https://orcid.org/0000-0002-4286-147X
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ABSTRACT
Background
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.
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 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.
Conclusions
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.
Graphical abstract
Abbreviations
| 95%CI: | = | Confidence interval at 95% |
| AA: | = | Amino acid |
| Df: | = | Degree of freedom |
| FN: | = | False negative |
| Hd: | = | Haplotype diversity |
| HRP2: | = | Histidine-rich protein 2 |
| HRP3: | = | Histidine-rich protein 3 |
| JBI: | = | Joanna Briggs Institute |
| LDH: | = | Lactate dehydrogenase |
| LDI: | = | Low density infections |
| LM: | = | Light microscopy |
| mAbs: | = | Monoclonal antibodies |
| N/A: | = | Not applicable |
| NCBI: | = | National Center for Biotechnology Information |
| PCR: | = | Polymerase chain reaction |
| Pf: | = | Plasmodium falciparum |
| PNG: | = | Papua New Guinea |
| Pp: | = | Pooled proportion |
| PRISMA: | = | Preferred Reporting Items for Systematic Reviews and Meta-analyses |
| RDT: | = | rapid diagnostic test |
| sSA: | = | sub-Saharan Africa |
| UTR: | = | Untranslated region |
| WHO: | = | World Health Organization |
Declarations of interests
The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
Reviewer disclosures
Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.
Author contributions
LPKF and VS conceived and designed the study. LPKF, JJ and GN performed search literature through the electronic databases and extracted data from eligible studies. LPKF and JJ extracted gene data from PlasmoDB and NCBI. LPKF conceived maps and performed meta-analysis. LPKF wrote the first version of the manuscript with the help of JJ and GN. VS read and revised the manuscript for important intellectual content, and supervised the work at all stages. All authors approved the final version of the manuscript before submission.
Data availability statement
The authors confirm that the data supporting the findings of this study are available within the article and supplemental materials.
Acknowledgments
Author LPKF was granted a prestigious Postgraduate Fellowship by the Department of Biotechnology (DBT), New Delhi, India, and The World Academy of Sciences (TWAS), Trieste, Italy. We are grateful to the anonymous reviewers for critical revision of the paper.
SUPPLEMENTARY MATERIAL
Supplemental data for this article can be accessed online at https://doi.org/10.1080/14737159.2023.2255136