By Dr. Derick Pasternak, Ambassador, Malaria Science & Research Coordinator, MPI
On July 2, the WHO published a 40-page pamphlet entitled Surveillance and Control of Anopheles stephensi; Country Experiences. It is accessible at https://www.who.int/health-topics/malaria#tab=tab_1.
A “Special Report” appeared on August 1, Joseph A, Behind the Malaria Vaccines: A 40-Year Quest Against One of Humanity’s Biggest Killers, https://www.statnews.com/2024/08/01/ malaria-vaccines-development-history-40-year-fight-mosquito-borne-disease/. After a general introduction, it starts describing the work of the wife-and-husband team of Ruth and Victor Nussenzweig, Brazilian scientists working at New York University. They discovered and described the circumsporozoite of the parasite and were instrumental during the early days of anti-Plasmodium falciparum vaccine development (co-sponsored by GlaxoSmithKline and the US Army at the time). Following this, several other key scientists are mentioned as well as the roles played by the Gates Foundation, PATH, GAVI, WHO, Oxford University in arriving the current status of two WHO approved vaccines being used in several countries in Africa. The article does not delve into work that is ongoing to find other, more effective and/or simpler-to-administer vaccines.
PEER REVIEWED ARTICLES (see notes after citations from non-peer-reviewed publications)
Prevention
Vaccines
Although Hanboonkunupakarn B & al.’s paper, A Randomised Trial of Malaria Vaccine R21/Matrix-M with and Without Antimalarial Drugs in Thai Adults, NPJ Vaccines. 2024 Jul 6; 9(1):124, https://doi.org/10.1038/s41541-024-00920-1 reports on events in SE Asia, it is great importance to the countries served by MPI, because the vaccine has been used in Côte d’Ivoire for the past few weeks and will no doubt be introduced in other African countries soon. This study was focused on the tolerability and safety of the vaccine after three monthly administrations and its potential interactions with antimalarial drugs. “The vaccine was well tolerated alone and in combination with the antimalarials. … There was no significant difference in the vaccine immunogenicity or in the pharmacokinetics of piperaquine given individually or in combination.”
Kurtovic L & al. purports to report on the immunologic response to the RTS,S vaccine in Antibody Mechanisms of Protection Against Malaria in RTS,S-Vaccinated Children: A Post-Hoc Serological Analysis of Phase 2 Trial, Lancet Microbe. 2024 Aug 7: 100898, https://doi.org/10.1016/s2666-5247(24)00130-7. While the authors’ results are in all likelihood scientifically valid (it has undergone peer review), it is evident from the abstract and the article that data are used from the 2003 trial of the vaccine using the AS02 adjuvant, which has since been replaced by the more effective AS01 adjuvant in the communities in which the vaccine is now used. That raises the question whether the conclusions of the paper are relevant to today’s situation.
“An adjuvant is a substance that enhances the immune system’s response to the presence of an antigen. They are commonly used to improve the effectiveness of a vaccine. Generally, they are injected alongside an antigen to help the immune system generate antibodies that fight the antigen.” (Moore S, What are Adjuvants? News-medical.net/life-sciences/) In Arunachalam PS & al., A Comparative Immunological Assessment of Multiple Clinical-Stage Adjuvants for the R21 Malaria Vaccine in Nonhuman Primates, Sci Transl Med. 2024 Jul 31; 16(758):eadn6605, https://doi.org/10.1126/scitranslmed.adn6605, results for the testing of an alternative to the Matrix-M adjuvant currently part of the R21 vaccine are presented. This adjuvant (3M) produced immunologic responses in macaques that are similar to those being currently used in the vaccine. While that is not an improvement, the authors consider their results as “highlight[ing] the promise of 3M as another adjuvant for malarial vaccines.”
Diawara H & al., Safety and Efficacy of PfSPZ Vaccine Against Malaria in Healthy Adults and Women Anticipating Pregnancy in Mali: Two Randomised, Double-Blind, Placebo-Controlled, Phase 1 and 2 Trials, Lancet Infect Dis, 2024 Aug 14, https://doi.org/10.1016/S1473-3099(24)00360-8 describes two “randomised, double-blind, placebo-controlled trials (phase 1 MLSPZV3 and phase 2 MLSPZV4) [that] were conducted at a clinical research centre in Mali. MLSPZV3 included adults aged 18–35 years and MLSPZV4 included non-pregnant women aged 18–38 years.” Two kinds of regimens each included three shots various weeks apart, followed by a booster one year later. Several groups of the participants received malaria treatment before vaccination, other groups did not. The authors conclude that the “PfSPZ Vaccine was safe and well tolerated in adults in Mali. The 9 × 105 and 1·8 × 106 doses of PfSPZ Vaccine administered as per the 4-week schedule, which incorporated presumptive antimalarial treatment before the first vaccine dose, showed significant efficacy against P falciparum parasitaemia and clinical malaria for two malaria transmission seasons in women of childbearing age and against pregnancy malaria. PfSPZ Vaccine without presumptive antimalarial treatment before the first vaccine dose did not show efficacy.” Yanow SK & Vinals DF, Preconception Immunisation to Prevent Pregnancy-Associated Malaria, Lancet Infect Dis, 2024 Aug 14, https://doi.org/10.1016/S1473-3099(24)00405-5 is a commentary, focused on the women’s trial, in the same issue of the journal.
Reacting to the fact that the currently WHO-approved vaccines require multiple injections, Sattler JM & al. “propose and test a new strategy for the generation of genetically attenuated parasites. [They] aimed to delete genes such that blood-stage parasites grow slow but still develop normally in the mosquito.” Then, when the mosquito bites and retransmits the attenuated strain, the authors theorize the development of immunity. When they tested this theory in the mouse model, they state in Experimental Vaccination by Single Dose Sporozoite Injection of Blood-Stage Attenuated Malaria Parasites EMBO Mol Med, 2024 Aug 5, https://doi.org/10.1038/s44321-024-00101-6 that “[i]mmunization of mice led to protection from disease after challenge with wild-type sporozoites.” They also claim to have developed two types of slow growing P. falciparum by gene deletion.
Cao Y & al state that “[t]ransmission-blocking vaccines interrupting malaria transmission within mosquitoes represent an ideal public health tool to eliminate malaria at the population level.” In Evaluation of Combination Vaccines Targeting Transmission of Plasmodium falciparum and P. vivax, Vaccine. 2024 Jul 19:126140, https://doi.org/10.1016/j.vaccine.2024.07.041, they present the results of laboratory work, combining various individual vaccines targeted at the two different species and apparently achieving improved immunologic results, in that immune substances produced in experimental mice reduced transmission activity in laboratory-bred mosquitoes.
The history of developing vaccines against malaria is one of slow and laborious progress with significant barriers that had to be overcome. This is reflected in the massive literature review by Tajudeen YA & al., A Landscape Review of Malaria Vaccine Candidates in the Pipeline, Trop Dis Travel Med Vaccines. 2024 Aug 1;10(1):19, https://doi.org/10.1186/s40794-024-00222-3. The authors conclude that the “use of a multi-antigen, multi-stage combinational vaccine is … essential in the context of global health. …Despite challenges, advancements in clinical trials and vaccination technology offer promising possibilities for novel approaches in malaria vaccine development.”
Vectors
In a literature review of the use of insecticide treated nets (ITNs) Doe PF & al. reviewed 24 publications on the subject that focused on Ghana. They report in Ownership and Usage of Insecticide-Treated Nets in Ghana: A Scoping Review of Facilitators and Barriers, Malaria J, 2024 Aug 10, 23:238, https://doi.org/10.1186/s12936-024-05072-0 that the published rates of use were extremely variable (20 to 94% of populations studied). “[F]actors facilitating ITN ownership were marital status, higher educational attainment, higher income levels, and being aged 25 years or older. In contrast, the factors for its use included community-level campaigns advocating for ITN use and awareness, individuals with secondary education or higher and those residing in urban areas. Missed opportunities in free distribution exercises and the unavailability of subsidized ITNs at health facilities were barriers to ownership.”
Oppong J & al., Mosquito Control Strategies and Insecticide Resistance of the Malaria Vector in Urbanized Land Use Types in Suame Municipality, Ghana, J Trop Med. 2024 Aug 1; 2024: 5843481, https://doi.org/10.1155/2024/5843481 is a study of “household mosquito control methods in two urbanized landscapes; industrial and residential human settlements, in Ghana and insecticide susceptibility of the inhabiting Anopheles populations.” The authors report that mosquitoes in the area were resistant to all but one of the insecticides used by the population and conclude based on responses to questionnaires that the use of ITNs in households is not common.
Ooko M & al. collected data on ITN use, mosquito bites, and malaria infection data from 13,735 individuals in 20 communities. They conclude after analyzing their data that use of the nets still left a 66% chance of being bitten indoors. It is of note that no mention of indoor residual spraying is made. The paper is Malaria Burden and Residual Transmission: Two Thirds of Mosquito Bites May Not Be Preventable with Current Vector Control Tools on Bioko Island, Equatorial Guinea, Int J Infect Dis. 2024 Aug 9: 107197, https://doi.org/10.1016/j.ijid.2024.107197.
Further to the Northeast in Africa, Elemo N & al., Long Lasting Insecticidal Nets Utilization and Associated Factors Among Households of West Arsi Zone, Oromia Region, Ethiopia, Sci Rep. 2024 Jul 30; 14(1):17498, https://doi.org/10.1038/s41598-024-68703-1 reports on a questionnaire-based assessment of ITN use. Using data from 2808 households in the Zone mentioned, the authors report 69.9% utilization rate for the nets. “Being female as household head,… number of separate rooms in the living house, [length of use of] nets …, knowledge status of the respondents … were significantly associated with [net] utilization.” Nonetheless the authors conclude that use of nets in this area is much lower than country-wide, which they claim to be over 85%.
“Elevated resistance to pyrethroids in major malaria vectors has led to the introduction of novel insecticides including neonicotinoids.” Thiomela RF &al. tested indoor residual spraying (IRS) with a proprietary combination of a pyrethroid, deltamethrin and a neonicotinoid, clothianidin, under experimental conditions against wild pyrethroid-resistant malaria vectors. They report in Indoor Residual Spraying of Experimental Huts in Cameroon Highlights the Potential of Fludora Fusion to Control Wild Pyrethroid-Resistant Malaria Vectors, BMC Infect Dis. 2024 Jul 25; 24(1):733, https://doi.org/10.1186/s12879-024-09630-4 that all mosquitoes were sensitive to the preparation and the benefit was due primarily to clothianidin.
“From 2018 to 2021, non-pyrethroid IRS was implemented annually in two regions of Burkina Faso with distinct malaria transmission patterns, concurrently with annual seasonal malaria chemoprevention (SMC), and a mass insecticide-treated net (ITN) distribution in 2019.” Hilton ER & al., An Observational Analysis of the Impact of Indoor Residual Spraying in Two Distinct Contexts of Burkina Faso, Malaria J, 2024 Aug 2, 23:229, https://doi.org/10.1186/s12936-024-05054-2 concludes that “[i]mplementation of IRS in Kampti, a tropical region of Burkina Faso, appeared to have a consistent significant beneficial impact on malaria case rates. An initial positive impact in Solenzo after the first IRS campaign was not sustained in the successive evaluated IRS campaigns.”
Hayes CC & Schal C state that “outcomes of indoor vector control (IVC) strategies, such as long-lasting insecticide-treated nets (LLINs) and indoor residual sprays (IRSs), are heavily influenced by individual and community-level perceptions and acceptance.” However, in Review on the Impacts of Indoor Vector Control on Domiciliary Pests: Good Intentions Challenged by Harsh Realities, Proc Biol Sci. 2024 Aug; 291(2027):20240609, https://doi.org/10.1098/rspb.2024.0609 they express their concern that when these control modalities don’t also control other pests such as bedbugs and cockroaches, the public might lose faith in malaria control. They acknowledge that there are no reliable research data on this issue and recommend exploring it.
According to Mahenge HH & al., “[b]iological control is a promising alternative or complementary approach for controlling vector populations in response to the spread of insecticide resistance in malaria vectors.” They report in Semi-Field Evaluation of Aquatic Predators for the Control of Anopheles funestus in Rural South-Eastern Tanzania, Malaria J, 2024 Aug 2, 23:228, https://doi.org/10.1186/s12936-024-05055-1 that in a controlled experimental setting, species of damselflies, backswimmers and dragonflies, were all effective in reducing the emergence of adult mosquitoes, in the order mentioned.
Two more articles have been published about ongoing trials of so-called Attractive Sugar Baits for malaria vector mosquitoes. Farhan M & al., Assessing the Potential of Nano-Formulated Chlorfenapyr and Clothianidin Insecticides-Treated Sugar Baits Against Anopheles funestus, Anopheles coluzzii and Culex quinquefasciatus Mosquitoes, Acta Trop. 2024 Aug; 256:107269, https://doi.org/10.1016/j.actatropica.2024.107269 address the formulation of the insecticides and its effect on the three species of mosquitoes mentioned in the title. Nano-formulation apparently means attaching the insecticide to nanoparticles in a way that is not readily discernible from the article. The results indicated excellent killing of the two Anopheles species mentioned with less efficacy of the Culex mosquito, which is a vector for several viral diseases as well as avian malaria. From Zambia, Orange E & al., Community Acceptance of a Novel Malaria Intervention, Attractive Targeted Sugar Baits, in the Zambia Phase III Trial, Malaria J, 2024 Aug 12, 23:240, https://doi.org/10.1186/s12936-024-05068-w reports high acceptability of the trial mentioned, with fewer than 10% of households in the study are expressing safety concerns. One of the barriers to acceptability reported by the authors was “association with satanism(!)”
“Spatial repellents can provide personal and household protection against biting vector mosquitoes by volatizing repellents into the air within a given area. Mosquito Shield™ is a transfluthrin passive emanator undergoing evaluation for malaria control.” Fongnikin A & al., Mosquito Shield™, a Transfluthrin Passive Emanator, Protects Against Pyrethroid-Resistant Anopheles gambiae sensu lato in Central Benin, Malaria J, 2024 Jul 31, 23:225, https://doi.org/10.1186/s12936-024-05043-5 is an assessment of “the impact of Mosquito Shield™ on the human landing rate of wild pyrethroid-resistant Anopheles gambiae sensu lato (s.l.) vector mosquitoes in houses” in a community in Benin. “…An. gambiae s.l. post-intervention human landing rates were significantly lower in houses in the Mosquito Shield™ arm … compared to the houses in the placebo control arm …. Over the lifespan of the product, Mosquito Shield™ provided a significant protective efficacy of 34.2% … against wild pyrethroid-resistant An. gambiae s.l. vectors compared to the placebo.”
Taylor R & al., Invasive Anopheles stephensi in Africa: insights from Asia, Trends Parasitol. 2024 Jul 24: S1471-4922(24)00166-1, https://doi.org/10.1016/j.pt.2024.06.008 is “a critical synthesis of literature from An. stephensi’s native range, focusing on the future of An. stephensi in a rapidly urbanising Africa, and highlighting key questions that warrant prioritisation by the global malaria vector control community.”
Two papers characterized Anopheles species collected in various Ethiopian regions. Data of Esayas E & al. from over 4500 specimens in the highlands and over 3200 specimens from the lowlands are published in Bionomic Characterization of Anopheles Mosquitoes in the Ethiopian Highlands and Lowlands, Parasit Vectors. 2024 Jul 16; 17(1):306, https://doi.org/10.1186/s13071-024-06378-3. An. gambiae sensu lato, a major vector species of malaria parasites was most prevalent in both geographic areas. Yimer M & al. showed different results in their paper, Species Composition, Infection Rate and Feeding Preference of Anopheles Mosquito Species (Diptera: Culicidae) in the West Amhara Region, Northwest Ethiopia, PLoS One. 2024 Jul 25; 19(7):e0307063, https://doi.org/10.1371/journal.pone.0307063. Among 261 Anopheles species identified, An. demeilloni was the most abundant. Further, “more than 50% of Anopheles mosquito species collected fed on cattle blood showing shifting of feeding behaviors.”
In a similar study from Benin, Adoha CJ & al. report in Diversity and Ecological Niche Model of Malaria Vector and Non-Vector Mosquito Species in Cove, Ouinhi, and Zangnanado, Southern Benin, Sci Rep. 2024 Jul 23; 14(1):16944, https://doi.org/10.1038/s41598-024-67919-5 that “[o]verall, mosquito density was higher in the wet season than in the dry season in all communes. … Habitat suitability of An. gambiae s.s., An. coluzzii, Cx. quinquefasciatus and Ma. africana was highly influenced by slope, isothermality, site aspect, elevation, and precipitation seasonality in both wet and dry seasons. Overall, depending on the season, the ecological preferences of the four main mosquito species were variable across study communes
Chemoprophylaxis
In “Guinea, where malaria represents the leading cause of morbidity and mortality among children, the seasonal malaria chemoprevention (SMC) is deployed only in areas with very seasonal modes of transmission.” Keita KS & al., The Monthly Trends of Malaria Cases in Children Under 5 Years of Age in Guinea: Comparative Analysis Between a Seasonal Malaria Chemoprevention (SMC) and a Non-SMC Health District, Malaria J, 2024 Aug 8, 23:237, https://doi.org/10.1186/s12936-024-05060-4 compares the rates of malaria in a district where SMC was applied to a district where it was not. The source of information was national data from 2015 to 2020. “he SMC programme contributed to a significant average reduction in the number of malaria cases of 225 cases per month in the intervention district …, compared to the control district.” Based on that infromation, the authors suggest “extending the SMC in other areas with high perennial seasonal transmission respecting the World Health Organization SMC eligibility criteria…”
The WHO 2016 antenatal care (ANC) policy recommends at least eight antenatal contacts during pregnancy. [Olapeiu B & al.] assessed “ANC8” uptake following policy implementation and explored the relationship between ANC attendance and intermittent preventive treatment in pregnancy (IPTp) coverage in sub-Saharan Africa. As they report in WHO Antenatal Care Policy and Prevention of Malaria in Pregnancy in Sub-Saharan Africa, Malaria J, 2024 Jul 23, 23:218, https://doi.org/10.1186/s12936-024-05037-3, only a small proportion of women (median = 3.9%) completed eight or more ANC contacts (ANC8 +). Factors significantly associated with increased odds of ANC8 + included early ANC attendance …, literacy …, and higher wealth quintile …. The pooled estimate across all countries showed a very slight increase in the odds of IPTp3 + among women with eight … compared to those with four contacts,” primarily in Ghana and Liberia.
Other
“Genetic modification for the control of mosquitoes is frequently cited as a solution for a variety of vector-borne diseases. There has been some success using non-insecticidal methods like sterile or incompatible insect techniques to control arbovirus diseases. However, control by genetic modifications to reduce mosquito populations or create mosquitoes that are refractory to infection with pathogens are less developed. The advent of CRISPR-Cas9-mediated gene drives may advance this mechanism of control.” Naidoo K & Oliver SV, Gene Drives: An Alternative Approach to Malaria Control, Gene Ther. 2024 Jul 22, https://doi.org/10.1038/s41434-024-00468-8 reviews the “use and progress of gene drives for vector control, particularly for malaria … A brief history of population suppression and replacement gene drives in mosquitoes, rapid advancement of the field over the last decade and how genetic modification fits into the current scope of vector control are described. Mechanisms of alternative vector control by genetic modification to modulate mosquitoes’ immune responses and anti-parasite effector molecules as part of a combinational strategy to combat malaria are considered. Finally, the limitations and ethics of using gene drives for mosquito control are discussed.”
The following is the entire abstract of Hartley S & al., Talking About Gene Drive in Uganda: The Need for Science Communication to Underpin Engagement, Sci Commun. 2024 Aug; 46(4):431-457, https://doi.org/10.1177/10755470241234048: “Uganda may host the world’s first field trials of gene drive mosquitoes for malaria control. Global North discourses pre-suppose African publics have access to information about gene drive and are ready to make decisions about its governance. We explore assumptions about the availability of this information in Uganda. We find a paucity of information available combined with a strong desire for information from lay publics. We discuss these findings in the context of Ugandan information infrastructures and political sensitivities to genetic technologies. If Ugandans are to decide about gene drive, they need independent information about the science to underpin engagement.”
Nankabirwa JI & al. describe “housing characteristics and their association with malaria burden in a moderate to high transmission setting in Uganda.” In a study of 1500 households, “[h]ouseholds were stratified as having modern houses (defined as having finished materials for roofs, walls, and floors and closed eaves) or traditional houses (those not meeting the definition of modern house) … Most (65.5%) of the households surveyed lived in traditional houses. Most of the houses had closed eaves (85.5%), however, the use of other protective features like window/vent screens and installed ceilings was limited … Participants living in modern houses had a significantly lower parasite prevalence by microscopy … compared to those in traditional houses. The article is The Uganda Housing Modification Study – Association Between Housing Characteristics and Malaria Burden in a Moderate to High Transmission Setting in Uganda, Malaria J, 2024 Jul 30, 23:223, https://doi.org/10.1186/s12936-024-05051-5.
Diagnosis
General diagnostics
Patiño LH & al. claim the development of a new reliable quantitative polymerase chain reaction (qPCR) test that reliably identifies several species of both Plasmodium and Babesia parasites. According to their article, the two species coexist in “Africa” without further geographic identification, which the CDC states babesiosis occurs in the US, Europe, and Asia, but not in Africa or Latin America. The distinction is important, because apparently on microscopy, one form of the Babesia parasite looks similar to the Plasmodium circumsporozoite. The paper is Validation of Real-Time PCR Assays for Detecting Plasmodium and Babesia DNA Species in Blood Samples, Acta Trop. 2024 Aug 10:107350, https://doi.org/10.1016/j.actatropica.2024.107350.
Field diagnostics
The results of rapid diagnostic testing (RDT) are dependent on the parasite containing unaltered Histidine Rich Protein. Either of two mutations in the parasite genome will interfere with the accuracy of this diagnostic method, much used in field testing. Kamaliddin C & al., A Countrywide Survey of hrp2/3 Deletions and kelch13 Mutation Co-Occurrence in Ethiopia, J Infect Dis. 2024 Jul 31: jiae373, https://doi.org/10.1093/infdis/jiae373 describes situations in which the parasite contains not only one or both of these mutations, but also a mutation that confers partial artemisinin resistance, allowing the parasite to evade both diagnosis and effective treatment. This article is also described below, under Treatment/Drug resistance.
New diagnostic methods
The third article this year on the use of the digital microscopic miLabTM comes from Malawi. Bae CY & al. refer to the device as “incorporating the solid hydrogel staining method was proposed for consistent blood film preparation, eliminating the use of complex equipment and liquid reagent maintenance. The miLab™ ensures consistent, high-quality, and reproducible blood films across various hematocrits by leveraging deformable staining patches.” In Embedded-Deep-Learning-Based Sample-to-Answer Device for on-Site Malaria Diagnosis, Front Bioeng Biotechnol, 2024 Jul 19: 12:1392269, https://doi.org/10.3389/fbioe.2024.1392269, they assert that “[c]linical validation performed in Malawi demonstrated an overall percent agreement of 92.21% [using microscopy and RDT as comparison].
Ramos JDS & al. promote computer assisted diagnostics in A Transfer Learning Approach to Identify Plasmodium in Microscopic Images, PLoS Comput Biol. 2024 Aug 5; 20(8):e1012327, https://doi.org/10.1371/journal.pcbi.1012327. They assessed a “transfer learning approach by using well-known pre-trained deep learning architectures. [They] considered a database with 6222 Region of Interest” comparing several programs on microscopic images and claim that the best, DenseNet201, exceeded over 99% accuracy. [However, it is unclear what control was used.}
According to Attaway C & al., No Longer Stuck in the Past: New Advances in Artificial Intelligence and Molecular Assays for Parasitology Screening and Diagnosis, Curr Opin Infect Dis. 2024 Aug 13, https://doi.org/10.1097/qco.0000000000001041, “[r]ecent implementation of artificial intelligence and digital microscopy has enabled swift smear screening and diagnosis, although widespread implementation remains limited. Simultaneously, molecular assays – both targeted and multiplex panels are promising and have demonstrated promise in numerous studies with some assays securing regulatory approval recently. Additional technologies are under investigation for their diagnostic utility and are compelling avenues for future proof-of-concept diagnostics.”
Treatment
Treatment results
“The location of Plasmodium falciparum within the body is determined by the life cycle of the parasite; young rings are in the peripheral blood, whereas mature parasites are sequestered in deep tissues. … a “ring ratio” [reflects] the proportion of parasites in the periphery to the total number of parasites in the body.” Saidi AM & al. “established the relationship between ring ratio and parasite clearance rate and used the ring ratio to determine if the benefit derived from artesunate treatment could be attributed to its broader effect on life cycle stages.” Results of the comparison between artesunate treatment versus quinine (historical control) for cerebral malaria, cited in their paper, Differential Effects of Antimalarial Drugs on Parasite Clearance Rates Are Reflected by Plasmodium falciparum Ring Ratio, Open Forum Infect Dis. 2023 Jul 19; 10(7):ofad380, https://doi.org/10.1093/ofid/ofad380, support “the hypothesis that more rapid parasite clearance rates in artesunate recipients are due to its superiority over quinine in killing ring-stage parasites.”
Whereas “Plasmodium vivax is now the main cause of malaria outside Africa,” it is also an important agent of disease in Ethiopia, Senegal, and other African countries. Therefore, Chaumeau V & al., Transmission-Blocking Activities of Artesunate, Chloroquine, and Methylene Blue on Plasmodium vivax Gametocytes, Antimicrob Agents Chemother. 2024 Jul 26: e0085324, https://doi.org/10.1128/aac.00853-24 is highly relevant to the activities of MPI. The authors’ results of testing the three drugs for ability to reduce the number of circulating gametocytes and therefore the potential for transmission to the vector indicate that artesunate and methylene blue were highly efficacious in this sphere, whereas chloroquine was not. “This suggests that patients with vivax malaria often remain infectious to anopheline mosquitos after treatment with chloroquine. Use of artemisinin combination therapies or immediate initiation of primaquine radical cure should reduce the transmissibility of P. vivax infections.”
Guidelines
Adherence to recommendations is the subject of Galick DS & al.’s Adapting Malaria Indicator Surveys to Investigate Treatment Adherence: A Pilot Study on Bioko Island, Equatorial Guinea, Malaria J, 2024 Aug 13, 23:244, https://doi.org/10.1186/s12936-024-05057-z. “A follow-up team visited the targeted households, physically observed treatment blisters where possible, and provided messaging to household members on the importance of adhering to the treatment guidelines to household members… adherence [to artemisinin combination therapy] on Bioko Island was low, around 50%, and this varied demographically and geographically. … Estimates of adherence from follow-up visits were much lower than survey-based estimates in the same households (52.5% versus 87.1%), suggesting that lack of proper adherence may be a much larger issue on Bioko Island than previously thought.”
Moffitt CA & al. “aimed to determine the impact of targeted interventions on adherence to the WHO severe malaria treatment guidelines in children at a Ugandan hospital as part of a quality improvement initiative.” They report in Improving Adherence to Severe Malaria Treatment Guidelines in Children at a Ugandan Regional Hospital: Assessment of a Quality Improvement Initiative, Malaria J, 2024 Aug 15, 23:245, https://doi.org/10.1186/s12936-024-05076-w that while “[a]ppropriate malaria diagnostic testing was performed in 85% of patients post-intervention compared to 66% of patients in the baseline” and 86 % of the post-intervention group received the minimum 3 doses of artesunate as opposed to 74% in the bseline, adherence to all WHO treatment guidelines was only 10% post-intervention (though it rose from 3%).
Side effects and complications
None this month
Drug resistance
Dhorda M & al., Artemisinin-Resistant Malaria in Africa Demands Urgent Action, Science. 2024 Jul 19;385(6706):252-254, https://www.science.org/doi/10.1126/science.adp5137 is an article aimed at the general scientific community and calling for concentrated action to respond to the rapid development of resistance to artemisinin combination therapy in various parts of Africa, where 94% of the world’s malaria infections occur.
The rapid “spread of partial resistance to artemisinin, first in southeast Asia and recently in East Africa, mainly Uganda and Rwanda” is the subject of Björkman A & al., Alarming Plasmodium falciparum Resistance to Artemisinin-Based Combination Therapy in Africa: The Critical Role of the Partner Drug, Lancet Infect Dis, 2024 Jul 22, https:/doi.org/10.1016/S1473-3099(24)00427-4 which calls attention to parallel development of parasites resistant to lumefantrine as well, because if “malaria transmission is high, frequent new reinfections can occur soon after treatment during the relatively long elimination phase of the partner drug, lumefantrine. … The second most used ACT combination in Africa is artesunate–amodiaquine. … However, the most efficient solution is most probably a 3-day triple combination (TACT) of artemisinin and two partner drugs, such as lumefantrine and amodiaquine. … The present WHO recommendation is to shift first-line antimalarial treatment when the cure rate falls to less than 90%. The alarming evolution of artemisinin resistance in East Africa, however, necessitates a shift of ACT much before such reduced efficacy is confirmed. A shift of partner drug is required immediately from lumefantrine to amodiaquine (or pyronaridine or piperaquine) in Uganda, Rwanda, and neighboring countries with confirmed K13 mutations.”
The kelch13 mutation is also a topic of Kamaliddin C & al., A Countrywide Survey of hrp2/3 Deletions and kelch13 Mutation Co-Occurrence in Ethiopia, J Infect Dis. 2024 Jul 31: jiae373, https://doi.org/10.1093/infdis/jiae373. The article describes situations in which the parasite contains not only the resistance mutation, but also mutations that interfere with RDT, allowing the parasite to evade both diagnosis and effective treatment. This article is also described above, under Diagnosis/Field diagnostics.
Awor P & al. present genetic evidence that the appearance and spread of artemisinin-resistant parasites in Uganda is of local origin. They also state in Indigenous Emergence and Spread of Kelch13 C469Y Artemisinin-Resistant Plasmodium falciparum in Uganda, Antimicrob Agents Chemother. 2024 Jul 19: e0165923, https://doi.org/10.1128/aac.01659-23 that their “data provide evidence of selection for the artemisinin-resistant C469Y mutation.”
On the same issue, and from the same country comes Ogwang R & al.’s article, A Retrospective Analysis of P. falciparum Drug Resistance Markers Detects an Early (2016/17) High Prevalence of the k13 C469Y Mutation in Asymptomatic Infections in Northern Uganda, Antimicrob Agents Chemother. 2024 Aug 13: e0157623, https://doi.org/10.1128/aac.01576-23. The authors returned to dry blood spots collected in 2016 and 2017 from adolescents with asymptomatic malaria and subjected them to genetic analysis. The analysis of the samples revealed several genetic markers in the parasites that are associated with resistance to artemisinin and sulfadoxine-pyrimethamine.
Ishengoma DS & al. also found artemisinin resistant genotypes in Tanzania. However, as they report in Evidence of Artemisinin Partial Resistance in Northwestern Tanzania: Clinical and Molecular Markers of Resistance, Lancet Infect Dis, 2024 Aug 16, https://doi.org/10.1016/S1473-3099(24)0362-1, “artemether–lumefantrine and artesunate–amodiaquine showed high efficacy” in the patients included in their study. The authors report that the risk of recurrent infection was much higher after treatment with artemether–lumefantrine than with artesunate–amodiaquine; recurrent infections occurred within 1 month in almost a third of children treated with artemether–lumefantrine. They recommend a “context-specific response strategy and vigilance to detect the reduced efficacy of current antimalarial treatments and ART-R [artemisinin partial resistance] in other parts of the country…” Mlugu EM & al., Resistant Malaria Parasites Gaining Momentum in Africa, Lancet Infect Dis, https://doi.org/10.1016/S1473-3099(24)00413-4 is a commentary on the above article in the same journal.
New drug research
Junior DBC & al. report the finding that nitrofurantoin, an antibiotic that has long been in use especially for urinary tract infections, is effective in vitro against chloroquine-resistant P. falciparum. However, the concentration in which it must be used creates a limitation. In Towards Development of New Antimalarial Compounds Through in silico and in vitro Assays, Comput Biol Chem. 2024 Aug; 111:108093, https://doi.org/10.1016/j.compbiolchem.2024.108093 they hypothesize that the problem is that the drug cannot effectively cross biological membranes. As a result, they developed several derivatives with improved ability to cross. Testing these new molecules for effectiveness and toxicity will be the next steps.
Another article that looks at both malaria and babesiosis is Vydyam P & al., In vitro Efficacy of Next-Generation Dihydrotriazines and Biguanides Against Babesiosis and Malaria Parasites, Antimicrob Agents Chemother. 2024 Aug 13: e0042324, https://doi.org/10.1128/aac.00423-24. It reports on the investigation of several drugs classified as “antifolates,” which are said to be generally efficacious against parasites that invade blood cells. They are also used in chemotherapy of cancer. Pyrimethamine, used in some artesunate combination regimens, is an antifolate.
Redway A & al. chose to investigate a class of compounds called “amides and thioamides with pyridine cores,” which have some chemical relationship to the components of genetic materials. In Discovery of Antiplasmodial Pyridine Carboxamides and Thiocarboxamides, Int J Parasitol Drugs Drug Resist. 2024 Aug; 25:100536, https://doi.org/10.1016/j.ijpddr.2024.100536 they report that twelve of the compounds they tested had effectiveness against P. falciparum, both the chloroquine-sensitive and chloroquine resistant strains studied. They also report extremely low toxicity against human cells. This work may eventually yield a new class of antimalarial drugs.
Plant extracts and traditional treatments
Artemisinins were developed as the result of traditional treatment of malaria by decoction of a Chinese plant. Two papers from Asia report antiplasmoidal effects of other plant extracts. Sawant SS & al., In vitro Effect on Plasmodium falciparum and in vivo Effect on Plasmodium berghei of Annomaal, an Oily Fraction Obtained from the Seeds of Annona squamosa, Molecules. 2023 Jul 17; 28(14):5472, https://doi.org/10.3390/molecules28145472 is a report of a substance extracted from the seeds of custard apples that grow in the Americas and Southeast Asia. “The oily fraction, Annomaal, demonstrated pronounced antimalarial activity … against P. falciparum in vitro. The [crude seed extract] and Annomaal significantly inhibited the growth of P. berghei parasites in vivo … Furthermore, the study demonstrated that oral administration of Annomaal … [resulted in] a complete cure to the P. berghei-infected mice.” Konyanee A & al. studied the root extract of “Ceylon ironwood” and state in Antiplasmodial Potential of Isolated Xanthones from Mesua ferrea Linn. Roots: An in vitro and in silico Molecular Docking and Pharmacokinetics Study, BMC Complement Med Ther. 2024 Jul 25; 24(1):282, https://doi.org/10.1186/s12906-024-04580-5 that “compounds isolated from M. ferrea exhibit activity against P. falciparum… [one of which] has significant potential as a scaffold for the development of potent antimalarial drugs.”
Strasseriolides A-D are fungal products isolated from the roots of a plant in New Zealand. They, especially Strasseriolide B, were found to have significant activity against Plasmodium parasites. Ghosh AK & Gulliver JP, Total Syntheses of Strasseriolide A and Strasseriolide B, Potent Antimalarial Agents, J Org Chem. 2024 Aug 9, https://doi.org/10.1021/acs.joc.4c01262 describes the process by which they synthesized two of these chemicals in the laboratory, which promises to result in better access to them for further research and possible future treatment of malaria.
Campaigns and Policies
“Improving the visibility and global coordination of malaria surveillance and data quality improvement initiatives is required to optimize sharing of best practices, tools, and approaches and to promote efficient, effective, and equitable distribution of resources. … Rollback Malaria’s Surveillance, Monitoring and Evaluation Working Group established the Surveillance Practice and Data Quality Committee in May 2021 [which distributed a] questionnaire that included questions on current project objectives, activities, geographic scope, and lessons learned was distributed among committee members and other [implementing parties (IPs)] …, information has been submitted regarding 49 projects by 25 IPs …. an interactive dashboard was published to the Rollback Malaria’s Global Malaria Dashboard website (endmalaria.org) in March 2021. It is the first time that multiple stakeholders have shared such information regarding surveillance projects.” The paper is Kayaalpli S & al., Improving Coordination to Strengthen Operationalization of Malaria Surveillance and Routine Data Quality: Landscape Analysis of Current Surveillance-Related Initiatives, Am J Trop Med Hyg. 2024 Jul 30: tpmd230460, https://doi.org/10.4269/ajtmh.23-0460
“To enhance the community knowledge and optimize the use of Artemisinin-based combination therapy (ACT), [Bawate C & al.] carried out a community training in Kamuli District, Uganda” and report in Community Education Training to Optimize the Use of Artemisinin-Based Combination Therapy in Kamuli District, Uganda, BMC Public Health. 2024 Jul 31; 24(1):2062, https://doi.org/10.1186/s12889-024-19619-y that “3420 community members were trained, 384 sampled to participate in pre-post-test assessment, with 76 healthcare workers (HCW)” Community members responded by significant increased awareness in all of ten parameters of knowledge, whereas healthcare workers were unimproved in only one, malaria transmission, in which they already demonstrated good knowledge at pre-testing.
Lot Quality Assurance Sampling is a statistical technique that has been used for decades in epidemiological studies of vaccination and other processes. Richardson S & al. used it while studying compliance with seasonal malaria chemoprevention. In Adaptation of Lot Quality Assurance Sampling to Monitor Seasonal Malaria Chemoprevention Delivery Performance, Trans R Soc Trop Med Hyg. 2024 Aug 10: trae051, https://doi.org/10.1093/trstmh/trae051, they “present a case study of its application … [in which] LQAS facilitated timely local performance assessment across 16 indicators.”
Please see the summary of Wallender E & al., Malaria Community Case Management Usage and Quality of Malaria Care in a Moderate Plasmodium falciparum Burden Region of Chadiza District, Zambia, Malaria J, 2024 Aug 1; 23:226, https://doi.org/10.1186/s12936-024-05047-1 under Epidemiology.
Epidemiology
Climate change, biodiversity and environment
Although climate change is not in the title of Nie P & al., Range Dynamics of Anopheles Mosquitoes in Africa Suggest a Significant Increase in the Malaria Transmission Risk, Ecol Evol. 2024 Jul 31;14(8):e70059, https://doi.org/10.1002/ece3.7005, the dynamics referred to clearly include the influence of anticipated warming ins sub-Saharan countries. The authors have modeled future ranges of “21 major Anopheles” species (specified in the article, but not the abstract) and comment on the increased risk of malaria that expansion of some of these ranges will bring about. This article could also be cited under Prevention/Vectors.
Risk factors
Studying a poor and poorly educated migrant population, a majority of whom sleep outside and in structures without mosquito screens, Mintah-Agyeman E & al. report in Patterns and Predictors of Malaria Among Head Porters: A Mobile Population in Ghana, Malaria J, 2024 Jul 27, 23:222, https://doi.org/10.10.1186/s12936-024-05000-2 that among 754 individuals malaria was diagnosed by RDT in 10.48%, but nearly half of them experienced malaria in the six months prior to the study.. “Receiving malaria education in the past 6 months reduced the odds of malaria infection whilst poor knowledge of malaria increased the odds of malaria infection among the porters.” As reported in the paper, but not the abstract, the “overall malaria prevalence found in this study was lower than the 14.1% national estimate reported by the 2019 Malaria Indicator Survey (MIS) carried out in [the] same year.” The authors speculate that the “relatively low prevalence could have resulted from the different age groups involved in the two studies. Participants of the MIS were children less than six years whilst median age of participants in this study was 23yrs.”
Also in Ghana, Peprah N & al. focused on mortality of children with malaria in Ghana. Based on 95 children who died versus 190 with severe malaria who survived, they conclude in Patient Socio-Demographics and Clinical Factors Associated with Malaria Mortality: A Case Control Study in the Northern Region of Ghana, Malaria J, 2024 Aug 4, 23:230, https://doi.org/10.1186/s12936-024-05038-2 that p]redictors of malaria mortality in the Northern region include children under 5 years, severe pallor, sepsis as an additional diagnosis, and use of oral anti-malarial.” It is of note that the data on which this conclusion is based were collected in 2015.
“In endemic locations, asymptomatic malaria is a major contribution to the rise in clinical malaria. [Kaghou MM & al. investigated] the prevalence and risk factors of asymptomatic malaria” in 246 apparently healthy children in a village in NW Cameroon. They discovered that 65.9% or 59.3% had Plasmodium parasites in their bloodstream, by PCR testing and microscopy, respectively. In their “analysis, the risk of developing asymptomatic malaria was associated several factors: previous malaria episode …, family history of malaria …, homestead near swampy areas …, non-utilization of insecticide treated nets …, non-usage of indoor residual spray (IRS) … and opened eaves …. No associations were established between asymptomatic malaria and the following factors: age group …, gender … and type of wall construction.” The article analysis, the risk of developing asymptomatic malaria was associated several factors: previous malaria episode (OR = 5.14; CI 2.94–9.01), family history of malaria (OR = 3.86; CI 2.21–6.74), homestead near swampy areas (OR = 3.56; CI 2.10–10.61), non-utilization of insecticide treated nets (OR = 4.36; CI 2.53–7.5), non-usage of indoor residual spray (IRS) (OR = 6.67; CI 3.75–11.86) and opened eaves (OR = 3.86; CI 2.21–6.74). No associations were established between asymptomatic malaria and the following factors: age group (p > 0.05), gender (p > 0.05) and type of wall construction (p > 0.05). The article is High Prevalence and Risk Factors Associated with Asymptomatic Malaria Among Children in Nkwen Village, Northwest Region, Cameroon, Malaria J, 2024 Aug 13, 23:243, https://doi.org/10.1186/s12936-024-05013-x
General epidemiology
Based on results of questionnaires administered to over 11,000 households in 73 communities Wallender E & al. report in Malaria Community Case Management Usage and Quality of Malaria Care in a Moderate Plasmodium falciparum Burden Region of Chadiza District, Zambia, Malaria J, 2024 Aug 1, 23:226, https://doi.org/10.1186/s12936-024-05047-1#Sec2 that the prevalence of malaria by RDT was 19.1%, with school-age children (5 to 14 years) having the highest prevalence (28.8%). “… 76.7% across all ages visited a CHW as part of care. Nearly 90% (87.8%) of people who visited a CHW reported a blood test compared with 73.5% seen only at a health facility and/or pharmacy (p < 0.001). Reported malaria treatment was similar by provider, and 85.9% of those with a reported positive malaria test reported getting malaria treatment … Age under 5 years, monthly or more frequent CHW home visits, and greater wealth were associated with increased odds of receiving healthcare.” This paper could also be reported under Campaigns or Diagnosis.
Studying 2012-2018 data among school-age children in the Lake Victoria Region of Kenya, Omondi P & al. found “Plasmodium prevalence [to be] 25.9% (2521/9724) by microscopy and 51.1% (4969/9724) by PCR… Among all infections detected by PCR, Pf, P. malariae (Pm), and P. ovale (Po) mono-infections were 58.6%, 3.1%, and 1.8%, respectively. Pf/Pm, Pf/Po, Pm/Po, and Pf/Pm/Po co-infections were 23.5%, 4.3%, 0.1%, and 8.6%.” The unexpected frequency of cross-species infections is pointed out in Non-Random Distribution of Plasmodium Species Infections and Associated Clinical Features in Children in the Lake Victoria Region, Kenya, 2012-2018, Trop Med Health, 2024 Aug 5; 52(1):52, https://doi.org/10.1186/s41182-024-00622-3.
In the past, several articles from East Africa commented on the coexistence of Burkitt’s lymphoma and malaria in children. Epstein-Barr virus (EBV), the cause of Burkitt’s and other cancers is associated with malaria elsewhere, too. According to Djuidje Chatue IA & al.’ s paper, Association Between Epstein-Barr Virus Reactivation and Severe Malaria in Pregnant Women Living in a Malaria-Endemic Region of Cameroon, PLOS Glob Public Health. 2024 Aug 12; 4(8):e0003556, https://doi.org/10.1371/journal.pgph.0003556, the “median parasitemia in pregnant women with latent EBV was lower than in those with EBV reactivation … [This] study revealed that lytic reactivation of EBV may be associated with the severity of malaria in pregnant women.”
Tiedje KE & al. “introduce a new endpoint ‘census population size’ to evaluate the epidemiology and control of Plasmodium falciparum infections, where the parasite, rather than the infected human host, is the unit of measurement.” As they state in Measuring Changes in Plasmodium falciparum Census Population Size in Response to Sequential Malaria Control Interventions, medRxiv [Preprint]. 2024 Jul 31: 2023.05.18.23290210, https://doi.org/10.1101/2023.05.18.23290210, the method depends on genetic differences of various parasite strains. By their method, they calculate that despite the significant reduction in clinical malaria in the area studied after sequential preventive interventions, the P. falciparum census population size did not vary much. MedRxiv is a free online archive and distribution server for unpublished manuscripts, or preprints, in the medical, clinical, and related health sciences. These articles have not been peer reviewed.
Spatiotemporal studies
Oyewole TA & al., Plasmodium falciparum Transmission Based on Merozoite Surface Protein 1 (Msp1) and 2 (Msp2) Gene Diversity and Antibody Responses in Ibadan, Nigeria, Parasite Epidemiol Control, 2024 Jul 4: 26:e00366, https://doi.org/10.1016/j.parepi.2024.e00366.
Osborne A & al., Plasmodium falciparum Population Dynamics in East Africa and Genomic Surveillance Along the Kenya-Uganda Border, Sci Rep, 2024 Aug 5; 14(1):18051, https://doi.org/10.1038/s41598-024-67623-4.