Malaria is a severe disease that continues to rank among the most prevalent infections in tropical areas, throughout the world. The fact that immunization with irradiated sporozoites can protect not only rodents, but also humans against this disease indicates that it might be feasible to develop an effective pre-erythrocytic vaccine, which would represent a valuable additional tool for the control of this disease. The overall aim of this proposal is to use a replication-defective recombinant adenovirus, expressing one or more plasmodial antigens, as a model system to characterize the protective immune response targeted against the liver stages of malaria parasites. My earlier studies have demonstrated that a single immunizing dose of this vector, expressing the circumsporozoite (CS) protein, unlike any other form of presentation of this plasmodial antigen, induces high levels of CS-specific CD8+ and CD4+T cells, and confers sterile immunity to a considerable percentage of mice. I also determined that this protection is primarily mediated by CD8+ T cells, but the molecular basis of this protective mechanisms remains to be elucidated. This I propose to pursue by the use of genetically manipulated, knock-out mice. Another important issue, particularly for future vaccine development relates to the exploration of various approaches aimed at enhancing the protective effect of a subunit vaccine based on recombinant adenovirus. These objectives will be pursued by: 1)Determining the level and persistence of humoral and cell- mediated anti-plasmodial responses and protection of mice receiving multiple immunizations with recombinant adenovirus vectors, or combined immunization with other immunogens containing the CS protein. 2) Determine whether immunization with an adenoviral vector co-expressing two or more pre-erythrocytic antigens, can potentiate the immune response which occurs upon immunization with one of these antigens. Investigate the possibility of modulating this immune response by administration of an adenovirus co- expressing a plasmodial antigen and a selected lymphokine/co- stimulatory molecule, and 3) Analyze the anti-plasmodial effector mechanisms of CD8+T cells and characterization of the molecules involved in the in vivo processing and presentation of the CSCD8+ epitope.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
1R29AI040656-01A1
Application #
2407748
Study Section
Tropical Medicine and Parasitology Study Section (TMP)
Project Start
1997-07-01
Project End
2002-06-30
Budget Start
1997-07-01
Budget End
1998-06-30
Support Year
1
Fiscal Year
1997
Total Cost
Indirect Cost
Name
New York University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
City
New York
State
NY
Country
United States
Zip Code
10016
Bruna-Romero, Oscar; Rocha, Carolina D; Tsuji, Moriya et al. (2004) Enhanced protective immunity against malaria by vaccination with a recombinant adenovirus encoding the circumsporozoite protein of Plasmodium lacking the GPI-anchoring motif. Vaccine 22:3575-84
Bruna-Romero, Oscar; Schmieg, John; Del Val, Margarita et al. (2003) The dendritic cell-specific chemokine, dendritic cell-derived CC chemokine 1, enhances protective cell-mediated immunity to murine malaria. J Immunol 170:3195-203
Gonzalez-Aseguinolaza, Gloria; Van Kaer, Luc; Bergmann, Cornelia C et al. (2002) Natural killer T cell ligand alpha-galactosylceramide enhances protective immunity induced by malaria vaccines. J Exp Med 195:617-24
Bruna-Romero, O; Gonzalez-Aseguinolaza, G; Hafalla, J C et al. (2001) Complete, long-lasting protection against malaria of mice primed and boosted with two distinct viral vectors expressing the same plasmodial antigen. Proc Natl Acad Sci U S A 98:11491-6
Tsuji, M; Rodrigues, E G; Nussenzweig, S (2001) Progress toward a malaria vaccine: efficient induction of protective anti-malaria immunity. Biol Chem 382:553-70
Tsuji, M; Zavala, F (2001) Peptide-based subunit vaccines against pre-erythrocytic stages of malaria parasites. Mol Immunol 38:433-42
Molano, A; Park, S H; Chiu, Y H et al. (2000) Cutting edge: the IgG response to the circumsporozoite protein is MHC class II-dependent and CD1d-independent: exploring the role of GPIs in NK T cell activation and antimalarial responses. J Immunol 164:5005-9
Nagaoka, H; Gonzalez-Aseguinolaza, G; Tsuji, M et al. (2000) Immunization and infection change the number of recombination activating gene (RAG)-expressing B cells in the periphery by altering immature lymphocyte production. J Exp Med 191:2113-20
Gonzalez-Aseguinolaza, G; de Oliveira, C; Tomaska, M et al. (2000) alpha -galactosylceramide-activated Valpha 14 natural killer T cells mediate protection against murine malaria. Proc Natl Acad Sci U S A 97:8461-6
Rodrigues, E G; Claassen, J; Lee, S et al. (2000) Interferon-gamma-independent CD8+ T cell-mediated protective anti-malaria immunity elicited by recombinant adenovirus. Parasite Immunol 22:157-60

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