Science & Research Report for May 2022

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

Three publications this past month seem important to emphasize in this report. The first, New Frontiers in Vector Control, is a summary of preventive measures, other than vaccines, that was published without author specified by the newsroom of the World Health Organization.  The other two, both from The Lancet, are summarized below under the Campaigns heading.  One of these also references a joint report of WHO and The Global Fund to Fight AIDS in late 2021, Tuberculosis and Malaria, State of Inequality: HIV, Tuberculosis and Malaria.

Prevention:

Vaccines 

Praet N, & al., Assessing the Safety, Impact and Effectiveness of RTS,S/AS01_E Malaria Vaccine Following Its Introduction in Three Sub-Saharan African Countries: Methodological Approaches and Study Set-Up, Malaria J, 2022 Apr 25, vol 21 art 132, doi: 10.1186/s12936-022-04144-3 is a description of the currently ongoing Phase IV study of the vaccine developed by GlaxoSmitKline and endorsed by WHO. A graphic describing the process is available in pdf format to anyone interested.

A different approach to vaccine development, Plasmodium falciparum sporozoites in Sanaria® PfSPZ Vaccine is the subject of James WR & al., A First for Human Vaccinology: GMP Compliant Radiation Attenuation of Plasmodium falciparum Sporozoites for Production of a Vaccine Against Malaria, Front Immunol, 2022 Feb 15; 13:851028. doi: 10.3389/fimmu.2022.851028.  They describe the radiation process that has obtained Good Manufacturing Process certification.

Vector control and protection from vectors

New Frontiers in Vector Control, WHO, 2022 April 11, https://www.who.int/news-room/feature-stories/detail/new-frontiers-in-vector-control.  This illustrated article summarizes developments in laymen’s terms in insecticide nets, outdoor mosquito control, spatial repellents, endectocides (drugs that when taken by humans will kill mosquitoes that bite them), and gene drives.

The usual problem of LLIN utilization is addressed by Klu D & al., Mixed Effect Analysis of Factors Influencing the Use of Insecticides Treated Bed Nets Among Pregnant Women in Ghana: Evidence from the 2019 Malaria Indicator Survey, BMC Pregnancy Childbirth, 2022 Mar 27; 22(1):258. doi: 10.1186/s12884-022-04586-2. “The study found that 49.2% of pregnant women in Ghana use [LLIN] to prevent malaria,” and specifies demographics of high and low user groups.

A number of articles refer to insect resistance to pyrethroids in long lasting insecticide nets (LLINs) and efforts to overcome it.  These include Meiwald A & al., Association of Reduced Long-Lasting Insecticidal Net Efficacy and Pyrethroid Insecticide Resistance With Overexpression of CYP6P4, CYP6P3, and CYP6Z1 in Populations of Anopheles coluzzii From Southeast Côte d’Ivoire, J Infect Dis, 2022 Apr 19; 225(8):1424-1434, doi: 10.1093/infdis/jiaa699, Syme T & al., Pyrethroid-Piperonyl Butoxide (PBO) Nets Reduce the Efficacy of Indoor Residual Spraying with Pirimiphos-Methyl Against Pyrethroid-Resistant Malaria Vectors, Sci Rep, 2022 Apr 27; 12(1):6857. doi: 10.1038/S41598-022-10953-Y, Mosha JF & al., Effectiveness and Cost-Effectiveness Against Malaria of Three Types of Dual-Active-Ingredient Long-Lasting Insecticidal Nets (LLINs) Compared With Pyrethroid-Only LLINs In Tanzania: A Four-Arm, Cluster-Randomised Trial, Lancet, 2022 Mar 26; 399(10331): 1227–1241. doi: 10.1016/S0140-6736(21)02499-5, and Okoth D, Novel Bed Nets Target Insecticide-Resistant Malaria, Nature Africa, 2022 Apr 19,  https://www.nature.com/articles/d44148-022-00055-2, which refers to the latter.

Kibondo UA & al., Influence of Testing Modality on Bioefficacy for the Evaluation of Interceptor ^® G2 Mosquito Nets to Combat Malaria Mosquitoes in Tanzania, Parasit Vectors, 2022 Apr 11; 15(1):124. doi: 10.1186/S13071-022-05207-9 studies a brand of LLINs that uses two non-pyrethroid insecticides against a previous version of the same brand that uses only one and concludes that the new product is superior in killing mosquitoes.

Somewhat similar is the thrust of Chanyalew T & al., Composition of Mosquito Fauna and Insecticide Resistance Status of Anopheles gambiae sensu lato in Itang Special District, Gambella, Southwestern Ethiopia, Malaria J, 2022 Apr 18, vol 21 art 125, doi: 10.1186/s12936-022-04150-5 in which mosquito resistance to indoor residual spraying (IRS) compounds was the subject.

Fongnikin A & al. studied a new formulation of a WHO recommended non-pyrethroid insecticide for IRS and report in Pirikool® 300 CS, a New Long-Lasting Capsule Suspension Formulation of the Organo-phosphate Insecticide Pirimiphos-Methyl for Indoor Residual Spraying Against Pyrethroid-Resistant Malaria Vectors, PLoS One, 2022 Apr 18; 17(4):E0267229, doi: 0.1371/Journal.Pone.0267229 that it is effective.

Diouf M & al. focus on the long-term “survival” of various insecticide treated nets in Survival of Eight LLIN Brands 6, 12, 24 And 36 Months After a Mass Distribution Campaign in Rural and Urban Settings in Senegal, BMC Public Health, 2022 Apr 11; 22(1):719. doi: 10.1186/S12889-022-13051-W. Of eight types of nets studied, only three types had 80% survival at 24 months; conical nets lasted longer than rectangular ones.

The addition of indoor residual spraying to LLIN use is found by Dulacha D & al. to lead to “a reduced malaria burden among populations protected by both non-pyrethroid IRS and LLINs implying a possible additional benefit afforded by the combined intervention in the malaria-endemic zone,” as reported in  Reduction in Malaria Burden Following the Introduction of Indoor Residual Spraying in Areas Protected by Long-Lasting Insecticidal Nets in Western Kenya, 2016-2018, PLoS One, 2022 Apr 20; 17(4):e0266736. doi: 10.1371/journal.pone.0266736. 

“Spatial repellents are widely used for prevention of mosquito bites and evidence is building on their public health value, but their efficacy against malaria incidence has never been evaluated in Africa.” Two papers with essentially identical titles, Ochomo EO al., Evaluation of the Protective Efficacy of a Spatial Repellent to Reduce Malaria Incidence in Children in Western Kenya Compared to Placebo: Study Protocol for a Cluster-Randomized Double-Blinded Control Trial (the AEGIS Program), Trials, 2022 Apr 5; 23(1):260, doi: 10.1186/S13063-022-06196-X and Van Hulle S & al., Evaluation of the Protective Efficacy of a Spatial Repellent to Reduce Malaria Incidence in Children in Mali Compared to Placebo: Study Protocol for a Cluster-Randomized Double-Blinded Control Trial (The AEGIS Program), Trials, 2022 Apr 5; 23(1):259, doi: 10.1186/S13063-022-06197-W describe how the studies will unfold. “Results will be submitted to the World Health Organization Vector Control Advisory Group for assessment of public health value towards an endorsement to recommend inclusion of spatial repellents in malaria control programs.”

Genetic engineering of Anopheles is another approach to vector control. Lacy K & al. report that The Economic Value of Genetically Engineered Mosquitoes as a Malaria Control Strategy Depends on Local Transmission Rates, Biotechnol J, 2022 Apr; 17(4):E2100373. doi: 10.1002/Biot.202100373. They found that this strategy is cost effective only in low-transmission communities.

Chemoprophylaxis

Kirakoya-Samadoulougou F & al., Assessing the Effect of Seasonal Malaria Chemoprevention [SMC] on Malaria Burden Among Children Under 5 Years in Burkina Faso, Malaria J, 2022 May 6, vol 21 art 143, doi: 10.1186/s12936-022-04172-z reports on the two year result of administering SMC with the resultant reduction of uncomplicated malaria by over 70%.

Looman L & Pell C, End-User Perspectives on Preventive Antimalarials: A Review of Qualitative Research, Glob Public Health, 2022 May; 17(5):753-767. doi: 10.1080/17441692.2021.1888388 is a meta-analysis of publications that reveals that in many communities distrust in this preventive approach is a significant factor.

Also on the basis of literature search Chu X & al. report in The Efficacy and Safety of Intermittent Preventive Treatment with Sulphadoxine-Pyrimethamine [ITP-SP] vs Artemisinin-Based Drugs [ACT] for Malaria: A Systematic Review and Meta-Analysis, Trans R Soc Trop Med Hyg, 2022 Apr 4; 116(4):298-309. doi: 10.1093/Trstmh/Trab158 that “[c]ombinations with ACTs appear promising as suitable alternatives for IPT-SP.”

Diagnosis:

“There are several methods to find out the existence of parasites within the blood. The oldest one is by microscopy, which is still a gold standard, although rapid diagnostic tests (RDTs) have rapidly become a primary diagnostic test in many endemic areas. Because of microscopy and RDTs limitation, novel serological and molecular methods have been developed. Many kinds of polymerase chain reaction (PCR) provide rapid results and higher specificity and sensitivity. The loop-mediated isothermal amplification (LAMP) and biosensing-based molecular techniques as point of care tests (POCT) will become a cost-effective approach to advance diagnostic testing. The article is Fitri LE & al., Malaria Diagnostic Update: From Conventional to Advanced Method, J Clin Lab Anal, 2022 Apr; 36(4):e24314. doi: 10.1002/jcla.24314.

One of the newer methods referred to in the above article is the topic of Das D & al., Field Evaluation of The Diagnostic Performance of EasyScan GO: A Digital Malaria Microscopy Device Based on Machine-Learning, Malaria J, 2022 Apr 12, vol 21 art 122. doi: 10.1186/s12936-022-04146-1.  The device functioned with high sensitivity and specificity when parasite density was high, but software improvements are needed to improve sensitivity in low parasitemia situations.

Assessing the accuracy of malaria diagnosis and treatment practices in three health care facilities in rural western Kenya, Otambo WO & al. found insufficient accuracy and compliance with guidelines.  They reported their findings in Health Care Provider Practices in Diagnosis and Treatment of Malaria in Rural Communities in Kisumu County, Kenya, Malaria J, 2022 Apr 22, vol 21 art 129, doi: 10.1186/s12936-022-04156-z.

Pourabed A & al., A Star Shaped Acoustofluidic Mixer Enhances Rapid Malaria Diagnostics Via Cell Lysis and Whole Blood Homogenisation in 2 Seconds, Lab Chip, 2022 May 3; 22(9):1829-1840. doi: 10.1039/D2lc00195k is a description of a new way to lyse red blood cells for thick smear preparation.

Rogers CL & al. published the British Society for Haematology Guidelines for the Laboratory Diagnosis of Malaria, Br J Haematol, 2022 May; 197(3):271-282. doi: 10.1111/bjh.18092  

The accuracy of rapid diagnostic tests performed in the field is often dependent on the presence of histidine-rich protein.  Gene deletions may cause false negative tests. Kaaya RD & al. address this situation in Deletions of the Plasmodium falciparum Histidine-Rich Protein 2/3 Genes Are Common in Field Isolates from North-Eastern Tanzania, Sci Rep, 2022 Apr 6; 12(1):5802, doi: 10.1038/S41598-022-09878-3, as do Nundu SS & al. in Low Prevalence of Plasmodium falciparum Parasites Lacking pfhrp2/3 Genes Among Asymptomatic and Symptomatic School-Age Children in Kinshasa, Democratic Republic of Congo, Malaria J, 2022 Apr 19, vol 21 art 126, doi:10.1186/s12936-022-04153.

The diagnosis is particularly difficult when other infections are also present.  Rugarabamu S & al. address this situation in Viral Haemorrhagic Fevers and Malaria Co-Infections Among Febrile Patients Seeking Health Care in Tanzania, Infect Dis Poverty, 2022 Apr 25; 11(1):33, doi: 10.1186/S40249-022-00959-Z. They conclude that “[c]o-infections of VHF and malaria are prevalent in Tanzania and affect more the older than the younger population. Since the overlapping symptoms in co-infected individuals may challenge accurate diagnosis, adequate laboratory diagnosis should be emphasized in the management of febrile illnesses.”

Treatment:

Therapeutic efficacy

Marwa K & al. confirm that current artemisinin combination therapies remain well over 95% effective in uncomplicated falciparum malaria.  Their report is Therapeutic Efficacy of Artemether-Lumefantrine, Artesunate-Amodiaquine and Dihydroartemisinin-Piperaquine in the Treatment of Uncomplicated Plasmodium Falciparum Malaria in Sub-Saharan Africa: A Systematic Review and Meta-Analysis, PLoS One, 2022 Mar 10; 17(3):e0264339. doi: 10.1371/journal.pone.0264339.

Singana BP & al., Prevalence of Malaria Among Febrile Patients and Assessment of Efficacy of Artemether-Lumefantrine and Artesunate-Amodiaquine for Uncomplicated Malaria in Dolisie, Republic of the Congo, Malaria J, 2022 May 2, vol 21 art 137, doi:10.1186/s12936-022-04143-4 is confirmatory of the effectiveness of combination therapy.

At the same time, Koko VS & al., Artesunate–Amodiaquine and Artemether–Lumefantrine for the Treatment of Uncomplicated falciparum Malaria in Liberia: In Vivo Efficacy and Frequency of Molecular Markers, Malaria J, 2022 Apr 27, vol 21 art 134, doi: 10.1186/s12936-022-04140-7 asserts that artesunate-amodiaquine is becoming slightly less effective, without evidence of specific drug resistance by the parasite.

Drug resistance

Kunasol C & al. provide a detailed genetic analysis in Comparative Analysis of Targeted Next-Generation Sequencing for Plasmodium falciparum Drug Resistance Markers, Sci Rep, 2022 Apr 1; 12(1):5563. doi: 10.1038/S41598-022-09474-5.

Zhu L & al., Artemisinin Resistance in the Malaria Parasite, Plasmodium falciparum, Originates From Its Initial Transcriptional Response, Commun Biol, 2022 Mar 28; 5(1):274. doi: 10.1038/S42003-022-03215-0 focuses on the transcription function of the parasite and states that the genetic underpinnings of resistance are likely to be complex.

Case Management

Miller JS & al. studied the adherence of community healthcare workers to published treatment protocols and concluded in Long-Term Quality of Integrated Community Case Management Care for Children in Bugoye Subcounty, Uganda: A Retrospective Observational Study, BMJOpen, 2022 Apr 22; 12(4):E051015. doi: 10.1136/Bmjopen-2021-051015 that compliance was around 74%.

New drug development

New drug development is recommended for treatment of pregnant women infected by malaria by El Gaaloul M & al. in Re-Orienting Anti-Malarial Drug Development to Better Serve Pregnant Women, Malaria J, 2022 Apr 12, vol 21 art 121, doi: 10.1186/s12936-022-04137-2.  Although the abstract does not explicitly mention it, artemisinin drugs are not safe to use in the first trimester, because of potential fetal abnormalities.

Peplow, M chronicles a “trial of the novel ganaplacide/lumefantrine drug combination in Burkina Faso, Gabon, Mali and Niger. The consortium brings together researchers from ten academic organizations across Africa and Europe.”  The article is African Leadership Underpins Success of Malaria Drug Trial, Nature Index, 2022 Mar 9, https://www.nature.com/articles/d41586-022-00573-x.

Another new drug, chronicled in Taft BR & al., Discovery and Preclinical Pharmacology of INE963, a Potent and Fast-Acting Blood-Stage Antimalarial with a High Barrier to Resistance and Potential for Single-Dose Cures in Uncomplicated Malaria, J Med Chem, 2022 Mar 10; 65(5):3798-3813. doi: 10.1021/acs.jmedchem.1c01995 does not have a commercial name yet, but is said to achieve “’artemisinin-like’ kill kinetics in vitro with a parasite clearance time of <24 h.” According to the authors, it is now ready for Phase 1 clinical trials.

Campaigns:

Not really a campaign report, but more a call to action is the apparently unsigned editorial, Malaria in 2022: a Year of Opportunity, Lancet, 2022 23-29 April; 399(10335): 1573, doi: 10.1016/S0140-6736(22)00729-2.

Hosseinpoor AR, Beren N, Kirkby K & al., Monitoring Inequalities is a Key Part of the Efforts to End AIDS, Tuberculosis, and Malaria, Lancet, 2022 26 March-1 April; 399(10331): 1208–1210. Online 2021 Dec 9. doi: 10.1016/S0140-6736(21)02756-2 is a summary of the WHO and The Global Fund to Fight AIDS report, Tuberculosis and Malaria, State of Inequality: HIV, Tuberculosis and Malaria, published in late 2021. “First, the report reveals major deficiencies in the availability of disaggregated data suitable for the monitoring of inequalities in HIV, tuberculosis, and malaria. … Second, the report shows there are widespread inequalities across many aspects of HIV, tuberculosis, and malaria, where data are available, including … care seeking for children with malaria symptoms… Third, the report identifies examples … interventions have successfully prioritised groups with the greatest need through targeted campaigns to achieve faster improvements among disadvantaged subgroups. For instance, several countries reported higher coverage of malaria prevention indicators related to insecticide-treated bednets among the poor, least educated, and rural subgroups, where the malaria burden is concentrated, compared with the richer, more educated, and urban subgroups. The encouraging examples described in the report contain important lessons for developing and scaling equity-oriented approaches to accelerate improvements among disadvantaged populations. Fourth, the report quantifies possibilities for improving national averages by eliminating inequalities. For example, by … eliminating economic-related inequalities in care seeking for children younger than 5 years with fever—an indicator related to malaria testing and treatment—there would be a 26% improvement in the weighted average across 28 countries…”

De-Gaulle VF & al., A Qualitative Assessment of the Health Systems Factors Influencing the Prevention of Malaria in Pregnancy Using Intermittent Preventive Treatment and Insecticide-Treated Nets in Ghana, Malaria J, 2022 Apr 27, vol 21 art 136, doi: 10.1186/s12936-022-04159-w could be a companion article to that of Klu & al., cited above in Prevention.  This article analyzes the unsatisfactory use of preventive measures by pregnant women, despite their increased participation in antenatal care.

Detailed plans for studying the effects of mass drug administration are described in Abdelmenan & al., Evaluation of the Effect of Targeted Mass Drug Administration and Reactive Case Detection on Malaria Transmission and Elimination in Eastern Hararghe Zone, Oromia, Ethiopia: A Cluster Randomized Control Trial, Trials, 2022 Apr 7; 23(1):267, doi: 10.1186/S13063-022-06199-8.

Results of another mass drug administration trial, in Zambia, showed 46% greater decrease in the incidence of malaria than in a comparison area, as reported by Fraser M & al. in Evaluating the Impact of Programmatic Mass Drug Administration for Malaria in Zambia Using Routine Incidence Data, J Infect Dis, 2022 Apr 19; 225(8):1415-1423, doi: 10.1093/infdis/jiaa434.

Yet another mass drug administration trial is described by, Dabira ED & al., Mass Drug Administration of Ivermectin and Dihydroartemisinin-Piperaquine Against Malaria in Settings with High Coverage of Standard Control Interventions: A Cluster-Randomised Controlled Trial in The Gambia, Lancet Infect Dis, 2022 Apr; 22(4):519-528. doi: 10.1016/S1473-3099(21)00557-0. This trial was different in that it also administered ivermectin, as an endectocide.  While the incidence of malaria was much reduced in the treated versus control area, it is unclear whether the addition of ivermectin to the antimalarials made a difference.

Chi PC & al., Ethical Considerations Around Volunteer Payments in a Malaria Human Infection Study in Kenya: An Embedded Empirical Ethics Study, BMC Med Ethics, 2022 Apr 20; 23(1):46, doi: 10.1186/ S12910-022-00783-Y is only tenuously connected to the topic of “Campaigns.” Nonetheless it is an important issue relating to whether a planned study should be supported.  Therefore it is reported here. Interestingly, [s]tudy volunteers were generally clear about the study aims at the point of recruitment, and this knowledge was retained over a year later, although most reported experiencing more burdens than anticipated at enrolment. Strict study screening procedures … suggested that the risks of serious harm were highly unlikely. Ethical concerns emerged in relation to volunteers’ attempts to conceal symptoms, hoping to prolong residency periods and increase study payments; and volunteers making decisions that compromised important family relationships and personal values.”   

Epidemiology:

Zhao Y & al. discuss how to obtain critical information for large scale epidemiological studies in A Direct, Sensitive and High-Throughput Genus and Species-Specific Molecular Assay for Large-Scale Malaria Screening, Infect Dis Poverty, 2022 Mar 7; 11(1):25, doi: 10.1186/S40249-022-00948-2.

Two papers report on malaria epidemiology in the Oromia region of Ethiopia: Tefera S & al., The Changing Malaria Trend and Control Efforts in Oromia Special Zone, Amhara Regional State, North-East Ethiopia, Malaria J, 2022 Apr 22, vol 21 art 128, doi: 10.1186/s12936-022-04149-y, which showed that while P. falciparum incidence decreased during the study period, the same was not true for P. vivax incidence. No reason has been found for this discrepancy. In response to a former report that tied changes in malaria incidence to climate change, Krsulovic FAM & al. assert in Epidemic Malaria Dynamics in Ethiopia: The Role of Self-Limiting, Poverty, HIV, Climate Change and Human Population Growth, Malaria J, 2022 Apr 27, vol 21 art 135, doi: 10.1186/s12936-022-04161-2 that many other factors may play a role and climate change cannot be reliably identified as a cause of change by itself.

Two other papers report on possible connection between climate factors and the incidence of malaria. Panzi EK & al., Geo-Climatic Factors of Malaria Morbidity in the Democratic Republic of Congo from 2001 to 2019, Int J Environ Res Public Health, 2022 Mar 23; 19(7):3811, doi: 10.3390/ijerph19073811 claims to show in an area where the rate of malaria infections rose “that the average number of malaria cases increased positively as a function of the average number of rainy days, the total quantity of rainfall and the average daily temperature.”  On a more global scale, Carlson CJ & al. “project how geoengineering could impact malaria risk by comparing current transmission suitability and populations-at-risk under moderate and high greenhouse gas emissions scenarios” in Solar Geoengineering Could Redistribute Malaria Risk in Developing Countries, Nature Communications, 2022 Apr 20, vol 13, art 2150. https://www.nature.com/articles/s41467-022-29613-w and conclude that “geoengineering strategies designed to offset warming are not guaranteed to unilaterally improve health outcomes, and could produce regional trade-offs among Global South countries…”

Bihoun B & al., Age-Modified Factors Associated with Placental Malaria in Rural Burkina Faso, BMC Pregnancy Childbirth, 2022 Mar 24; 22(1):248. doi: 10.1186/S12884-022-04568-4 reports on a variety of age-related (under 30 vs. over 30) factors associated with placental malaria, which was found to be present in over 80% of pregnant women who had Plasmodium in their peripheral blood. There was little, if any consistency in the findings.

Odeyemi AO & al. studied febrile children admitted to a single Nigerian hospital and reported in Malaria Parasitaemia and its Associated Factors Among Febrile Children in a Tertiary Hospital in Southwest Nigeria, West Afr J Med, 2022 Mar 30; 39(3):214-319 that 70% of these children tested positive for P. falciparum. While the history of having slept under LLIN was significantly associated with negative tests for the malaria parasite, other factors, such as maternal education, etc., were not.

Altahir O & al., Blood Meal Profile and Positivity Rate with Malaria Parasites Among Different Malaria Vectors in Sudan, Malaria J, 2022 Apr 15, vol 21 art 122, doi: 10.1186/s12936-022-04157-y identifies that only one of three of Anopheles species that are common in the study area were positive for Plasmodium, even though all three species fed on humas as well as several animal species.