A Multivalent and Cross-Protective Vaccine Strategy against Arenaviruses Associated with Human Disease

PLoS Pathogens

Michael J. Buchmeier¹  Joey Ting¹  Lori Giancola²  Valerie Pasquetto²  Jason A. Greenbaum²  Alessandro Sette²  Howard Grey²  Carla Oseroff²  Bjoern Peters²  John Sidney²  Maya F. Kotturi²  Huynh-Hoa Bui²  Matt Maybeno²  Josie Babin²  Jeff Alexander³  Lo Vang³  Jason Botten⁴  Danh Do⁴ 

[1] Departments of Molecular Biology and Biochemistry and Community and Environmental Medicine, University of California, Irvine, California, United States of America;Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, La Jolla, California, United States of America;Pharmexa-Epimmune, San Diego, California, United States of America;Vermont Center for Immunology and Infectious Diseases, The University of Vermont College of Medicine, Burlington, Vermont, United States of America

关键词: T cells;    Cytotoxic T cells;    Mouse models;    Arenaviruses;    Antigen-presenting cells;    Immune response;    Enzyme-linked immunoassays;    Vaccines;   

DOI  :  10.1371/journal.ppat.1000695

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

Arenaviruses are the causative pathogens of severe hemorrhagic fever and aseptic meningitis in humans, for which no licensed vaccines are currently available. Pathogen heterogeneity within the Arenaviridae family poses a significant challenge for vaccine development. The main hypothesis we tested in the present study was whether it is possible to design a universal vaccine strategy capable of inducing simultaneous HLA-restricted CD8+ T cell responses against 7 pathogenic arenaviruses (including the lymphocytic choriomeningitis, Lassa, Guanarito, Junin, Machupo, Sabia, and Whitewater Arroyo viruses), either through the identification of widely conserved epitopes, or by the identification of a collection of epitopes derived from multiple arenavirus species. By inoculating HLA transgenic mice with a panel of recombinant vaccinia viruses (rVACVs) expressing the different arenavirus proteins, we identified 10 HLA-A02 and 10 HLA-A03-restricted epitopes that are naturally processed in human antigen-presenting cells. For some of these epitopes we were able to demonstrate cross-reactive CD8+ T cell responses, further increasing the coverage afforded by the epitope set against each different arenavirus species. Importantly, we showed that immunization of HLA transgenic mice with an epitope cocktail generated simultaneous CD8+ T cell responses against all 7 arenaviruses, and protected mice against challenge with rVACVs expressing either Old or New World arenavirus glycoproteins. In conclusion, the set of identified epitopes allows broad, non-ethnically biased coverage of all 7 viral species targeted by our studies.

【 授权许可】

CC BY