Abstract
Recently, we showed that combined intranasal and subcutaneous immunization with a non-replicating adenoviral vector expressing NP of influenza A, strain PR8, induced long-standing protection against a range of influenza A viruses. However, H-2b mice challenged with an influenza A strain mutated in the dominant NP366 epitope were not efficiently protected. To address this problem, we envision the use of a cocktail of adenovectors targeting different internal proteins of influenza A virus. Consequently, we investigated the possibility of using PB1 as a target for an adenovector-based vaccine against influenza A. Our results showed that PB1 is not as immunogenic as the NP protein. However, by tethering PB1 to the murine invariant chain we were able to circumvent this problem and raise quite high numbers of PB1-specific CD8+ T cells in the circulation. Nevertheless, mice immunized against PB1 were not as efficiently protected against influenza A challenge as similarly NP-vaccinated animals. The reason for this is not a difference in the quality of the primed cells, nor in functional avidity. However, under similar conditions of immunization fewer PB1-specific cells were recruited to the airways, and surface expression of the dominant PB1 peptide, PB1703, was less stable than in the case of NP366.
Highlights
Influenza A virus is a very common respiratory virus causing 3–5 million cases of severe disease each year worldwide[1]
Adenovirus encoding PB1 linked to invariant chain induces high number of antigen-specific CD8+ T cells
Adenovirus vaccines encoding PB1 with or without invariant chain (AdPB1 or AdIiPB1) were used to vaccinate mice s.c. in the foot pad; an adenovector expressing invariant chain combined with an irrelevant antigen was used as control
Summary
Influenza A virus is a very common respiratory virus causing 3–5 million cases of severe disease each year worldwide[1]. In contrast to antibody mediated immunity, CD8+ T-cell immunity targets the conserved internal proteins of influenza Several studies, in both mice and man, have identified CD8+ T cells to be of major importance for clearance of influenza virus infections, and CD8+ memory T cells can remain for at least a couple of years after the infection is cleared[3,4,5,6,7]. Even though the internal proteins are highly conserved between influenza A strains, variations do exist which could cause the virus to escape CD8+ T-cell mediated immunity. To circumvent this problem, we propose a vaccine-cocktail, targeting several of the internal proteins of the influenza virus, creating a vaccine able to protect against challenge with a broad variety of strains. A vaccine targeting PB1 is not sufficient as a stand-alone vaccine, even when tethered to Ii, but PB1 may be included in a combination with other internal genes of influenza
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