Malaria immunity and emerging antimalarial drug resistance

New research reveals the importance of malaria immunity in understanding antimalarial drug resistance

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Aug 21, 2019
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by Katherine O'Flaherty and Freya Fowkes - Burnet Institute, Australia


Malaria control and elimination efforts have resulted in remarkable success over the past two decades. Globally, there has been a significant reduction in morbidity and mortality attributed to malaria since 2000 [1], largely attributable to insecticide treated bed-nets and highly efficacious treatments [2]. Effective treatment of malaria relies on Artemisinin Combination Therapies (ACTs), the current first-line antimalarial for the deadliest human infecting species, Plasmodium falciparum. Alarmingly, for the last decade artemisinin resistant strains of P. falciparum have emerged and spread throughout mainland South East Asia.

Artemisinin resistance is characterised clinically by an increase in the time taken for patients to clear parasitemia in therapeutic efficacy studies [3]. Antimalarial immunity, which develops in response to repeated exposure to Plasmodium spp., is known to contribute to the efficacy of antimalarial treatments through additional parasite clearance, particularly antimalarial IgG responses [4]. Immunity may therefore give the impression of efficacious treatment during infection with drug resistant parasite strains and/or sub-standard dosing [5]. The functional antibody mechanisms associated with parasite clearance during treatment, however, are yet to be quantified. Detailed understanding of the effects of antibody functions that contribute to parasite clearance facilitates accurate estimation of within host parasite dynamics and the continued monitoring of the therapeutic efficacy of artemisinin treatments. We therefore sought to identify the mechanism of antibody mediated contribution to parasite clearance time and measures used to phenotypically monitor artemisinin resistance [6].

https://academic.oup.com/jid/advance-article/doi/10.1093/infdis/jiz247/5487931

Utilising samples collected from nearly one thousand participants of a multinational clinical efficacy study of artemisinin across eleven South East Asian study sites, we probed the function of antimalarial IgG antibody responses to determine to what extent they impact phenotypic measures used in the surveillance of emerging artemisinin resistance. IgG subclasses (IgG1 and IgG3) were measured in response to parasite antigens known to induce antibody responses associated with protection from clinical symptoms. Results demonstrated that IgG3, but not IgG1 antibodies, were associated with faster parasite clearance; the main metric currently used to assess the efficacy of artemisinin treatment and the emergence of reduced susceptibility to the drug. Additionally, antibody-mediated opsonic phagocytosis of parasites, and fixation of early complement proteins on parasite surface antigens were measured and found to have the largest magnitude of effect on reducing parasite clearance time. Furthermore, functional IgG responses were lowest in regions of Western Cambodia and Eastern Thailand where the highest proportion of participants infected with an artemisinin resistant parasite strain were surveyed. These findings provide novel insight into the current understanding of the role of functional antibody mechanisms in the phenotype of artemisinin resistance, and to parasite clearance and antimalarial treatment efficacy more broadly.

Presently, there are no replacements for the artemisinins, and current reliance on ACTs is great with hundreds of millions of courses procured annually. The spread of artemisinin resistant P. falciparum strains to regions of intense malaria transmission could have devastating consequences. The most up to date data demonstrates that the spread and consolidation of drug resistance in the GMS is worsening, and rising ACT treatment failure is compounded by parasite strains resistant to partner drugs [7]. It is therefore vital that surveillance of artemisinin resistant P. falciparum incorporates detailed understanding of the contribution of host factors, including naturally acquired immunity. These findings further our current understanding of the role of acquired immunity during antimalarial treatment and its contribution to phenotypic surveillance of emerging antimalarial drug resistance.


Image credit - Burnet Institute


References:

1.         WHO, World Malaria Report 2016. World Health Organization Geneva, 2016.

2.         Bhatt, S., et al., The effect of malaria control on Plasmodium falciparum in Africa between 2000 and 2015. Nature, 2015. 526(7572): p. 207-211.

3.         Ashley, E.A., et al., Spread of artemisinin resistance in Plasmodium falciparum malaria. N Engl J Med, 2014. 371(5): p. 411-23.

4.         Ataide, R., et al., Host immunity to Plasmodium falciparum and the assessment of emerging artemisinin resistance in a multinational cohort. Proc Natl Acad Sci U S A, 2017.

5.         O'Flaherty, K., et al., Immunity as a predictor of anti-malarial treatment failure: a systematic review. Malar J, 2017. 16(1): p. 158.

6.         O'Flaherty, K., et al., The contribution of functional antimalarial immunity to measures of parasite clearance in therapeutic efficacy studies of artemisinin derivatives. J Infect Dis, 2019.

7.         van der Pluijm, R.W., et al., Determinants of dihydroartemisinin-piperaquine treatment failure in Plasmodium falciparum malaria in Cambodia, Thailand, and Vietnam: a prospective clinical, pharmacological, and genetic study. Lancet Infect Dis, 2019.


Go to the profile of James Beeson

James Beeson

Deputy Director and Research Fellow, Burnet Institute

James is a public health physician and PhD graduate who has worked on the pathogenesis and immunology of malaria for many years through clinical and population studies and clinical trials. The major focus of his research is aimed at understanding the targets and mechanisms of protective immunity to malaria in humans, how protective immunity is acquired and maintained, and using this knowledge to advance malaria vaccine development and evaluation.

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