We have shown that live influenza viruses expressing foreign epitopes can induce an efficient antibody and cytotoxic T cell (CTL) response. Specifically, we generated recombinant influenza viruses expressing CTL and B cell epitopes of the circumsporozoite (CS) protein of P. yoelii. Immunization of mice with these recombinant influenza viruses, alone or followed by a recombinant vaccinia virus expressing the entire CS protein, induced protective immunity against this murine malaria. We now propose to expand this approach and extend it to human malaria caused by P. falciparum. This work should generate data necessary for defining the optimal design of recombinant viruses for their future use as vaccines against malaria and possibly also against other infectious diseases. For this purpose we plan to: 1. Construct recombinant influenza viruses, expressing B and T cell epitopes of the CS protein of the human malaria parasite, P. falciparum. 2. Determine the degree of attenuation of these constructs in mice, and characterize the influenza-specific immune responses of animals exposed to the viral vectors. 3. Characterize the humoral and T cell mediated anti-malaria immune responses of mice immunized with recombinant influenza-CS viruses. 4. Construct additional influenza viruses expressing selected sequences of a second P. falciparum antigen, the Trombospondin Related Anonymous Protein (TRAP), and assess their immunogenicity in mice. Also define the immune response to influenza viruses expressing both CS and TRAP epitopes. 5. Attempt to potentiate these immune responses by priming and boosting with transfectants of two subtypes of influenza viruses, or two entirely different viral vectors, both expressing the same foreign epitopes.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI036526-04
Application #
2429434
Study Section
Special Emphasis Panel (SRC (35))
Project Start
1994-09-01
Project End
1998-05-31
Budget Start
1997-06-01
Budget End
1998-05-31
Support Year
4
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, 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
Zavala, F; Rodrigues, M; Rodriguez, D et al. (2001) A striking property of recombinant poxviruses: efficient inducers of in vivo expansion of primed CD8(+) T cells. Virology 280:155-9
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
Nardin, E; Zavala, F; Nussenzweig, V et al. (1999) Pre-erythrocytic malaria vaccine: mechanisms of protective immunity and human vaccine trials. Parassitologia 41:397-402
Miyahira, Y; Garcia-Sastre, A; Rodriguez, D et al. (1998) Recombinant viruses expressing a human malaria antigen can elicit potentially protective immune CD8+ responses in mice. Proc Natl Acad Sci U S A 95:3954-9
Rodrigues, E G; Zavala, F; Eichinger, D et al. (1997) Single immunizing dose of recombinant adenovirus efficiently induces CD8+ T cell-mediated protective immunity against malaria. J Immunol 158:1268-74
Murata, K; Garcia-Sastre, A; Tsuji, M et al. (1996) Characterization of in vivo primary and secondary CD8+ T cell responses induced by recombinant influenza and vaccinia viruses. Cell Immunol 173:96-107