1. Technical Field
The present invention relates generally to compositions and methods for preventing, treating and detecting leishmaniasis in patients. More particularly, the invention relates to compositions and methods comprising Leishmania fusion polypeptides, as well as polynucleotides encoding such fusion polypeptides.
2. Description of the Related Art
Leishmania organisms are obligate intracellular parasites that cause a large clinical spectrum of diseases named leishmaniasis. Leishmania organisms are intracellular protozoan parasites of the genus Leishmania. Leishmania organisms target host macrophages; thus causing a wide spectrum of clinical diseases in humans and domestic animals, primarily dogs. In some infections, the parasite may lie dormant for many years. In other cases, the host may develop one of a variety of forms of leishmaniasis. Leishmaniases are roughly classified into three types of diseases, cutaneous leishmaniasis (CL), mucosal leishmaniasis (ML) and visceral leishmaniasis (VL), according to the clinical manifestations.
Leishmaniasis is a serious problem in much of the world, including Brazil, China, East Africa, India and areas of the Middle East. The disease is also endemic in the Mediterranean region, including southern France, Italy, Greece, Spain, Portugal and North Africa. The number of cases of leishmaniasis has increased dramatically in the last 20 years, and millions of cases of this disease now exist worldwide. About 2 million new cases are diagnosed each year, 25% of which are visceral leishmaniasis.
Visceral leishmaniasis (VL) has been reported in 88 countries, but roughly 90% of VL cases occur in Brazil, India, Sudan, Bangladesh, and Nepal (Mendez et al. J Immunol 2001; 166(8): pp. 5122-8). The annual incidence is estimated to be approximately 500,000 cases of VL, and the population at risk is 350 million (Engwerda et al. Eur J Immunol 1998; 28(2): pp. 669-80; Squires et al. J Immunol 1989; 143(12): pp. 4244-9). VL is generally caused by species of the L. donovani complex, i.e. L. donovani and L. infantum (chagasi). L. donovani is the causative agent of VL in Africa and Asia, L. infantum/chagasi in Mediterranean countries and in the New World (Piedrafita et al. J Immunol 1999; 163(3): pp. 1467-72). VL is a severe debilitating disease that evolves with visceral infection involving the spleen, liver and lymph nodes, which, untreated, is generally a fatal disease. Symptoms of acute VL include hepatosplenomegaly, fever, leukopenia, anemia and hypergammaglobulinemia. Active VL is generally fatal unless properly treated.
Leishmania parasites are transmitted by the bite of sandflies and the infecting promastigotes differentiate into and replicate as amastigotes within macrophages in the mammalian host. In common with other intracellular pathogens, cellular immune responses are critical for protection against leishmaniasis. Th1 immune responses play an important role in mediating protection against Leishmania, including roles for CD4+ and CD8+ T cells, IFN-γ, IL-12, TNF-α and NO, whereas inhibitory effects have been reported for IL-10 and TGF-β (Engwerda et al. Eur J Immunol 1998; 28(2): pp. 669-80; Murphy et al. Eur J. Immunol. 2001; 31(10): pp. 2848-56; Murray et al. J Exp Med. 1999; 189(4): pp. 741-6; Murray et al. Infect Immun. 2000; 68(11): pp. 6289-93; Squires et al. J Immunol 1989; 143(12): pp. 4244-9 6; Taylor and Murray. J Exp Med. 1997; 185(7): pp. 1231-9; Kaye and Bancroft. Infect Immun. 1992; 60(10): pp. 4335-42; Stern et al. J. Immunol. 1988; 140(11): pp. 3971-7; Wilson et al. J. Immunol. 1998; 161(11): pp. 6148-55).
Immunization against leishmaniasis in animal models can be effected by delivery of antigen-encoding DNA vectors (Gurunathan et al. J Exp Med. 1997; 186(7): pp. 1137-47; Piedrafita et al. J. Immunol. 1999; 163(3):1467-72; Mendez et al. J. Immunol. 2001; 166(8): pp. 5122-8) or by administration of proteins formulated with Th1-inducing adjuvants including IL-12 (Afonso et al. Science. 1994; 263(5144): pp. 235-7; Stobie et al. Proc Natl Acad Sci USA. 2000; 97(15): pp. 8427-32; Kenney et al. J. Immunol. 1999; 163(8): pp. 4481-8) or TLR ligands such as CpG oligonucleotides (Rhee et al. J Exp Med. 2002; 195(12): pp. 1565-73; Stacey and Blackwell. Infect Immun. 1999; 67(8): pp. 3719-26; Walker et al. Proc Natl Acad Sci USA. 1999; 96(12): pp. 6970-5) and monophosphoryl lipid A (Coler et al. Infect Immun. 2002; 70(8): pp. 4215-25; Skeiky et al. Vaccine. 2002; 20(2728): pp. 3292-303).
In spite of some evidence that sub-unit vaccines may be effective in certain models of VL (Basu et al. J. Immunol. 2005; 174(11): pp. 7160-71; Stager et al. J. Immunol. 2000; 165(12): pp. 7064-71; Ghosh et al. Vaccine. 2001; 20(12): pp. 59-66; Wilson et al. Infect Immun. 1995; 63(5): pp. 2062-9; Tewary et al. J Infect Dis. 2005; 191(12): pp. 2130-7; Aguilar-Be et al. Infect Immun. 2005; 73(2): pp. 812-9. Rafati et al. Vaccine. 2006; 24(12):2169-75), progress toward defining antigen candidates effective against VL in vivo has been lacking.
Strategies employing vaccines consisting of whole organisms for preventing or treating leishmaniasis have not been effective in humans. Accordingly, there remains a significant need for immunogenic compositions and vaccines that can effectively prevent and/or treat leishmaniasis in humans and other mammals (e.g., canines). The present invention fulfills these needs and offers other related advantages
USPTO Backgrounds
USPTO Backgrounds