The in-vivo dynamics of Plasmodium falciparum HRP2: implications for the use of rapid diagnostic tests in malaria elimination

Abstract

Background: Rapid diagnostic tests (RDTs) that rely on the detection of Plasmodium falciparum histidine-rich protein 2 (PfHRP2) have become key tools for diagnosing P. falciparum infection. The utility of RDTs can be limited by PfHRP2 persistence, however it can be a potential benefit in low transmission settings where detection of persistent PfHRP2 using newer ultra-sensitive PfHRP2 based RDTs can serve as a surveillance tool to identify recent exposure. Better understanding of the dynamics of PfHRP2 over the course of a malaria infection can inform optimal use of RDTs.

Methods: A previously published mathematical model was refined to mimic the production and decay of PfHRP2 during a malaria infection. Data from 15 individuals from volunteer infection studies were used to update the original model and estimate key model parameters. The refined model was applied to a cohort of patients from Namibia who received treatment for clinical malaria infection for whom longitudinal PfHRP2 concentrations were measured.

Results: The refinement of the PfHRP2 dynamic model indicated that in malaria naïve hosts, P. falciparum parasites of the 3D7 strain produce 33.6 × 10^-15 g (95% CI 25.0-42.1 × 10^-15 g) of PfHRP2 in vivo per parasite replication cycle, with an elimination half-life of 1.67 days (95% CI 1.11-3.40 days). The refined model included these updated parameters and incorporated individualized body fluid volume calculations, which improved predictive accuracy when compared to the original model. The performance of the model in predicting clearance of PfHRP2 post treatment in clinical samples from six adults with P. falciparum infection in Namibia improved when using a longer elimination half-life of 4.5 days, with 14% to 67% of observations for each individual within the predicted range.

Conclusions: The updated mathematical model can predict the growth and clearance of PfHRP2 during the production and decay of a mono-infection with P. falciparum, increasing the understanding of PfHRP2 antigen dynamics. This model can guide the optimal use of PfHRP2-based RDTs for reliable diagnosis of P. falciparum infection and re-infection in endemic settings, but also for malaria surveillance and elimination programmes in low transmission areas.

Keywords: Antigen dynamics; Elimination and surveillance; Histidine rich protein; Plasmodium falciparum; Rapid diagnostic tests.

Fig. 1

Parasitaemia and PfHRP2 concentration over study period for three anti-malarial treatments in IBSM studies. Relationship between mean parasitaemia (Grey solid line) and mean PfHRP2 concentration (Black dashed line) over the study period used for model development for each of the three anti-malarial treatments in the IBSM study. Bars at each time-point represent minimum and maximum

Fig. 2

PfHRP2 concentration over time post administration of anti-malarial treatment for estimation of PfHRP2 elimination half-life. PfHRP2 concentration over time post administration of anti-malarial drug for the 10 IBSM individuals with maximum PfHRP2 concentrations exceeding 300 pg/mL that were used to estimate the PfHRP2 elimination half-life. The red dashed line is the reported limit of detection (LOD) for Q-plex ELISA 2-Plex (LOD 5 pg/mL)

Fig. 3

Example fits of the Base Model and the Final Model for two IBSM individuals. The observed parasitaemia over the course of infection is represented by black solid line, observed PfHRP2 concentration is represented by circles (pre-treatment in solid circles and post-treatment in open circles), and the predicted minimum and maximum PfHRP2 concentration from the model is shown as blue and red dashed lines, respectively

Fig. 4

Fits of the final model with elimination half-life of 4.5 days to the Namibia study. Fits of the final PfHRP2 model with elimination half-life of 4.5 days to the 6 individuals from the Namibia study, with observed PfHRP2 concentration represented by closed circles, and minimum and maximum predicted PfHRP2 concentration represented by the blue and red dashed lines, respectively. The dashed grey horizontal line represents the threshold of 800 pg/mL and the solid grey horizontal line represents the threshold of 80 pg/mL which correspond to the positivity threshold of an RDT and usRDT, respectively