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

Here is the last set of publications on which we report this year.  There will of course be other papers yet from 2021 to report.  Happy Holidays to all.

Prevention:

More work on various vaccines is being reported every month, this past one being no exception.  Even though the WHO has now approved the use of the RTS,S vaccine, other candidates for eventual distribution are also being investigated.  One such alternate is the PfSPZ Vaccine, a metabolically active, non-replicating, whole malaria sporozoite vaccine.  In a Phase 1 clinical trial in Mali, Sissoko MS & al. administered the three doses of the vaccine in various concentrations to adult non-pregnant volunteers.  The report in Safety and Efficacy of a Three-Dose Regimen of Plasmodium falciparum Sporozoite Vaccine in Adults During an Intense Malaria Transmission Season in Mali: A Randomised, Controlled Phase 1 Trial, Lancet Inf Dis, 2021 Nov 18, doi.org/10.1016/S1473-3099(21)00332-7 that the vaccine was “safe, well tolerated, and conferred 51% vaccine efficacy against intense natural P falciparum transmission…” The duration of surveillance in this study was 24 months.  In the same publication, Daubenberger C, Assessment of Experimental Malaria Vaccine-Induced Protection in pre-Exposed Populations, Lancet Inf Dis, 2021 Nov 18, doi.org/10.1016/S1473-309(21)00359-5 focuses on the same vaccine, while acknowledging the work done on others as well.

Mohamed NS & al. state that “[t]he currently used malaria vaccine, RTS,S, is designed based on the Plasmodium falciparum circumsporozoite protein (PfCSP). The pfcsp gene, besides having different polymorphic patterns, can vary between P. falciparum isolates …”  Their study, Assessment of Genetic Diversity of Plasmodium falciparum Circumsporozoite Protein in Sudan: The RTS,S Leading Malaria Vaccine Candidate, Malaria J, 2021 Nov 10, vol 20, art 436.  https://malariajournal.biomedcentral.com/ articles/10.1186/s12936-021-03971-0 “assessed the genetic diversity of P. falciparum in Sudan based on the pfcsp gene by investigating the diversity at the N-terminal, central repeat, and the C-terminal regions… the results indicated a high conservation at the pfcsp gene,” presumably indicating that I the region studies, the vaccine should be effective..

Mugo RM & al., Seven-Year Kinetics of RTS, S/AS01-Induced Anti-CSP Antibodies in Young Kenyan Children, Malaria J, 2021 Dec 2, vol 20 art 452.  https://malariajournal.biomedcentral.com/ articles/10.1186/s12936-021-03961-2 is a very recent publication of a long term study.  The authors found “high levels of anti-CSP IgG antibodies which exhibited a rapid waning over 6.5 months post-vaccination, followed by a slower decay over the subsequent years. RTS,S/AS01-induced anti-CSP IgG antibodies remained elevated above the control group levels throughout the 7 years follow-up period… Natural exposure induces anti-CSP IgM antibodies in children, which increases with age, but does not induce substantial levels of anti-CSP IgG antibodies.” The persistence of IgG antibodies is an indicator of residual protection of a degree against infection.

Based on experience with the RTS.S/A501 vaccine so far, Unwin HJT, & al., Analysis of the Potential for a Malaria Vaccine to Reduce Gaps in Malaria Intervention Coverage, Malaria J, 2021 Nov 17, vol 20 art 238. https://malariajournal.biomedcentral.com/articles/10.1186/s12936-021-03966-x extrapolate the benefit of the vaccine by using data on diphtheria-tetanus-pertussis (DTP3) vaccination and insecticide treated nets (ITNs).  They conclude that vaccinating  “those 23 million children who receive DTP3 but do not use an ITN could avert up to an estimated 9.7 million (range 8.5–10.8 million) clinical malaria cases each year, assuming all children who receive DTP3 are administered all four RTS,S doses. An additional 10.8 million (9.5–12.0 million) cases could be averted by vaccinating those 24 million children who receive the DTP3 vaccine and use an ITN.”   Galactionova K & al., Insights from Modelling Malaria Vaccines for Policy Decisions: The Focus on RTS,S, Malaria J, 2021 Nov 18, vol 20 art 239. https://malariajournal.biomedcentral.com/articles/10.1186/s12936-021-03973-y is a review of the modeling process, focusing on “its link to the development of policy guidance for the first licensed product, RTS,S/AS01. The main contributions of modelling studies have been in inferring the mechanism of action and efficacy profile of RTS,S; to predicting the public health impact; and economic modelling mainly comprising cost-effectiveness analysis.”

As before, malaria in pregnancy is of major concern.  Mahamar I & al. looked at pregnancy outcomes for women who had intermittent preventive treatment with sulfadoxine-pyrimethamine (IPTp-SP) as well as prompt treatment regardless of symptoms given upon malaria diagnosis using microscopy and polymerase chain reaction (PCR) analysis.  Their report, Malaria Infection Is Common and Associated With Perinatal Mortality and Preterm Delivery Despite Widespread Use of Chemoprevention in Mali: An Observational Study 2010 to 2014, Clin Infect Dis, 2021 Oct 20;73(8):1355-1361.  doi: 10.1093/cid/ciab301.  Likewise, Mlugu EM & al. in Tanzania were concerned about the inadequacy of IPTp-SP prevention and used and alternate regime.  They “investigated the effectiveness of intermittent preventive treatment in pregnancy with monthly dihydroartemisinin-piperaquine (IPTp-DHP) as an alternative option” and report in Effectiveness of Intermittent Preventive Treatment With Dihydroartemisinin-Piperaqunine Against Malaria in Pregnancy in Tanzania: A Randomized Controlled Trial, Clin Pharmacol Ther, 2021 Dec;110(6):1478-1489. doi: 10.1002/cpt.2273 that the incidence [of] symptomatic-malaria … and parasitemia during pregnancy … were significantly lower in the IPTp-DHP group than in the IPTp-SP group. [Also, while the] prevalence of any adverse birth outcomes (composite) was not significantly …different between IPTp-DHP … and IPTp-SP …, the prevalence of [low birth weight] LBW … was significantly lower in IPTp-DHP compared with IPTp-SP.” They conclude “superior protective efficacy of monthly IPTp-DHP against malaria in pregnancy and LBW than IPTp-SP.”

Wallender E & al., Identifying an Optimal Dihydroartemisinin-Piperaquine Dosing Regimen for Malaria Prevention in Young Ugandan Children, Nature Comm, 2021 Nov 18, vol 12 art 6714. www.nature.com/  articles/s41467-021-27051-8 recommends dosing infants and children aged 2 to 24 months every 4 weeks with this combination, for 95% reduction of malaria hazard.

Two studies on prevention originated from Ghana.  Ansah PO & al., Evaluation of Pilot Implementation of Seasonal Malaria Chemoprevention on Morbidity in Young Children in Northern Sahelian Ghana Malaria J, 2021 Nov 18, vol 20 art 440. https://malariajournal.biomedcentral.com/articles/ 10.1186/ s12936-021-03974-x report success with chemoprevention, using “sulfadoxine-pyrimethamine plus amodiaquine and standard WHO protocols. Before and after surveys for malaria parasitaemia and haemoglobin levels as well as monitoring for malaria morbidity and mortality were undertaken.” The results document “high study retention, reduction in malaria parasitaemia and anaemia during the wet season.”  Elsewhere, Orish VN & al. report high ownership of insecticide treated nets, “but relatively low utilization among the community members.”  Their publication is Assessing Health-Seeking Behaviour and Malaria Prevention Practices Among Communities in Four Districts of the Volta Region of Ghana, Malaria J, 2021 Nov 27, vol 20, art 450. https://malariajournal.biomedcentral.com/articles/10.1186/ s12936-021-03986-7

Yaro JB & al., Risk Factors Associated with House Entry of Malaria Vectors in an Area of Burkina Faso With High, Persistent Malaria Transmission and High Insecticide Resistance, Malaria J, 2021 Oct 10, vol 20, art 397. https://malariajournal.biomedcentral.com/articles/10.1186/s12936-021-03926-5 covers a different aspect of malaria prevention. They relied on the count of Anopheles mosquitoes caught within certain types of buildings in Burkina Faso. They report that the mosquito count was 45% lower in sleeping spaces with a metal roof, compared to those with thatch roofs.

Diagnosis:

Similar to results already reported, Mischlinger J & al, Predictive Performance of Rapid Diagnostic Tests for Falciparum Malaria and Its Modeled Impact on Integrated Community Case Management of Malaria in Sub-Saharan African Febrile Children, Clin Infect Dis, 2021 Sep 7;73(5):e1158-e1167.  doi: 10.1093/cid/ciaa1942 document significant variability in the reliability of rapid diagnostic tests in various Sub-Saharan countries, with discrepancies as wide as between 17% and 95% positive predictive value in one assay and somewhat less dramatic but nonetheless significant discrepancy in another.

Kigozi RN & al., Determinants of Malaria Testing at Health Facilities: The Case of Uganda, Malaria J, 2021 Dec 4, vol 20, art 456.  malariajournal.biomedcentral.com/articles/10.1186/s12936-021-03992-9  is another article concerning rapid diagnostic tests.  However, it appears to be simply descriptive statistics on its use in hospitals, without reference to reliability.

No diagnostic tests are of much value if they are not used properly.  Omale UI, Knowledge, Attitude, and Practice of the National Guidelines for Diagnosis and Treatment of Malaria Among Medical Doctors in Ebonyi State, Nigeria: A Cross-Sectional Survey, PLoS One, 2021 Sep 20;16(9):e0257600.  doi: 10.1371/journal.pone.0257600 reports that in one state in Nigeria, only slightly over one third of medical doctors complied with national diagnostic and treatment guidelines for malaria, despite the fact that the large majority of them were familiar with the guidelines.

Tamomh AG and ElKhalifa AME assessed the effect of malaria infection in the hematological parameters of Sudanese population. They report in Artificial Neural Network as a Tool for Appraising Hematological Parameters in Sudanese Patients with Malaria, Clin Lab, 2021 Sep 1;67(9). doi: 10.7754/Clin.Lab.2021.201141 that packed cell volume (PCV, or hematocrit) abnormality may lead to earlier diagnosis of malaria.

It appears that there remains a lack of “reliable diagnostic biomarkers for the identification of disease severity, especially in endemic areas where the diagnosis of cerebral malaria is very difficult and requires the exclusion of all other possible causes, according to Omar M & al., Host Blood Gene Signatures Can Detect the Progression to Severe and Cerebral Malaria, Front Cell Infect Microbiol, 2021 Oct 22;11:743616.  doi: 10.3389/fcimb.2021.743616. They state that they “identified 28-gene and 32-gene signatures that can reliably distinguish severe and cerebral malaria, respectively.” 

Treatment:

The threat of emergence of artemisinin-resistant parasites has led to a number of articles, some among them relevant to the African continent. One of these is Owoloye A & al., Prevalence of Potential Mediators of Artemisinin Resistance in African Isolates of Plasmodium falciparum Malaria J, 2021 Dec 2 Vol 20 art 451. https://malariajournal.biomedcentral.com/articles/10.1186/s12936-021-03987-6.  Through a meta-analysis of reports on over 37,000 P. falciparum isolates, they identified a number of genetic mutations in areas of the parasite genome known to be associated with resistance. The origins of these were widespread on the continent.  Further, Pommier de Santi V & al. state that they “document resistance of Plasmodium falciparum to dihydroartemisinin/piperaquine” in Role of Anopheles stephensi Mosquitoes in Malaria Outbreak, Djibouti, 2019, Emerg Infect Dis, 2021; 27(6):1697-1700.  doi: 10.3201/eid2706.204557.  On the other hand, Ikegbunam M & al. found an Absence of Plasmodium falciparum Artemisinin Resistance Gene Mutations Eleven Years After the Adoption Of Artemisinin-Based Combination Therapy in Nigeria, Malaria J, 2021 Nov 10, vol 20 art 434.  https://malariajournal.biomedcentral.com/articles/10.1186/s12936-021-03968-9.

In view of the potential emergence of artemisinin resistance, the discovery of new antiparasitic agents is good news.  The fungus Strasseria geniculata {a fungus widely reported in Europe, but rare elsewhere, DP} elaborates strasseriolides A-D compounds, which are macrolides {related to erythromycin DP} and apparently effective against Plasmodium species in the laboratory. Annang F & al., Preclinical Evaluation of Strasseriolides A–D, Potent Antiplasmodial Macrolides Isolated from Strasseria geniculata CF-247,251, Malaria J, 2021 Dec 5, vol 20, art 457. malariajournal.biomedcentral.com/articles/ 10.1186/s12936-021-03993-8 found on testing with mice that one of these antibiotics, Strasseriolide D is non-toxic, is apparently free of drug-drig interactions, and lowers parasitemia levels. 

Shah MP & al. searched the literature to assess the sustained effect of mass drug administration with antimalarial drugs on the reduction in malaria transmission in moderate- to high-transmission settings and the interruption of transmission in very low- to low-transmission settings. In their report, Mass Drug Administration for Malaria, Cochrane Database Syst Rev, 2021 Sep 29;9(9):CD008846.  doi: 10.1002/14651858.CD008846.pub3, their discouraging conclusion states: “In moderate- to high-transmission settings, no studies reported important effects on P falciparum parasitaemia prevalence within six months after MDA. In very low- to low-transmission settings, parasitaemia prevalence and incidence were reduced initially for up to three months for both P falciparum and P vivax; longer-term data did not demonstrate an effect after four months, but absolute risks in both intervention and control groups were low. No studies provided evidence of interruption of malaria transmission.”

Ashraf S & al., REAP (Rapid Elimination of Active Plasmodium): A Photodynamic Strategy Exploiting Intrinsic Kinetics of the Parasite to Combat Severe Malaria, J Photochem Photobiol B, 2021 Oct; 223:112286.  doi: 10.1016/j.jphotobiol.2021.112286 reports on a “light-based photochemical approach, Photodynamic Therapy (PDT) built on delta-aminolevulinic acid-protoporphyrin IX (ALA-PpIX) synthesis … This modality was effective at destruction of both resistant and susceptible strains of parasites, including at a high load mimicking severe drug resistant malaria.”  Whether this approach is feasible in areas of Africa at risk is not addressed in the abstract.

The reutilization of an old standby is the topic of Asare KK al., The Emergence of Chloroquine-Sensitive Plasmodium falciparum is Influenced by Selected Communities in Some Parts of the Central Region of Ghana, Malaria J, 2021 Nov 25, vol 20 art 447. https://malariajournal.biomedcentral.com/ articles/10.1186/s12936-021-03985-8. They state that they found a high incidence of genetic markers of chloroquine sensitivity in parasites isolated in the regions they studied. 

Campaigns:

Two papers on this subject come from Ethiopia.

Abamecha F & al., Acceptability of Peer Learning and Education Approach on Malaria Prevention (PLEA-Malaria) Through Primary Schools Communities in Rural Ethiopia: Peer Educators’ Perspectives, Malaria J, 2021 Nov 17 vol 20 art 437.  malariajournal.biomedcentral.com/articles/10.1186/s12936-021-03965-y was a process evaluation study, “aimed to examine the success of the school-based PLEA-malaria that was implemented in 75 primary schools in Jimma from 2017 to 2019. A mixed research method was employed to collect post-intervention data from 404 peer educators and key stakeholders. Data were collected using a structured questionnaire and interview guide… The results [imply that] the strategy is promising in promoting malaria prevention in primary schools.”

 Aliye M & Hong T, Role of Health Extension Workers in the Relationship Between Vector Control Interventions and Malaria in Ethiopia, BMC Infect Dis, 2021 Nov 8;21(1):1140.  doi: 10.1186/s12879-021-06040-8. The abstract of this paper is difficult to decipher but implies that the combined use of insecticide treated nets and indoor residual spraying, which is known to reduce the incidence of malaria, is more likely if these workers (whose qualifications are not defined) are involved in the campaign.

Murindahabi MM & al.  implemented a 1-year citizen science program for malaria mosquito surveillance in five villages of Rwanda. “In total, 112 volunteer citizens were enrolled and reported monthly data on mosquitoes collected in their peridomestic environment using handmade carbon-dioxide baited traps.” Their report, Citizen Science for Monitoring the Spatial and Temporal Dynamics of Malaria Vectors in Relation to Environmental Risk Factors in Ruhuha, Rwanda, Malaria J, 2021 Dec 3, vol 20, art 453 https://malariajournal.biomedcentral.com/articles/10.1186/s12936-021-03989-4, concludes that a “citizen science approach can contribute to mosquito monitoring, and can help to identify areas that, in view of limited resources for control, are at higher risk of malaria.”

Epidemiology:

Five cross-sectional surveys were conducted at the end of the peak transmission season (August-September) on 4892 school children aged between 6 and 14 years in two distinct ecological settings in Ghana between 2013 and 2017 by Mensah BA & al. The children were screened for malaria parasites by microscopic examination of Giemsa-stained thin and thick blood films. The results, reported in Prevalence and Risk Factors Associated with Asymptomatic Malaria Among School Children: Repeated Cross-Sectional Surveys of School Children in Two Ecological Zones in Ghana, BMC Public Health, 2021 Sep 17;21(1):1697.  doi: 10.1186/s12889-021-11714-8 show that there “is a considerable burden of asymptomatic malaria in the two regions of Ghana, which is associated with males, older children, anaemia, and stunted growth in children…”

Basic Research:

Fleck K & al.,“Reading” a New Chapter in Protozoan Parasite Transcriptional Regulation, PLoS Pathogens, 2021 Dec 2, https://doi.org/10.1371/journal.ppat.1010056

Flores-Garcia Y & al., The P. falciparum CSP Repeat Region Contains Three Distinct Epitopes Required for Protection by Antibodies In Vivo, PLoS Pathogens, 2021 Nov 8; https://doi.org/10.1371/ journal.ppat.1010042

Hedberg P & al., Red Blood Cell Blood Group A Antigen Level Affects the Ability of Heparin And Pfemp1 Antibodies to Disrupt Plasmodium falciparum Rosettes Malaria J 2021 Nov 18, vol 20 art 441. https://malariajournal.biomedcentral.com/articles/10.1186/s12936-021-03975-w

Inbar E & al., Knockout of Anopheles stephensi Immune Gene LRIM1 by CRISPR-Cas9 Reveals Its Unexpected Role in Reproduction and Vector Competence, PLoS Pathogens, 2021 Nov 16, https://doi.org/10.1371/journal.ppat.1009770

Little TS & al., Analysis of pir Gene Expression Across the Plasmodium Life Cycle, Malaria J, 2021 Nov 25 vol 20 art 445. https://malariajournal.biomedcentral.com/articles/10.1186/s12936-021-03979-6

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.

Opadokun T & Rohrbach P, Extracellular Vesicles in Malaria: An Agglomeration of Two Decades of Research, Malaria J, 2021 Nov 20, Vol 20 art 442.  malariajournal.biomedcentral.com/articles/ 10.1186/s12936-021-03969-8