Lineage-Specific Expansion of Plasmodium falciparum Parasites With pfhrp2 Deletion in the Greater Mekong Subregion

Gibbons, Justin; Qin, Junling; Malla, Pallavi; Wang, Zenglei; Brashear, Awtum; Wang, Chengqi; Miao, Jun; Adams, John; Kim, Kami; Jiang, Rays H. Y.

doi:10.1093/infdis/jiaa250

Cited by 11 publications

(16 citation statements)

References 42 publications

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“…This suggests that there likely have been an outbreak of dual hrp2/3 -deleted P. falciparum in the Northern Red Sea zone during the 2015–2016 transmission season. Importantly, our data, combined with several recent reports of significant proportions of single exon deletion of hrp2/3 genes in other areas 8 , 13 , suggest molecular assays focusing on only one of the exons in hrp2/3 genes 14 – 16 could underestimate a large proportions of hrp2/3 -deleted parasites in some areas.…”

Section: Discussionsupporting

confidence: 53%

Epidemiology of mutant Plasmodium falciparum parasites lacking histidine-rich protein 2/3 genes in Eritrea 2 years after switching from HRP2-based RDTs

Mihreteab

Anderson

Pasay

et al. 2021

Sci Rep

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Eritrea was the first African country to complete a nationwide switch in 2016 away from HRP2-based RDTs due to high rates of false-negative RDT results caused by Plasmodium falciparum parasites lacking hrp2/hrp3 genes. A cross-sectional survey was conducted during 2019 enrolling symptomatic malaria patients from nine health facilities across three zones consecutively to investigate the epidemiology of P. falciparum lacking hrp2/3 after the RDT switch. Molecular analyses of 715 samples revealed the overall prevalence of hrp2-, hrp3-, and dual hrp2/3-deleted parasites as 9.4% (95%CI 7.4–11.7%), 41.7% (95% CI 38.1–45.3%) and 7.6% (95% CI 5.8–9.7%), respectively. The prevalence of hrp2- and hrp3-deletion is heterogeneous within and between zones: highest in Anseba (27.1% and 57.9%), followed by Gash Barka (6.4% and 37.9%) and Debub zone (5.2% and 43.8%). hrp2/3-deleted parasites have multiple diverse haplotypes, with many shared or connected among parasites of different hrp2/3 status, indicating mutant parasites have likely evolved from multiple and local parasite genetic backgrounds. The findings show although prevalence of hrp2/3-deleted parasites is lower 2 years after RDT switching, HRP2-based RDTs remain unsuitable for malaria diagnosis in Eritrea. Continued surveillance of hrp2/3-deleted parasites in Eritrea and neighbouring countries is required to monitor the trend.

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Section: Discussionsupporting

confidence: 53%

Epidemiology of mutant Plasmodium falciparum parasites lacking histidine-rich protein 2/3 genes in Eritrea 2 years after switching from HRP2-based RDTs

Mihreteab

Anderson

Pasay

et al. 2021

Sci Rep

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“…(5-13) pfhrp2-/3+ , with an additional 15.9% (11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22) pfhrp2+/3-( Supplementary Figure 3 ). Interestingly, of samples HRP2+ by both RDTs, pfhrp3 could not be amplified in 42.6% (38)(39)(40)(41)(42)(43)(44)(45)(46)(47)(48).…”

Section: Pfhrp2/3 Deletion Pcr Genotypingmentioning

confidence: 99%

Emergence and evolution of Plasmodium falciparum histidine-rich protein 2 and 3 deletion mutant parasites in Ethiopia

Feleke

Hathaway

Cunningham

et al. 2021

Preprint

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Malaria diagnostic testing in Africa is threatened by Plasmodium falciparum parasites lacking histidine-rich protein 2 (pfhrp2) and 3 (pfhrp3) genes. Among 12,572 subjects enrolled along Ethiopia’s borders with Eritrea, Sudan, and South Sudan and using multiple assays, we estimate HRP2-based rapid diagnostic tests would miss 9.7% (95% CI 8.5-11.1) of falciparum malaria cases due to pfhrp2 deletion. Established and novel genomic tools reveal distinct subtelomeric deletion patterns, well-established pfhrp3 deletions, and recent expansion of pfhrp2 deletion. Current diagnostic strategies need to be urgently reconsidered in Ethiopia, and expanded surveillance is needed throughout the Horn of Africa.

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“…Improved PCR and serological approaches can be used to increase confidence in deletion prevalence estimates [11][12][13] , but our understanding of the evolutionary history of pfhrp2/3-deleted P. falciparum is limited and largely informed by analysis of a small number of microsatellite markers [14][15][16] . Recent genomic analyses have begun to expand our understanding of pfhrp2/3-deleted P. falciparum [17][18][19] but continue to be hindered by the challenges of assembling the highly repetitive and paralogous sequences of P. falciparum subtelomeres 20 .…”

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confidence: 99%

Plasmodium falciparum is evolving to escape malaria rapid diagnostic tests in Ethiopia

et al. 2021

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In Africa, most rapid diagnostic tests (RDTs) for falciparum malaria recognize histidine-rich protein 2 antigen. Plasmodium falciparum parasites lacking histidine-rich protein 2 (pfhrp2) and 3 (pfhrp3) genes escape detection by these RDTs, but it is not known whether these deletions confer sufficient selective advantage to drive rapid population expansion. By studying blood samples from a cohort of 12,572 participants enroled in a prospective, cross-sectional survey along Ethiopia’s borders with Eritrea, Sudan and South Sudan using RDTs, PCR, an ultrasensitive bead-based immunoassay for antigen detection and next-generation sequencing, we estimate that histidine-rich protein 2-based RDTs would miss 9.7% (95% confidence interval 8.5–11.1) of P. falciparum malaria cases owing to pfhrp2 deletion. We applied a molecular inversion probe-targeted deep sequencing approach to identify distinct subtelomeric deletion patterns and well-established pfhrp3 deletions and to uncover recent expansion of a singular pfhrp2 deletion in all regions sampled. We propose a model in which pfhrp3 deletions have arisen independently multiple times, followed by strong positive selection for pfhrp2 deletion owing to RDT-based test-and-treatment. Existing diagnostic strategies need to be urgently reconsidered in Ethiopia, and improved surveillance for pfhrp2 deletion is needed throughout the Horn of Africa.

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Lineage-Specific Expansion of Plasmodium falciparum Parasites With pfhrp2 Deletion in the Greater Mekong Subregion

Cited by 11 publications

References 42 publications

Epidemiology of mutant Plasmodium falciparum parasites lacking histidine-rich protein 2/3 genes in Eritrea 2 years after switching from HRP2-based RDTs

Epidemiology of mutant Plasmodium falciparum parasites lacking histidine-rich protein 2/3 genes in Eritrea 2 years after switching from HRP2-based RDTs

Emergence and evolution of Plasmodium falciparum histidine-rich protein 2 and 3 deletion mutant parasites in Ethiopia

Plasmodium falciparum is evolving to escape malaria rapid diagnostic tests in Ethiopia

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