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Drugs for Malaria: Need to Overcome Resistance to Artemisinins and Eliminate All Stages of Parasites in a Wide Range of Transmission and Disease Settings

In their second post honoring World Malaria Day, Kasturi Haldar, Editor-in-Chief of PLOS Pathogens, and Margaret Phillips comment on the challenges for drug development and the path to malaria control, elimination and eradication.

For additional analysis, see their first linked post here.

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Targeting the parasite: a malarial sporozoite in an infected epithelial cell. Image credit: Frevert et al. 10.1371/journal.pbio.0030192

The second decade of the 21st century has been infused with optimism for malaria eradication. Although deadlines have been breached, it appears that the cumulative and long haul fight against malaria is yielding impactful results: reduction of malaria deaths from a staggering 1.2 million to ~ 600,000 from 2000 to 2013 provides a realistic context for elimination and eradication agendas. But the path forward is not just details. Major discoveries in basic, translational and capacity building research supported by commensurate funding are urgently needed to navigate challenges posed by dynamic and heterogeneous disease frontiers.

Drugs have been the mainstay of reducing the malaria burden through treatment of patients. Drug research in malaria started with blood stages of Plasmodium falciparum, the most dangerous and prevalent of human malarias. But it has expanded to other stages as well as to Plasmodium vivax a second parasite species that causes widespread disease but is not as virulent as P.falciparum. Treatment to cure the patient remains a primary goal. However, malaria elimination and eradication also require reducing transmission to the mosquito stages and clearance of latent infection in the liver. Severe disease like cerebral malaria and severe malarial anemia are frequently fatal and need renewed attention since they are impacted by natural immunity to malaria, which is changing in context of control measures. This is reflected in the Malaria: Targets and Drugs for All Stages Collection, which was originally assembled in April 2013 and now includes papers published after the collection’s launch through April 25, 2015. Over the last two years there has been a marked increase of papers in host (human and mosquito) response to infection, liver stage infection, transmission and severe malaria and coincident infections, how to measure their burden and treat them, both in human disease and animal models. The collection also includes studies on mechanisms of drug resistance and the spread of resistant parasites in human populations including (but not limited to) resistance to frontline artemisinins and their combination therapies. The selected papers represent significant research at the highest levels: they are only a portion of the literature but well reflect the tools being developed in the larger malaria drug discovery endeavor to overcome major hurdles for malaria elimination.

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Targeting the host: A female Anopheles gambiae, the world’s most important vector of human malaria, resting on a flower of the flame tree, Caesalpinia pulcherrima. Image credit: Thierry Lefèvre 10.1371/journal.ppat.1003365

Molecular understanding of markers and mechanisms of artemisinin resistance has rapidly progressed over the last two years, but replacement drugs for artemisinin are not yet available. The most advanced of the new chemical agents are in human efficacy studies, but none are licensed as approved drugs yet. The tenacious persistence of artemisinin resistant parasites in asymptomatic individuals is a troublesome reservoir: their spread to Africa where transmission and parasite burdens are much higher could precipitate a health crisis of global proportions. Therefore malaria treatments need to be responsive to a wide range of disease setting, ranging from high transmission areas where partial immunity may work in conjunction with drugs to eliminate parasites, to low transmission areas where in absence of immunity there is need for near sterile protection by fast acting therapies that are also stable over months to prevent re-infection.

Malaria eradication is a demanding but hopeful agenda. Expanding drug discovery and development as well as training to build innovative research capacity in endemic areas, can secure continuous reduction of malaria burdens on the path to control, elimination and eradication.

We dedicate this article to the late Dr. Martin John Rogers, Program Officer, Parasitology and International Programs Branch, National Institute for Allergy and Infectious Diseases, for his leadership in antimalarial drug discovery.

 

Discussion
  1. […] In their second post honoring World Malaria Day, Kasturi Haldar, Editor-in-Chief of PLOS Pathogens, and Margaret Phillips comment on the challenges for drug development and the path to malaria control, elimination and eradication. For additional analysis, see their first linked … Continue reading » […]

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