Author: Kasturi Haldar

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.


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 a new Appendix of 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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Malaria: Targets and Drugs for All Stages

This is the updated Malaria: Targets and Drugs for All Stages Collection, which was originally published on April 25, 2013. Articles published by an expanded number of PLOS journals after the collection’s launch through April 25, 2015 are now included in the Appendix.

For additional analysis from Katsuri Haldar and Margaret Phillips, see their second linked post here.

More drugs for malaria: time to expand the antimalarial portfolio

Malaria is an ancient enemy. Its treatments predate modern drug discovery, most notably the use of the Qinghao plant in ancient China (2nd century BC to 340 CE) and Peruvian bark in the early 17th century, the medicines from which are now known to be artemisinin and quinine respectively. Calls for the eradication of malaria have brought renewed focus on tools to control malaria.  Yet, although disease burdens have been lowered in the last five years, malaria remains endemic in over 100 countries and, with an estimated seven hundred thousand deaths in 2010, is still a leading cause of mortality and morbidity worldwide.

Drug research in malaria often focuses on blood stage parasites because they are responsible for the symptoms of the disease and are easier to manipulate in the laboratory.   The assembled PLOS Collection describes multiple parasite and host processes engaged in infection in blood, the blocking of which could stop human illness. However, control and eradication of malaria will also require the development of drugs against stages responsible for mosquito transmission and those that remain latent in the liver, also summarized in the collection. Although these selected papers represent significant research at the highest levels, they are only a fraction of the malaria drug discovery literature.

Despite research, a significant historical hurdle was the market failure of the pharmaceutical industry to invest in the discovery and development of new antimalarials.  Thus new partnerships have arisen that bring together academic and pharmaceutical work.  For example, the not-for-profit product development partnership Medicines for Malaria Venture (MMV) was established in 1999 to discover, develop and deliver new antimalarials in collaboration with both the public and private sector.  They are joined by the Bill and Melinda Gates Foundation , multiple agencies including the National Institutes of Health , the Wellcome Trust, Medical Research Council and others. Never before have philanthropic, public and large Pharma resources been better integrated for antimalarials, progressing research in early stages to testing drugs in humans, subsequent registration and delivery to patients.
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