Global polymorphism of <i>Plasmodium falciparum</i> histidine rich proteins 2/3 and impact on malaria rapid diagnostic test detection: a systematic review and meta-analysis

This review presents an overview of field findings on sequence variation of Plasmodium falciparum histidine-rich proteins 2/3 (PfHRP2/3) for which reference types (1–24) have been identified, and its critical impact on PfHRP2-based rapid diagnostic test (RDT) detection. This systematic review and meta-analysis was registered with PROSPERO, CRD42022316027, and conducted as per the PRISMA guidelines, and the methodological quality of studies was assessed. Of the 2184 records identified, 34 studies were included mostly from Africa (47.1%) and Asia (35.3%). The reference PfHRP2 types 1, 2, 3, 6, and 7 are invariably found at proportions ≥ 80–100% in all areas with the exception of The Americas where their proportion is very low. The proteins exhibited high diversity of variants/unknown types, especially for types 1, 2, 4, and 7. Eleven major PfHRP2 epitopes were found at pooled proportion > 90%. The existing models to predict RDT detection are greatly limited by the impact of factors such as low (very low) parasitemia, RDT brand, and PfHRP3 cross-reactivity. PfHRP2 length and presence/number of a given reference repeat type/variant did not seem to impact RDT detection. PfHRP2/3 are highly polymorphic and current findings are insufficient, conflicting and not convincing enough to conclude on the role of PfHRP2/3 sequence polymorphism in PfHRP2-based RDT detection.