PB1 as a potential target for increasing the breadth of T-cell mediated immunity to Influenza A

Abstract

Abstract Current influenza vaccines are inducing antibody-mediated immunity toward the surface proteins hemagglutinin and neuraminidase. High variability of these proteins results in costly annual evaluation and production of new vaccines, not providing protection against heterosubtypic or emerging pandemic strains. Consequently, there is a need for a new universal influenza vaccine strategy. Unlike the surface proteins, the internal proteins of influenza are highly conserved. By vaccinating systemically and locally with nucleoprotein encoded in an adenovirus (AdNP) we could induce a protective CD8 T-cell response, that lasted up to at least 8 month post vaccination. To increase the breadth of our vaccine by combining construct, we studied the vaccine potential of another influenza protein. We showed that an adenovirus encoding PB1 elicits high numbers of antigen-specific CD8 T cells in mice. However, in vivo killing of peptide loaded cells was lower in PB1-vaccinated mice than in NP-vaccinated mice. This correlated with a poorer protection against challenge. To explain this, T cells from vaccinated mice were co-incubated with naïve splenocytes loaded with decreasing concentrations of peptide. If T cells were immediately added to the co-cultures, similar dose/response curves regarding IFNγ production was observed. However, if the T cells were added 6 hours after loading, cells from PB1-vaccinated mice required a much higher initial concentration of peptide to be activated compared with NP specific cells, indicating a lower stability of the MHC-PB1peptide complex. These results underscore that not only are T-cell quality and quantity crucial to consider in future vaccine design, but also MHC-peptide interactions.