| Summary: | Vaccines that induce T cells which recognize conserved viral proteins could confer cross-strain protection against pathogens with fast-mutating B cell epitopes. Influenza is an example of such a pathogen for which there is a pressing need for a universal vaccine. Lentiviral vectors are a counterintuitive choice as vaccines since they have low inherent immunogenicity. However, their efficient transduction of non-dividing cells and high capacity permits transduction of antigen presenting cells with not only antigen but also molecular adjuvants that directly or indirectly enhance the T cell response. We therefore investigated the potential of two such adjuvants: viral flice-like inhibitor protein, which activates dendritic cells through nuclear factor kappa-B, and 4-1BB ligand, which activates T cells directly through 4-1BB. By co-encoding these with influenza nucleoprotein, we have shown that the influenza-specific T cell response to lentiviral vector vaccination is significantly enhanced in mice. Furthermore, we have demonstrated that intranasally delivered lentiviral vectors transduce alveolar macrophages with high efficiency, recalling and expanding large and sustained populations of nucleoprotein-specific CD8+ T cells in the lung and airway in mice that have been primed subcutaneously or previously exposed to influenza. These lung-resident T cell populations persist for at least 4 months and are sufficiently abundant to rapidly control a mouse-adapted lethal influenza challenge without invocation of a secondary cytokine response, weight loss or lung injury. Furthermore, dendritic cells expressing 4-1BBL potently trans-activate bystander dendritic cells, both in vitro and in vivo, demonstrating an indirect mechanism by which the 4-1BBL:4-1BB signaling axis can enhance T cell responses.
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