Plasmodium is the causative agent of malaria, one of the world's deadliest parasitic diseases. Malaria affects over 300 million people worldwide, causing more than 1 million deaths annually, particularly in young children and pregnant women in sub-Saharan Africa. Currently, there is no vaccine available, and there is widespread resistance to common anti-malarial drugs. RTS,S, a leading vaccine candidate which targets the initial infection of the liver, achieved only partial efficacy (Olotu, et al. 2013 N Engl J Med 368(12):1111-1120). However, clinical manifestations of the disease are caused by the blood-stage parasites. These disease-causing forms of the parasite primarily reside within the red blood cells (RBC), which, upon maturation (schizont), releases merozoites, the invasive form of Plasmodium that invades new RBCs. Therefore, vaccines targeting the erythrocytic forms of the parasite are desirable for efficient disease control measures.
Apicomplexan parasites have specialized secretory organelles (rhoptries and micronemes) that release their contents during host cell invasion. The micronemes possess the protein apical membrane antigen 1 (AMA1). AMA1 is an essential merozoite surface protein and was previously considered one of the leading blood-stage vaccine candidates (Stowers, et al. 2002 Infect Immun 70(12):6961-6967 and Dutta, et al. (2009) PLoS One 4(12):e8138). Despite the vaccines' ability to elicit high-titred AMA1-specific antibodies, Phase 2 clinical trials showed only weak efficacy (http://www.ncbi.nlm.nih.gov/pubmed/21916638, Mahamadou, et al. 2011 New England J Med 365(11):1004-13), even against homologous parasite (Spring, et al. 2009 PLoS One 4(4):e5254, Ouattara, et al. 2010 Malar J 9:175 and Thera, et al. 2011 N Engl J Med 365(11):1004-1013). Recent efforts to cover the polymorphism in AMA1 demonstrated that combining 4-5 different AMA1 alleles could overcome the strain-specific barrier in vitro (Miura, et al. 2013 Infect Immun 81(5):1491-1501, Dutta, et al. 2013 PLoS Pathog 9(12):e1003840 and Remarque, et al. 2008 Infect Immun 76(6):2660-2670).
The rhoptry neck sub-compartment possesses a distinct protein repertoire, including rhoptry neck protein (RON2).
USPTO Backgrounds
USPTO Backgrounds