Plasmodium vivax in Sub-Saharan Africa: An Advancing Threat to Malaria Elimination?

Mary Aigbiremo Oboh-Imafidon Postdoctoral Research Fellow I, Malaria Population Biology, Disease Control and Elimination Theme, Medical Research Council, The Gambia Unit at London School of Hygiene and Tropical Medicine, Serrekunda, Gambia;

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Peter A. Zimmerman Professor of International Health, Genetics and Biology, The Center for Global Health & Diseases, Case Western Reserve University, Cleveland, Ohio

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Malaria in sub-Saharan Africa (sSA) is principally due to Plasmodium falciparum.1 The association between P. falciparum and severe morbidity and mortality and its capacity to evolve mechanisms to resist and tolerate historically important drugs (sulfadoxine-pyrimethamine, chloroquine,2 and artemisinins3), requires focus on this dangerous malaria species. Although there are cases of single and mixed species infections of P. malariae and P. ovale with and without P. falciparum,48 cases of P. vivax have been thought to be absent in sSA due to the erythrocyte silent Duffy-negative phenotype across a substantial number of African ethnicities.9,10 As has become a paradigm in the malaria literature, P. vivax appears to require the Duffy antigen to invade human erythrocytes.11 A mutation in the GATA-1 transcription factor binding site of the gene promoter (T->C at nucleotide -33) significantly blocks expression of the Duffy antigen on circulating erythrocytes12 to establish a protective barrier that strongly inhibits P. vivax erythrocyte (but not hepatocyte) invasion.

Over the past 15 years, consistent evidence has accumulated to revise perspectives on P. vivax infections and associated illness in African populations.1319 Much of the evidence emerges when malaria epidemiological studies perform PCR surveys that include detection of P. vivax. In this issue of the AJTMH, van Loon et al. add to evidence demonstrating P. vivax infections in African populations, this time from the Huye District of Rwanda’s Southern Province.20 In their study, they detected P. vivax in 21 individuals, all heterozygous carriers of the Duffy-negative SNP (rs2814778 T/C; Duffy-negative allele frequency 1.5%), in the presence of mono and mixed Plasmodium species infections. The authors provide evidence that uncomplicated malaria due to P. vivax is not rare in southern Rwanda (their PCR-based surveys detected P. vivax in consecutive surveys in 8.2% and 7.9% of malaria patients in 2018 and 2019, respectively), and they call attention to the fact that P. vivax is rarely studied in Rwanda.

Numerous factors beyond Duffy-negative status contribute to the potential for under-estimating P. vivax in sSA. The parasite’s affinity for reticulocytes has been used to explain consistently low density blood stage parasitemia.21 With lower parasitemia, there is an increased chance of misdiagnosis, especially by inexperienced microscopists who have not had sufficient in-depth training to identify P. vivax. This is particularly true in mixed species infections, with which expert microscopists also struggle to identify low density species.22 Routine microscopy training delivered in sSA has under-emphasized the identification of P. vivax in blood samples due to the paradigm of the absence of P. vivax in Duffy-negative Africans. This continues today, when microscopy training under-exposes trainees to slides including P. vivax (in two recent studies <5%23 and <10%24 of slides contained P. vivax) or excludes P. vivax slides in training altogether.25 Moreover, from 2017 to 2021, of 1.57 billion malaria rapid diagnostic kits (RDTs) purchased for use by sSA national malaria control programs, 79.4% were P. falciparum-only tests focused on identifying P. falciparum (Pf histidine rich-protein II tests) with the remainder being combination tests (Pf/Pan tests) lacking P. vivax-specificity.1 Thus, the predominant approach for malaria diagnosis across Africa has no ability to specifically detect P. vivax.1

As the evidence continues to build that P. vivax is transmitted throughout much of Duffy-negative Africa, a pertinent question remains to be answered. Is P. vivax a threat to malaria elimination in Africa? The answer is complex and dependent on the financial resources available for malaria elimination. Vigilance must remain in studying the therapeutic efficacy of ACTs against P. falciparum as the species develops resistance-associated mutations in Pfkelch13 and other markers that reduce the effectiveness of these essential treatments in Africa.26-28 Therefore, pushing to address P. vivax in Africa at the expense of bolstering defenses against P. falciparum would foolishly destabilize malaria elimination. However, the evidence that vivax malaria was annually reported from 2010 to 2021 in only 2 of 45 countries in the WHO African Region (Eritrea and Ethiopia) while being detected in at least 29 countries19,29,30 suggests neglect, potentially facilitating the hidden transmission of vivax malaria and threatening malaria elimination.

Much remains poorly understood regarding P. vivax malaria throughout Africa, including the extent of the hypnozoite reservoir, its biomass distribution in infected individuals, and its mechanisms of pathogenesis.29,31 How might we start to turn the page on our myopic view of this very important malaria parasite? Emphasis to microscopists of all malaria species transmitted in Africa, including in-depth training, is essential. The power of RDTs is only partially being realized—new inexpensive RDTs must be better at diagnosing Plasmodium species diversity and identifying P. vivax specifically. A system must be developed to report species diversity to the WHO because malaria is not a single-species disease. If these initial steps are taken, test-and-treat approaches will need to incorporate reliable and inexpensive point-of-care tests to diagnose glucose-6-phosphate dehydrogenase deficiency to enable safe treatment with primaquine or tafenoquine. It is important to recognize that there are costs with all of these suggested changes, some more than others. However, confronting P. vivax wherever it exists in Africa is critical, as its transmission is certain.

As a result of the new paper by van Loon et al.,20 we are reminded that P. vivax is not only an interesting component of molecular diagnostic surveys: it is also causing malarial illness. Given the overall disregard of P. vivax, there is minimal understanding of its impact on individual and public health. So, while attention to falciparum malaria remains essential, failing to study and take action against vivax malaria levies a significant cost against affected populations. It is time to start studying P. vivax in Africa. We cannot afford to neglect this species any longer.

ACKNOWLEDGEMENTS

The authors thank Drs. Mamadou Alpha Diallo (Cheikh Anta Diop University, Dakar, Senegal), Godwin Ntadom (National Malaria Elimination Programme (NMEP), Federal Ministry of Health, Abuja, Nigeria), Abdoulaye Djimde (University of Science, Techniques and Technology of Bamako, Mali), Arsene Ratsimbasoa (University of Fianarantsoa, Madagascar), Kevin Baird (Eijkman-Oxford Clinical Research Unit, Eijkman Institute of Molecular Biology, Jakarta, Indonesia) for review and comments during development of this editorial.

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    Ndwiga L et al.., 2021. A review of the frequencies of Plasmodium falciparum Kelch 13 artemisinin resistance mutations in Africa. Int J Parasitol Drugs Drug Resist 16 : 155161.

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    Rosenthal PJ, 2021. Are Artemisinin-Based Combination Therapies For Malaria Beginning To Fail in Africa? Am J Trop Med Hyg 105 : 857858.

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    Baird JK, 2022. African Plasmodium vivax malaria improbably rare or benign. Trends Parasitol 38 : 683696.

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    Wilairatana P, Masangkay FR, Kotepui KU, De Jesus Milanez G, Kotepui M, 2022. Prevalence and risk of Plasmodium vivax infection among Duffy-negative individuals: a systematic review and meta-analysis. Sci Rep 12 : 3998.

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Author Notes

Address correspondence to Peter A. Zimmerman, Biomedical Research Building, Room 426, 2109 Adelbert Rd, Cleveland, OH 44106-4983. E-mail: paz@case.edu

Financial support: This work was supported by and NIH grant R01 AI148469 to PAZ and Scott M. Williams.

Authors’ addresses: Mary Aigbiremo Oboh-Imafidon, The Gambia Unit at London School of Hygiene and Tropical Medicine, Serrekunda, Gambia. Email: mary.oboh@lshtm.ac.uk. Peter A. Zimmerman, Case Western Reserve University, Cleveland, OH. Email: paz@case.edu.

  • 1.

    World Health Organization , 2022. The World Malaria Report 2022. Geneva: World Health Organization, 372.

  • 2.

    Gregson A, Plowe CV, 2005. Mechanisms of resistance of malaria parasites to antifolates. Pharmacol Rev 57 : 11745.

  • 3.

    Dhorda M, Amaratunga C, Dondorp AM, 2021. Artemisinin and multidrug-resistant Plasmodium falciparum - a threat for malaria control and elimination. Curr Opin Infect Dis 34 : 432439.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 4.

    Abdulraheem MA, Ernest M, Ugwuanyi I, Abkallo HM, Nishikawa S, Adeleke M, Orimadegun AE, Culleton R, 2022. High prevalence of Plasmodium malariae and Plasmodium ovale in co-infections with Plasmodium falciparum in asymptomatic malaria parasite carriers in southwestern Nigeria. Int J Parasitol 52 : 2333.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 5.

    Boundenga L, Bignoumba M, Dibakou SE, Mombo LE, Moukagni-Mussadji CJ, Wora DM, Kassa-Kassa F, Bisseye C, Onanga R, 2023. Decrease on malaria clinical cases from 2017 to 2019 in Franceville, Southeast Gabon, Central Africa. J Public Health Afr 14 : 1865.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 6.

    Nguiffo-Nguete D, Nongley Nkemngo F, Ndo C, Agbor JP, Boussougou-Sambe ST, Salako Djogbenou L, Ntoumi F, Adegnika AA, Borrmann S, Wondji CS, 2023. Plasmodium malariae contributes to high levels of malaria transmission in a forest-savannah transition area in Cameroon. Parasit Vectors 16 : 31.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 7.

    Oyibo W et al.., 2023. Malaria parasite density and detailed qualitative microscopy enhances large-scale profiling of infection endemicity in Nigeria. Sci Rep 13 : 1599.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 8.

    Sendor R et al.., 2023. Similar Prevalence of Plasmodium falciparum and Non-P. falciparum Malaria Infections among Schoolchildren, Tanzania(1). Emerg Infect Dis 29 : 11431153.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 9.

    Howes RE et al.., 2011. The global distribution of the Duffy blood group. Nat Commun 2 : 266.

  • 10.

    Zimmerman PA, Ferreira MU, Howes RE, Mercereau-Puijalon O, Hay SI, Price RN & Baird JK Advances in Parasitology. London: Elsevier, 2776.

  • 11.

    Miller LH, Mason SJ, Clyde DF, McGinniss MH, 1976. The resistance factor to Plasmodium vivax in blacks. The Duffy-blood- group genotype, FyFy. N Engl J Med 295 : 3024.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 12.

    Tournamille C, Colin Y, Cartron JP, Le Van Kim C, 1995. Disruption of a GATA motif in the Duffy gene promoter abolishes erythroid gene expression in Duffy-negative individuals. Nat Genet 10 : 2248.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 13.

    Oboh MA, Badiane AS, Ntadom G, Ndiaye YD, Diongue K, Diallo MA, Ndiaye D, 2018. Molecular identification of Plasmodium species responsible for malaria reveals Plasmodium vivax isolates in Duffy negative individuals from southwestern Nigeria. Malar J 17 : 439.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 14.

    Oboh MA, Singh US, Ndiaye D, Badiane AS, Ali NA, Bharti PK, Das A, 2020. Presence of additional Plasmodium vivax malaria in Duffy negative individuals from Southwestern Nigeria. Malar J 19 : 229.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 15.

    Niangaly A et al.., 2017. Plasmodium vivax infections over three years in Duffy blood group negative Malians in Bandiagara, Mali. Am J Trop Med Hyg 97 : 744752.

  • 16.

    Lo E et al.., 2021. Contrasting epidemiology and genetic variation of Plasmodium vivax infecting Duffy-negative individuals across Africa. Int J Infect Dis 108 : 6371.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 17.

    Brazeau NF et al.., 2021. The epidemiology of Plasmodium vivax among adults in the Democratic Republic of the Congo. Nat Commun 12 : 4169.

  • 18.

    Zimmerman PA, 2017. Plasmodium vivax infection in Duffy-negative people in Africa. Am J Trop Med Hyg 97 : 636638.

  • 19.

    Twohig KA, Pfeffer DA, Baird JK, Price RN, Zimmerman PA, Hay SI, Gething PW, Battle KE, Howes RE, 2019. Growing evidence of Plasmodium vivax across malaria-endemic Africa. PLoS Negl Trop Dis 13 : e0007140.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 20.

    van Loon W et al.., 2023. Plasmodium vivax malaria in Duffy-positive patients in Rwanda. Am J Trop Med Hyg 109 : 621623.

  • 21.

    Kitchen SF, 1938. The infection of reticulocytes by Plasmodium vivax. Am J Trop Med 18 : 347353.

  • 22.

    Maguire JD et al.., 2006. Production and validation of durable, high quality standardized malaria microscopy slides for teaching, testing and quality assurance during an era of declining diagnostic proficiency. Malar J 5 : 92.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 23.

    Aiyenigba B, Ojo A, Aisiri A, Uzim J, Adeusi O, Mwenesi H, 2017. Immediate assessment of performance of medical laboratory scientists following a 10-day malaria microscopy training programme in Nigeria. Glob Health Res Policy 2 : 32.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 24.

    Worges M, Whitehurst N, Saye R, Ndiaye D, Yamo E, Yukich J, 2019. Performance Outcomes from Africa-Based Malaria Diagnostic Competency Assessment Courses. Am J Trop Med Hyg 100 : 851860.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 25.

    Tetteh M, Dwomoh D, Asamoah A, Kupeh EK, Malm K, Nonvignon J, 2021. Impact of malaria diagnostic refresher training programme on competencies and skills in malaria diagnosis among medical laboratory professionals: evidence from Ghana 2015-2019. Malar J 20 : 255.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 26.

    Kayiba NK et al.., 2021. Spatial and molecular mapping of Pfkelch13 gene polymorphism in Africa in the era of emerging Plasmodium falciparum resistance to artemisinin: a systematic review. Lancet Infect Dis 21 : e82e92.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 27.

    Ndwiga L et al.., 2021. A review of the frequencies of Plasmodium falciparum Kelch 13 artemisinin resistance mutations in Africa. Int J Parasitol Drugs Drug Resist 16 : 155161.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 28.

    Rosenthal PJ, 2021. Are Artemisinin-Based Combination Therapies For Malaria Beginning To Fail in Africa? Am J Trop Med Hyg 105 : 857858.

  • 29.

    Baird JK, 2022. African Plasmodium vivax malaria improbably rare or benign. Trends Parasitol 38 : 683696.

  • 30.

    Wilairatana P, Masangkay FR, Kotepui KU, De Jesus Milanez G, Kotepui M, 2022. Prevalence and risk of Plasmodium vivax infection among Duffy-negative individuals: a systematic review and meta-analysis. Sci Rep 12 : 3998.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 31.

    Baird JK, 2013. Evidence and implications of mortality associated with acute Plasmodium vivax malaria. Clin Microbiol Rev 26 : 3657.

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