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By Dr. Derick Pasternak, Malaria Science & Research Coordinator, Malaria Partners International

The profusion of scientific literature about malaria continues; counting only peer-reviewed ones in PubMed, we are over 1600 for the year!  We hope that the readers of these newsletters gain useful information from these selections.  However, this is the 14th such report, and so far there has not been a single request for the full articles that have been placed in the Library.  Accordingly, we suspend the practice of keeping full articles until such time as there is significant demand for them.

Prevention:

The “hottest” news on prevention is that coming from Burkina Faso, regarding the remarkably effective vaccine which meets the criterion of effectiveness set by the WHO.  A special discussion of that vaccine was on the agenda of our Board meeting of May 12. This was first reported by The Guardian in April as well as elsewhere.  “The R21/Matrix-M vaccine, developed by the Clinical Research Unit of Nanoro (CRUN), Burkina Faso and their partners at the University of Oxford in the UK, is the first malaria vaccine to reach the 75 percent efficacy target set by the WHO.” (https://medicalxpress.com/news/2021-05-malaria-vaccine-efficacy.html). The recently published article in Lancet by Datoo MS & al., describes the development of the vaccine and the clinical study and its results : Efficacy of a Low-Dose Candidate Malaria Vaccine, R21 In Adjuvant Matrix-M, With Seasonal Administration To Children in Burkina Faso: a Randomised Controlled Trial, Lancet 2021 May 5, https://doi.org/10.1016/S0140-6736(21)00943-0

Other vaccine-related literature includes  Doritchamou JYA & al., Progress and New Horizons Toward a VAR2CSA-Based Placental Malaria Vaccine, Expert Rev Vaccines, 2021 Feb;20(2):215-226.  doi: 10.1080/14760584.2021.1878029.

A different vaccine approach is the development of transmission blocking vaccines, such as that described in McCoy KD & al., Are Malaria Transmission-Blocking Vaccines Acceptable to High Burden Communities? Results from a Mixed Methods Study in Bo, Sierra Leone, Malar J, 2021 Apr 13;20(1):183.  doi: 10.1186/s12936-021-03723-0.  Apparently these vaccines do not prevent acquisition of malaria, but those vaccinated will not transmit the parasite to other mosquitoes.  Duffy PE, Transmission-Blocking Vaccines: Harnessing Herd Immunity for Malaria Elimination, Expert Rev Vaccines, 2021 Feb;20(2):185-198.  doi: 10.1080/14760584.2021.1878028 is a description of the “concept and biology behind TBV, and … an update on clinical development of the leading vaccine candidate antigens.”

Keita M & al. state that “[h]igh resistance to pyrethroids and carbamates and susceptibility to organophosphates was observed at all sites. The introduction of pirimiphos-methyl based IRS for vector control resulted in a significant decrease in malaria transmission. An. gambiae s.l., the main malaria vector in the area, was resistant to pyrethroids and carbamates but remained susceptible to the organophosphate pirimiphos-methyl” in Performance of Pirimiphos-Methyl Based Indoor Residual Spraying on Entomological Parameters of Malaria Transmission in the Pyrethroid Resistance Region of Koulikoro, Mali, Acta Trop, 2021 Apr;216:105820. doi: 10.1016/j.actatropica.2020.105820.

A study in South Africa demonstrates that the population demonstrates “appropriate knowledge about malaria transmission and a positive treatment-seeking behaviour. However, economic barriers are responsible for the inadequate use of bed nets. Therefore, distribution of bed nets to the community should be considered to improve practice of malaria prevention measures.” The article is Munzhedzi M & al., Community Knowledge, Attitudes and Practices Towards Malaria in Ha-Lambani, Limpopo Province, South Africa: A Cross-Sectional Household Survey, Malar J, 2021 Apr 17;20(1):188.  doi: 10.1186/s12936-021-03724-z.

Two articles this month relate to the influence of housing on the incidence of malaria. In this section, we report on  Furnival-Adams J & al., House Modifications for Preventing Malaria, Cochrane Database Syst Rev, . 2021 Jan 20;1:CD013398. doi: 10.1002/14651858.CD013398.pub3, which is a meta-analysis of studies reported from several countries. “All trials assessed screening of windows, doors, eaves, ceilings or any combination of these; this was either alone, or in combination with eave closure, roof modification or eave tube installation (a ‘lure and kill’ device that reduces mosquito entry whilst maintaining some airflow).” Not all the trials on which they report have been completed.

Diagnosis:

The introduction of loop-mediated isothermal amplification (LAMP)-based malaria screening is said to result in “[b]lood film microscopy and RDT workloads [decreasing} substantially in the year following LAMP implementation (by 90% and 46%, respectively,) despite similar numbers of patients tested and positivity rates for malaria compared with historical data.  The article is McGinnis E & al., Malaria Screening Using Front-Line Loop-Mediated Isothermal Amplification, Am J Clin Pathol, 2021 Apr 26;155(5):690-697. doi: 10.1093/ajcp/aqaa173.

Although P. vivax infection is not fully acknowledged as malignant malaria, recently life-threatening complications have been reported to occur in many studies, according to Aqeel S & al., Biomarkers of Disease Severity in Vivax Malaria, Parasitol Res, 2021 Apr;120(4):1437-1446. doi: 10.1007/s00436-021-07065-3.  They investigated “whether protein carbonylation (PC), lipid peroxidation (LPO) and superoxide dismutase (SOD) could suffice as a biomarker for severe vivax malaria or not.” They found that protein carbonylation was a more reliable indicator of vivax malaria severity than lipid peroxidation.

According to Gebreweld A & al., Thrombocytopenia as a Diagnostic Marker for Malaria in Patients with Acute Febrile Illness, J Trop Med, 2021 Apr 10;2021:5585272.  doi: 10.1155/2021/ 5585272,

“[t]hrombocytopenia is a very good discriminatory test for the presence or absence of malaria with 79.5% sensitivity and 86.3% specificity. Therefore, this may be used in addition to the clinical and microscopic parameters to heighten the suspicion of malaria.”

Not strictly a paper about diagnosis,  Lima MN & al., Neurovascular Interactions in Malaria, Neuroimmunomodulation, 2021 May 5;1-10. doi: 10.1159/000515557 reviews situations in which patients who survived an episode of cerebral malaria (CM), an increasing occurrence, develop late neurovascular sequelae.  In this review they “approach the main changes that happen in the cells of the NVU [neurovascular unit] due to neuroinflammation caused by malaria infection, and elucidate how the systemic pathophysiology is involved in the onset and progression of CM.”

Treatment:

Rouamba T & al., Asymptomatic Malaria and Anaemia Among Pregnant Women During High and Low Malaria Transmission Seasons in Burkina Faso: Household-Based Cross-Sectional Surveys in Burkina Faso, 2013 and 2017, Malar J, 2021 May 1;20(1):211.  doi: 10.1186/s12936-021-03703-4 is one of two articles this month dealing with malaria in pregnancy. This study revealed that the prevalence of malaria asymptomatic carriage and anemia among pregnant women at the community level remain high throughout the year. “Thus, more efforts are needed to increase prevention measures such as IPTp-SP [intermittent preventive treatment of pregnancy – sulfadoxine-pyrimethamine] coverage in order to reduce anemia and contribute to preventing low birthweight and poor pregnancy outcomes.”

The second article relating to pregnancy, Mahamar A & al., Malaria Infection Is Common and Chemoprevention In Mali: An Observational Study 2010 to 2014, Clin Infect Dis, 2021 Apr 13;ciab301.  doi: 10.1093/cid/ciab301, concludes that  “[m]alaria treatment after diagnosis, alongside IPTp-SP, is insufficient to prevent malaria-related stillbirth, early neonatal death and PTD [pre-term delivery]. While IPTp-SP was beneficial in Mali during the study period, new tools are needed to improve pregnancy outcomes.”

Rosenthal PJ, Has Artemisinin Resistance Emerged in Africa? Lancet Inf Dis 14 Apr 2021 DOI:https://doi.org/10.1016/S1473-3099(21)00168-7 is regrettably not available for review, nor has been an abstract published,  However, the emerging resistance to artemisinin around the world has generated a number of papers addressing the issue.  Pessanha de Carvalho L & al., Drug Repurposing: A Review of Old and New Antibiotics for the Treatment of Malaria: Identifying Antibiotics with a Fast Onset of Antiplasmodial Action, Molecules, 2021 Apr 15;26(8):2304. doi: 10.3390/molecules26082304 asserts that a number of rapid acting sulfa drugs and antibiotics may be useful in the treatment of malaria.  Another approach is espoused by Bangbose T & al., in Functional Food for the Stimulation of the Immune System Against Malaria, Probiotics Antimicrob Proteins, 2021 Apr 1;1-13. doi: 10.1007/s12602-021-09780-w. They speculate that the studies connecting gut microbiota to the prevention of malaria transmission and severity point in the direction of “the search for lactic acid bacteria expressing α-Gal and those that exhibit the desired immune stimulating properties for the development of functional food and probiotics for malaria control.”  Yet a different avenue is evident in Pontes KAO & al., Eugenol Disrupts Plasmodium falciparum Intracellular Development During the Erythrocytic Cycle and Protects Against Cerebral Malaria, Biochim Biophys Acta Gen Subj, 2021 Mar;1865(3):129813.  doi: 10.1016/j.bbagen.2020.129813, demonstrating the anti-Plasmodium effectiveness of this substance derived from clove bud essential oil, in the evolution from schizont to ring forms, inducing important morphological changes, indicating a disruption in the development of the erythrocytic cycle.

Less positive are the results published by Kiguba R & al., Quality of Care for Adult In-Patients with Malaria in a Tertiary Hospital in Uganda, Malar J, 2021 Apr 9;20(1):178. doi: 10.1186/s12936-021-03712-3.  This study of the care received by adult patients with malaria in a large referral hospital revealed that “[o]nly 13% (11/83) of in-patients who received in-hospital injectable artesunate (AS) or quinine (Q) received follow-up oral artemether-lumefantrine (AL); 2 of 18 severe malaria cases received follow-up oral AL.”  Anti-malarial treatment was delayed by at least a day in one quarter of patients admitted with the diagnosis of malaria.

Campaigns:

Another study showing less than satisfactory outcomes is Mohammed MA & Hong T, Role of Vector Control in Fighting Against Malaria: Evidence from Ethiopian Health-Related Indicators, J Infect Public Health, 2021 Apr;14(4):527-532. doi:10.1016/j.jiph.2020.12.002. This study reports on “the impact of vector control interventions on malaria based on panel data of 10 malaria endemic-regions from 2000 to 2018.”  The results show an increase in malaria incidence after implementation of indoor residual spraying and insecticide-treated mosquito nets.  Reasons for this increase are not given.

González-Silva M & Rabinovich NR state in Some Lessons for Malaria from the Global Polio Eradication Initiative, Malar J, 2021 May 1;20(1):210.  doi: 10.1186/s12936-021-03690-6 that despite “the deep differences between both diseases and the stages they are in their path towards eradication, this paper draws from the history of GPEI and highlights relevant insights into what it takes to eradicate a pathogen in fields as varied as priority setting, global governance, strategy, community engagement, surveillance systems, and research.”

The interaction of public health and politics is the subject of Parkhurst J & al., Competing Interests, Clashing Ideas and Institutionalizing Influence: Insights into the Political Economy of Malaria Control from Seven African Countries, Health Policy Plan, 2021 Mar 3;36(1):35-44. doi: 10.1093/heapol/ czaa166. “Malaria control is often assumed to be a technically driven exercise: the remit of public health experts and epidemiologists who utilize available data to select the most effective package of activities given available resources. Yet research conducted with national and international stakeholders shows how the realities of malaria control decision-making are often more nuanced. … Results from qualitative interviews in seven malaria-endemic countries indicate that malaria decision-making is constrained or directed by multiple competing objectives, including a need to balance overarching global goals with local realities, as well as a need for National Malaria Control Programmes to manage and coordinate a range of non-state stakeholders who may divide up regions and tasks within countries.”

Epidemiology:

Another article relating to house structure is Sikalima J & al., House Structure Is Associated with Malaria among Febrile Patients in a High-Transmission Region of Zambia, Am J Trop Med Hyg, 2021 Apr 12;tpmd201378.  doi: 10.4269/ajtmh.20-1378.  Based on a “cross-sectional study of febrile patients (n = 282) at two rural health clinics in a high malaria-transmission area of northern Zambia,” they conclude that residing in a house with thatched roof carried a higher risk, as did lower income and lesser educational attainment.  On the other hand “[n]either IRS [indoor residual spraying] nor bed net use was associated with malaria risk despite large, local investments in these vector control interventions” in this population.

 Two studies reported on the prevalence of malaria in children. Tegegne Y & al, The Prevalence of Malaria among Children in Ethiopia: A Systematic Review and Meta-Analysis, J Parasitol Res, 2021 Apr 13;2021:6697294.  doi: 10.1155/2021/6697294 reports an overall prevalence of 9.07% (95% confidence range), based on pooled data of unknown extent.  This is broken down to 6.67% in asymptomatic children and 27.17% in symptomatic ones.  Significantly higher rates are reported in Emina JBO  & al., Profiling Malaria Infection Among Under-Five Children in the Democratic Republic of Congo, PLoS One, 2021 May 6;16(5):e0250550. doi:10.1371/journal.pone.0250550. In a sample of 8,500+ children from 2013 DRC Demographic and Health Survey the prevalence of malaria was 25%. “Four variables-child’s age, mother’s education, province, and wealth index-were statistically associated with the prevalence of malaria infection in bivariate analysis and multivariate analysis (CHAID and logistic regression). The prevalence of malaria infection increases with child’s age and decreases significantly with mother’s education and the household wealth index.”

Gies S & al., Risk of malaria in young children after periconceptional iron supplementation, Matern Child Nutr, 2021 Apr;17(2):e13106. doi: 10.1111/mcn.13106 report on a child safety survey “in the peak month of malaria transmission towards the end of the trial to assess child iron biomarkers, nutritional status, anaemia and malaria outcomes. Antenatal iron biomarkers, preterm birth, fetal growth restriction and placental pathology for malaria and chorioamnionitis were assessed.  Factors associated with childhood parasitaemia were third trimester C-reactive protein level.., active placental malaria … and child body iron stores. Chorioamnionitis was associated with reduced risk of child parasitaemia.

According to the WHO, Mozambique has the third highest number of malaria cases in the world, representing approximately 5% of the world total cases. Ferrão J, & al., Mapping Risk of Malaria as a Function of Anthropic and Environmental Conditions in Sussundenga Village, Mozambique, Int J Environ Res Public Health, 2021 Mar 5;18(5):2568. doi: 10.3390/ijerph18052568 examined a district with particularly high rates of infection and conclude that “[h]igh malaria risk areas are most often located in densely populated areas and areas close to water bodies.”

Likewise, Kassam NA & al., Ten Years of Monitoring Malaria Trend and Factors Associated with Malaria Test Positivity Rates in Lower Moshi, Malar J, 2021 Apr 20;20(1):193. doi: 10.1186/s12936-021-03730-1 focuses on a limited geographic area, this time in a high-altitude, low malaria transmission setting, south of Mount Kilimanjaro.  While relatively low (0.68% to 1.67%), “[m]alaria test positivity rates were positively associated with average monthly minimum temperatures and negatively associated with average monthly maximum temperatures… Mass distribution of LLINs [long lasting insecticidal nets] did not have an effect in this area with already very low malaria transmission.”

Nissan H & al., Climate-proofing a Malaria Eradication Strategy, Malar J, 2021 Apr 17;20(1):190. doi: 10.1186/s12936-021-03718-x refers to two recently published malaria eradication strategies (by WHO and Lancet), which are said to “rely on a climate-driven model of malaria transmission to conclude that long-term trends in climate will assist eradication efforts overall and, consequently, neither prioritize strategies to manage the effects of climate variability and change on malaria programming.” This conclusion is not supported by the article, which proposes a “range of practical measures … to climate-proof a malaria eradication strategy, which can be implemented today and will ensure that climate variability and change do not derail progress towards eradication.”

Finally, two articles deal with the coexistence of malaria and HIV disease, Roberds A & al., HIV-1 Impact on Malaria Transmission: A Complex and Relevant Global Health Concern, Front Cell Infect Microbiol, 2021 Apr 12;11:656938.  doi: 10.3389/ fcimb.2021.656938 and Obebe OO & Falohun OO, Epidemiology of Malaria Among HIV/AIDS Patients in Sub-Saharan Africa: A Systematic Review and Meta-Analysis of Observational Studies, Acta Trop, 2021 Mar;215:105798. doi: 10.1016/j.actatropica.2020.105798. While the former reviews pathophysiologic phenomena in patients suffering from both diseases, the latter, a meta-analysis, observes that the likelihood that an HIV positive patient will develop malaria is linked to CD4 and T cell counts, as well as the clinical stage of the disease.

Basic Research:

Guha R & al. Plasmodium falciparum Malaria Drives Epigenetic Reprogramming of Human Monocytes Toward a Regulatory Phenotype, PLOS Pathogens, 2021 Apr 6, https://doi.org/10.1371/ journal.ppat.1009430.

Neafsey DE & al., Advances and Opportunities in Malaria Population Genomics, Nat Rev Genet, 2021 Apr 8;1-16.  doi: 10.1038/s41576-021-00349-5. Online ahead of print.

Reiss T & al., Acquisition of Human Plasminogen Facilitates Complement Evasion by the Malaria Parasite Plasmodium falciparum, Eur J Immunol, 2021 Feb;51(2):490-493. doi: 10.1002/eji.202048718.

Voorberg-van der Wel A & al., Modeling Relapsing Malaria: Emerging Technologies to Study Parasite-Host Interactions in the Liver, Front Cell Infect Microbiol, 2021 Jan 29;10:606033.  doi: 10.3389/fcimb.2020.606033.