Developing sero-diagnostic tests to facilitate Plasmodium vivax Serological Test-and-Treat approaches: modeling the balance between public health impact and overtreatment

Abstract

Background Eliminating Plasmodium vivax will require targeting the hidden liver-stage reservoir of hypnozoites. This necessitates new interventions balancing the benefit of reducing vivax transmission against the risk of over-treating some individuals with drugs which may induce haemolysis. By measuring antibodies to a panel of vivax antigens, a strategy of serological-testing-and-treatment (PvSeroTAT) can identify individuals with recent blood-stage infections who are likely to carry hypnozoites and target them for radical cure. This provides a potential solution to selectively treat the vivax reservoir with 8-aminoquinolines. Methods PvSeroTAT can identify likely hypnozoite carriers with ~80% sensitivity and specificity. Diagnostic test sensitivities and specificities ranging 50–100% were incorporated into a mathematical model of vivax transmission to explore how they affect the risks and benefits of different PvSeroTAT strategies involving hypnozoiticidal regimens. Risk was measured as the rate of overtreatment and benefit as reduction of community-level vivax transmission. Results Across a wide range of combinations of diagnostic sensitivity and specificity, PvSeroTAT was substantially more effective than bloodstage mass screen and treat strategies and only marginally less effective than mass drug administration. The key test characteristic determining of the benefit of PvSeroTAT strategies is diagnostic sensitivity, with higher values leading to more hypnozoite carriers effectively treated and greater reductions in vivax transmission. The key determinant of risk is diagnostic specificity: higher specificity ensures that a lower proportion of uninfected individuals are unnecessarily treated with primaquine. These relationships are maintained in both moderate and low transmission settings (qPCR prevalence 10% and 2%). Increased treatment efficacy and adherence can partially compensate for lower test performance. Multiple rounds of PvSeroTAT with a lower performing test may lead to similar or higher reductions in vivax transmission than fewer rounds with a higher performing test, albeit with higher rate of overtreatment. Conclusions At current performance, PvSeroTAT is predicted to be a safe and efficacious option for targeting the hypnozoite reservoir towards vivax elimination. P. vivax sero-diagnostic tests should aim for both high performance and ease of use in the field. The target product profiles informing such development should thus reflect the trade-offs between impact, overtreatment, and ease of programmatic implementation.

Modelling the within-host dynamics ofPlasmodium vivaxhypnozoite activation: an analysis of the SPf66 vaccine trial

“…There has been recent interest in using a multiplex serological assay to identify individuals who have had a recent bloodstream P. vivax infection [41, 42]. The serological test is based on a panel of 8 P. vivax specific antibodies and is estimated to have > 80% specificity and > 80% sensitivity in detecting bloodstream infections which occurred within the previous 9 months.…”

Plasmodium vivax malaria serological exposure markers: Assessing the degree and implications of cross-reactivity with P. knowlesi

“…Alongside these laboratory and product development goals, a modeling approach is being applied to determine the benefits and risks, the ideal balance of sensitivity and specificity, and the schedule and frequency of screening and treatment required for effectively reducing P. vivax transmission. 56 …”

Accelerating towards P. vivax elimination with a novel serological test-and-treat strategy: a modelling case study in Brazil

“…We simulate a range of scenarios using a previously described individual-based P. vivax transmission model calibrated to Brazilian settings ( Table 1 ). 5 , 12 , 20 The detailed individual-based simulation model of P. vivax transmission with both human and mosquito compartments was previously calibrated to data from epidemiological studies in Papua New Guinea and the Solomon Islands. 5 This model captures the contributions of relapse infections which are vital for P. vivax transmission dynamics.…”

“…Pv SeroTAT interventions are implemented to screen individuals with P. vivax infection within the previous nine months for the various treatment pathways. 20 Performance of the serological diagnostic tool modelled are based on sensitivity and specificity estimates from previous studies. 19 , 20 Calibration for Brazilian settings of baseline incidence, G6PD deficiency prevalence, and occupational exposure risk are detailed in the Supplementary Materials and in a previous publication by the authors.…”

“…However, increased sensitivity is traded-off against reduced specificity, and a higher proportion of overtreatment where false positives are given radical cure. 20 What is currently not yet well understood is the potential population-level impact of this novel intervention in real-world settings in addition to what would be the most favourable deployment strategies to achieve greatest transmission reduction and acceleration to pre-elimination phases.…”