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By Dr. Derick Pasternak, Ambassador, Malaria Science & Research Coordinator, MPI

On 25 October, Lancet Global Health published world-wide data about mortality in 2021 of infants and children under 5 and children and adolescents aged 5 to 19 years (see more complete citation below). Of the 5.1 million deaths of the under 5 group, 8.8% were attributed to malaria. Of the older group’s 1.4 million deaths, malaria was said to cause 6.1%.

On 22 November, a joint press release by Gavi (the Vaccine Alliance), WHO, and UNICEF highlighted the following:

  • More than 330 000 doses of WHO-recommended RTS,S malaria vaccine arrived last night in Cameroon – a historic step towards broader vaccination against one of the deadliest diseases for African children
  • Malaria burden is the highest on the African continent, which accounted for approximately 95% of global malaria cases and 96% of related deaths in 2021
  • With several African countries now finalizing roll-out plans, an additional 1.7 million doses are set for delivery to Burkina Faso, Liberia, Niger and Sierra Leone in the coming weeks
  • These shipments signal that malaria vaccination is moving out of its pilot phase, and lay the groundwork for countries to begin vaccinations through Gavi-supported routine immunization programmes in Q1 2024

PEER REVIEWED ARTICLES

Prevention

Vaccines

“To investigate a reduced immune response to vaccination as a potential mechanism behind lower efficacy in high transmission areas, [Bell GJ & al. examined] initial vaccine antibody (anti-CSP IgG) response and vaccine efficacy against the first case of malaria (to exclude the effect of naturally acquired immunity) using data from three study areas ([in Ghana, Malawi, and Gabon]) from the 2009-2014 phase III trial.” Finding “that antibody responses to the primary three-dose vaccination series were higher in Ghana than in Malawi and Gabon, but that neither antibody levels nor vaccine efficacy against the first case of malaria varied by background incidence or parasitemia during the primary vaccination series,” the authors conclude “that vaccine efficacy is unrelated to infections during vaccination. Contributing to a conflicting literature, [their] results suggest that vaccine efficacy is also unrelated to infections before vaccination, meaning that control-group immunity is likely a major reason for lower efficacy in high transmission settings, not reduced immune responses to RTS,S/AS01.” The paper is    Background Malaria Incidence and Parasitemia During the Three-Dose RTS,S/AS01 Vaccination Series Do Not Reduce Magnitude of Antibody Response nor Efficacy Against the First Case of Malaria, BMC Infect Dis. 2023 Oct 23; 23(1):716, https://doi.org/10.1186/s12879-023-08699-7.

Looking forward to the time when the RTS,S vaccine is more widely available, Ajayi MY & Emeto DC, Awareness and Acceptability of Malaria Vaccine Among Caregivers of Under-5 Children in Northern Nigeria, Malaria J, 2023 Oct 31, 22:329, https://doi.org/10.1186/s12936-023-04768-z is a report of interviews conducted with 504 caregivers of children under age five in four Northern Nigerian States.  While awareness of the existence of the vaccine was “only” 40.3%, well over 90% of those queried signaled acceptability.  It is unstated whether the 40-item questionnaire included reference to the need for multiple injections over a prolonged period.  The authors list factors that predisposed to acceptability and mentioned reasons for reluctance to accept the vaccine.  They recommend further information to acquaint parents with the anticipated availability of the vaccine in the country.

Hamilton A & al. present a “compartmental model estimating cases, drug-resistant cases, and deaths averted from 2021 to 2030 with a vaccine against Plasmodium falciparum infectionn administered yearly to 1-year-olds in 42 African countries. Three vaccine efficacy (VE) scenarios and one scenario of rapidly increasing drug resistance are modeled.” In all scenarios modeled, “deployment of a malaria vaccine could substantially reduce health burden in Africa. Maintaining VE longer may be more impactful than a higher initial VE that falls rapidly.” The paper is Modeling of Malaria Vaccine Effectiveness on Disease Burden and Drug Resistance in 42 African Countries, Commun Med (Lond). 2023 Oct 13; 3(1):144, https://doi.org/10.1038/s43856-023-00373-y.

Trial of a different vaccine is described by Ouédraogo A & al. in Safety and Immunogenicity of BK-SE36/CpG Malaria Vaccine in Healthy Burkinabe Adults and Children: A Phase 1b Randomised, Controlled, Double-Blinded, Age De-Escalation Trial, Front Immunol. 2023 Oct 16; 14:1267372, https://doi.org/10.3389/fimmu.2023.1267372. “BK-SE36/CpG is a recombinant blood-stage malaria vaccine candidate based on the N-terminal Plasmodium falciparumserine repeat antigen5 (SE36…” It was administered in a series of three doses to three groups of individuals, based on age (young children, older children, adults). The authors conclude that in each group, “BK-SE36/CpG was well-tolerated and immunogenic.”

Okoth WA & al., A CAF01-Adjuvanted Whole Asexual Blood-Stage Liposomal Malaria Vaccine Induces a CD4+ T-Cell-Dependent Strain-Transcending Protective Immunity in Rodent Models, mBio. 2023 Nov 14: e0254723, https://doi.org/10.1128/mbio.02547-23 is yet another vaccine-research based article.  It focused on the rodent model and is basic science oriented.

Borkens Y, Malaria & mRNA Vaccines: A Possible Salvation from One of the Most Relevant Infectious Diseases of the Global South, Acta Parasitol. 2023 Oct 12, https://doi.org/10.1007/s11686-023-00712-y is a somewhat speculative article about the effect of the newest change in vaccine development may affect the fight against malaria. “Many pharmaceutical companies (including the German companies BioNTech and CureVac) have already confirmed that they are researching mRNA vaccines against malaria. However, this is not an easy task.”

“Malaria transmission-blocking vaccines target mosquito-stage parasites and will support elimination programmes. Gamete vaccine Pfs230D1-EPA/Alhydrogel induced superior activity to zygote vaccine Pfs25-EPA/Alhydrogel in malaria-naive US adults.” As reported by Sagara I & al. in Malaria Transmission-Blocking Vaccines Pfs230D1-EPA and Pfs25-EPA in Alhydrogel in Healthy Malian Adults; A Phase 1, Randomised, Controlled Trial, Lancet Infect Dis.2023 Nov; 23(11):1266-1279, https://doi.org/10.1016/s1473-3099(23)00276-1, the authors “compared these vaccines in malaria-experienced Malians.” After an elaborate double-blind volunteer-based experiment they concluded that “Pfs230D1 but not Pfs25 vaccine induces durable serum functional activity in Malian adults. Direct skin feed assays detect parasite transmission to mosquitoes but increased event rates are needed to assess vaccine effectiveness.” This seems to indicate questionable efficacy even for Pfs230D1.

Vector control and protection from vectors

“In 2018, the Rwandan malaria program strategic approach included the use of newer types of ITNs such as pyrethroid plus piperonyl butoxide (PBO) synergist-treated nets to counter pyrethroid resistance.” Kabera M & al. report on, Impact of Pyrethroid Plus Piperonyl Butoxide {PBO} Synergist-Treated Nets on Malaria Incidence 24 Months after a National Distribution Campaign in Rwanda, in Am J Trop Med Hyg. 2023 Oct 23: tpmd230317, https://doi.org/10.4269/ajtmh.23-0317. Some districts distributed only standard pyrethroid impregnated nets, others handed out nets pyrethroid plus PBO treated nets. “One year after net distribution, all districts had a significant reduction in malaria incidence rate (incidence rate ratio < 1). In the second year, incidence in districts with PBO nets continued to decrease, whereas in districts with standard nets, incidences were similar to predistribution levels.” The Rotarian who will be managing a recently awarded MPI small grant in Rwanda is a coauthor of this paper.

No matter what the mosquito nets are treated with, they cannot protect people if they are not used. Terefe B & al. report the bad news in Insecticide-Treated Net Utilization and Associated Factors Among Pregnant Women in East Africa: Evidence from the Recent National Demographic and Health Surveys, 2011–2022, Malaria J, 2023 Nov 14, 22:349, https://doi.org/10.1186/s12936-023-04779-w. base on the “most recent DHS (Demographic and Health Survey) data for the 11 East African countries from 2011 to 2022, … 13,729 pregnant women were examined… The survey found that just 47.05% (95% CI 46.21, 47.88) of pregnant mothers reported using ITNs. The highest and lowest values were seen in Uganda (64.13%) and Zimbabwe (6.08%).” On further analysis the authors conclude that “[w]ith a variety of risk variables, including age, wealth, family size, and education, pregnant women in East Africa rarely use ITNs. There is a need to create and strengthen malaria prevention programmes, especially among pregnant women who do not use ITNs, based on the variables mentioned.”

Likewise, according to Hunde OY & al., Assessment of Long-Lasting Insecticide Nets Coverage, Utilization, and Associated Factors Among Households in Malaria Elimination Districts of Arsi Zone, Oromia Region, Ethiopia: A Cross-Sectional Study, PLoS One. 2023 Nov 2; 18(11):e0293728.

https://doi.org/10.1371/journal.pone.0293728 among 1250 households surveyed over five districts, 99.5% (!) owned insecticide impregnated nets, but fewer than 30% actually used them the night before they were queried. The remedies to this doleful information they propose are “intensified health education activities.”

Acford-Palmer H & al. “developed an amplicon sequencing (“Amp-seq”) approach targeting An. funestus, and using multiplex PCR, dual index barcoding, and next-generation sequencing…[and] screened 80 An. funestus field isolates from the DRC across a panel of nine genes with mutations linked to insecticide resistance.” In their paper, Detection of Insecticide Resistance Markers in Anopheles funestus from the Democratic Republic of the Congo Using a Targeted Amplicon Sequencing Panel, Sci Rep. 2023 Oct 13; 13(1):17363, https://doi.org/10.1038/s41598-023-44457-0, they state that their “panel represents an extendable and much-needed method for the molecular surveillance of insecticide resistance in An. funestus populations.”

Similarly, Natchema S & al., Entomological Longitudinal Surveys in Two Contrasted Eco-Climatic Settings in Cameroon Reveal a High Malaria Transmission from Anopheles funestus Associated with GSTe2 Metabolic Resistance, BMC Infect Dis. 2023 Oct 28; 23(1):738, https://doi.org/10.1186/s12879-023-08698-8 reports on the mechanism of resistance of the same species of mosquito in two regions of Cameroon.  They found that An. funestusthat carried the so-called “GSTe2 metabolic resistance,” which is gene based, were more likely to transmit malaria than those of the species that did not carry the gene.

“Indoor residual spraying {IRS} has been a key national malaria prevention and control strategy in Ethiopia.” Amanuel M & al., House-Wall Modification After Indoor Residual Spraying in Shashogo District, Southern Ethiopia, Malaria J, 2023 Oct 31, 22:328, https://doi.org/ 10.1186/s12936-023-04759-0 explored the rate at which house walls were then modified before the potency of the insecticide faded and found that this occurred in 30.4% of situations monitored. They list several risk factors for this happening.

“Indoor residual spraying (IRS) is a common vector control strategy in countries with high malaria burden. Historically, social norms have prevented women from working in IRS programmes. The Bioko Island Malaria Elimination Project has actively sought to reduce gender inequality in malaria control operations for many years by promoting women’s participation in IRS.” DeBoer KR & al., Assessing IRS Performance in a Gender-Integrated Vector Control Programme on Bioko Island, Equatorial Guinea, 2010–2021, Malaria J, 2023 Oct 25, 22:323 https://doi.org/10.1186/s12936-023-04755-4 is report of a study that “investigated the progress of female engagement and compared spray productivity by gender from 2010 to 2021, using inferential tests and multivariable regression. Spray productivity was measured…” and found that “quantitative analyses of spray productivity are counter to stigmatizing beliefs that women are less capable than male counterparts during IRS spray rounds.”

Nzioki I & al. “assessed the biting patterns of potentially infectious malaria vectors at various hours, locations, and associated human behaviors in different ecological settings in western Kenya.” After sampling mosquitoes from 19:00 to 07:00 for four consecutive nights in four houses per village studied, they report in Differences in Malaria Vector Biting Behavior and Changing Vulnerability to Malaria Transmission in Contrasting Ecosystems of Western Kenya, Parasit Vectors. 2023 Oct 21; 16(1):376, https://doi.org/10.1186/s13071-023-05944-5 that “peak biting occurred in early morning between 04:30 and 06:30 in the lowlands for An. funestus both indoors and outdoors. In the highlands, the peak biting of An. gambiae occurred between 01:00 and 02:00 indoors.”

“Attractive targeted sugar bait (ATSB) is a novel approach to vector control, offering an alternative mode of insecticide delivery via the insect alimentary canal, with potential to deliver a variety of compounds… The pyrrole chlorfenapyr is an insecticide new to malaria vector control.” N’Guessan R & al., Attractive targeted sugar bait: the pyrrole insecticide chlorfenapyr and the anti-malarial pharmaceutical artemether–lumefantrine arrest Plasmodium falciparumdevelopment inside wild pyrethroid-resistant Anopheles gambiae s.s. mosquitoes, Malaria J 2023 Nov 9, 22:344, https://doi.org/10.1186/s12936-023-04758-1 demonstrates that under laboratory conditions, chlorphenapyr, “in addition to its direct killing effect on the vector, has the capacity to block Plasmodium transmission by interfering with oocyte development inside pyrethroid-resistant mosquitoes, and through this dual action may potentiate its impact under field conditions.”

Two articles deal with the approach of autodissemination of pyripoxifen. “Pyriproxyfen (PPF), is a juvenile hormone analogue (JHA) that interferes with the mosquito metamorphosis process, preventing the emergence of adult mosquitoes. Pyriproxyfen presents desirable characteristics of insecticides either for both convectional larviciding and the auto-dissemination approach… The autodissemination approach relies on adult mosquitoes exposed to contaminated resting sites to disperse the picked insecticide to larval breeding habitats and disrupt normal mosquito developmental processes.” Tarimo FS & al., Community Perception of the Autodissemination of Pyriproxyfen for Controlling Malaria Vectors in South-Eastern Tanzania, Malaria J, 2023 Nov 3, 22:333, https://doi.org/10.1186/s12936-023-04773-2 describes community reaction to the possibility of applying PPF in this manner.  Results showed poor familiarity with the process but very high (over 90%) acceptability once the process, including its potential risks, was explained. In a more general article, Current and Future Opportunities of Autodissemination of Pyriproxyfen Approach of Malaria Vector Control in Urban and Rural Africa, Wellcome Open Res. 2023 Oct 30; 8:119, https://doi.org/10.12688/wellcomeopenres.19131.2, Mmbaga AT & Lwetoijera DW review “the evidence for efficacy of the autodissemination approach using PPF and [discuss] its potential as efficient and affordable complementary malaria vector control intervention in Africa. In the previous studies that were done in controlled semi-field environments, autodissemination with PPF demonstrated its potential in reducing densities of captive population of malaria vectors such as Anopheles gambiae and Anopheles arabiensis.”

Tsegaye A & al. found that different larval habitats had variable productivity in different seasons, and that physical and physicochemical features like ammonium and nitrate, as well as the distance between larval habitats and households, are related to larval production. [They recommend that] vector control should take into account the seasonality of Anopheles larval habitat as well as the impact of pesticide application on larval source management. The paper is Anopheles Larval Habitats Seasonality and Environmental Factors Affecting Larval Abundance and Distribution in Arjo-Didessa Sugar Cane Plantation, Ethiopia, Malaria J, 2023 Nov 15, 22:350, https://doi.org/10.1186/s12936-023-04782-1.

“Gene drive technologies (GDTs) have been proposed as a potential new way to alleviate the burden of malaria yet have also raised ethical questions. A central ethical question regarding GDTs relates to whether it is morally permissible to intentionally modify or eradicate mosquitoes in this way and how the inherent worth of humans and non-human organisms should be factored into determining this.” de Graeff N & al., Alleviating the Burden of Malaria with Gene Drive Technologies? A Biocentric Analysis of the Moral Permissibility of Modifying Malaria Mosquitoes, J Med Ethics. 2023 Nov; 49(11):765-771, https://doi.org/10.1136/jme-2022-108359 reconsiders “the implications of taking a biocentric approach and highlight nuances that may not be evident at first glance. …[The authors] explore how conflicting claims towards different organisms should be prioritised from this perspective and subsequently apply this to the context of malaria control using GDTs. [Their] ethical analysis shows that this context invokes the principle of self-defence, which could override the … concerns that a biocentrist would have against modifying malaria mosquitoes in this way if certain conditions are met.

Chemoprophylaxis

“Cameroon adopted the Seasonal Malaria Chemoprevention (SMC) in 2016 and has implemented it each year since its adoption.” Fokam AF & al. “aimed to assess the effect of SMC in Cameroon during the period 2016–2021 on malaria morbidity in children under 5 years of age using routine data.”  After extracting data from the Cameroon Health Monitoring Information System (HMIS) from January 1, 2011, to December 31, 2021, they report in A Bayesian Spatio-Temporal Framework to Assess the Effect of Seasonal Malaria Chemoprevention on Children Under 5 Years in Cameroon from 2016 to 2021 Using Routine Data, Malaria J, 2023 Nov 11, 22:347, https://doi.org/10.1186/s12936-023-04677-1 that “SMC implementation was associated with a reduction in the incidence of uncomplicated malaria cases during the high-transmission periods from 2016 to 2021. Regarding the incidence of severe malaria during the high-transmission period, a reduction was found over the period 2016–2019. The highest reduction was registered during the second year of implementation in 2017:15% … of uncomplicated malaria cases and 51% … of confirmed severe malaria cases.

Likewise, in South Sudan, Molina-de la Fuente I & al. report success of SMC when amodiaquine was added to the traditional sulfadoxine-pyrimethamine formulation because of reported resistance. “… five cycles of SMC using SPAQ were administered to children 3–59 months during a period of high malaria transmission (July–December 2019) in 21 villages in South Sudan.” The results were favorable: “Incidence of uncomplicated malaria was reduced from 6.6 per 100 to an average of 3.2 per 100 after SMC administration (mean reduction: 53%) and incidence of severe malaria showed a reduction from 21 per 10,000 before SMC campaign to a mean of 3.3 per 10,000 after each cycle (mean reduction: 84%) in the target group when compared to before the SMC campaign.” The paper is Seasonal Malaria Chemoprevention in a Context of High Presumed Sulfadoxine-Pyrimethamine Resistance: Malaria Morbidity and Molecular Drug Resistance Profiles in South Sudan, Malaria J, 2023 Nov 10, 22:345, https://doi.org/10.1186/s12936-023-04740-x.

In an editorial, Fixed Prevalence of Sulfadoxine-Pyrimethamine Resistance Markers After 3 Years of Drug Pressure, Lancet Glob Health. 2023 Nov; 11(11):e1676-e1677, https://doi.org/10.1016/s2214-109x(23)00435-7, Duah-Quashie NO & Tandoh KZ comment on “scientific-based evidence in support of the continuous usage of sulfadoxine–pyrimethamine for intermittent preventive treatment of malaria in pregnancy (IPTp).” That was the subject of Figueroa-Romero A & al., Prevalence of Molecular Markers of Resistance to Sulfadoxine-Pyrimethamine Before and After Community Delivery of Intermittent Preventive Treatment of Malaria in Pregnancy in Sub-Saharan Africa: A Multi-Country Evaluation, Lancet Glob Health, 2023 Nov; 11(11):e1765-e1774, https://doi.org/10.1016/S2214-109X(23)00414-X, reviewed in last month’s report.

As stated in the title of Muthoka EN & al.’s article, Safety and Tolerability of Repeated Doses of Dihydroartemisinin-Piperaquine {DP} of Malaria in Pregnancy {IPTp}: A Systematic Review and an Aggregated Data Meta-Analysis of Randomized Controlled Trials, Malaria J, 2023 Oct 21, 22:320, https://doi.org/10.1186/s12936-023-04757-2, the authors reviewed six randomized controlled trials involving 7969 participants in Sub-Saharan Africa. Despite some increase in adverse events in comparison to the WHO-recommended sulfadoxine-piperaquine {SP} IPTp, apparently no one in the studies abandoned the DP regimen because of these events. “DP was also better tolerated in these studies as compared to most alternatives that have been proposed to replace SP which have proved to be too poorly tolerated in IPTp use.”

Other

Emiru T & al. report on Evidence for a Role of Anopheles stephensi in the Spread of Drug and Diagnosis-Resistant Malaria in Africa, in Nature Med, 2023 Oct 26, https://doi.org/10.1038/s41591-023-02641-9. They cite an epidemic in the Ethiopian town of Dire Dawa in 2022. “Screening contacts of malaria patients and febrile controls revealed spatial clustering of P. falciparum infections around malaria patients in strong association with An. stephensipresence in the household vicinity.” Another article making reference to the same outbreak in Dire Dawa is Samake JN & al., Population Genomic Analyses Reveal Population Structure and Major Hubs of Invasive Anopheles stephensiin the Horn of Africa, Mol Ecol, 2023 Nov; 32(21):5695-5708, https://doi.org/10.1111/mec.17136. It mentions that An. stephensi was found in the Horn of Africa as early as 2018.

“Long-acting injectable medications, such as atovaquone, offer the prospect of a “chemical vaccine” for malaria, combining drug efficacy with vaccine durability. However, selection and transmission of drug-resistant parasites is of concern.” Balta VA & al., Clinically Relevant Atovaquone-Resistant Human Malaria Parasites Fail to Transmit by Mosquito, Nat Commun. 2023 Oct 12; 14(1):6415, https://doi.org/10.1038/s41467-023-42030-x demonstrates under laboratory conditions that the “severe-to-lethal fitness cost of clinically relevant atovaquone resistance to P. falciparum in the mosquito substantially lessens the likelihood of its transmission in the field.”

“The source of malaria vector populations that re-establish at the beginning of the rainy season is still unclear, yet knowledge of mosquito behaviour is required to effectively institute control measures. Alternative hypotheses like aestivation, local refugia, migration between neighbouring sites, and long-distance migration (LDM) are stipulated to support mosquito persistence.” Mwima R & al., Potential Persistence Mechanisms of the Major Anopheles gambiaeSpecies Complex Malaria Vectors in Sub-Saharan Africa: A Narrative Review, Malaria J, 2023 Nov 7, 22:336, https://doi.org/10.1186/s12936-023-04775-0 “assessed the malaria vector persistence dynamics and examined various studies done on vector survival” and concluded that no good answers can be gleaned from the publications reviewed. They call for “further investigations emphasizing the use of ecological experiments under controlled conditions in the laboratory or semi-field, and genetic approaches, as they are known to complement each other.”

The benefit of certain types of home improvement to control vector invasion and thereby reduce the incidence of malaria has been demonstrated, Mponzi WP & al., Exploring the Potential of Village Community Banking as a Community-Based Financing System for House Improvements and Malaria Vector Control in Rural Tanzania, PLOS Glob Public Health. 2023 Nov 3; 3(11):e0002395, https://doi.org/10.1371/journal.pgph.0002395 reports on a questionnaire-based study on how local financing mechanisms may  be utilized for these purposes.

Diagnosis

General diagnostics

“In the thirteen years since the first report of pfhrp2-deleted parasites in 2010, the World Health Organization (WHO) has found that 40 of 47 countries surveyed worldwide have reported pfhrp2/3 gene deletions. Due to a high prevalence of pfhrp2/3 deletions causing false-negative HRP2 RDTs, in the last five years, Eritrea, Djibouti and Ethiopia have switched or started switching to using alternative RDTs…” In Global Risk of Selection and Spread of Plasmodium falciparumHistidine-Rich Protein 2 and 3 Gene Deletions, medRxiv. 2023 Oct 22: 2023.10.21.23297352, https://doi.org/10.1101/2023.10.21.23297352, Watson OJ & al. “explore the variation in modelled timelines through an extensive parameter sensitivity analysis and despite wide uncertainties, … identify four countries that have not yet switched RDTs (Senegal, Zambia, Kenya and Zambia) that are robustly identified as high risk for pfhrp2/3 deletions.”

In view of the considerations expressed in the article above, Kayode TA & al., Welcome to the Next Generation of Malaria Rapid Diagnostic Tests: Comparative Analysis of NxTek Eliminate Malaria P.f, Biocredit Malaria Ag Pf, and SD Bioline Malaria Ag Pf for Plasmodium falciparum Diagnosis in Ghana, Res Sq. 2023 Oct 19: rs.3.rs-3459263, https://doi.org/10.21203/rs.3.rs-3459263/v1 raises interesting expectations.  However, one of the three tests investigated, which relies on HRP2 for diagnosis, performed as well as the one that included HRP2 plus Lactic Dehydrogenase (LDH).

Zhang Y & al. propose a new method of diagnosis for any of the four species of Plasmodium in Rapid Detection of Malaria Based on Hairpin-Mediated Amplification and Lateral Flow Detection {HMA-LFD}, Micromachines (Basel).2023 Oct 9; 14(10):1917, https://doi.org/10.3390/mi14101917.  Although the concordance was very high (96.2%) between HMA-LFD and qualitative PCR methods of diagnosis on “78 blood samples” of unspecified source, the Abstract is not clear whether this method of proposed diagnosis is species specific or just signals a Plasmodium infection of some kind.

Another new method is proposed in Zheng M & al., Rapid, Sensitive, and Convenient Detection of Plasmodium falciparum Infection Based on CRISPR and Its Application in Detection of Asymptomatic Infection, Acta Trop. 2023 Nov 1: 107062, https://doi.org/10.1016/j.actatropica.2023.107062. Without going into specifics in the abstract, the authors claim that the method is specific to P. falciparum and will not detect P. vivax. They also state that “the diagnostic method they describe will be for clinical testing and large-scale community screening in Africa and possibly other places, contributing to the accurate diagnosis and control of malaria.”

Negative results of a study are important to communicate as well. In view of the difficulty in collecting blood for diagnosis in small children, Imboumy-Limoukou RK & al. explored alternative body fluids and products for malaria diagnosis. Their paper, Detection of Plasmodium falciparum in Saliva and Stool Samples from Children Living in Franceville, a Highly Endemic Region of Gabon, Diagnostics (Basel). 2023 Oct 20; 13(20):3271,https://doi.org/10.3390/diagnostics13203271 conclusively shows that at least in the community studied, saliva and stool samples are not reliable sources of malaria diagnosis.

Field diagnostics

“Low peripheral parasitaemia caused by sequestration of Plasmodium falciparum in the placenta hampers the diagnosis of malaria in pregnant women, leading to microscopy or conventional rapid diagnostic tests (RDTs) false-negative results.”Tshiongo JK & al. studied the performance of a commercially available ultrasensistive RDT (uRDT), which is said to be considerably more sensitive to circulating histidine-rich protein 2 (HRP 2).  Their results, measured against quantitative polymerase chain reaction (qPCR) as reference, indicated that microscopy was only 55% sensitive, while RDT was 81.7% and uRDT 88% sensitive. Specificity was marginally higher for RDT than uRDT.  However, in situations of very low parasite density, as measured by qPCR, uRDT, while higher than RDT, was only 68% sensitive. The article is Performance of Ultra-Sensitive Malaria Rapid Diagnostic Test to Detect Plasmodium falciparum Infection in Pregnant Women in Kinshasa, the Democratic Republic of the Congo, Malaria J, 2023 Oct 23, 22:322, https://doi.org/10.1186/s12936-023-04749-2

New diagnostic methods

  • None this month

Treatment

Treatment results

  • None this month

Adherence to guidelines

  • None this month

Side effects and complications

Onyamboko MA & al., Factors Affecting Haemoglobin Dynamics in African Children with Acute Uncomplicated Plasmodium falciparum Malaria Treated with Single Low-Dose Primaquine {SLDPQ} or Placebo, BMC Med. 2023 Oct 20; 21(1):397, https://doi.org/10.1186/s12916-023-03105-0 is a report of a “randomised, double-blind, placebo-controlled, safety trial … [conducted in 1137] Congolese and Ugandan children aged 6 months-11 years with acute uncomplicated P. falciparum and day (D) 0 Hbs ≥ 6 g/dL who were treated with age-dosed SLDPQ/placebo and weight-dosed artemether lumefantrine (AL) or dihydroartemisinin piperaquine (DHAPP).” Based on their data, the authors conclude that “[i]n these falciparum-infected African children, posttreatment Hb changes were unaffected by SLDPQ, and G6PDd patients had favourable posttreatment Hb changes and a higher probability of Hb recovery. These reassuring findings support SLDPQ deployment without G6PD screening in Africa.”

Drug resistance

 

“Emerging resistance against artemisinin (ART) poses a major challenge in controlling malaria. Parasites with mutations in PfKelch13, the major marker for ART resistance, are known to reduce hemoglobin endocytosis, induce unfolded protein response (UPR), elevate phosphatidylinositol-3-phosphate (PI3P) levels, and stimulate autophagy. Nonetheless, PfKelch13-independent resistance is also reported, …. These findings implicate that there may not be a single ‘universal identifier’ of ART resistance.” Pandit K & al., The Many Paths to Artemisinin Resistance in Plasmodium falciparum,Trends Parasitol. 2023 Oct 11: S1471-4922(23)00232-5, https://doi.org/10.1016/j.pt.2023.09.011 claims to shed “light on the molecular, transcriptional, and metabolic pathways associated with ART resistance, while also highlighting the interplay between cellular heterogeneity, environmental stress, and ART sensitivity.”

Reyser T & al. state that “artemisinin-resistant parasites are able, in the presence of artemisinins, to stop their cell cycles. This quiescent state can alter the activity of artemisinin partner drugs leading to a secondary drug resistance and thus threatens malaria eradication strategies.” In search of effective approaches to oversome this situation, they turn to the idea of “[d]rugs targeting epigenetic mechanisms (namely epidrugs). In Epidrugs as Promising Tools to Eliminate Plasmodium falciparum Artemisinin-Resistant and Quiescent Parasites, Pharmaceutics. 2023 Oct 10; 15(10):2440, https://doi.org/10.3390/pharmaceutics15102440 they find after testing 32 possible candidates that “four epidrugs targeting both histone methylation or deacetylation as well as DNA methylation decrease the ability of artemisinin-resistant parasites to recover after artemisinin exposure.”

Sulfadoxine-pyrimethamine (SP) is the combination used in malaria chemoprophylaxis of pregnant women, and of children when combined with amodiaquine. Its use “is threatened by the accumulation of mutations in … Plasmodium falciparum…” Guémas E & al. collected samples “at 18 health-care centres in seven [Sub-Saharan African] countries from patients who showed possible symptoms of malaria …. Samples that were positive for P falciparum were transported to a laboratory in Toulouse, France, and genotyped.” They report in Evolution and Spread of Plasmodium falciparum Mutations Associated with Resistance to Sulfadoxine-Pyrimethamine in Central Africa: A Cross-Sectional Study, Lancet Microbe. 2023 Oct 18: S2666-5247(23)00211-2, https://doi.org/10.1016/s2666-5247(23)00211-2 that mutations associated with resistance to SP were found in many samples, including over 50% of samples from Northern Cameroon. Even though the article does not comment on actual evidence of clinical resistance to SP, the authors raise concern about implications of the genetic findings.

New drug research

“Flavonoids, such as the baicalein class of compounds, are known to have antimalarial properties.” Gudla CS & al., Novel Baicalein-Derived Inhibitors of Plasmodium falciparum, Pathogens. 2023 Oct 13; 12(10):1242, https://doi.org/10.3390/pathogens12101242 describes a “compound, FNDR-10132, that displayed potent in vitro antimalarial activity against Plasmodium falciparum (P. falciparum), both chloroquine-sensitive … and chloroquine-resistant … parasites. FNDR-10132 was evaluated for its antimalarial activity in vivo against the chloroquine-resistant strain Plasmodium yoelii N67 in Swiss mice… [with] 44% parasite suppression on day 4…. Also, FNDR-10132 displayed equivalent activity against the resistant strains of P. falciparum … [The authors claim this to be] a novel series of antimalarial compounds that could be developed into potent drugs against chloroquine-resistant malarial parasites through further chemistry and DMPK optimization.”

Despite their article’s title, Mee-Udorn P & al., In Silico and In Vitro Potential of FDA-Approved Drugs for Antimalarial Drug Repurposing against Plasmodium Serine Hydroxymethyltransferases, ACS Omega. 2023 Sep 18; 8(39):35580-35591, https://doi.org/10.1021/acsomega.3c01309 focuses on a single drug, Amphotericin B, which is used intravenously for severe fungal infections only, because of its potential toxicity. The authors claim that their “findings identify a promising new … inhibitor, albeit with less inhibitory activity, and suggest a core structure that differs from that of previous … inhibitors, thus being a rational approach for novel antimalarial drug design.”

Lampejo T, Monoclonal Antibodies for the Prevention of Plasmodium falciparum Malaria: A Multi-Target Approach, Infect Dis (Lond). 2023 Nov 3 :1-5, https://doi.org/10.1080/23744235.2023.2274897 has a uniquely unrevealing abstract and the article is a available only upon payment of a fee.

Ivermectin has been used as a transmission blocking agent. Ekoka Mbassi D & al. researched its tolerability and efficacy against P. falciparum infections and report in Efficacy and Safety of Ivermectin for the Treatment of Plasmodium falciparum Infections in Asymptomatic Male and Female Gabonese Adults – A Pilot Randomized, Double-Blind, Placebo-Controlled Single-Centre Phase Ib/IIa Clinical Trial, EBioMedicine. 2023 Oct 13; 97:104814, https://doi.org/10.1016/j.ebiom.2023.104814 that among 29 participants who completed the trial, none suffered adverse side effects and 90% reduction of parasite density was achieved 8 hours (25%) quicker than with placebo (!).  While safety at the dose administered was achieved in this small trial, whether this is a clinically meaningful result is uncertain. Why were parasites 90% reduced with placebo?

Plant extracts and traditional treatments

 

According to Kaushik M & al., the leaf extract of the cashew nut tree (Anacardium occidentale) “has been used traditionally for the treatment of malaria.” The plant is native to Brazil and also cultivated in India. In Antimalarial Activity of Anacardium occidentale Leaf Extracts Against Plasmodium falciparum Transketolase (PfTK), Acta Parasitol. 2023 Oct 13, https://doi.org/10.1007/s11686-023-00718-6 they report that the extract inhibited the enzyme mentioned in the article’s title, but also that at higher concentrations, it was toxic to some laboratory animals.

Laryea MK &al., Antimalarial Compounds from the Climbing Stems of Salacia debilis, Nat Prod Res. 2023 Oct 22: 1-10, https://doi.org/10.1080/14786419.2023.2272288 presents data of exposing laboratory strains of P. falciparum andP. berghei to three ethanolic extracts of the climbing plant mentioned, which is used in folk medicine in West Africa against malaria. The results showed that “compounds of S. debilis possess antimalarial effects. The isolated compounds may be responsible, at least in part, for the observed activities of the extract.”

Chromoleana odorata is a rapidly growing perennial bush, also known as “Jack in the bush.” It is said to have been imported into West Africa, where it is considered a nuisance. In the past it was apparently noted to be larvicidal for mosquitoes. Elebiyo TC & al. investigated the effect on malaria of its extracts in the mouse model. Their paper, Anti-Malarial and Haematological Evaluation of the Ethanolic, Ethyl Acetate and Aqueous Fractions of Chromolaena odorata, BMC Complement Med Ther. 2023 Nov 9; 23(1):402, https://doi.org/10.1186/s12906-023-04200-8 reports “high antimalarial activity displayed by the ethanolic fraction …. The findings suggest that the fractions from C. odorata could serve as an alternative source of malaria therapy, particularly in sub-Saharan Africa.”

Other

Highly interesting in view of the recent presentation of Dr. Hammond at our Board meeting is the information contained in Safeukui I & al., Simultaneous Adjunctive Treatment of Malaria and its Coevolved Genetic Disorder Sickle Cell Anemia, Blood Adv. 2023 Oct 10; 7(19):5970-5981, https://doi.org/10.1182/bloodadvances.2022009124.  While the sickle cell gene provides relative protection against malaria, there are patients with sickle cell disease who nevertheless contract malaria. Treatment of the sickle cell anemia with hydroxyurea (HU) in patients also suffering from malaria may increase the effectiveness of antimalarial therapy, if the results of the laboratory tests on the effects of HU on P. falciparum infected red blood cells are confirmed in human trials.

Treatment can only be provided if the home caregivers recognize illness in their children and take them to competent treatment facilities. Okitawutshu J & al., Assessing Caregivers’ Perceptions of Treatment-Seeking for Suspected Severe Malaria in the Democratic Republic of the Congo, Malaria J. 2023 Oct 13; 22:308, https://doi.org/10.1186/s12936-023-04737-6 is a report of household surveys in remote villages before and after the implementation of rectal artesunate treatment of severe malaria (RAS) in primary care sites. “Caregiver’s recognition of severe malaria signs was poor, while knowledge of symptoms of uncomplicated malaria seemed high. Despite this, danger signs significantly increased the odds of seeking treatment … the same was found for the “least poor” quintile … as well as residents of Kingandu … ‘Doing something at home’ against fever negatively affected treatment-seeking …. RAS acceptance was high, at almost 100%.”

 

Campaigns and Policies

“The slow progress in malaria control efforts and increasing challenges have prompted a need to accelerate the research and development (R&D), launch and scaling of effective interventions for malaria elimination.” Mao W & al. “identified the following challenges along the end-to-end scale-up pathway of malaria interventions. Underinvestment in malaria R&D persists, and developers from low-resource settings are not commonly included in the R&D process. Unpredictable or unclear regulatory and policy pathways have been a hurdle. The private sector has not been fully engaged, which results in a less competitive market with few manufacturers, and consequently, a low supply of products. Persistent challenges also exist in the scaling of malaria interventions, such as the fragmentation of malaria programmes.” They also identify six recommendations in their article, Scaling Malaria Interventions: Bottlenecks to Malaria Elimination, BMJ Glob Health. 2023 Nov; 8(11):e013378, https://doi.org/10.1136/bmjgh-2023-013378.

Epidemiology

Climate change, biodiversity and environment

  • None this month

Risk factors

“… intra-urban malaria risk maps act as a key decision-making tool for targeting malaria control interventions, especially in resource-limited settings.” Morlighem C & al., Spatial Optimization Methods for Malaria Risk Mapping in Sub-Saharan African Cities Using Demographic and Health Surveys, Geohealth. 2023 Oct 6; 7(10):e2023GH000787, https://doi.org/10.1029/2023gh000787 is a report of modeling  “malaria risk using a random forest regressor and remotely sensed covariates depicting the urban climate, the land cover and the land use… Building on [their] results, [the authors] highlight potential adaptations to the [Demographic Health Survey] sampling strategy that would make them more reliable for predicting malaria risk at the intra-urban scale.”

“In Tanzania … transmission [of malaria] is heterogeneously distributed. In order to effectively control and prevent the spread of malaria, it is essential to understand the spatial distribution and transmission patterns of the disease” state Mwangungulu SP &al. in Geospatial Based Model for Malaria Risk Prediction in Kilombero Valley, South-Eastern, Tanzania, PLoS One. 2023 Oct 24; 18(10):e0293201, https://doi.org/10.1371/journal.pone.0293201. Using a “geospatial based model to predict and map out malaria risk area in Kilombero Valley, [they generated a risk map] by a weighted overlay of the altitude, slope, curvature, aspect, rainfall distribution, and distance to streams in Geographic Information Systems (GIS). Finally, the risk map was created by overlaying components of malaria risk including hazards, elements at risk, and vulnerability.” They found that “the majority of the study area falls under moderate risk level (61%), followed by the low risk level (31%), while the high malaria risk area covers a small area, which occupies only 8% of the total area.”

 

Jugha VT & al., Association Between Malaria and Undernutrition Among Pregnant Women at Presentation for Antenatal Care in Health Facilities in the Mount Cameroon Region, PLoS One. 2023 Oct 12; 18(10):e0292550, https://doi.org/10.1371/journal.pone.0292550 demonstrates the very high incidence of undernutrition of women seeking antenatal care in the region studied and surmise that the it plays a role if not in the frequency, but in the severity of malaria in pregnancy.  However, while “the association between malaria and [a measure of poor nutrition] was statistically significant,” they present no data as to causality.

Natuhamya C & al. set out to “determine the complete sources of cluster variation on the risk of under-five malaria and risk factors associated with under-five malaria in Uganda. {They] applied a multilevel-weighted mixed effects logistic regression model to account for both individual and contextual factors.” As reported in Complete Sources of Cluster Variation on the Risk of Under-Five Malaria in Uganda: A Multilevel-Weighted Mixed Effects Logistic Regression Model Approach, Malaria J. 2023 Oct 19; 22:317, https://doi.org/10.1186/s12936-023-04756-3, “[e]very additional year in a child’s age was positively associated with malaria infection …. Children whose mothers had at least a secondary school education were less likely to suffer from malaria infection … as well as those who dwelled in households in the two highest wealth quintiles … An increase in altitude by 1 m was negatively associated with malaria infection…”

General epidemiology

 

“Almost 6·5 million children and adolescents younger than 20 years died globally in 2021, the vast majority from preventable causes. Reliable and timely data on causes of death are needed to better focus the attention of the global community on improving the survival of children and adolescents and to guide effective policy and programmes. But no less importantly, these data must be publicly available and easily accessible.” Villavicencio F & al., “introduce an open data portal with yearly estimates on causes of death for children and adolescents younger than 20 years for the period 2000–21. The data hosted in this portal are part of a joint effort between the Child and Adolescent Causes of Death Estimation (CA CODE) project and the United Nations Inter-Agency Group for Child Mortality Estimation (UN IGME). The portal is managed by UNICEF and was first launched in 2008 by UN IGME, reporting global, regional, and national age-specific all-cause mortality estimates for stillbirths, children, and adolescents. Cause-specific mortality estimates produced by the CA CODE project have now been incorporated for the first time, aiming to start a dialogue with countries about their mortality data to improve cause-specific estimates while increasing data transparency and use at the country level.” The article is Global, Regional, and National Causes of Death in Children and Adolescents Younger than 20 Years: An Open Data Portal with Estimates for 2000–21, Lancet Glob Health, 2023 Oct 25, https://doi.or/10.1016/S2214-109X(23)00496-5.

The most salient point made by Duguma T & al. in Prevalence of Asymptomatic Malaria and Associated Factors Among Pregnant Women in Ethiopia: Systematic Review and Meta-Analysis, Front Reprod Health. 2023 Oct 11, 5:1258952, https://doi.org/10.3389/frph.2023.1258952 is “that pregnant women have a high pooled prevalence of asymptomatic malaria. Women living in rural areas near stagnant water and those who never used insecticide-treated nets had a two-, four-, or six-fold higher prevalence of asymptomatic malaria, respectively.” The overall prevalence of asymptomatic malaria in all the articles reviewed was about 1 in 14 (7.20%) by microscopy, which may well be an underestimate.

Munsey A & al. explored whether analyzing prevalence rates in pregnant women as the present for antenatal care (ANC) may be used in predicting community-wide infections. They used community-wide data of malaria in children and correlated them with data obtained during ANC visits and report in Assessing the Utility of Pregnant Women as a Sentinel Surveillance Population for Malaria in Geita, Tanzania, 2019 – 2021, Int J Infect Dis. 2023 Nov; 136:57-63, https://doi.org/10.1016/j.ijid.2023.08.007 that “[t]rends in parasitemia among ANC attendees were predictive of trends in parasitemia among children” in the community.

“Despite malaria prevalence being linked to surface water through vector breeding, spatial malaria predictors representing surface water often predict malaria poorly. Furthermore, precipitation, which precursors surface water, often performs better.” Kalthof MWML & al.’s “… goal is to determine whether novel surface water exposure indices that take malaria dispersal mechanisms into account, derived from new high-resolution surface water data, can be stronger predictors of malaria prevalence compared to precipitation.” As reported in Predicting Continental Scale Malaria with Land Surface Water Predictors Based on Malaria Dispersal Mechanisms and High-Resolution Earth Observation Data, Geohealth. 2023 Oct 10; 7(10):e2023GH000811, https://doi.org/10.1029/2023gh000811, they “benchmarked the performance and Relative Contribution of this set of novel predictors to models using precipitation instead of surface water predictors, alternative lower resolution predictors, and simpler surface water predictors used in previous studies. The predictive performance of the novel indices rivaled or surpassed that of precipitation predictors. … Surface water derived indices can be strong predictors of malaria, if the spatial resolution is sufficiently high to detect small waterbodies and dispersal mechanisms of malaria related to surface water in human and vector water exposure assessment are incorporated.”

Wong W & al., Evaluating the Performance of Plasmodium falciparum Genetics for Inferring National Malaria Control Program Reported Incidence in Senegal, Res Sq. 2023 Nov 1: rs.3.rs-3516287, https://doi.org/10.21203/rs.3.rs-3516287/v1 asserts that investigating genetics of P falciparum in areas of more than minimal incidence can yield information about the actual incidence of infection. Schaffner SF & al., Malaria Surveillance Reveals Parasite Relatedness, Signatures of Selection, and Correlates of Transmission Across Senegal, Nat Commun. 2023 Nov 10; 14(1):7268, https://doi.org/10.1038/s41467-023-43087-4 is another paper by the same group of researchers on the same topic.

It has been held for long that the Duffy antigen on the surface of the red blood cell is necessary for P. vivax to infect a person. Bradley L, Yewhalaw D & al. published two articles to the contrary this month. Comparison of Plasmodium vivax Infections in Duffy Negatives from Community and Health Center Collections in Ethiopia, Res Sq. 2023 Oct 3: rs.3.rs-3385916, https://doi.org/10.21203/rs.3.rs-3385916/v1 negates that view by reporting that “Duffy negativity does not offer complete protection against infection by P. vivax, and cases of P. vivax in Duffy negatives are widespread in Ethiopia, being found in asymptomatic volunteers from communities and in febrile patients from health centers.” While it is true that the vast majority of those infected by P. vivax are Duffy positive, the authors’ report on testing of over 10,000 individuals supports this conclusion. Their other article, Determination of Plasmodium vivax and Plasmodium falciparum Malaria Exposure in Two Ethiopian Communities and Its Relationship to Duffy Expression, Am J Trop Med Hyg. 2023 Oct 16; 109(5):1028-1035,

https://doi.org/10.4269/ajtmh.22-0644 is focused on the immunologic aspects of this situation, noting that they found “[a]ntibodies to three of the four P. vivax blood stage antigens examined, RBP2b, EBP2, and DBPIISal-1, were significantly lower … in Duffy-negative individuals relative to Duffy-positive individuals.” Thus, they conclude “lack of erythroid Duffy expression is associated with reduced serologic responses, indicative of less naturally acquired immunity and less cumulative exposure to blood stage P. vivax parasites relative to Duffy positive individuals living in the same communities.”

Although the subject of Jajosky RP & al., Plasmodium knowlesi (Pk) Malaria: A Review & Proposal of Therapeutically Rational Exchange (T-REX) of Pk-Resistant Red Blood Cells, Trop Med Infect Dis. 2023 Oct 20; 8(10):478, https://doi.org/10.3390/tropicalmed8100478 is prevalent only in Southeast Asia at the moment, it is important to understand that this parasite, thought to be invasive only in animals, has been showing up with some regularity in humans, where it is frequently misdiagnosed, occasionally with fatal consequences.  The article also comments on the fact that Duffy antigen on the surface of the red blood cell (also involved in P. ovale infections) is required for P. knowlesito be able to invade them and deform them. That leads to a proposed treatment.

Msugupakulya BJ & al. report on a literature search in Changes in Contributions of Different Anopheles Vector Species to Malaria Transmission in East and Southern Africa from 2000 to 2022, Parasit Vectors. 2023 Nov 7; 16(1):408, https://doi.org/10.1186/s13071-023-06019-1.  The changes reported in this paper are primarily the emergence of An. funestus as the primary vector over the last decade. Interestingly, even though eight other Anopheles species merit mention as “secondary” vectors in the area covered, there is only a single mention of An. stephensi in the introduction as a newly recognized vector.  It must be stated that the “Horn of Africa” was not part of the geography covered by the article.

Spatiotemporal studies

Gemechu T & al., Asymptomatic Malaria During Pregnancy: Prevalence, Influence on Anemia and Associated Factors in West Guji Zone, Ethiopia – A Community-Based Study, Infect Drug Resist. 2023 Oct 19; 16:6747-6755, https://doi.org/10.2147/idr.s431877

Sendor R & al., Epidemiology of Plasmodium malariae and Plasmodium ovale spp. in Kinshasa Province, Democratic Republic of Congo, Nat Commun. 2023 Oct 19; 14(1):6618, https://doi.org/10.1038/s41467-023-42190-w

Ocen E & al., Severe Malaria Burden, Clinical Spectrum and Outcomes at Apac District Hospital, Uganda: A Retrospective Study of Routine Health Facility-Based Data, Malaria J, 2023 Oct 25, 22:325, https://doi.org/10.1186/s12936-023-04761-6

Muleba M & al., Spatial–Temporal Vector Abundance and Malaria Transmission Dynamics in Nchelenge and Lake Mweru Islands, a Region with a High Burden of Malaria in Northern Zambia, Malaria J, 2023 Oct 29, 22:327, https://doi.org/10.1186/s12936-023-04746-5

Lelisa K & al., Malaria Positivity Rate Trend Analysis at Water Resources Development Project of Wonji Sugar Estate Oromia, Ethiopia, Parasitol Res. 2023 Oct; 122(10):2259-2266, https://doi.org/10.1007/s00436-023-07923-2

Getachew H & al., Asymptomatic and Submicroscopic Malaria Infections in Sugar Cane and Rice Development Areas of Ethiopia, Malaria J, 2023 Nov 8, 22:341, https//doi.org/10.1186/s12936-023-04762-5

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