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Global sequence variation in the histidine-rich proteins 2 and 3 of Plasmodium falciparum: implications for the performance of malaria rapid diagnostic tests

Joanne Baker121, Mei-Fong Ho12, Anita Pelecanos23, Michelle Gatton23, Nanhua Chen1, Salim Abdullah4, Audrey Albertini5, Frederic Ariey6, John Barnwell7, David Bell58, Jane Cunningham9, Djibrine Djalle10, Diego F Echeverry11, Dionicia Gamboa1213, Jeffery Hii14, Myat Phone Kyaw15, Jennifer Luchavez16, Christopher Membi4, Didier Menard17, Claribel Murillo11, Sina Nhem6, Bernhards Ogutu18, Pamela Onyor18, Wellington Oyibo19, Shan Qing Wang20, James McCarthy2 and Qin Cheng13*

Author Affiliations

1 Department of Drug Resistance and Diagnostics, Australian Army Malaria Institute, Brisbane, Australia

2 Clinical Tropical Medicine Laboratory, Queensland Institute of Medical Research, University of Queensland, Herston, Australia

3 Malaria Drug Resistance and Chemotherapy Laboratory, Queensland Institute of Medical Research, Herston, Australia

4 Bagamoyo/Ifakara Health Research and Development Centre, Ifakara, United Republic of Tanzania

5 Foundation for Innovative and New Diagnostics, Geneva, Switzerland

6 Pasteur Institute of Cambodia, Phnom Penh, Cambodia

7 Centre for Disease Control and Prevention, Atlanta, USA

8 Global Malaria Programme, World Health Organization, Geneva, Switzerland

9 UNICEF/UNDP/World Bank/WHO Special Programme for Research and Training in Tropical Diseases (TDR), Geneva, Switzerland

10 Institut Pasteur de Bangui, Bangui, Central African Republic

11 Centro Internacional de Entrenamiento e Investigaciones Medicas (CIDEIM), Cali, Colombia

12 Instituto de Medicina Tropical Alexander Von Humboldt, Universidad Peruana Cayetano Heredia, Peru

13 Departamento de Bioquimica, Biologia Molecular y Farmacologia, Facultad de Ciencias y Filosofia, Universidad Peruana Cayetano Heredia, Peru

14 Western Pacific Regional Office of the World Health Organization, Solomon Islands

15 Department of Medical Research (Lower Myanmar), Yangon, Myanmar

16 Research Institute for Tropical Medicine, Alabang, The Philippines

17 Institut Pasteur de Madagascar, Madagascar

18 Centre for Clinical Research, Kenya Medical Research Institute, Kisumu, Kenya

19 College of Medicine, University of Lagos, Odoaraba, Lagos, Nigeria

20 Hainan Provincial Centre for Disease Control and Prevention, Haikou, Hainan, China

21 School of Population Health, University of Queensland, Herston, Queensland, Australia

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Malaria Journal 2010, 9:129  doi:10.1186/1475-2875-9-129

Published: 17 May 2010



Accurate diagnosis is essential for prompt and appropriate treatment of malaria. While rapid diagnostic tests (RDTs) offer great potential to improve malaria diagnosis, the sensitivity of RDTs has been reported to be highly variable. One possible factor contributing to variable test performance is the diversity of parasite antigens. This is of particular concern for Plasmodium falciparum histidine-rich protein 2 (PfHRP2)-detecting RDTs since PfHRP2 has been reported to be highly variable in isolates of the Asia-Pacific region.


The pfhrp2 exon 2 fragment from 458 isolates of P. falciparum collected from 38 countries was amplified and sequenced. For a subset of 80 isolates, the exon 2 fragment of histidine-rich protein 3 (pfhrp3) was also amplified and sequenced. DNA sequence and statistical analysis of the variation observed in these genes was conducted. The potential impact of the pfhrp2 variation on RDT detection rates was examined by analysing the relationship between sequence characteristics of this gene and the results of the WHO product testing of malaria RDTs: Round 1 (2008), for 34 PfHRP2-detecting RDTs.


Sequence analysis revealed extensive variations in the number and arrangement of various repeats encoded by the genes in parasite populations world-wide. However, no statistically robust correlation between gene structure and RDT detection rate for P. falciparum parasites at 200 parasites per microlitre was identified.


The results suggest that despite extreme sequence variation, diversity of PfHRP2 does not appear to be a major cause of RDT sensitivity variation.