Genetic diversity and deletion of Plasmodium falciparum histidine-rich protein 2 and 3: a threat to diagnosis of P. falciparum malaria

Abstract

Background: PfHRP2-based rapid diagnostic tests (RDTs), based on the recognition of the Plasmodium falciparum histidine-rich protein 2, are currently the most used tests in malaria detection. Most of the antibodies used in RDTs also detect PfHRP3. However, false-negative results were reported. Significant variation in the pfhrp2 gene could lead to the expression of a modified protein that would no longer be recognized by the antibodies used in PfHRP2-based RDTs. Additionally, parasites lacking the PfHRP2 do not express the protein and are, therefore, not identifiable.

Aims: This review aims to assess the pfhrp2 and pfhrp3 genetic variation or the prevalence of gene deletion in areas where malaria is endemic and describe its implications on RDT use.

Sources: Publications of interest were identified using PubMed, Google Scholar and Google.

Content: More than 18 types of amino acid repeats were identified from the PfHRP2 sequences. Sequencing analysis revealed high-level genetic variation in the pfhrp2 and pfhrp3 genes (>90% of variation in Madagascar, Nigeria or Senegal) both within and between countries. However, genetic variation of PfHRP2 and PfHRP3 does not seem to be a major cause of false-negative results. The countries that showed the highest proportions of pfhrp2-negative parasites were Peru (20%-100%) and Guyana (41%) in South America, Ghana (36%) and Rwanda (23%) in Africa. High prevalence of pfhrp2 deletion causes a high rate of false-negatives results.

Implications: Presence of parasites lacking the pfhrp2 gene may pose a major threat to malaria control programmes because P. falciparum-infected individuals are not diagnosed and properly treated.

Keywords: Antigen detection; Deletion; Malaria; Plasmodium falciparum; Rapid diagnostic test; pfhrp2; pfhrp3.