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Background  The  Plasmodium falciparum  antigen histidine rich protein 2 (HRP2) is a preferred target for malaria rapid diagnostic tests (RDTs) because of its abundant production by the parasite and thermal stability. As a result, a majority of RDTs procured globally target this antigen. However, previous reports from South America and recent reports from sub-Saharan Africa and Asia indicate that certain  P. falciparum  parasites have deletions of the gene coding for HRP2. The HRP2 antigen is paralogous to another  P. falciparum  antigen HRP3 and some antibodies to HRP2 cross-react with HRP3. Multiple parasites have been described with deletions of one or both  hrp2  and  hrp3  genes. It is unclear how the various combinations of  hrp2  and  hrp3  deletion genotypes affect clinical sensitivity of HRP2-based RDTs.    Methods  Cross-reactivity between HRP2 and HRP3 was tested on malaria RDTs using culture-adapted  P. falciparum  parasites with both  hrp2  and  hrp3  intact or with one or both genes deleted. Ten-fold serial dilutions of four culture-adapted  P. falciparum  parasites [3D7 ( hrp2 +/ hrp3 +), Dd2 ( hrp2 −/ hrp3 +), HB3 ( hrp2 +/ hrp3 −) and 3BD5 ( hrp2 −/ hrp3 −)] ranging from 100,000 to 0.01 parasites/µL were prepared. HRP2,  Plasmodium  lactate dehydrogenase (pLDH) and aldolase concentrations were determined for the diluted samples using a multiplex bead assay. The samples were subsequently tested on three RDT products designed to detect  P. falciparum  by HRP2 alone or in combination with pLDH.    Results  At parasite densities of approximately 1000 parasites/µL, parasites that expressed either  hrp2  or  hrp3  were detected by all three RDTs. Multiplex based antigen measurement using HRP2- conjugated beads demonstrated higher antigen concentration when both  hrp2  and  hrp3  genes were intact (3D7 parasites, 47.9 ng/ml) compared to HB3 (3.02 ng/mL) and Dd2 (0.20 ng/mL) strains that had one gene deleted. 3D7 at 10 parasites/µL (0.45 ng/mL) was reactive on all three RDT products whereas none of the other parasites were reactive at that density.    Conclusions  Above a certain antigen threshold, HRP3 cross-reactivity on HRP2-based RDTs is sufficient to mask the effects of deletions of  hrp2  only. Studies of  hrp2  deletion and its effects on HRP2-based RDTs must be studied alongside  hrp3  deletions and include clinical sample reactivity on HRP2-based tests.

HRP2 and HRP3 cross-reactivity and implications for HRP2-based RDT use in regions with Plasmodium falciparum hrp2 gene deletions