Profiling the Targets of Protective CD8 + T Cell Responses to Infection

• Published in: Molecular therapy. Methods & clinical development Vol. 7; no. C; pp. 20 - 31
• Main Authors: Bruder, Joseph T, Chen, Ping, Ekberg, Greg, Smith, Emily C, Lazarski, Christopher A, Myers, Bennett A, Bolton, Jessica, Sedegah, Martha, Villasante, Eileen, Richie, Thomas L, King, C Richter, Aguiar, Joao C, Doolan, Denise L, Brough, Douglas E
• Format: Journal Article
• Language: English
• Published: United States Elsevier Limited 15.12.2017; American Society of Gene & Cell Therapy; Elsevier
• Subjects: adenovirus; Adenoviruses; antigen; antigen discovery; Antigens; CD8 antigen; Cell-mediated immunity; Cloning vectors; Expression vectors; Genes; Genomes; HIV; Human immunodeficiency virus; Immunization; Immunoglobulins; Infections; Liver; Lymphocytes; Lymphocytes T; Malaria; Parasites; Pathogens; Plasmids; Proteins; R&D; Research & development; screen; T cell; Tuberculosis; vaccine; Vaccine development; Vaccines; vector; viral vector; vaccine; T cell; adenovirus; screen; vector; antigen; antigen discovery; viral vector; malaria
• ISSN: 2329-0501; 2329-0501
• DOI: 10.1016/j.omtm.2017.08.003

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 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.