The effector functions of specific CD8 T cells are crucial in mediating influenza heterologous protection. However, new approaches for influenza vaccines that can trigger effective CD8 T cell responses have not been extensively explored. Here, we report the generation of single cycle infectious influenza virus that lacks a functional HA gene on an X31 genetic background and demonstrate its potential for triggering protective CD8 T cell immunity against heterologous influenza challenge. In vitro, X31-sciIV can infect MDCK cells, but infectious virions are not produced unless HA is trans-complimented. In vivo, intranasal immunization with X31-sciIV does not cause any clinical symptoms in mice but generate influenza specific CD8 T cells in lymphoid (MLN and spleen) and non-lymphoid tissues including lung and BAL as measured by H2-Db NP366 and PA224 tetramer staining. In addition, a significant proportion of X31-sciIV induce, antigen specific respiratory CD8 T cells expressed VLA-1, a marker that is associated with heterologous influenza protection. Further, these influenza specific CD8 T cells produce antiviral cytokines when stimulated with NP366 and PA224 peptides, indicating CD8 T cells triggered by X31-sciIV are functional. When challenged with a lethal dose of heterologous PR8 virus, X31-sciIV primed mice were fully protected from death. However, when CD8 T cells were depleted after priming or before priming, mice could not effectively control virus replication or survive the lethal challenge, indicating X31-sciIV induced memory CD8 T cells mediate the heterologous protection. Thus, our results demonstrate the potential for sciIV as a CD8 T cell inducing vaccine.
[Show abstract][Hide abstract] ABSTRACT: Seasonal influenza vaccines provide protection against matching influenza A virus (IAV) strains mainly through the induction of neutralizing serum IgG antibodies. However, these antibodies fail to confer a protective effect against mismatched IAV. This lack of efficacy against heterologous influenza strains has spurred the vaccine development community to look for other influenza vaccine concepts, which have the ability to elicit cross-protective immune responses. One of the concepts that is currently been worked on is that of influenza vaccines inducing influenza-specific T cell responses. T cells are able to lyse infected host cells, thereby clearing the virus. More interestingly, these T cells can recognize highly conserved epitopes of internal influenza proteins, making cellular responses less vulnerable to antigenic variability. T cells are therefore cross-reactive against many influenza strains, and thus are a promising concept for future influenza vaccines. Despite their potential, there are currently no T cell-based IAV vaccines on the market. Selection of the proper antigen, appropriate vaccine formulation and evaluation of the efficacy of T cell vaccines remains challenging, both in preclinical and clinical settings. In this review, we will discuss the current developments in influenza T cell vaccines, focusing on existing protein-based and novel peptide-based vaccine formulations. Furthermore, we will discuss the feasibility of influenza T cell vaccines and their possible use in the future.
Frontiers in Immunology 05/2015; 6. DOI:10.3389/fimmu.2015.00237
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