ACT: artemisinin-based combination therapy
CDC: Centers for Disease Control and Prevention
CNS: central nervous system
CSA: chondroitin sulfate A
CSF: cerebrospinal fluid
cytbc1: cytochrome bc1
DEET: N, N′-diethylmetatoluamide
FDA: Food and Drug Administration
G6PD: glucose-6-phosphate dehydrogenase
IND: investigational new drug (application)
pfCRT: Plasmodium falciparum chloroquine resistance transporter
pfMRP: Plasmodium facliparum multidrug resistance-associated protein
GLOBAL IMPACT OF MALARIA
Malaria remains among the top five causes of death among children younger than 5 years, affects about a quarter of a billion people, and causes almost 900,000 deaths annually (GBD_2013_Collaborators, 2015). Malarial transmission occurs in regions of Africa, Latin and South America, Asia, the Middle East, the South Pacific, and the Caribbean (Figure 53–1). This disease is caused by infection with protozoan parasites of the genus Plasmodium. Five Plasmodium spp. are known to infect humans: P. falciparum, P. vivax, P. ovale, P. malariae, and P. knowlesi. Plasmodium falciparum and P. vivax cause most malarial infections worldwide. Plasmodium falciparum accounts for the majority of the burden of malaria in sub-Saharan Africa and is associated with the most severe disease. Plasmodium vivax accounts for half of the malaria burden in South and East Asia and more than 80% of the malarial infections in the Americas and has been underappreciated as a cause of severe malaria (Baird, 2013).
Malaria-endemic countries. A. Eastern Hemisphere; B. Western Hemisphere. A country is shaded orange even if malaria is endemic in just a portion of that country. Large regions not shown on the maps (e.g., Scandinavia, Russia, Canada, U.S.A., Tasmania, New Zealand) are non-endemic for malaria. (Reproduced from Centers for Disease Control and Prevention. https://wwwnc.cdc.gov/travel/yellowbook/2018/infectious-diseases-related-to-travel/malaria; accessed July 29, 2017). In areas of endemic malaria, the disease is largely chloroquine-resistant. For up-to-date information, consult the online CDC Malaria Map (https://www.cdc.gov/malaria/travelers/about_maps.html) and the CDC’s Malaria Information and Prophylaxis, by Country (http://www.cdc.gov/malaria/travelers/country_table/a.html).
Over the past half-century, malaria parasites worldwide—primarily P. falciparum and P. vivax—have become increasingly resistant to antimalarial drugs, including chloroquine (Djimde et al., 2001; Warhurst, 2001); mefloquine (White et al., 2014); quinine (White et al., 2014); sulfadoxine/pyrimethamine (Artimovich et al., 2015; Plowe et al., 1995, Sibley et al., 2001); and atovaquone (Garcia-Bustos et al., 2013; Kessl et al., 2007). In response, new, multiprong international public-private partnerships as well as other funding agencies and sources have emerged to create new pipelines that advance drug candidates from discovery to clinical development (Hemingway et al., 2016; Wells et al., 2010, 2015).
BIOLOGY OF MALARIAL INFECTION