Ultra-sensitive RDT performance and antigen dynamics in a high-transmission Plasmodium falciparum setting in Mali

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Malaria Journal Open Access

RESEARCH

Ultra‑sensitive RDT performance and antigen dynamics in a high‑transmission Plasmodium falciparum setting in Mali Emily N. Reichert1, Jen C. C. Hume2, Issaka Sagara3, Sara A. Healy2, Mahamadoun H. Assadou3, Merepen A. Guindo3, Rebecca Barney1, Andy Rashid1, Ihn Kyung Yang1, Allison Golden1, Gonzalo J. Domingo1*, Patrick E. Duffy2 and Hannah C. Slater1* 

Abstract  Background:  The recent expansion of tools designed to accurately quantify malaria parasite-produced antigens has enabled us to evaluate the performance of rapid diagnostic tests (RDTs) as a function of the antigens they detect— typically histidine rich protein 2 (HRP2) or lactate dehydrogenase (LDH). Methods:  For this analysis, whole blood specimens from a longitudinal study in Bancoumana, Mali were used to evaluate the performance of the ultra-sensitive HRP2-based Alere™ Malaria Ag P.f RDT (uRDT). The samples were collected as part of a transmission-blocking vaccine trial in a high transmission region for Plasmodium falciparum malaria. Furthermore, antigen dynamics after successful anti-malarial drug treatment were evaluated in these samples using the Q-Plex Human Malaria Array (4-Plex) to quantify antigen concentrations. Results:  The uRDT had a 50% probability of a positive result at 207 pg/mL HRP2 [95% credible interval (CrI) 160–268]. Individuals with symptomatic infection remained positive by uRDT for a median of 33 days [95% confidence interval (CI) 28–47] post anti-malarial drug treatment. Biphasic exponential decay models accurately captured the population level post-treatment dynamics of both HRP2 and Plasmodium LDH (pLDH), with the latter decaying more rapidly. Motivated by these differences in rates of decay, a novel algorithm that used HRP2:pLDH ratios to predict if an individual had active versus recently cleared P. falciparum infection was developed. The algorithm had 77.5% accuracy in correctly classifying antigen-positive individuals as those with and without active infection. Conclusions:  These results characterize the performance of the ultra-sensitive RDT and demonstrate the potential for emerging antigen-quantifying technologies in the field of malaria diagnostics to be helpful tools in distinguishing between active versus recently cleared malaria infections. Keywords:  Malaria, Ultra-sensitive RDT, Antigenemia, HRP2, pLDH Background Malaria is most commonly diagnosed in humans by either microscopy or rapid diagnostic tests (RDTs), which detect antigens produced by malaria parasites [1, 2]. *Correspondence: [email protected]; [email protected] 1 Diagnostics Program, PATH, Seattle, WA, USA Full list of author information is available at the end of the article

The antigens histidine rich protein 2 (HRP2) and lactate dehydrogenase (LDH) are those most commonly targeted by RDTs. HRP2 antigen is expressed only by Plasmodium falciparum malaria, and RDTs targeting P. falciparum infections typically detect HRP2, while LDH is a constitutive enzyme expressed by all Plasmodium species. RDTs can specificall

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