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The following are the relevant articles for your attention this month: 

Prevention: 

Vaccines   

“Recently, the … (WHO) approved RTS, S/AS01 (RTS, S) as the world’s first malaria vaccine for partial malaria protection in young children at risk. While this immunization drive begins during the … pandemic of the SARS-CoV-2 Virus, the WHO has also approved 7 Vaccines in 2021 for the vaccination of children at risk.” Shah PA & al., Vaccine Dilemma for Children at Risk: Recently Approved Malaria Vaccine Versus Ongoing COVID-19 Vaccination Campaign, Ann Med Surg (Lond). 2022 Jul; 79:104011, https://doi.org/10.1016/j.amsu.2022.104011explores the quandary that would occur to the officials in charge of carrying out large vaccination campaigns against these two deadly infectious illnesses in several regions including the continent of Africa.” 

Vector control and protection from vectors 

Last month, this column commented on the plethora of articles that recount use of vector control modalities by the population. Kouakou G & al., Qualitative Study on the Use and Maintenance of Long-Lasting Insecticidal Nets (LLINs) in Bouaké (Côte D’ivoire), 17 Months After the Last Mass Distribution Campaign, Malaria J, 2022 Jul 29, vol 21 art 228, doi: 10.1186/s12936-022-04243-1 is one of these. It concludes that utilization could be better.   

Similarly, Djoufounna J & al., Population Knowledge, Attitudes and Practices Towards Malaria Prevention in the Locality of Makenene, Centre-Cameroon, Malaria J, 2022 Aug 5, vol 21 art 234, doi: 10.1186/s12936-022-04253-z  found that the “majority of participants had good knowledge (55.93%; n = 231), good practices (71.67%, n = 296) but moderate attitudes (47.94%; n = 198) towards malaria control and fight.” 

Mbwambo SG & al. “explored utility of cone bioassays for pre-delivery QA of pyrethroid ITNs to test the assumption that cone bioassays are consistent across locations, mosquito strains, and laboratories.” Their report, Comparison of Cone Bioassay Estimates at Two Laboratories with Different Anopheles Mosquitoes for Quality Assurance of Pyrethroid Insecticide-Treated Nets, Malaria J, 2022 Jul 7, vol 21 art 214, doi: 10.1186/s12936-022-04217-3, verifies the usefulness of these tests. 

The emergence of pyrethroid-resistant mosquitoes is the subject of Njoroge H & al., Identification of a Rapidly-Spreading Triple Mutant for High-Level Metabolic Insecticide Resistance in Anopheles gambiae Provides a Real-Time Molecular Diagnostic for Anti-Malarial Intervention Deployment, Mol Ecol. 2022 Jul 1, https://doi.org/10.1111/mec.16591They identify a “triple-mutant haplotype [that] is strongly associated with increased expression of genes able to metabolise pyrethroids and is strongly predictive of resistance to pyrethroids…” At the same time, they noted “increased mortality in mosquitoes carrying the triple-mutation when exposed to nets co-treated with the synergist piperonyl butoxide (PBO).” Since “[f]requencies of the triple-mutant haplotype remain spatially variable within countries, They suggest that the triple-mutant haplotype is “an effective marker system to guide deployment decisions for limited supplies of PBO-pyrethroid co-treated LLINs across African countries.” 

Zhou Y & al.,  Effectiveness of Indoor Residual Spraying on Malaria Control: A Systematic Review and Meta-Analysis, Infect Dis Poverty, 2022 Jul 23; 11(1):83, https://doi.org/10.1186/s40249-022-01005-8 reports on 38 articles including 81 reports and 1,174,970 individuals in their analysis. “… significantly higher effectiveness was observed in IRS coverage ≥ 80% than in IRS coverage < 80%.” 

In southern Mozambique, the mosquito species that is the most prevalent vector for malaria is Anopheles funestus. Alafo C & al. conclude in To Spray or Target Mosquitoes Another Way: Focused Entomological Intelligence Guides the Implementation of Indoor Residual Spraying in Southern Mozambique, Malaria J, 2022 Jul 11, vol 21 art 215, doi: 10.1186/s12936-022-04233-3 that indoor residual spraying in combination with other measures is an effective method of protection against malaria.   

Sadoine ML & al evaluated “the effect of indoor residual spraying (IRS) on the relationship between malaria and environment (i.e. rainfall, temperatures, humidity, and vegetation) using data from a dynamic cohort of children from three sub-counties in Uganda.” Their report, The Influence of the Environment and Indoor Residual Spraying on Malaria Risk in a Cohort of Children in Uganda, Sci Rep, 2022 Jul 7; 12(1):11537, doi: 10.1038/s41598-022-15654-0, point to the need to “control for interventions when they are performed to properly estimate the environmental influence on malaria. Local models are more informative to guide intervention program compared to national models.” 

Sawadogo SP &al., Comparison of Entomological Impacts of Two Methods of Intervention Designed to Control Anopheles gambiae s.l. Via Swarm Killing in Western Burkina Faso, Sci Rep, 2022 Jul 20;12(1):12397, https://doi.org/10.1038/s41598-022-16649-7 is a report a new “vector control approach for rapidly crashing mosquito populations and disrupting malaria transmission in Africa. This method targets the … swarming and outdoor nocturnal behaviors of both male and female Anopheles mosquitoes. It involved accurate identification and targeted spraying of mosquito swarms to suppress adult malaria vector populations and their vectorial capacities. The impact of targeted spraying was compared to broadcast spraying and evaluated simultaneously. The effects of the two interventions were very similar…” 

Screening the openings of dwellings is an adjunctive method of protection from vectors. Njoroge MM & al., Less is More: Repellent-Treated Fabric Strips as a Substitute for Full Screening of Open Eave Gaps for Indoor and Outdoor Protection from Malaria Mosquito Bites, Parasit Vectors, 2022 Jul 20, 15(1):259, doi: 10.1186/s13071-022-05384-7 concludes “that transfluthrin-treated fabric strips can provide a substitute for complete eave screens. They are a simple, easy-to-handle tool for protecting people from malaria mosquito bites indoors” and more economical than full screens. 

Leung S & al. compared the “performance of two different gene drive systems—‘classic’ and ‘integral’” and modeled their outcomes in various transmission settings. They report in Population Replacement Gene Drive Characteristics for Malaria Elimination in a Range of Seasonal Transmission Settings: A Modelling Study, Malaria J, 2022 Jul 26, vol 21 art 226, doi: 10.1186/s12936-022-04242-2 that both methods, “in combination with traditional forms of vector control, can likely locally eliminate malaria in low to moderate transmission regimes within the Sahel. In a high transmission regime, higher levels of transmission-blocking effectiveness than are currently available may be required.” 

Peterson RKD and Rolston MG tested the effect of larvicides versus genetic manipulation on water quality in Africa and conclude in Larval Mosquito Management and Risk to Aquatic Ecosystems: A Comparative Approach Including Current Tactics and Gene-Drive Anopheles Techniques, Transgenic Res, 2022 Jul 7, doi: 10.1007/s11248-022-00315-9 that genetic manipulation of mosquitoes “is unlikely to result in risks to aquatic environments that exceed current tactics for larval mosquitoes. As such, these new techniques would likely comply with currently recommended safety standards.” 

Essential oils as larvicides are the subject of Yohana R & al., Anti-Mosquito Properties of Pelargonium roseum (Geraniaceae) and Juniperus virginiana (Cupressaceae) Essential Oils Against Dominant Malaria Vectors in Africa, Malaria J, 2022 Jul 14, vol 21 art 220, doi: 10.1186/s12936-022-04220-8. They compared the effects of the two sources of oils and concluded that Pelargonium roseum essential oils (a combination of citronellol, linalool, and geraniol) was the more effective one and it was more effective than each of its individual components. 

de Oliveira AC & al. studied another larvicidal oil and report in Essential Oil of Piper purusanum C.DC (Piperaceae) and Its Main Sesquiterpenes: Biodefensives Against Malaria and Dengue Vectors, Without Lethal Effect on Non-Target Aquatic Fauna, Environ Sci Pollut Res Int, 2022 Jul; 29(31):47242-47253, doi: 10.1007/s11356-022-19196-w that under experimental conditions, the material studied is safe for several aquatic species exposed to it.  

Chemoprophylaxis 

The use of intermittent preventive treatment in pregnancy to reduce unfavorable birth outcomes has been demonstrated in a number of studies. The results published in Kamau A & al., The Impact of Intermittent Presumptive Treatment for Malaria in Pregnancy on Hospital Birth Outcomes on the Kenyan Coast, Clin Infect Dis, 2022 Jun 22:ciac509, doi: 10.1093/cid/ciac509 concur with this. “Among 27,786 deliveries, three or more doses of IPTp-SP were associated with a 27% reduction in the risk of LBW {low birth weight}… compared to no-dose. A dose-response association was observed with increasing doses of SP from the second trimester linked to increasing protection against LBW deliveries. Three or more doses of IPTp-SP were also associated with a 21% reduction in stillbirth deliveries…” 

Torrential rains and subsequent flooding are frequently followed by explosions of mosquito populations Boyce RM & al. report that “[t]hree rounds of chemoprevention with DP delivered under pragmatic conditions reduced the incidence of malaria after severe flooding in western Uganda. These findings provide a proof-of-concept for the use of malaria chemoprevention to reduce excess disease burden associated with severe flooding.” The article is Dihydroartemisinin-Piperaquine Chemoprevention and Malaria Incidence After Severe Flooding: Evaluation of a Pragmatic Intervention in Rural Uganda, Clin Infect Dis, 2022 Jul 6; 74(12):2191-2199. doi: 10.1093/cid/ciab781. 

Wu RL & al. report in Low-Dose Subcutaneous or Intravenous Monoclonal Antibody to Prevent Malaria, N Engl J Med, 2022 Aug 4; 387(5):397-407, doi: 10.1056/NEJMoa2203067 that in a small Phase 1 clinical study of three concentrations of a specific monoclonal antibody (L9LS), all volunteer recipients of the two higher doses were protected from parasitemia after and injection of Plasmodium falciparum, as well as the majority of those who received 5% of the highest dose.  All of the control subjects developed parasitemia.  The authors state that there were no “evident safety concerns.” An echo of this article appeared on Science News on the same day. 

Diagnosis: 

Rapid diagnostic tests (RDTs) that rely on the detection of Plasmodium falciparum histidine-rich protein 2 (PfHRP2) have become key tools for diagnosing P. falciparum infection. The utility of RDTs can be limited by PfHRP2 persistence, however it can be a potential benefit in low transmission settings where detection of persistent PfHRP2 using newer ultra-sensitive PfHRP2 based RDTs can serve as a surveillance tool to identify recent exposure, according to Marquart L & al., The in-Vivo Dynamics of Plasmodium falciparum HRP2: Implications for the Use of Rapid Diagnostic Tests in Malaria Elimination, Malaria J, 2022 Aug 3, vol 21 art 233, doi: 10.1186/s12936-022-04245-z. 

According to Bohle LF & al., Knowledge, Attitudes and Practices Towards Malaria Diagnostics Among Healthcare Providers and Healthcare-Seekers in Kondoa District, Tanzania: A Multi-Methodological Situation Analysis, Malaria J, 2022 Jul 21, vol 21 art 224, doi: 10.1186/s12936-022-04244-0#Sec2, health care practitioners in the area of Tanzania studied generally distrust the results of Rapid Diagnostic Tests when they are negative. Some move to microscopy, others will treat for malaria, based on their clinical judgment. The authors express concern about this state of affairs.  

Lyimo BM & al. discuss “the promise and challenges of NGS and CRISPR-Cas in the context of malaria as Africa moves towards malaria elimination” in Potential Opportunities and Challenges of Deploying Next Generation Sequencing and CRISPR-Cas Systems to Support Diagnostics and Surveillance Towards Malaria Control and Elimination in Africa, Front Cell Infect Microbiol, 2022 Jul 13; 12:757844,  doi: 10.3389/fcimb.2022.757844. According to the authors, these “innovative tools are urgently needed to strengthen the current diagnostic and surveillance systems. We discuss ongoing efforts to deploy these tools for malaria detection and molecular surveillance highlighting potential opportunities presented by these innovative technologies as well as challenges in adopting them.” 

Watson JA & al. are also concerned about possible overdiagnosis of malaria in severely ill children, as they indicate in their paper, Improving the Diagnosis of Severe Malaria in African Children Using Platelet Counts and Plasma PfHRP2 Concentrations, Sci Transl Med, 2022 Jul 20; 14(654):eabn5040. https://doi.org/10.1126/scitranslmed.abn5040.  They propose that using platelet count and level of plasma histidine rich protein concentration are reliable tools for diagnosing severe malaria. 

Treatment: 

White NJ, The Assessment of Antimalarial Drug Efficacy in Vivo, Trends Parasitol, 2022 Aug; 38(8):660-672.  doi: 10.1016/j.pt.2022.05.008 is an article promoting the use of “pharmacometric antimalarial resistance monitoring (PARM) approach … for evaluating slowly eliminated antimalarial drugs in areas of high transmission. In PARM antimalarial drug concentrations at recurrent parasitaemia are measured to identify outliers (i.e., recurrent parasitaemias in the presence of normally suppressive drug concentrations) and to evaluate changes over time. … PARM does not require parasite genotyping and can be applied to the assessment of both prevention and treatment.” 

“Artesunate reduces mortality compared to quinine for both adults and children in Asia and Africa including cerebral malaria [and] … artemisinin derivatives remain the best treatment for severe malaria but their comparative clinical effectiveness is yet to be fully explored” are the conclusions of Nyaaba N & al. in Comparative Efficacy and Safety of the Artemisinin Derivatives Compared to Quinine for Treating Severe Malaria in Children And Adults: A Systematic Update of Literature and Network Meta-Analysis, PLoS One, 2022 Jul 20; 17(7):e0269391. https://doi.org/10.1371/journal.pone.0269391, based on their literature review and analysis. 

Masserey T & al. reflect concern over the emerging resistance of the malaria parasite to artemisinin derivatives. They propose to slow the progress of partial artemisinin resistance by a variety of methods, described in their article, The Influence of Biological, Epidemiological, and Treatment Factors on the Establishment and Spread of Drug-Resistant Plasmodium falciparum, Elife 2022 Jul 7; 11:e77634, doi: 10.7554/elife.77634. 

Among the many approaches to develop new antimalarial drugs, Rattaprasert P & al., Inhibitory Effects of Anthracyclines on Partially Purified 5′–3′ DNA Helicase of Plasmodium falciparum, Malaria J, 2022 Jul 11, vol 21 art 216, doi: 10.1186/s12936-022-04238-y reports on the investigation of anthracyclines, a class of drugs that inhibit the unwinding of parasite DNA, which is necessary for all metabolic activity. They identify one candidate more effective than others, but toxicity to the host remains an issue. 

Malaria in persons suffering from sickle cell disease (SS disease) is of special concern where the latter condition is prevalent, such as Ghana. Aninagyei E & al., Oxidative Stress and Associated Clinical Manifestations in Malaria and Sickle Cell (HbSS) Comorbidity, PLoS One, 2022 Jun 8; 17(6):e0269720, doi: 10.1371/journal.pone.0269720 describes a variety of ways in which malaria may induce sickle cell crisis in these persons. 

Also in Ghana, Appiah EO & al. conducted in depth interviews with 20 women and report in Practices of Herbal Management of Malaria Among Trading Mothers in Shai Osudoku District, Accra, PLoS One, 2022 Jul 18;17(7):e0271669, doi: 10.1371/journal.pone.0271669 that there was preference for herbal treatments in this group, but the abstract is silent on the extent of that preference. 

Campaigns: 

As mentioned by several articles in this and other reports, gene drive is a method of vector control.  Toe LP & al., Operationalizing Stakeholder Engagement for Gene Drive Research in Malaria Elimination in Africa—Translating Guidance Into Practice, Malaria J, 2022 Jul 23, vol 21 art 225, doi: 10.1186/s12936-022-04241-3 advocates various ways in which this method may become integral part of antimalarial campaigns. 

Guan Q & al claim to have developed “a framework to help policy-makers decide how to allocate limited resources in realtime for malaria control. We formalize a policy for the resource allocation as a sequence of decisions, one per intervention decision, that map up-to-date disease related information to a resource allocation.”  Their paper is A Spatiotemporal Recommendation Engine for Malaria Control, Biostatistics, 2022 Jul 18; 23(3):1023-1038, doi: 10.1093/biostatistics/kxab010. 

In their paper, Spatio-Temporal Monitoring of Health Facility-Level Malaria Trends in Zambia and Adaptive Scaling for Operational Intervention, Commun Med (Lond), 2022 Jul 1; 2:79, doi: 10.1038/s43856-022-00144-1, Lubinda J & al. note that there are areas within Zambia where malaria is trending toward more infections, whereas elsewhere the trends are more favorable. They particularly note that there were “[s]trong clusters along borders with highly endemic countries in the north and south of Zambia…” They advocate campaigns that take local data into account. It is of note that their paper covers the time frame between 2009 and 2015, so their data are significantly out of date. 

Somewhat more up to date with data from Zambia is Mtalimanja M & al., Tracking Malaria Health Disbursements by Source in Zambia, 2009-2018: An Economic Modelling Study, Cost Eff Resour Alloc, 2022 Jul 21; 20(1):34, https://doi.org/10.1186/s12962-022-00371-2. They note that “Zambia has made profound strides in reducing both the incidence and prevalence of malaria followed by reducing malaria related deaths between 2009 and 2018. The number of partners providing malaria funding has significantly increased in the same period.” The analysis they conducted supports the proposition that the increase in and diversity of funding has played a significant role in reducing the incidence of malaria in Zambia. 

Paintain L & al., Using Donor Funding to Catalyse Investment in Malaria Prevention in Ghana: An Analysis of the Potential Impact on Public and Private Sector Expenditure, Malar J, 2022 Jun 27; vol 21 art 203, doi: 10.1186/s12936-022-04218-2 is a report on the effects of the three-year Private Sector Malaria Prevention (PSMP) project, … [an] intervention to catalyse private sector investment in malaria prevention in Ghana. Follow up study during each of five years after the conclusion of the project tracked non-donor expenditures in malaria control.  These declined over the years, but over the first four years non-donor expenditures exceeded the investment by the donors. Thus the authors conclude that the project was successful. 

Epidemiology: 

According to Hergott DEB & al., asymptomatic infections “threaten control efforts and may impact vaccine and therapeutic drug studies. Simple, cost-effective methods are needed to study the natural history of asymptomatic submicroscopic parasitaemia. Self-collected dried blood spots (DBS) analysed using pooled and individual quantitative reverse transcription polymerase chain reaction (qRT-PCR) provide such a solution.” Their article, Feasibility of Community At-Home Dried Blood Spot Collection Combined with Pooled Reverse Transcription PCR as a Viable and Convenient Method for Malaria Epidemiology Studies, Malaria J, 2022 Jul 14, vol 21 art 221, doi: 10.1186/s12936-022-04239-x, concludes that “[a]t-home DBS collection is a feasible, acceptable, and robust method to obtain blood to evaluate the natural history of low-density Plasmodium infections by qRT-PCR.” 

With climate change, the likelihood arises that mosquito behavior or at least prevalence may also change in certain geographic areas. Villena OC & al., Temperature Impacts the Environmental Suitability for Malaria Transmission by Anopheles gambiae and Anopheles stephensi, Ecology, 2022 Aug; 103(8):e3685, doi: 10.1002/ecy.3685 addresses this matter. The study concludes that there are “significant differences in the upper thermal limit between parasites spread by the same mosquito (A. stephensi) and between mosquitoes carrying P. falciparum.” 

“Multiplexed PCR amplicon sequencing (AmpSeq) is an increasingly popular application for cost-effective monitoring of threatened species and managed wildlife populations, and shows strong potential for the genomic epidemiology of infectious disease. AmpSeq data from infectious microbes can inform disease control in multiple ways, such as by measuring drug resistance marker prevalence, distinguishing imported from local cases, and determining the effectiveness of therapeutics,” according to LaVerriere E & al. , Design and Implementation of Multiplexed Amplicon Sequencing Panels to Serve Genomic Epidemiology of Infectious Disease: A Malaria Case Study, Mol Ecol Resour, 2022 Aug; 22(6):2285-2303, doi: 10.1111/1755-0998.13622.  The article describes “the design and comparative evaluation of two new AmpSeq assays for Plasmodium falciparum malaria parasites: a four-locus panel (“4CAST”) composed of highly diverse antigens, and a 129-locus panel (“AMPLseq”) composed of drug resistance markers, highly diverse loci for inferring relatedness, and a locus to detect Plasmodium vivax co-infection.” 

 

“Malaria hotspots have been the focus of public health managers for several years due to the potential elimination gains that can be obtained from targeting them.” Sedda L & al. report in Hotspots and Super-Spreaders: Modelling Fine-Scale Malaria Parasite Transmission Using Mosquito Flight Behaviour, PLoS Pathog, 2022 Jul 6; 18(7):e1010622, doi: 10.1371/journal.ppat.1010622 that they employed [an] algorithm to identify clusters of super-spreader houses and their related stable hotspots by accounting for mosquito flight capabilities and the spatial configuration of malaria infections at the house level. {The] results show that the number of super-spreading houses and hotspots is dependent on the spatial configuration of the villages. In addition, super-spreaders are also associated to house characteristics such as livestock and family composition. … most of the transmission is associated with winds between 6pm and 10pm although later hours are also important.”  

Agonhossou R & al., P. falciparum msp1 and msp2 Genetic Diversity in P. falciparum Single and Mixed Infection with P. malariae Among the Asymptomatic Population in Southern Benin, Parasitol Int, 2022 Aug; 89:102590, doi: 10.1016/j.parint.2022.102590 documents the diversity declared in the title of their paper.  The immediate implications of this diversity for malaria infection are unclear from the abstract of the article.  

Also on the topic of genetic diversity of the parasite, Hanitriniaina V & al., DNA Recovery from Used Malaria RDT to Detect Plasmodium Species and to Assess Plasmodium falciparum Genetic Diversity: A Pilot Study in Madagascar, Malaria J, 2022 Jul 26 vol 21 art 227, doi: 10.1186/s12936-022-04246-y highlights that “malaria diagnosis and molecular analysis are possible by using used malaria RDT. Just as above, the implications are unclear. 

While vivax malaria is less prevalent than falciparum malaria in Africa, it remains an important cause of morbidity in countries such as Ethiopia. Abate A & al., Vivax Malaria in Duffy-Negative Patients Shows Invariably Low Asexual Parasitaemia: Implication Towards Malaria Control in Ethiopia, Malaria J, 2022 Aug 1, vol 21 art 230, doi: 10.1186/s12936-022-04250-2 contends that the inhibitory effect of “Duffy negative” genotype persons on entry of the parasite into young red blood cells may actually create reservoirs of asymptomatic parasitemia, which in turn hinders efforts to control the disease. 

Just as with the topic of Prevention, there continues to be a surfeit of articles detailing the prevalence and risk factors for malaria within individual districts in many countries in Sub-Saharan Africa.  To be sure, they do all record data that will inform epidemiologists, who can then do more high level analyses, but for our purposes, these articles do not add new knowledge. Therefore they will be simply mentioned in this section and in the future as well.

Ahadzie-Soglie A & al., Prevalence and Risk Factors of Malaria And Anaemia and the Impact of Preventive Methods Among Pregnant Women: A Case Study at the Akatsi South District in Ghana, PLoS One, 2022 Jul 25; 17(7):e0271211, https://doi.org/10.1371/journal.pone.0271211. 

Duguma T & al., Malaria Prevalence and Risk Factors Among Patients Visiting Mizan Tepi University Teaching Hospital, Southwest Ethiopia, PLoS One, 2022 Jul 28; 17(7):e0271771, doi: 10.1371/journal.pone.0271771.  

 

Ibeji JU & al., Spatial Variation and Risk Factors of Malaria and Anaemia Among Children Aged 0 to 59 Months: A Cross-Sectional Study of 2010 and 2015 Datasets, Sci Rep, 2022 Jul 7; 12(1):11498, doi: 10.1038/s41598-022-15561-4. (Nigeria) 

Lingani M & al., Prevalence and Risk Factors of Malaria Among First Antenatal Care Attendees in Rural Burkinal Faso, Trop Med Health, 2022 Jul 25; 50(1):49, doi: 10.1186/s41182-022-00442-3. 

Ochwedo KO & al., Malaria Epidemic and Transmission Foci in Highland of Kisii, Western Kenya, Parasite Epidemiol Control, 2022 Jul 20; 18:e00263. https://doi.org/10.1016/j.parepi.2022.e00263.