UMMS Affiliation

Department of Medicine

Publication Date


Document Type



Analytical, Diagnostic and Therapeutic Techniques and Equipment | Immunology and Infectious Disease | Microbiology | Parasitic Diseases


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.


Diagnostic markers, Malaria, Structural variation

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Copyright © The Author(s) 2021. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit

DOI of Published Version



Feleke SM, Reichert EN, Mohammed H, Brhane BG, Mekete K, Mamo H, Petros B, Solomon H, Abate E, Hennelly C, Denton M, Keeler C, Hathaway NJ, Juliano JJ, Bailey JA, Rogier E, Cunningham J, Aydemir O, Parr JB. Plasmodium falciparum is evolving to escape malaria rapid diagnostic tests in Ethiopia. Nat Microbiol. 2021 Oct;6(10):1289-1299. doi: 10.1038/s41564-021-00962-4. Epub 2021 Sep 27. PMID: 34580442; PMCID: PMC8478644. Link to article on publisher's site

Journal/Book/Conference Title

Nature microbiology


Full author list omitted for brevity. For the full list of authors, see article.

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Creative Commons License

Creative Commons Attribution 4.0 License
This work is licensed under a Creative Commons Attribution 4.0 License.