Dataset Information

Implications of population-level immunity for the emergence of artemisinin-resistant malaria: a mathematical model.

ABSTRACT:

Background

Artemisinin-resistant Plasmodium falciparum has emerged in the Greater Mekong Subregion, an area of relatively low transmission, but has yet to be reported in Africa. A population-based mathematical model was used to investigate the relationship between P. falciparum prevalence, exposure-acquired immunity and time-to-emergence of artemisinin resistance. The possible implication for the emergence of resistance across Africa was assessed.

Methods

The model included human and mosquito populations, two strains of malaria ("wild-type", "mutant"), three levels of human exposure-acquired immunity (none, low, high) with two types of immunity for each level (sporozoite/liver stage immunity and blood-stage/gametocyte immunity) and drug pressure based on per-capita treatment numbers.

Results

The model predicted that artemisinin-resistant strains may circulate up to 10 years longer in high compared to low P. falciparum prevalence areas before resistance is confirmed. Decreased time-to-resistance in low prevalence areas was explained by low genetic diversity and immunity, which resulted in increased probability of selection and spread of artemisinin-resistant strains. Artemisinin resistance was estimated to be established by 2020 in areas of Africa with low (?25%) prevalence areas, respectively.

Conclusions

Areas of low transmission and low immunity give rise to a more rapid expansion of artemisinin-resistant parasites, corroborating historical observations of anti-malarial resistance emergence. Populations where control strategies are in place that reduce malaria transmission, and hence immunity, may be prone to a rapid emergence and spread of artemisinin-resistant strains and thus should be carefully monitored.

SUBMITTER: Scott N

PROVIDER: S-EPMC6071336 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

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Publications

Implications of population-level immunity for the emergence of artemisinin-resistant malaria: a mathematical model.

Scott Nick N Ataide Ricardo R Wilson David P DP Hellard Margaret M Price Ric N RN Simpson Julie A JA Fowkes Freya J I FJI

Malaria journal 20180802 1

<h4>Background</h4>Artemisinin-resistant Plasmodium falciparum has emerged in the Greater Mekong Subregion, an area of relatively low transmission, but has yet to be reported in Africa. A population-based mathematical model was used to investigate the relationship between P. falciparum prevalence, exposure-acquired immunity and time-to-emergence of artemisinin resistance. The possible implication for the emergence of resistance across Africa was assessed.<h4>Methods</h4>The model included human ...[more]

PMID: 30071877

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Project description:BackgroundDespite a resurgence in control efforts, malaria remains a serious public-health problem, causing millions of deaths each year. One factor that complicates malaria-control efforts is clinical immunity, the acquired immune response that protects individuals from symptoms despite the presence of parasites. Clinical immunity protects individuals against disease, but its effects at the population level are complex. It has been previously suggested that under certain circumstances, malaria is bistable: it can persist, if established, in areas where it would not be able to invade. This phenomenon has important implications for control: in areas where malaria is bistable, if malaria could be eliminated until immunity wanes, it would not be able to re-invade.MethodsHere, we formulate an analytically tractable, dynamical model of malaria transmission to explore the possibility that clinical immunity can lead to bistable malaria dynamics. We summarize what is known and unknown about the parameters underlying this simple model, and solve the model to find a criterion that determines under which conditions we expect bistability to occur.ResultsWe show that bistability can only occur when clinically immune individuals are more "effective" at transmitting malaria than naïve individuals are. We show how this "effectiveness" includes susceptibility, ability to transmit, and duration of infectiousness. We also show that the amount of extra effectiveness necessary depends on the ratio between the duration of infectiousness and the time scale at which immunity is lost. Thus, if the duration of immunity is long, even a small amount of extra transmission effectiveness by clinically immune individuals could lead to bistability.ConclusionsWe demonstrate a simple, plausible mechanism by which clinical immunity may be causing bistability in human malaria transmission. We suggest that simple summary parameters--in particular, the relative transmission effectiveness of clinically immune individuals and the time scale at which clinical immunity is lost--are key to determining where and whether bistability is happening. We hope these findings will guide future efforts to measure transmission parameters and to guide malaria control efforts.

Project description:BackgroundMpumalanga in South Africa is committed to eliminating malaria by 2018 and efforts are increasing beyond that necessary for malaria control. Differential Equation models may be used to study the incidence and spread of disease with an important benefit being the ability to enact exogenous change on the system to predict impact without committing any real resources. The model is a deterministic non-linear ordinary differential equation representation of the dynamics of the human population. The model is fitted to weekly data of treated cases from 2002 to 2008, and then validated with data from 2009 to 2012. Elimination-focused interventions such as the scale-up of vector control, mass drug administration, a focused mass screen and treat campaign and foreign source reduction are applied to the model to assess their potential impact on transmission.ResultsScaling up vector control by 10% and 20% resulted in substantial predicted decreases in local infections with little impact on imported infections. Mass drug administration is a high impact but short-lived intervention with predicted decreases in local infections of less that one infection per year. However, transmission reverted to pre-intervention levels within three years. Focused mass screen and treat campaigns at border-entry points are predicted to result in a knock-on decrease in local infections through a reduction in the infectious reservoir. This knock-on decrease in local infections was also predicted to be achieved through foreign source reduction. Elimination was only predicted to be possible under the scenario of zero imported infections in Mpumalanga.ConclusionsA constant influx of imported infections show that vector control alone will not be able to eliminate local malaria as it is insufficient to interrupt transmission. Both mass interventions have a large and immediate impact. Yet in countries with a large migrant population, these interventions may fail due to the reintroduction of parasites and their impact may be short-lived. While all strategies (in isolation or combined) contributed to decreasing local infections, none was predicted to decrease local infections to zero. The number of imported infections highlights the importance of reducing imported infections at source, and a regional approach to malaria elimination.

Project description:BackgroundAlthough the clinical efficacy of antimalarial artemisinin-based combination therapies in Africa remains high, the recent emergence of partial resistance to artemisinin in Plasmodium falciparum on the continent is troubling, given the lack of alternative treatments.MethodsIn this study, we used data from drug-efficacy studies conducted between 2016 and 2019 that evaluated 3-day courses of artemisinin-based combination therapy (artesunate-amodiaquine or artemether-lumefantrine) for uncomplicated malaria in Eritrea to estimate the percentage of patients with day-3 positivity (i.e., persistent P. falciparum parasitemia 3 days after the initiation of therapy). We also assayed parasites for mutations in Pfkelch13 as predictive markers of partial resistance to artemisinin and screened for deletions in hrp2 and hrp3 that result in variable performance of histidine rich protein 2 (HRP2)-based rapid diagnostic tests for malaria.ResultsWe noted an increase in the percentage of patients with day-3 positivity from 0.4% (1 of 273) in 2016 to 1.9% (4 of 209) in 2017 and 4.2% (15 of 359) in 2019. An increase was also noted in the prevalence of the Pfkelch13 R622I mutation, which was detected in 109 of 818 isolates before treatment, from 8.6% (24 of 278) in 2016 to 21.0% (69 of 329) in 2019. The odds of day-3 positivity increased by a factor of 6.2 (95% confidence interval, 2.5 to 15.5) among the patients with Pfkelch13 622I variant parasites. Partial resistance to artemisinin, as defined by the World Health Organization, was observed in Eritrea. More than 5% of the patients younger than 15 years of age with day-3 positivity also had parasites that carried Pfkelch13 R622I. In vitro, the R622I mutation conferred a low level of resistance to artemisinin when edited into NF54 and Dd2 parasite lines. Deletions in both hrp2 and hrp3 were identified in 16.9% of the parasites that carried the Pfkelch13 R622I mutation, which made them potentially undetectable by HRP2-based rapid diagnostic tests.ConclusionsThe emergence and spread of P. falciparum lineages with both Pfkelch13-mediated partial resistance to artemisinin and deletions in hrp2 and hrp3 in Eritrea threaten to compromise regional malaria control and elimination campaigns. (Funded by the Bill and Melinda Gates Foundation and others; Australian New Zealand Clinical Trials Registry numbers, ACTRN12618001223224, ACTRN12618000353291, and ACTRN12619000859189.).

Dataset Information

Implications of population-level immunity for the emergence of artemisinin-resistant malaria: a mathematical model.

Background

Methods

Results

Conclusions

Publications

Implications of population-level immunity for the emergence of artemisinin-resistant malaria: a mathematical model.

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