Monthly Science & Research Report for August 2021

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

Many of the articles on malaria contain information from other published studies, this report highlights the most relevant articles in recent months. 

Prevention:

Topazian HM & al.,  Effectiveness of a National Mass Distribution Campaign of Long-Lasting Insecticide-Treated Nets and Indoor Residual Spraying on Clinical Malaria in Malawi, 2018-2020, BMJ Glob Health. 2021 May;6(5):e005447. doi: 10.1136/bmjgh-2021-005447.  This article reports on a comprehensive study of preventive measures countrywide.  The results indicate that the effectiveness of LLINs was shorter than 3 years and that “[p]iperonyl butoxide (PBO)-treated LLINs were more effective than pyrethroid-treated LLINs…”

“…malaria vector resistance to pyrethroids is widespread in sub-Saharan Africa.” Oxborough RM & al. studied another substance, chlorfenapyr. As reported in Determination of the Discriminating Concentration of Chlorfenapyr (Pyrrole) and Anopheles gambiae sensu lato Susceptibility Testing in Preparation for Distribution of Interceptor® G2 Insecticide-Treated Nets, Malaria J, 14 Jul 2021, 20:Article 316, “[t]esting in 16 countries in sub-Saharan Africa demonstrated vector susceptibility to chlorfenapyr, including mosquitoes with multiple resistance mechanisms to pyrethroids.”

“CRISPR-based gene-drives targeting the gene doublesex in the malaria vector Anopheles gambiae effectively suppressed the reproductive capability of mosquito populations reared in small laboratory cages. To bridge the gap between laboratory and the field, this gene-drive technology must be challenged with vector ecology.” Hammond A, & al., Gene-Drive Suppression of Mosquito Populations in Large Cages as a Bridge Between Lab and Field, Nature Communications 2021 Jul 28, vol 12 art. 4589; https://www.nature.com/articles/s41467-021-24790-6 report “the suppressive activity of the gene-drive in age-structured An. gambiae populations in large indoor cages that permit complex feeding and reproductive behaviours.”

“…despite progress towards improved larvicides and new tools for mapping or treating mosquito-breeding sites, little is known about the optimal deployment strategies for larviciding in different transmission and seasonality settings.” Runge M & al., Evaluation of Different Deployment Strategies for Larviciding to Control Malaria: A Simulation Study, Malaria J, 2021 Jul 27, vol. 20 art 324, https://malariajournal.biomedcentral.com/articles/ 10.1186/s12936-021-03854-4 conclude that “larviciding would be more effective in settings with low and seasonal transmission, and at the beginning and during the peak densities of the target species populations.”

Among several articles relating to malaria vaccine development, the following three cover different aspects of their development and use.

Mwakingme-Omari A & al.,  Two Chemoattenuated PfSPZ Malaria Vaccines Induce Sterile Hepatic Immunity, Nature, 2021 Jul;595(7866):289-294.  doi: 10.1038/s41586-021-03684-z reports on a small in vivo study of “chemoprophylaxis vaccination (CVac), for which aseptic, purified, cryopreserved, infectious Plasmodium falciparum sporozoites (PfSPZ) were inoculated under prophylactic cover with pyrimethamine (PYR) (Sanaria PfSPZ-CVac(PYR)) or chloroquine (CQ) (PfSPZ-CVac(CQ))-which kill liver-stage and blood-stage parasites, respectively.”  They “assessed vaccine efficacy against homologous (that is, the same strain as the vaccine) and heterologous (a different strain) controlled human malaria infection (CHMI) three months after immunization” and found that at relatively high dose, the vaccine was highly effective.

Studying the acceptance of the RTS,S vaccine in Ghana, Tabiri D, & al report in Factors Associated with Malaria Vaccine Uptake in Sunyani Municipality, Ghana, Malaria J, 2021 Jul 27, vol. 20 art 325 https://malariajournal.biomedcentral.com/articles/10.1186/s12936-021-03857-1 that while the first two doses of the vaccine were received by 90.6% of eligible children, the “uptake” dropped to 78% for the third dose.  The authors speculate on reasons for this drop-off.

The Reuters news agency reported that BioNTech is exploring vaccine production in Africa in https://www.reuters.com/business/healthcare-pharmaceuticals/biontech-aims-develop-mrna-based-malaria-vaccine-2021-07-26/  “BioNTech (22UAy.DE) wants to build on its success in COVID-19 by developing the first vaccine for malaria based on mRNA technology and aims to start clinical testing by the end on 2022, in an attempt to eradicate the mosquito-borne illness. The Mainz, Germany-based company, which developed a COVID-19 vaccine with its partner Pfizer (PFE.N) in ten months, said on Monday it is also exploring vaccine production in Africa as part of efforts to build up manufacturing capacity on the continent.”

Diagnosis:

Gimenez AM & al., Diagnostic Methods for Non-Falciparum Malaria, Front Cell Infect Microbiol, 2021 Jun 17;11:681063. doi: 10.3389/fcimb.2021.681063 argues that with attention being focused of P. falciparum, the diagnosis of other forms of malaria may be missed.  Unfortunately the abstract is not revealing of the methods they espouse for more accurate diagnosis and the article is not readily available for review.

More about pathogenesis than diagnosis is the study by Thomson-Luque R & al.  They studied the relationship of red blood cell physiology to severity of infection.  Their report, Plasmodium falciparum Transcription in Different Clinical Presentations of Malaria Associates with Circulation Time of Infected Erythrocytes, Nature Comm 30 Jul 2021, vol. 12 art. 4711, www.nature.com/articles/s41467-021-25062-z, states that “the size of circulating infected erythrocytes is inversely related to parasite density and disease severity. {They] propose that enhanced adhesiveness of infected erythrocytes leads to a rapid increase in parasite burden, promoting higher parasitaemia and increased disease severity.”

Treatment:

Cherif MS & al., Malaria Epidemiology and Anti-Malarial Drug Efficacy in Guinea: A Review of Clinical and Molecular Studies, Malaria J, 2021 Jun 16;20(1):272.  doi: 10.1186/s12936-021-03809-9.  This report indicates that for the time being, artemisinin-based combination therapy (ACT) is 95% effective in Guinea.  However, they do report “widespread usage of counterfeit medicines…”

The situation is apparently somewhat different in Burkina Faso.  Rasmussen C & Ringwald P report that “reviewing the available data collected since 2008 on ACT efficacy in Burkina Faso, the analysis shows that the reported efficacy of the tested ACT varies greatly. Most of the studies have considerable methodological deviations and challenges, especially in PCR correction done to distinguish between recrudescence and re-infection, and in the failure to omit re-infections in the calculation of efficacy rates.”  They authored Is There Evidence of Anti-Malarial Multidrug Resistance in Burkina Faso? Malaria J, 2021 Jul 19, vol. 20:art. 320. https://malariajournal.biomedcentral.com/articles/10.1186/ s12936-021-03845-5.

Notwithstanding the above two papers, resistance to ACT is a fact in some countries, especially in Southeast Asia.  It is likely to spread to other parts of the world. Therefore it is important to continue searching for other possible treatments, especially since a universally effective vaccine is not going to be available for some time. Ali F & al., Analysing the Essential Proteins Set of Plasmodium falciparum PF3D7 for Novel Drug Targets Identification Against Malaria, Malaria J, 2021 Aug 3, vol 20, art. 335, https://malariajournal.biomedcentral.com/articles/10.1186/s12936-021-03865-1 report on some proteins that may be targeted by new medications.  These “druggable” proteins “seem novel and promising drug targets against P. falciparum due to their key protein–protein interactions features in pathogen-specific biological pathways and to hold appropriate drug-like molecule binding pockets.” Further “in-vitro and in-vivo studies might be promising for additional validation of these prioritized lists of drug targets against malaria.”

Another approach to the problem of drug resistance is addressed by Memvanga PB & Nkanga CI, Liposomes for Malaria Management: The Evolution from 1980 to 2020, Malaria J, 2021 Jul 27, vol. 20 art 327. https://malariajournal.biomedcentral.com/articles/10.1186/s12936-021-03858-0. They also identify “other shortcomings of anti-malarial drugs.”  These include “poor aqueous solubility, low permeability, poor bioavailability, and non-specific targeting of intracellular parasites, resulting in high dose requirements and toxic side effects. To address these limitations, liposome-based nanotechnology has been extensively explored as a new solution in malaria management. Liposome technology improves anti-malarial drug encapsulation, bioavailability, target delivery, and controlled release, resulting in increased effectiveness, reduced resistance progression, and fewer adverse effects.”  The authors hope that their paper will facilitate “the research and development of several available and affordable anti-malarial-based liposomes and liposomal malaria vaccines by allowing a thorough evaluation of liposomes developed to date for the management of malaria.”

Feng, X & al. claim in Traditional Application and Modern Pharmacological Research of Artemisia annua L., Pharm & Ther Dec 2020, 216:107650, https://doi.org/10.1016/j.pharmthera.2020.107650 that “A. annua has been revealed to show inhibitory effects against parasites (e.g. Plasmodium, Toxoplasma gondii, Leishmania, Acanthamoeba, Schistosoma), viruses (e.g. hepatitis A virus, herpes simplex viruses 1 and 2, human immunodeficiency virus), fungi (Candida, Malassezia, Saccharomyces spp.) and bacteria (Enterococcus, Streptococcus, Staphylococcus, Bacillus, Listeria, Haemophilus, Escherichia, Pseudomonas, Klebsiella, Acinetobacter, Salmonella, Yersinia spp.). A. annua has also been reported to possess anti-inflammatory and anti-cancer actions and been employed for the treatment of osteoarthritis, leukemia, colon cancer, renal cell carcinoma, breast cancer, non-small cell lung cancer, prostate cancre and hepatoma. Besides, the immunoregulation, anti-adipogenic, anti-ulcerogenic, anti-asthmatic, anti-nociceptive and anti-osteoporotic activities of A. annua were also evaluated.” 

In view of the expansive view expressed in the article above, it may be well to review the WHO Position Statement (June 2012) on Effectiveness of Non-Pharmaceutical Forms of Artemisia annua L. Against Malaria.  It unequivocally states: “WHO does not recommend the use of A. annua plant material, in any form, including tea, for the treatment or the prevention of malaria.”

Campaigns:

Teh RN & al., Insecticide-Treated Net Ownership, Utilization and Knowledge of Malaria in Children Residing in Batoke–Limbe, Mount Cameroon Area: Effect on Malariometric and Haematological Indices, Malaria J 29 Jul 2021 vol. 20 art 333 https://malariajournal.biomedcentral.com/ articles/10.1186/s12936-021-03860-6. “A community-based cross-sectional study involving a total of 405 children aged between 6 months and 14 years living in Batoke–Limbe was carried out between July and October 2017. A semi-structured questionnaire was used to document demographic status, knowledge on malaria and ITN ownership and usage. Venous blood sample was collected from each child to determine the prevalence and intensity of parasitaemia. … A multilinear regression model was used to determine the relationship between haematological parameter as dependent variable and the independent variables.” The effective use of insecticide treated nets (ITNs) was poor (29.9%) in this population. The authors describe relationships between malaria knowledge and use of ITNs on one hand and various hematologic parameters on the other, but without clear cut conclusions other than the “need for more sensitization on the benefits of using the ITNs…”

The conclusion is similar in a study conducted by Savi MK & al., reported as Emerging Properties of Malaria Transmission and Persistence in Urban Accra, Ghana: Evidence from a Participatory System Approach, Malaria J, 2021 Jul 19, 20:Art. 321. https://malariajournal.biomedcentral.com/articles/ 10.1186/s12936-021-03851-7.  They identified “45 determinants interplaying through 56 linkages, and three subsystems: urbanization-related transmission, infection-prone behaviour and healthcare efficiency, and Plasmodium resistance… Apart from the number of breeding sites and malaria-positive cases, other determinants such as drug prescription and the awareness of householders were identified by the network analysis as leverage points and emergent properties of the system of transmission and persistence of malaria.” Ultimately they conclude that “the ongoing efforts to control malaria, such as the use of insecticide-treated bed nets and larvicide applications should continue, and new ones focusing on the public awareness and malaria literacy of city dwellers should be included.”

Samuels AM & al. studied the efficacy of repeated rounds of community-based mass testing and treatment (MTaT) on malaria infection prevalence in western Kenya. The primary outcome was the effect size of MTaT on parasite prevalence by microscopy between arms by year, adjusted for age, reported LLIN use, enhanced vegetative index, and socioeconomic status. According to their apparently discouraging report, Impact of Community-Based Mass Testing and Treatment on Malaria Infection Prevalence in a High-Transmission Area of Western Kenya: A Cluster Randomized Controlled Trial, Clin Infect Dis, 2021 Jun 1;72(11):1927-1935, doi: 10.1093/cid/ciaa471, “MTaT performed 3 times per year over 2 years did not reduce malaria parasite prevalence in this high-transmission area.”

A major paper from the London School of Hygiene and Tropical Medicine was published as 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, as referred to in the preamble to this monthly compendium. “This article explores how malaria control in sub-Saharan Africa is shaped in important ways by political and economic considerations within the contexts of aid-recipient nations and the global health community. 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. Hegemonic ideas and interests of global actors, as well as the national and global institutional arrangements through which malaria control is funded and implemented, can all influence how national actors respond to malaria. 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. Finally, beyond the influence that political and economic concerns have over programmatic decisions and action, our analysis further finds that malaria control efforts have institutionalized systems, structures and processes that may have implications for local capacity development.”

Epidemiology:

Donkor E & al., A Bayesian Spatio-Temporal Analysis of Malaria in the Greater Accra Region of Ghana from 2015 to 2019. Int J Environ Res Pub Health. 2021 Jun 4;18(11):6080. doi: 10.3390/ijerph18116080 may be considered a companion piece to the one by Savi MK & al. above. While some of the abstract is too dense for this statistically challenged reviewer, the following is clear: “… overall malaria incidence for the region was approximately 47 per 1000 population. Malaria transmission was highly seasonal with an irregular inter-annual pattern. Monthly malaria case incidence was found to decrease by 2.3% (95% credible interval: 0.7-4.2%) for each 1 °C increase in monthly minimum temperature. Only five districts located in the south-central part of the region had a malaria incidence rate lower than the regional average at >95% probability level. The distribution of malaria cases was heterogeneous, seasonal, and significantly associated with climatic variables.”

Brazeau NF & al. report on The Epidemiology of Plasmodium vivax Among Adults in the Democratic Republic of the Congo, Nature Communications 7 Jul 2021, doi.org/10.1083/s41467-021-24216-3.  They “screened over 17,000 adults in the Democratic Republic of the Congo (DRC) for P. vivax using samples from the 2013-2014 Demographic Health Survey. Overall, we found a 2.97% (95% CI: 2.28%, 3.65%) prevalence of P. vivax infections across the DRC. Infections were associated with few risk-factors and demonstrated a relatively flat distribution of prevalence across space with focal regions of relatively higher prevalence in the north and northeast… P. vivax is diffusely spread across the DRC at a low prevalence, which may be associated with long-term carriage of low parasitemia, frequent relapses, or a general pool of infections with limited forward propagation.”

In view of the very recent UN report on climate change, Chemison A & al., Impact of an Accelerated Melting of Greenland on Malaria Distribution over Africa, Nature Communications 2021 Jun 25, vol. 12 art 3971 https://www.nature.com/articles/s41467-021-24134-4 may be considered a relevant additional analysis to the topic. The results of their analysis reveal that their “melting scenario could moderate the simulated increase in malaria risk over East Africa, due to cooling and drying effects, cause a largest decrease in malaria transmission risk over West Africa and drive malaria emergence in southern Africa associated with a significant southward shift of the African rain-belt. [They] argue that the effect of such ice-sheet melting should be investigated further in future public health and agriculture climate change risk assessments.”

Basic Research:

Pamplona A & Silva-Santos B, γδ T Cells in Malaria: A Double-Edged Sword, FEBS J. 2021 Feb; 288(4): 1118–1129. doi: 10.1111/febs.15494.

Niu G, Cui Y, Wang X & al., Studies of the Parasite-Midgut Interaction Reveal Plasmodium Proteins Important for Malaria Transmission to Mosquitoes, Front Cell Infect Microbiol, 2021 Jun 28;11:654216. doi: 10.3389/fcimb.2021.654216

Xu K & al., Structural Basis of LAIR1 Targeting by Polymorphic Plasmodium RIFINs, Nature Communications, 2021 Jul 9, doi.org/10.1038/s41467-021-24291-6. 

Saini E, & al., Plasmodium falciparum PhIL1-Associated Complex Plays an Essential Role in Merozoite Reorientation and Invasion of Host Erythrocytes, PLoS Pathogens, 2021 Jul 29,  doi.org/10.1371/ journal.ppat.1009750

Lu XM, & Le Roch K,  Strand-Specific RNA-Seq Applied to Malaria Samples, Methods Mol Biol. 2021; 2170:19-33.  doi: 10.1007/978-1-0716-0743-5_2