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To generate broadly protective T cell responses more similar to those acquired after vaccination with radiation-attenuated Plasmodium falciparum sporozoites, we have constructed candidate subunit malaria vaccines expressing six preerythrocytic antigens linked together to produce a 3240-aa-long polyprotein (L3SEPTL). This polyprotein was expressed by a plasmid DNA vaccine vector (DNA) and by two attenuated poxvirus vectors, modified vaccinia virus Ankara (MVA) and fowlpox virus of the FP9 strain. MVAL3SEPTL boosted anti-thrombospondin-related adhesive protein (anti-TRAP) and anti-liver stage antigen 1 (anti-LSA1) CD8(+) T cell responses when primed by single antigen TRAP- or LSA1-expressing DNAs, respectively, but not by DNA-L3SEPTL. However, prime boost regimes involving two heterologous viral vectors expressing L3SEPTL induced a strong cellular response directed against an LSA1 peptide located in the C-terminal region of the polyprotein. Peptide-specific T cells secreted IFN-gamma and were cytotoxic. IFN-gamma-secreting T cells specific for each of the six antigens were induced after vaccination with L3SEPTL, supporting the use of polyprotein inserts to induce multispecific T cells against P. falciparum. The use of polyprotein constructs in nonreplicating poxviruses should broaden the target antigen range of vaccine-induced immunity and increase the number of potential epitopes available for immunogenetically diverse human populations.

Original publication

DOI

10.1073/pnas.0307158101

Type

Journal article

Journal

Proc Natl Acad Sci U S A

Publication Date

06/01/2004

Volume

101

Pages

290 - 295

Keywords

Animals, Antigens, Protozoan, CD8-Positive T-Lymphocytes, Cytotoxicity, Immunologic, Female, Fowlpox virus, Genetic Vectors, Interferon-gamma, Malaria Vaccines, Malaria, Falciparum, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Plasmodium falciparum, Protozoan Proteins, Vaccines, DNA, Vaccinia virus