Akira Kaneko Project - Malaria elimination on islands
Malaria is a disease related to poverty. Islands provide a natural environment for ecological experiments and a great potential for intervention studies. Cooperating with endemic communities on islands in Vanuatu, Oceania since 1987 and in Lake Victoria, Kenya since 2008, Akira has studied the feasibility and sustainability of malaria elimination with the ultimate aim of proposing a community-directed strategy of sustainable malaria freedom and development towards global malaria eradication.
Human and parasite polymorphism on islands in Lake Victoria: implications for mass drug administration and malaria elimination
Using island models in Lake Victoria, Kenya, we examine the feasibility of malaria elimination in tropical Africa. Today, 11 countries in Africa are embarking upon malaria elimination. Although malaria elimination should be feasible for countries in peripheral Africa with low and unstable malaria transmission, it is unclear how feasible it is to eliminate malaria in tropical Africa, where malaria transmission is hyper-endemic.
Kenya launched its second National Malaria Strategy for the period 2009-2017 with a notably ambitious vision for a “malaria free Kenya”. We believe that the current scaling-up of interventions in the national malaria control programs (ITN, ACT, & RDT) is capable of bringing parasite rates down to lower than 1% in low to moderate transmission settings. However these tools are not sufficient in hyper-endemic settings such as our project site in Lake Victoria, Kenya, where more specific measures are necessary in the attack phase.
Low-density submicroscopic infections, most of which are asymptomatic, represent a major challenge for malaria elimination programs. Interventions that aim to eliminate malaria should ideally include all symptomatic and asymptomatic parasite carriers. While sensitive molecular detection methods are increasingly common in malariometric surveys, logistical difficulties prevent the detection of all parasitemic individuals prior to drug administration. However, this can be circumvented by treating all individuals in mass drug administration (MDA) campaigns, regardless of parasitaemia.
Together with schizontocidal drugs primaquine has been an important but underused partner drug. The main limitation to the use of primaquine is the risk of hemolysis in patients who are glucose 6-phosphate dehydrogenase (G6PD) deficient. Recent review of studies suggests that a lower primaquine dose would be equally effective but safer. These lower doses could be safely deployed together with ACTs without prior testing of G6PD status in Africa to interrupt malaria transmission. Human cytochrome P-450 isoenzyme 2D6 (CYP2D6) may be a key enzyme involved in metabolizing primaquine into redoxactive metabolites that kill gametocytes.
On Aneityum island in Vanuatu, Oceania, we previously demonstrated that malaria can be eliminated on isolated islands with well-adapted short-term MDA and sustained vector control if there is a high degree of community participation (Kaneko A, et al. Lancet 2000). We intend to apply the Aneityum strategy to our study site on islands in Lake Victoria, to examine whether malaria can be eliminated by well-adapted short-term mass drug administration of ACT with a low dose of primaquine and sustained vector control with a high degree of community participation. We specifically aim to examine: 1) the efficacy (against P. falciparum gametocytes) and safety (risk of intravascular hemolysis) of a low dose of primaquine with ACT, in relation to CYP2D6 and G6PD status, respectively, 2) the impacts of MDA on P. falciparum population dynamics, and 3) the roles of community involvement in malaria elimination. We ultimately aim to address the feasibility of malaria elimination in hyper-endemic settings, and to propose a community-directed malaria elimination strategy for tropical Africa.
Insecticide-treated ceiling nets to combat malaria in tropical Africa
Novel vector control tools, such as Olyset®Plus ceiling net (2% permethrin+1% piperonyl butoxide), are needed to fight the malaria resurgence reported since 2016, especially in sub-Saharan Africa. We evaluated the protective effectiveness of adding Olyset®Plus ceiling net to existing control interventions on Plasmodium falciparum malaria prevalence and incidence.
We conducted a two-arm, parallel-group, superiority cluster randomized controlled trial with 10 clusters per arm from November 2021–May 2023 on Mfangano Island in western Kenya. Olyset®Plus ceiling nets were installed in eligible households in the intervention arm. The primary outcome, malaria prevalence in children (3–15 years old) at 12 months post-intervention, was measured during cross-sectional school surveys. The secondary outcome, cumulative malaria incidence in all age groups during a 12-month follow-up post-intervention, was tracked monthly for 12 months in a community cohort. Malaria infection was determined using a malaria rapid diagnostic test (Paracheck-Pf® Orchid Biomedical Systems, India).
Olyset®Plus ceiling nets were installed in 1006 houses (mean coverage: 93.4%). Eight hundred six eligible children were recruited in the control- and 831 in the intervention- arms to determine malaria prevalence. At 12 months post-intervention, malaria prevalence was 30.1% (95%CI: 27.1–33.3) in the control- and 16.4% (14.0–19.2) in the intervention- arms (prevalence ratio 0.55; 95% CI: 0.33–0.91, p=0.056). Two hundred six eligible persons were recruited in the control- and 266 in the intervention- arms to determine malaria incidence. During the 12-month follow-up, malaria incidence was 0.11 per person-year (ppy) (0.07–0.15) in the control- and 0.05 (0.02–0.09) ppy (1.21–1.65) in the intervention- arms (incidence rate ratio 0.47; 95% CI: 0.24–0.95, p=0.030).
Olyset®Plus ceiling nets protect against malaria in addition to the effects of existing control interventions. Multi-county studies across different malaria transmission intensities are needed for wider adoption to complement existing vector control interventions.
Artemisinin resistance has now emerged in eastern Africa, and urgent action is needed to prevent a surge in malaria-related morbidity and mortality. In the past, the spread of antimalarial resistance resulted in millions of avoidable deaths. Without radical action, this history will repeat itself. We propose a multipronged approach to reduce and permanently interrupt malaria transmission in East Africa, including the insecticide-treated ceiling nets (Dhorda M, Kaneko A, et al. Science 2024).
Homabay Laboratory to understand human immune responses to malaria
Mtakai Ngara
Introduction
Having received the 2020 International Postdoc grant from VR, I embarked on establishing a study aimed at understanding human immune response to malaria in the Lake Victoria Basin in Western Kenya. While Kenya has recorded a decline in malaria prevalence, a national average less than 10% including the coastal region, the disease has been persistent within the Lake Victoria basin and the neighboring mainland with certain hotspots reporting over 40% prevalence. It is also an area where the Malaria Island group led by Prof. Kaneko, have conducted several epidemiological, vectoral and transmission studies for more than a decade and are currently running an integrated malaria elimination project.
Research work and interests
While single cell genomics have had massive impact on life sciences these technologies remain unexplored in malaria endemic settings where resources are often limited, and the infrastructure is underdeveloped. In my studies, I am interested in optimizing and applying single cell transcriptomics (especially scRNA-seq) to the host (human) immune cells with the aim of describing how they shape the distinct phenotypes from malaria infections. In our ongoing integrated malaria control studies along Lake Victoria basin, we have observed heterogeneity in infections with clear phenotypes of disease severity. These are symptomatic (submicroscopic, mild/moderate and severe) or asymptomatic (sub-microscopic and microscopic) infections. However, the mechanism(s) underpinning these different fates is unclear, especially in populations living in malaria endemic settings. With the global aim to eliminate malaria, the molecular understanding and control of asymptomatic and submicroscopic infections is also critical. These infections are often undetected and untreated, thereby forming an important source of gametocytes for local mosquito vectors and onward transmission and have become a major obstacle in the context of global malaria eradication.
To this end, we are currently optimizing and using scRNA-seq protocols that do not require expensive and technically demanding cell isolation platforms (e.g. microfluidics, FACS) to profile the primary immune cells from high resolution longitudinal cohorts. These protocols would enable getting sequencing-ready libraries as close to the research setting as possible and mitigate the immense logistical challenge of shipping live cells to distant laboratories for processing. For 12 months we have actively monitored a cohort of healthy individuals aged 5 - 65 years, established an efficient and safe field protocol for sampling and processing participants’ samples both at the field and our reference laboratory in Homa Bay County referral hospital. Additionally, we have successfully carried out PBMC and plasma isolation creating a rich biobank that would enable a broad range of cellular investigations including a multi-omic approaches using complementing technologies in both existing and anticipated collaborations.
With the above samples and technologies, I am interested in investigating the following questions in the short term:
- Which T cell subpopulations (starting with CD8+ T cells) correlate with infection and disease outcomes in malaria endemic settings?
- Which distinct TCR repertoire exist within the population and how do they modulate immune response during malaria infection and disease?
- What potential mechanism(s) are employed by these T cell subpopulations, with defined TCR makeup, in determining malaria phenotypes? What are their target parasite antigens?
- Which T cell clonal dynamics correlate with malaria phenotypes in field setting?
- Can pool-split barcoding strategy in scRNA-seq accurately profile immune cells, in malaria transmission setting?
The immune state, both in disease and health, is complex and requires an integrated approach. Hence in the long term I am interested in gaining a holistic understanding of the host immune response and how it shapes the distinct malaria infection outcomes. By leveraging other molecular modalities (cytokines, TCR repertoires, antibodies) and using machine learning methods we could determine predictive immune cell repertoires and states that are significant to host response and establish putative diagnostic and vaccine targets. Additionally, enhancing genomics research capacity in remote and resource constrained settings is a key pursuit. This would allow for the advanced understanding of important but often understudied infectious diseases and broaden genomics knowledge by including diverse populations.
Capacity building and infrastructure
For the last three years we have assembled a network of researchers and students from Sweden, mainly from KI, Japan and Kenyan Universities, established a reference molecular laboratory at the Homa Bay County hospital where we can undertake malaria parasite microscopy, PCR, blood sample processing, PBMC isolations and storage (liquid nitrogen, -80C freezers). Since the project’s inception, we have trained 7 medical research students, most of them assigned to us by the hospital and Kenyan universities, 3 interns and 4 hospital staff on basic molecular techniques (e.g., DNA/RNA purification from blood, PCR, Gel electrophoresis), PBMC isolation, sample handling and storage and insights in malaria research. We have established a mutually beneficially relationship with the hospital’s laboratory providing access to some equipment and consumables (e.g., purified water/de-ionized water, Sysmex system for parasitology).
Bio
Akira Kaneko graduated from Hirosaki University School of Medicine, Japan in 1982 (M.D.) and after clinical training got D.T.M.&H. from Mahidol University, Thailand in 1984 As malariologist AK worked in the coastal Asahan, North Sumatra, Indonesia, 1985-1987 (JICA), and on islands in Vanuatu, 1987 - 1994 (WHO). He was Associate Professor in Tokyo Women's Medical University, 1994-2004. Akira Kaneko defended thesis, Malaria on islands in 1999 (PhD) and got docent in 2004 at Karolinska Institutet.
He has organized multidisciplinary malaria research ventures between Sweden, Japan, UK and USA since 1995 with partners from Vanuatu, PNG, Malawi, Kenya, Ghana, Cambodia, Madagascar and Zanzibar.
Akira Kaneko has been Professor of Global health, Karolinska Institutet since 2011 and holds Island Malaria Group at MTC. He is also affiliated to Osaka City University Graduate School of Medicine and Nagasaki University Institute of Tropical Medicine, Japan.
Akira Kaneko has been academic coordinator to Japan since 2011.
Group members
Akira Kaneko Publications
Dhorda M, Kaneko A, Komatsu R, Kc A, Mshamu S, Gesase S, Kapologwe N, Assefa A, Opigo J, Adoke Y, Ebong C, Karema C, Uwimana A, Mangara JN, Amaratunga C, Peto TJ, Tripura R, Callery JJ, Adhikari B, Mukaka M, Cheah PY, Mutesa L, Day NPJ, Barnes KI, Dondorp A, Rosenthal PJ, White NJ, von Seidlein L. Artemisinin-resistant malaria in Africa demands urgent action. Science. 2024 Jul 19;385(6706):252-254. doi: 10.1126/science.adp5137. Epub 2024 Jul 18. PMID: 39024426.
Matsumoto T, Nagashima M, Kagaya W, Kongere J, Gitaka J, Kaneko A. Evaluation of a financial incentive intervention on malaria prevalence among the residents in Lake Victoria basin, Kenya: study protocol for a cluster-randomized controlled trial. Trials. 2024;25(1):165. doi: 10.1186/s13063-024-07991-4. PMID: 38438925; PMCID: PMC10913238.
Sekine S, Chan CW, Kalkoa M, Yamar S, Iata H, Taleo G, Kc A, Kagaya W, Kido Y, Kaneko A. Tracing the origins of Plasmodium vivax resurgence after malaria elimination on Aneityum Island in Vanuatu. Commun Med (Lond). 2024 May 18;4(1):91. doi: 10.1038/s43856-024-00524-9. PMID: 38762604; PMCID: PMC11102431.
Kagaya W, Chan CW, Kongere J, Kanoi BN, Ngara M, Omondi P, Osborne A, Barbieri L, Kc A, Minakawa N, Gitaka J, Kaneko A. Evaluation of the protective efficacy of Olyset®Plus ceiling net on reducing malaria prevalence in children in Lake Victoria Basin, Kenya: study protocol for a cluster-randomized controlled trial. Trials. 2023 May 25;24(1):354. doi:10.1186/s13063-023-07372-3. PMID: 37231429; PMCID: PMC10210418.
Kalenda NK, Tshibangu-Kabamba E, Nakagama Y, Kaku N, Kaneko A, Speybroeck N, Kido Y. Usefulness of seasonal malaria chemoprevention in the Sahel. Lancet Infect Dis. 2023:269-270. doi: 10.1016/S1473-3099(22)00654-5. Epub 2022 Oct 31. PMID: 36327998.
Idris ZM, Chan CW, Kongere J, Hall J, Logedi J, Gitaka J, Drakeley C, Kaneko A. Naturally acquired antibody response to Plasmodium falciparum describes heterogeneity in transmission on islands in Lake Victoria. Sci Rep. 2017 Aug 22;7(1):9123. doi:10.1038/s41598-017-09585-4.
Idris ZM, Chan CW, Kongere J, Gitaka J, Logedi J, Omar A, Obonyo C, Machini BK, Isozumi R, Teramoto I, Kimura M, Kaneko A. High and heterogeneous prevalence of asymptomatic and sub-microscopic malaria infections on islands in Lake Victoria, Kenya. Sci Rep. 2016 Nov 14;6:36958. doi: 10.1038/srep36958.
Chan CW, Sakihama N, Tachibana S, Idris ZM, Lum JK, Tanabe K, Kaneko A. Plasmodium vivax and Plasmodium falciparum at the crossroads of exchange among islands in Vanuatu: implications for malaria elimination strategies. PLoS One. 2015 Mar 20;10(3):e0119475. doi: 10.1371/journal.pone.0119475. eCollection 2015. PubMed PMID: 25793260; PubMed Central PMCID: PMC4368729.
Kaneko A, Chaves LF, Taleo G, Kalkoa M, Isozumi R, Wickremasinghe R, Perlmann H, Takeo S, Tsuboi T, Tachibana S, Kimura M, Björkman A, Troye-Blomberg M, Tanabe K, Drakeley C. Characteristic age distribution of Plasmodium vivax infections after malaria elimination on Aneityum Island, Vanuatu. Infect Immun. 2014 Jan;82(1):243-52. doi: 10.1128/IAI.00931-13. Epub 2013 Oct 28. PubMed PMID: 24166950; PubMed Central PMCID: PMC3911855.
Awah N, Kaneko A. Iron deficiency and severe Plasmodium falciparum malaria. Clin Infect Dis. 2012; ;54:1145-7. DOI: 10.1093/cid/cis020.
Kaneko A. A community-directed strategy for sustainable malaria elimination on islands: short-term MDA integrated with ITNs and robust surveillance. Acta Trop 2010; 114:177-83.
Yoshiura K, Kinoshita A, Ishida T, Ninokata A, Ishikawa T, Kaname T, Bannai M, Tokunaga K, Sonoda S, Komaki R, Ihara M, Saenko VA, Alipov GK, Sekine I, Komatsu K, Takahashi H, Nakashima M, Sosonkina N, Mapendano CK, Ghadami M, Nomura M, Liang DS, Miwa N, Kim DK, Garidkhuu A, Natsume N, Ohta T, Tomita H, Kaneko A, Kikuchi M, Russomando G, Hirayama K, Ishibashi M, Takahashi A, Saitou N, Murray JC, Saito S, Nakamura Y, Niikawa N. A SNP in the ABCC11 gene is the determinant of human earwax type. Nat Genet 2006;38:324-330.
Tsukahara T, Hombhanje FW, Lum JK, Hwaihwanje I, Masta A, Kaneko A, Kobayakawa T. Austronesian origin of the 27-bp deletion of the erythrocyte band 3 gene in East Sepik, Papua New Guinea inferred from mtDNA analysis. J Hum Genet 2006; 51: 244-248.
*Hombhanje FW, Hwaihwanje I, Tsukahara T, Saruwatari J, Nakagawa M, Osawa H, Paniu MM, Takahashi N, Lum JK, Aumora B, Masta A, Sapuri M, Kobayakawa T, Kaneko A, Ishizaki T. The disposition of oral amodiaquine in Papua New Guinean children with falciparum malaria. Br J Clin Pharmacol 2004; 59: 298-301.
*Mita T, Kaneko A, Lum JK, Zungu IL, Tsukahara T, Eto H, Kobayakawa T, Björkman A, Tanabe K. Expansion of wild type allele rather than back mutation in pfcrt explains the recent recovery of chloroquine sensitivity of Plasmodium falciparum in Malawi. Mol Biochem Parasitol 2004; 135: 159-163.
*Lum JK, Kaneko A, Tanabe K, Takahashi N, Björkman A, Kobayakawa T. Malaria dispersal among islands: human mediated Plasmodium falciparum gene flow in Vanuatu, Melanesia. Acta Trop 2004; 90: 181-185.
*Bwijo B, Kaneko A, Takechi M, Zungu I L, Moriyama Y, Lum J K, Tsukahara T, Mita T, Takahashi N, Bergqvist Y, Björkman A, Kobayakawa T. High prevalence of quintuple mutant dhps/dhfr genes in Plasmodium falciparum infections seven years after introduction of sulfadoxine and pyrimethamine as first line treatment in Malawi. Acta Trop 2003; 85: 363-373.
*Mita T, Kaneko A, Lum J K, Bwijo B, Takechi M, Zungu I L, Tsukahara T, Kobayakawa T, Björkman A. Recovery of chloroquine sensitivity and low prevalence of Pfcrt K76T in Plasmodium falciparum following withdrawal of chloroquine use in Malawi. Am J Trop Med Hyg 2003; 68: 413-415.
Kaneko A, Taleo G, Kalkoa M, Yamar S, Kobayakawa T, Björkman A. Malaria eradication on islands. Lancet 2000; 356: 1560-1564.
Kaneko A, Lum JK, Yaviong J, Takahashi N, Ishizaki T, Bertilson L, Kobabayakawa T, Björkman A. High and variable frequencies of CYP2C19 mutations: medical consequences of poor drug metabolism in Vanuatu and other Pacific islands. Pharmacogenetics 1999a; 9: 581-590.
Kaneko A, Bergqvist Y, Taleo G, Kobayakawa T, Ishizaki T, Björkman A. Proguanil disposition and toxicity in malaria patient from Vanuatu with high frequencies of CYP2C19 mutations. Pharmacogenetics 1999b; 9: 317-326.
Kaneko A, Bergqvist Y, Takechi M, Kalkoa M, Kaneko O, Kobayakawa T, Ishizaki T, Björkman A. Intrinsic efficacy of proguanil against falciparum and vivax malaria independent of the metabolite cycloguanil. J Infect Dis 1999c;179:974-979．
Kaneko A, Taleo G, Kalkoa M, Yaviong J, Reeve P A, Ganczakowski M, Shirakawa C, Palmer K, Kobayakawa T, Björkman A. Malaria epidemiology, glucose 6-phosphate dehydrogenase deficiency and human settlement in Vanuatu Archipelago. Acta Trop 1998; 70: 285-302.
Kaneko A, Kaneko O, Taleo G, Björkman A, Kobayakawa T. High frequencies of CYP2C19 mutations and poor metabolism of proguanil in Vanuatu. Lancet 1997;349: 921-922.
Ganczakowski M, Town M, Bowden DK, Vulliamy TJ, Kaneko A, Clegg JB, Weatherall DJ, Luzzatto L. Multiple glucose 6-phosphate dehydrogenase-deficient variants correlate with malaria endemicity in the Vanuatu Archipelago (South-western Pacific). Am J Hum Genet 1995; 56: 294-301.
Kaneko A, Kamei K, Suzuki T, Ishii A, Siagian R, Panjaitan W. Gametocytocidal effect of primaquine in a chemotherapeutic malaria control trial in North Sumatra, Indonesia. Southeast Asian J Trop Med Public Health 1989a;20:351-359.