. report on their continuing research on a compound they had previously described in From DC18 to MR07: A Metabolically Stable 4,4′-Oxybisbenzoyl Amide as Low-Nanomolar Growth Inhibitor of P. falciparum, ChemMedChem, 2022 Sep 11, doi: 10.1002/cmdc.202200355. This paper refers to the encouraging results they have had, pointing to in vivo testing soon.
Edgar RCS & al. have identified a parasite enzyme that is essential for its metabolism and suggest that it be targeted in new antiplasmodial drug research in Genetic and Chemical Validation of Plasmodium falciparum Aminopeptidase PfA-M17 as a Drug Target in the Hemoglobin Digestion Pathway, Elife. 2022 Sep 13; 11:e80813, doi: org/10.7554/elife.80813.

Yet another approach to new drug development is the subject of Garg S & al., Susceptibilities of Ugandan Plasmodium falciparum Isolates to Proteasome Inhibitors, Antimicrob Agents Chemother, 2022 Sep 12: e0081722, doi: 10.1128/aac.00817-22. {“Proteasome is a highly sophisticated protease complex designed to carry out selective, efficient and processive hydrolysis of client proteins. …The highly organized proteasome plays a prominent role in the control of a diverse array of basic cellular activities by rapidly and unidirectionally catalyzing biological reactions, – Tanaka K, The Proteasome; Overview of Structure and Function, Proc Jpn Acad Ser B Phys Biol Sci. 2009 Jan; 85(1): 12–36}.

Therapy by preventing human-to-mosquito transmission of malaria parasites is the subject of Reader J & al.’s work on a new agent that attack the gametocytes. Their paper, New Transmission-Selective Antimalarial Agents Through Hit-To-Lead Optimization of 2-([1,1′-biphenyl]-4-carboxamido)benzoic Acid Derivatives, Chembiochem, 2022 Sep 15, doi: 10.1002/cbic.202200427, describes the process of selection of potential agents for further study.

Traditional treatments
Given the history of malaria long before Western medications became available, the populations of various regions in Africa developed their own treatment regimens, of various efficacy. Nigussie G & Wale M, Medicinal Plants Used in Traditional Treatment of Malaria in Ethiopia: A Review of Ethnomedicine, Anti-Malarial and Toxicity Studies, Malaria J, 2022 Sep 13, vol 21, art 262 doi: 10.1186/s12936-022-04264-w reviewed 51 plant species (28 families) that have been used to treat malaria in Ethiopia. The study databases included original articles published in peer reviewed journals covering anti-malarial plants, dated until October 2021. Seven species of plants were thoroughly studied. Leaves were used more frequently as a therapeutic preparation than other parts. Plant extracts were found to have very good, good, and moderate anti-malarial activity in mice with rodent Plasmodium species.

Campaigns:

“Proactive community case management (pro-CCM) has been shown to increase access to diagnosis and treatment and reduce malaria burden. However, lack of experimental evidence may hinder the wider adoption of this intervention,” according to Ratovoson R & al. In Proactive Community Case Management Decreased Malaria Prevalence in Rural Madagascar: Results From a Cluster Randomized Trial, BMC Med. 2022 Oct 4; 20:322. doi: 10.1186/s12916-022-02530-x they report the details of the campaign and are encouraged by the results, which indicated a 30% reduction of overall prevalence in the communities that underwent pro-CCM, essentially among children age 15 or less. Prevalence among adults was not affected.

Campaigns may focus on a variety of aspects of vector control and disease prevention. Matindo AY, & al., The Role of Community Participation in Planning and Executing Malaria Interventions: Experience from Implementation of Biolarviciding for Malaria Vector Control in Southern Tanzania, Biomed Res Int. 2022 Sep 23; doi: 10.1155/2022/8046496 reports poor participation in a larviciding campaign; “lack of incentive to community volunteers was one major barrier to community participation.”

Effiong FB & al., Prospects of Malaria Vaccination in Nigeria: Anticipated Challenges and Lessons from Previous Vaccination Campaigns, Ann Med Surg (Lond), 2022 Aug 17; 81:104385, doi: 10.1016/j.amsu.2022.104385 “highlights some of the lessons learned from previous vaccination programs in Nigeria and how the insight gotten can be pivotal in ensuring the success of a prospective malaria vaccination programme in Nigeria.”

The relationship between agricultural pesticide use and insecticide resistance was explored by Matowo NS & al. in Tanzania though interviews, workshops and training. Their report, Participatory Approaches for Raising Awareness Among Subsistence Farmers in Tanzania About the Spread of Insecticide Resistance in Malaria Vectors and the Possible Link to Improper Agricultural Pesticide Use, Malaria J, 2022 Sep 30, vol 21 art 277, doi: 10.1186/s12936-022-04289-1 documents ins=complete knowledge of these issues among those interviewed. They emphasize “the significance of enhancing subsistence farmers’ awareness of mosquito ecology as well as merging public health and agricultural pest management measures. Participatory techniques have the potential to raise stakeholder awareness and engagement, resulting in more effective resistance management.”

“To make travel and trade safe, the WHO adopted the International Health Regulations (IHR) which provides a legal framework for the prevention, detection, and containment of public health risks at source, according to Perera R & al., Malaria Control, Elimination, and Prevention as Components of Health Security: A Review, Am J Trop Med Hyg, 2022 Sep 6: tpmd220038, doi: 10.4269/ajtmh.22-0038. However, they are of the opinion “that malaria has not been prioritized as part of the IHR nor has the IHR focused on vector-borne diseases such as malaria.” They urge that “the application of IHR for malaria should be urgently reviewed and included as part of the IHR.”

Epidemiology:

Climate change, biodiversity, and malaria
“Biodiversity in ecosystems plays an important role in supporting human welfare, including regulating the transmission of infectious diseases. Many of these services are not fully-appreciated due to complex environmental dynamics and lack of baseline data. Multicontinental amphibian decline due to the fungal pathogen Batrachochytrium dendrobatidis (Bd) provides a stark example. Even though amphibians are known to affect natural food webs—including mosquitoes that transmit human diseases—the human health impacts connected to their massive decline have received little attention. Here we leverage a unique ensemble of ecological surveys, satellite data, and newly digitized public health records to show an empirical link between a wave of Bd-driven collapse of amphibians in Costa Rica and Panama and increased human malaria incidence. Subsequent to the estimated date of Bd-driven amphibian decline in each ‘county’ (canton or distrito), we find that malaria cases are significantly elevated for several years.” This is reported in Springborn MR & al., Amphibian Collapses Increased Malaria Incidence in Central America, Environmental Research Letters, 2022 Sep 20, Vol 17, Num 10, doi: 10.1088/1748-9326/ac8e1d.

Population dynamics
Abate A & al. studied how mosquitoes become infected by Plasmodium species, if feeding on someone with malaria. They used a technique called membrane feeding assay and reported their results in Infectivity of Symptomatic Patients and Their Contribution for Infectiousness of Mosquitoes Following a Membrane Feeding Assay in Ethiopia, Microbiol Spectr, 2022 Sep 6: e0062822, doi: 10.1128/spectrum.00628-22. The study yielded the expected result, namely that over two thirds of the mosquitoes in question had the parasite in their digestive system, while half of them also became infectious in that the parasite was found in their salivary glands.

“Zambia had an ambitious strategy of reaching the entire population with malaria vector control campaigns by late 2020 or early 2021, but they lacked the requisite accurate and up-to-date data on infrastructure and population distribution. To address this gap, the Geo-Referenced Infrastructure and Demographic Data for Development (GRID3) program, Akros, and other partners developed maps and planning templates to aid Zambia’s National Malaria Elimination Program (NMEP) in operationalizing its strategy.” This is described by Borkovska O & al. in Developing High-Resolution Population and Settlement Data for Impactful Malaria Interventions in Zambia, J Environ Public Health. 2022 Sep 27; doi: 10.1155/2022/2941013.

Tension between economic activity and population health is highlighted by Zhou G & al., Irrigation-Induced Environmental Changes Sustain Malaria Transmission and Compromise Intervention Effectiveness, J Infect Dis, 2022 Sep 3: jiac361, doi: 10.1093/infdis/jiac361. They found increased malaria in areas where irrigation is used in agriculture. Spraying reduced the incidence of malaria, but less so in areas that were irrigated than in non-irrigated areas.

Spatiotemporal studies
Lapp Z & al., Plasmodium falciparum Genetic Diversity in Coincident Human and Mosquito Hosts, mBio, 2022 Sep 8:e0227722, doi: 10.1128/mbio.02277-22.

Reda AG & al., Temporal Dynamics of Plasmodium falciparum Population in Metehara, East-Central Ethiopia, Malaria J, 2022 Sep 15, vol 21 art 267, doi: 10.1186/s12936-022-04277-5.

Zeleke MT, Gelaye KA, Yenesew MA, Spatiotemporal Variation of Malaria Incidence in Parasite Clearance Interventions and Non-Intervention Areas in the Amhara Regional State, Ethiopia, PLoS One, 2022 Sep 19; 17(9):e0274500, doi: 10.1371/journal.pone.0274500.

Damien BG & al., Bayesian Spatial Modelling of Malaria Burden in Two Contrasted Eco-Epidemiological Facies in Benin (West Africa): Call for Localized Interventions, BMC Public Health. 2022 Sep 16; 22(1):1754, doi: 10.1186/s12889-022-14032-9

Maniga JN & al., Trend of Malaria Burden Among Residents of Kisii County, Kenya After More Than a Decade Usage of Artemisinin Combined Therapies, 11-Year Laboratory Based Retrospective Study, Infect Drug Resist, 2022 Sep 6; 15:5221-5232, doi: 10.2147/idr.s370218.

Chiuya TM & al., Molecular Screening Reveals Non-Uniform Malaria Transmission in Western Kenya and Absence Of Rickettsia africae and Selected Arboviruses in Hospital Patients, Malaria J, 2022 Sep 17, vol 21 art 268, doi: 10.1186/s12936-022-04287-3.

Otambo WO & al., Influence of Landscape Heterogeneity on Entomological and Parasitological Indices of Malaria in Kisumu, Western Kenya, Parasit Vectors. 2022 Sep 27; 15(1):340, doi: 10.1186/s13071-022-05447-9

Otambo WO & al., Clinical Malaria Incidence and Health Seeking Pattern in Geographically Heterogeneous Landscape of Western Kenya, BMC Infect Dis. 2022 Oct 3; 22:768, doi: 10.1186/s12879-022-07757-w.

Other
Sissoko B & al., Social Representations of Malaria in a Southern Malian Community: An Ethnographic Qualitative Study, Malaria J, 2022 Sep 29, vol 21 art 276, doi: 10.1186/s12936-022-04298-0 reports the following: “Mosquitoes are the principal agent of the transmission of malaria. However, the ubiquitous yet casually-claimed aetiological agents, causative, nosographic entities differ from—although sometimes integrated into—the biomedical dimension. For example, some communities perceive Kono, a complicated and pernicious form of malaria that often occurs among children, to originate from a supernatural force. “Bird disease” is another term used for Kono in Mali and other West African countries. Thus, overall, Kono is defined through the entanglements with cultural factors, namely the idiosyncratic habits, customs, and beliefs of the population of Wayerema II neighbourhood in the health district of Sikasso, Southern Mali. Wayerema II residents particularly tend to link therapeutic recourse amongst the afflicted not only to biomedical models but to sociocultural and popular perceptions and representations of malaria.”