Abstract
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.
Highlights
Pathogen heterogeneity is a commonly encountered challenge for vaccine design
We show that immunization with a cocktail of these epitopes protects human class I MHC (HLA) transgenic mice from challenge with recombinant vaccinia viruses (rVACVs) expressing antigens from different arenavirus species
The gene sequences encoding the different arenavirus proteins were derived from prototypic virus strains (Table S1), and the constructs were engineered into the Western Reserve (WR) strain of VACV
Summary
Pathogen heterogeneity is a commonly encountered challenge for vaccine design. A considerable fraction of unmet vaccine needs for infectious disease is associated with pathogens naturally displaying significant levels of genetic diversity. A prominent example includes arenaviruses, which are categorized in different complexes with distinct geographical locations, and continue to provide a formidable challenge for vaccine development. The Arenaviridae family, consisting of a single genus (Arenavirus), contains 22 known viral species, which are classified phylogenetically into Old World and New World complexes [1]. The latter complex is further divided into three Clades (A, B, and C). The New World Clade B contains some of the most pathogenic agents, including Guanarito virus (GTOV), Junin virus (JUNV), Machupo virus (MACV), Sabia virus (SABV), and the recombinant Clade A/B arenavirus, Whitewater Arroyo virus (WWAV). Arenaviruses are enveloped viruses, with a ,10.7 kb RNA genome that encodes four viral proteins, including the glycoprotein precursor (GPC), nucleocapsid protein (NP), RNAdependent RNA polymerase (L), and the zinc-finger binding protein (Z) [2]
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