Global Polymorphism of Histidine Rich Proteins 2/3 and Impact on Malaria Rapid Diagnostic Test Detection: a Systematic Review and Meta-analysis

Background: This review presents an overview of field findings on sequence variation of histidine-rich proteins 2/3 (HRP2/3) for which reference types (1-24) have been identified, and its critical impact on HRP2-based rapid diagnostic test (RDT) detection.

Research Design And Methods: 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.

Results: Of the 2184 records identified, 34 studies were included mostly from Africa (47.1%) and Asia (35.3%). The reference HRP2 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 HRP2 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 HRP3 cross-reactivity. HRP2 length and presence/number of a given reference repeat type/variant did not seem to impact RDT detection.

Conclusions: HRP2/3 are highly polymorphic and current findings are insufficient, conflicting and not convincing enough to conclude on the role of HRP2/3 sequence polymorphism in HRP2-based RDT detection.