Open research questions in Malaria Research and Control

What the literature leaves open

• Causal inference from environmental pollutant exposure through microbiome dysbiosis to human malaria incidence has not been directly established; the evi- dence base consists primarily of laboratory-based associa- tions and experimentally inferred mechanisms with limited field validation. The microbiome may represent a potentially relevant but currently understudied determinant of transmission outcomes.

  The Invisible Intermediary: Environmental Drivers of the Anopheles Microbiome in Malaria Transmission · 2026 · DOI

• Despite their widespread use, these techniques remain poorly validated under realistic operational conditions, with limited evidence on their precision and accuracy across different parity rates, GC, and species.

  How reliable is the use of ovarian dilatations for mosquito age-grading? A blinded multi-rater validation of the Polovodova method in Anopheles mosquitoes. · 2026 · DOI

• Piperaquine (PPQ), an important partner drug in artemisinin-based combination therapies exhibits a unique bimodal dose-response phenotype associated with reduced susceptibility, yet the biological mechanism underlying this phenotype remains unknown.

  A Multidimensional Analysis of the Bimodal Piperaquine Response in Plasmodium falciparum · 2026 · DOI

• WHO prequalification (PQ) and UN procurement In 2021 WHO recommended use of RTS,S/AS01 for children in malaria prone regions. In 2023 WHO updated guidelines to include R21/Matrix‑M as alternative or complement to RTS,S/AS01 PQ assesses quality, safety, efficacy, and manufacturing to enable UN procurement.

  Advances in the development of malaria vaccines · 2026 · DOI

• Because criteria to define motile SPZs are dependent on the study and are often qualitative, it remains unclear if sub-selection of motile tracks introduces biases in characterization of SPZ movement in vivo.

  Data selection choices influence the inferred movement patterns of Plasmodium sporozoites in skin · 2026 · DOI

• 65. Fox, R., Kitt, J., Leeson, P., Aye, C. Y. & Lewandowski, A. J. Preeclampsia: risk factors, diagnosis, management, and the cardiovascular impact on the offspring. J. Clin. Med. 8, 1625 (2019). 66. Luo, Z. C. et al. The effects and mechanisms of primiparity on the risk of pre-eclampsia: a systematic review. Paediatr. Perinat. Epidemiol. 21, 36–45 (2007). 67. Akinnawo, A. et al. Assessing the relationship between gravidity and placental malaria among pregnant women in a high transmission area in Ghana. Malar. J. 21, 240 (2022). 68. Magee, L. A., Nicolaides, K. H. & Von Dadelszen, P. Preeclampsia. N. Engl. J. Med. 386, 1817–1832 (2022). 69. Nagashima, M. et al. A loss of tuning of both pro-coagulant and 70. inflammatory responses in monocytes in patients with preeclampsia. J. Reprod. Immunol. 166, 104334 (2024). Imamura, T., Sugiyama, T., Cuevas, L. E., Makunde, R. & Nakamura, S. Expression of tissue factor, the clotting initiator, on macrophages in Plasmodium falciparum–infected placentas. J. Infect. Dis. 186, 436–440 (2002).

  Evidence and opportunities for preeclampsia and cardiovascular disease prevention in malaria endemic settings · 2026 · DOI

• McDonald, C. R. et al. Malaria in pregnancy alters l-arginine 46. Venkatesan, M., Alifrangis, M., Roper, C. & Plowe, C. V. Monitoring bioavailability and placental vascular development. Sci. Transl. Med. 10, eaan6007 (2018). antifolate resistance in intermittent preventive therapy for malaria. Trends Parasitol. 29, 497–504 (2013). 28. Dorman, E. et al. Impaired uteroplacental blood flow in pregnancies complicated by falciparum malaria. Ultrasound Obstet. Gynecol. 19, 165–170 (2002). 29. Griffin, J. B. et al. Plasmodium falciparum parasitaemia in the first half of pregnancy, uterine and umbilical artery blood flow, and foetal growth: a longitudinal Doppler ultrasound study. Malar. J. 11, 319 (2012). 30. Tatsuya, & M. Complement activation by an angiogenic imbalance leads to systemic vascular endothelial dysfunction: a new proposal for the pathophysiology of preeclampsia. J. Reprod. Immunol. 103322. https://doi.org/10.1016/j.jri.2021.103322 (2022). 31. Conroy, A. L. et al. Complement activation and the resulting placental vascular insufficiency drives fetal growth restriction associated with placental malaria. Cell Host Microbe13, 215–226 (2013). 32. Muehlenbachs, A. M. T., Edmonds, S., Fried, M. & Duffy, P. E. Hypertension and maternal–fetal conflict during placental malaria. PLoS Med. 3, e446 (2006). 33. Bujold, E. et al. Evidence supporting that the excess of the sVEGFR-1 concentration in maternal plasma in preeclampsia has a uterine origin. J. Matern. Fetal Neonatal Med. 18, 9–16 (2005). 34. Staff, A. C. et al. Failure of physiological transformation and spiral artery atherosis: their roles in preeclampsia. Am. J. Obstet. Gynecol. 226, S895–S906 (2022). 35. Yin J., et al. The role of ANGPT2 in pathogenesis of preeclampsia. Placenta. (2025). 36. Satapathy, P. et al. Adverse pregnancy outcomes in maternal malarial infection: a systematic review and meta-analysis. N. Microbes N. Infect. 62, 101474 (2024). 37. Thompson, J. M. et al. Relationship between pregnancy-associated malaria and adverse pregnancy outcomes: a systematic review and meta-analysis. J. Trop. Pediatrics 66, 327–338 (2020). 38. Kosińska-Kaczyńska, K. Placental syndromes—a new paradigm in perinatology. Int. J. Environ. Res. Public Health 19, 7392 (2022). 39. Obiri, D. et al. Histopathological lesions and exposure to Plasmodium falciparum infections in the placenta increases the risk of preeclampsia among pregnant women. Sci. Rep. 10, 8280 (2020). 40. World Health Organization. WHO evidence review group on intermittent preventive treatment (IPT) of malaria in pregnancy. Accessed 7th April 2026, https://www.who.int/docs/default-source/ malaria/mpac-documentation/mpac-sep13-erg-ipt-malariapregnancy-report.pdf. 41. Diawara, H. et 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. 24, 1366–1382 (2024). 42.

  Evidence and opportunities for preeclampsia and cardiovascular disease prevention in malaria endemic settings · 2026 · DOI

• malaria-endemic countries should capture malaria status, timing of infec- tion, and use of IPTp-SP in women with preeclampsia or eclampsia. Finally, this agenda must be framed within a broader equity and climate-justice lens. Climate change is shifting the geographic distribution and seasonality of malaria transmission, including expansion into pre- viously low-risk areas, with disproportionate implications for pregnant women and health systems in resource-limited settings, thereby compli- to preeclampsia prevention59,60. Beyond cating existing approaches immediate pregnancy outcomes, both malaria in pregnancy and hyper- tensive disorders of pregnancy may have intergenerational effects, with evidence linking these exposures to altered fetal development and long-term cardiometabolic risk in offspring61,62. Evidence linking Plasmodium falci- parum infection and placental malaria to preeclampsia, together with strong biological plausibility and overlapping epidemiologic patterns, calls for a re- examination of current preeclampsia risk and broader hypertensive dis- orders of pregnancy models and prevention strategies.

  Evidence and opportunities for preeclampsia and cardiovascular disease prevention in malaria endemic settings · 2026 · DOI

• factor and decreased angiopoietin-1 and increased angiopoietin-2 levels, resulting in an elevated angiopoietin-2/angiopoietin-1 (Angpt2/1) ratio alongside other placental pathology such as syncytial knots that impair nutrient and oxygen transfer to the fetus14,24,30–35. These pathological changes are associated with similar adverse pregnancy outcomes, such as intrau- terine growth restriction, low birthweight, and preterm births36,37 (Table 1). These pathological changes can be conceptualized within the framework of Placental Associated Syndromes (PAS), a unifying concept that encom- passes conditions arising from abnormal placentation and placental vas- cular dysfunction, including malaria in pregnancy, preeclampsia, placental abruption, fetal growth restriction, and intrauterine fetal death38. Histopathologic analysis from Ghana demonstrates that both active and past placental malaria markedly increase the risk of preeclampsia, with active infections associated with a more than 6-fold increase (adjusted OR = 6.7, 95% CI: 2.3, 19.1) and past infections with a more than 12-fold increase (adjusted OR 12.4, 95% CI 3.0, 51.0). Overall, in the full cohort, 64 (48.1% of 133) placentas had active parasitemia (acute and chronic infec- tions), 21 (15.8% of 133) had evidence of past infection, and 48 (36.1% of 133) showed no infection. In addition, malaria-related placental lesions independently elevated preeclampsia risk (AOR 3.0, 95% CI 1.2–7.5)39. Together, these epidemiologic and mechanistic findings suggest that in malaria-endemic regions, Plasmodium falciparum infection in particular represents a plausible, biologically grounded, but overlooked contributor to the high burden of hypertensive disorders of pregnancy, especially preeclampsia.

  Evidence and opportunities for preeclampsia and cardiovascular disease prevention in malaria endemic settings · 2026 · DOI

• design, exposure timing, and populations, which further limits comparability. These gaps highlight the need for well-designed prospective studies with standardized definitions17. Malaria in pregnancy caused by Plasmodium falciparum can result in placental malaria through sequestration of infected erythrocytes within the placenta7–9. Placental malaria and preeclampsia share pathophysiological mechanisms through endothelial dysfunction, impaired angiogenesis, impaired trophoblast invasion, and inadequate spiral artery remodeling leading to placental insufficiency (Table 1). In placental malaria, Plasmodium falciparum-infected erythrocytes expressing VAR2CSA, a malariaspecific protein, bind to placental chondroitin sulfate A, resulting in placental sequestration and localized inflammatory responses within the intervillous space7–9. This sequestration promotes accumulation of monocytes and macrophages and elevated tumor necrosis factor-α (TNF-α), inflammation and dysfunction, as contributing to chronic placental observed in human placental studies and supported by experimental models19,20. Similarly, preeclampsia is characterized by placental inflammation with immune cell infiltration and elevated TNF-α, reinforcing shared inflammatory pathways across both conditions20. Enhanced placental inflammation is associated with increased intervillous and perivillous fibrin deposition in both placental malaria and preeclampsia10,11. This may contribute to ischemia-reperfusion injury and placental malperfusion in both contexts21,22. Physical disruption of syncytiotrophoblast is another shared characteristic, with breakages of the syncytium and oxidative damage contributing to cellular damage and dysfunction23,24. While these changes have been reported in preeclampsia and placental malaria, reported prevalence varies widely across studies and is not directly comparable between conditions10,19,23,24 (Table 1). Endothelial dysfunction represents another mechanism of overlap. Both placental malaria and preeclampsia are associated with reduced nitric oxide bioavailability, endothelial activation, and loss of vascular integrity, leading to widespread vascular dysfunction and impaired uteroplacental blood flow25,26. In placental malaria, human studies demonstrate reduced nitric oxide bioavailability, with higher circulating dimethylarginine (ADMA) (P < 0.05) and symmetric dimethylarginine (SDMA) (P < 0.001) and a lower L-arginine/ADMA ratio (P < 0.01) in infected women compared with uninfected controls27. Additionally, impaired trophoblast invasion and incomplete spiral artery remodeling are well-established features of preeclampsia and have also been suggested in malaria in pregnancy, potentially contributing to reduced placental perfusion and insufficiency13,14,28,29.

  Evidence and opportunities for preeclampsia and cardiovascular disease prevention in malaria endemic settings · 2026 · DOI

• Evidence and opportunities for preeclampsia and cardiovascular disease prevention in malaria endemic settings https://doi.org/10.1038/s43856-026-01729-w Ifeoma M. Obionu1, Julie M. Moore 2,3, Safiya Zahradeen4, Hadiza Galadanci5, Mark D.

  Evidence and opportunities for preeclampsia and cardiovascular disease prevention in malaria endemic settings · 2026 · DOI

• infection burdens future features, elimination. Parasitology, 138(12), 1559-1568. and Sinka, M. E., Pironon, S., Massey, N. C., Longbottom, J., Hemingway, J., Moyes, C. L., & Willis, K. J. (2020). A new malaria vector in Africa: Predicting the expansion range of Anopheles stephensi and identifying the urban populations at risk. Proceedings of the National Academy of Sciences, 117(40), 24900- 24908. Sovi, A., Adoha, C. J., Yovogan, B., Cross, C. L., Dee, D. P., Konkon, A. K.,... & Messenger, L. A. (2024). The effect of next-generation, dual-active-ingredient, long-lasting insecticidal net deployment on insecticide resistance in malaria vectors in Benin: results of a 3-year, three-arm, cluster-randomised, controlled trial. The Lancet Planetary Health, 8(11), e894-e905. Wei, Y. L., Wu, Z., Li, R. L., & Tang, F. (2026). Review of selected mosquito-borne diseases: arboviruses (dengue, chikungunya, Zika, West Nile, Japanese lymphatic encephalitis, yellow fever) and parasitic diseases (malaria, Filariasis). Frontiers in Public Health, 13, 1712094.

  Investigating Mosquito Borne Parasitic Diseases and Vector Control Strategies · 2026 · DOI

• 1. Increase ITN coverage and use by verifying the number of usable nets per sleeping space, replacing damaged nets conducting household follow-up after distribution.

  FACTORS CONTRIBUTING TO THE RISING PREVALENCE OF MALARIA IN COPPERBELT PROVINCE, ZAMBIA: A CROSS-SECTIONAL STUDY IN KAWAMA EAST COMPOUND · 2026 · DOI

• The major strength of the study is its local focus. By concentrating on Kawama East Compound, the study provides practical evidence for districtlevel planning rather than relying only on national or provincial averages. The sample size of 355 participants allowed meaningful descriptive and regression analysis, and inclusion of demographic, preventive and environmental variables made the analysis relevant for public health action. The study also has limitations. Because the design was cross-sectional, associations cannot be interpreted as proof of causation. Self-reported preventive behaviour may be affected by recall or social desirability bias. Some variables, such as household income, housing quality, net condition, timing of mosquito exposure and laboratory confirmation details, were not deeply measured in the converted research paper. Future include direct household studies observation, and longitudinal follow-up across rainy and dry seasons.

  FACTORS CONTRIBUTING TO THE RISING PREVALENCE OF MALARIA IN COPPERBELT PROVINCE, ZAMBIA: A CROSS-SECTIONAL STUDY IN KAWAMA EAST COMPOUND · 2026 · DOI

• Parasite-induced host cell remodeling is essential for Plasmodium falciparum survival during the intraerythrocytic developmental cycle (IDC), yet the transcriptional regulatory mechanisms that coordinate this process remain poorly understood.

  Malaria parasites coordinate host cell remodeling through the AP2-HCR DNA-binding protein · 2026 · DOI

• FGDs and IDIs as data collection methods allowed for a comprehensive exploration of participants’ experiences and percep- tions, tapping into the richness and depth of their everyday lives. Conducting interviews in Pidgin English, Ijaw, and English based on participants’ linguistic preferences ensured effective communication and understanding. This study, however, has several limitations. First, it was conducted in two rural communities in Bayelsa State, which may limit the transferability of findings to other regions or urban settings with different sociocultural and health system contexts. However, the insights gen- erated provide a valuable, context-specific understanding of factors influencing IPTp-SP uptake in rural Nigerian settings. Second, some interviews were conducted in Ijaw or Nigerian Pidgin and later translated into English for analysis, intro- ducing the potential for translation bias or loss of nuanced meanings. To minimize this risk, translations were reviewed by bilingual research assistants familiar with the local dialects and context, and the research team engaged in regular discus- sions to confirm the accuracy and intent of translated expressions. Third, the cross-sectional design limits the ability to assess attitude–behaviour consistency over time. Longitudinal stud- ies could provide deeper insight into how women’s beliefs and intentions regarding IPTp-SP evolve across pregnancy and influence actual preventive health behaviors.

  “No culture stops me from taking tablets”: Exploring community-level factors influencing pregnant women’s IPTp-SP uptake in Nigeria · 2026 · DOI

• Our study had several limitations. We were unable to distinguish between initial and relapse infections in our incidence data, a limitation shared with prior observational studies of Pv66,67. We would expect that weather would influence initial and relapse cases over different lag periods, but our analysis was not able to investigate this. A follow-up study using genomic methods or a longitudinal cohort study with temporally dense testing to differentiate between initial and relapse infections could elucidate if weather differentially influences primary versus relapse infections. We were also unable to distinguish which cases were identified via passive versus active case detection, which were done as malaria control efforts by the Peruvian Ministry of Health, greatly affecting case detection and potentially creating bias in our results. However, these interventions were rare and generally done as a reaction to higher passively detected caseloads, suggesting that passive surveillance-detected incidence was already higher when active case detection was done. The study period also included two years (2021 and early 2022) where control efforts for the COVID-19 pandemic likely limited malaria transmission as well. While we selected ERA-5 Land remote sensing data for its temporal coverage and lack of missingness, its 11 km spatial resolution prevented identification of small-scale microclimates, such as those created by forest cover and topographical features, and thus did not capture small- resolution variation that may have a large effect on mosquito breeding and survival habitat.68 Fine-resolution drone imagery,68 as used in other studies, may help overcome this limitation. While we initially considered land cover variables, they were limited in statistical power. Additionally, publicly available surface water data did not reflect our ground observations of surface water in the study site, so we did not include it in this analysis. Further research that considers the influence of non-weather environmental covariates could help elucidate the complicated, heterogeneous dynamics of malaria transmission in this region, and consider mediation under changing climatic conditions. This study was also correlational, and inferred relationships with individual weather variables may be confounded by collinearity and ARTICLE IN PRESSACCEPTED MANUSCRIPTARTICLE IN PRESS correlation with other weather variables and thus made it difficult to tease out individual direct effects. CONCLUSIONS In our study of malaria incidence in Amazonian Peru, we observed generally positive associations with higher temperatures and higher rainfall for extended lag periods beginning 4–5 weeks after an initial weather event and enduring for 1–4 months. We also found lower incidence during El Niño years and higher incidence in riverine communities, which may be used to concentrate resources and time malaria interventions to achieve elimination in this setting. Our findings indicated that malaria burden in this region may be positively associated with higher temperatures. As the successes or failures of malaria interventions may be in part due to weather initiating long-lasting Pv malaria cycles, these findings provide critical context to ongoing malaria elimination efforts in the Amazon region. DECLARATIONS Ethics approval and consent to participate This study was approved by the Institutional Review Board of Stanford University (72291) and by the Dirección Universitaria de Asuntos Regulatorios de la Investigación de la Universidad Peruana Cayetano Heredia (211747).

  Associations between weather and Plasmodium vivax malaria in an Amazonian elimination setting: a distributed lag analysis from 2017 to 2024 · 2026 · DOI

• ovale; – laboratory errors: these errors were caused by insufficient knowledge of parasite morphology and improperly prepared specimens [4, 18, 23].

  Epidemiology and clinical features of severe imported falciparum malaria among adults upon hospital admission: a four-year retrospective single-center study in Moscow, Russia · 2026 · DOI

• annua-based and formulations, confirm tolerability, and the safety, therapeutic relevance of the species in allergic, infectious, and oncological conditions, although further phase III trials are warranted to fully validate efficacy and optimize dosing regimens.

  A Review of the Medicinal, Anticancer and Antimicrobial Effects of Artemisia annua · 2026 · DOI

• Indeed, the uniformly high kdr frequen- cies across sites contrasted with the variability in mor- tality rates observed between districts and insecticides, indicating that kdr alone is insufficient to account for the intensity and heterogeneity of pyrethroid resist- ance.

  Widespread pyrethroid resistance and high kdr L995F allele frequencies in Anopheles gambiae sensu lato populations from Southern Benin, West Africa · 2026 · DOI

• PBO is known to inhibit the degradation of pyrethroids and other insecticide classes, but little is known about other biological or behavioural effects of PBO exposure.

  Assessing the additional effects of piperonyl butoxide (PBO) exposure on Anopheles mosquitoes · 2026 · DOI

• Although we were unable to prove a statistically significant impact of LM, likely due to the small number of cases prior to LM, it is important to add to the limited evidence-based for Accelerator Strategies in countries approaching the elimination of malaria.

  Last Mile elimination activities in Cambodia, October 2019 to December 2023 · 2026 · DOI

• Despite decades of global investment in malaria control, under-5 mortality in Sub-Saharan Africa (SSA) remains unacceptably high, and the governance conditions under which malaria programmes translate into child survival gains are poorly understood.

  Malaria and Child Survival in Sub-Saharan Africa: Does Institutional Quality Modify the Malaria-Mortality Relationship? · 2026 · DOI

• One of the most abundant proteins is PfMSP2, which is likely an ancestral protein that has been maintained in the Plasmodium falciparum lineage and is a focus of vaccine development, whose function remains unknown.

  An abundant merozoite surface protein of Plasmodium falciparum modulates susceptibility to inhibitory antibodies · 2026 · DOI

• MaRNAV-1 is an RNA virus recently identified in Plasmodium vivax-infected samples, but definitive evidence that it infects the parasite and influences malaria pathogenesis remains unknown.

  MaRNAV-1, an intracellular virus of Plasmodium vivax, is associated with increased parasite transmission and altered host immune response · 2026 · DOI

Most-cited papers in Malaria Research and Control

• The effect of malaria control on Plasmodium falciparum in Africa between 2000 and 2015 · Nature · 2015 · 2,700 citations
• Safety and efficacy of malaria vaccine candidate R21/Matrix-M in African children: a multicentre, double-blind, randomised, phase 3 trial · The Lancet · 2024 · 341 citations
• The 2023 WHO World malaria report · The Lancet Microbe · 2024 · 316 citations
• Pf7: an open dataset of Plasmodium falciparum genome variation in 20,000 worldwide samples · Wellcome Open Research · 2023 · 140 citations
• An open dataset of Plasmodium falciparum genome variation in 7,000 worldwide samples · Wellcome Open Research · 2021 · 119 citations
• Risk factors for persisting neurological and cognitive impairments following cerebral malaria · Archives of Disease in Childhood · 2005 · 109 citations
• Safety of chloroquine in chemosuppression of malaria during pregnancy. · BMJ · 1985 · 109 citations
• Evidence of artemisinin partial resistance in northwestern Tanzania: clinical and molecular markers of resistance · The Lancet Infectious Diseases · 2024 · 93 citations
• Subcutaneous Administration of a Monoclonal Antibody to Prevent Malaria · New England Journal of Medicine · 2024 · 86 citations
• Hypoglycaemia and antimalarial drugs: quinidine and release of insulin. · BMJ · 1986 · 71 citations

Most recent work

• The Human Chk1 Inhibitor CHIR-124 Shows Multistage Activity Against the Human Malaria Parasite Plasmodium falciparum via Polypharmacological Inhibition of PfArk1 and Hemozoin Formation · bioRxiv · 2026
• Oocyst: knowns and unknowns about the lengthiest life stage of the malaria parasite · Open Biology · 2026
• Impact of introducing RTS,S/AS01E malaria vaccine on mortality in young children in Ghana, Kenya, and Malawi: an observational evaluation of a cluster-randomised implementation programme · The Lancet · 2026
• Indoor residual spraying of distinct insecticide formulations in a household‐scale micro‐mosaic format: Feasibility and effectiveness for malaria vector control in rural Zambia · Medical and Veterinary Entomology · 2026
• Global-scale population genetic analysis of Plasmodium falciparum identifies region-specific patterns of malaria parasite adaptation · Nature Communications · 2026
• De novo assembly of complete Plasmodium falciparum isolate genomes using PacBio HiFi sequencing technology · bioRxiv · 2026
• Distinct <i>Plasmodium falciparum</i> Erythrocyte Membrane Protein 1 Domain Cassette-Associated Antibody Gaps Specific to Cerebral Malaria and Severe Malarial Anemia · The Journal of Infectious Diseases · 2026
• Single-cell analysis of Plasmodium falciparum transcripts after drug perturbation identifies feedback regulation as well as increased transmission potential · bioRxiv · 2026
• Spatial and temporal description of antimalarial drug resistance markers in Ghana using targeted amplicon deep sequencing · Antimicrobial Agents and Chemotherapy · 2026
• An abundant merozoite surface protein of Plasmodium falciparum modulates susceptibility to inhibitory antibodies · bioRxiv · 2026

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