Bruder, Joseph T., Chen, Ping, Ekberg, Greg, Smith, Emily C., Lazarski, Christopher A., Myers, Bennett A., Bolton, Jessica, Sedegah, Martha, Villasante, Eileen, Richie, Thomas, King, C. Richter, Aguiar, Joao C., Doolan, Denise L., and Brough, Douglas E. (2017) Profiling the targets of protective CD8(+) T cell responses to infection. Molecular Therapy: methods & clinical development, 7. pp. 20-31.

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Abstract

T cells are critical effectors of host immunity that target intracellular pathogens, such as the causative agents of HIV, tuberculosis, and malaria. The development of vaccines that induce effective cell-mediated immunity against such pathogens has proved challenging; for tuberculosis and malaria, many of the antigens targeted by protective T cells are not known. Here, we report a novel approach for screening large numbers of antigens as potential targets of T cells. Malaria provides an excellent model to test this antigen discovery platform because T cells are critical mediators of protection following immunization with live sporozoite vaccines and the specific antigen targets are unknown. We generated an adenovirus array by cloning 312 highly expressed pre-erythrocytic Plasmodium yoelii antigens into adenovirus vectors using high-throughput methodologies. The array was screened to identify antigen-specific CD8(+) T cells induced by a live sporozoite vaccine regimen known to provide high levels of sterile protection mediated by CD8(+) T cells. We identified 69 antigens that were targeted by CD8(+) T cells induced by this vaccine regimen. The antigen that recalled the highest frequency of CD8(+) T cells, PY02605, induced protective responses in mice, demonstrating proof of principle for this approach in identifying antigens for vaccine development.

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