Abstract
Consecutive cases of human infection with H7N9 influenza viruses since 2013 in China have prompted efforts to develop an effective treatment. Subunit vaccines introduced by intranasal administration can block an infection at its primary site; flagellin (fliC) and polyethyleneimine (PEI) have been shown to be potent adjuvants. We previously generated the hemagglutinin (HA)1–2-fliC fusion protein consisting of the globular head domain (HA1–2; amino acids 62–284) of HA fused with Salmonella typhimurium fliC. In the present study, we investigated its effectiveness of both flagellin and PEI as mucosal adjuvants for the H7N9 influenza subunit vaccine. Mice immunized intranasally with HA1–2-fliC and HA1–2-PEI showed higher HA1–2-specific immunoglobulin (Ig)G and IgA titers in serum, nasal wash, and bronchial alveolar lavage fluid. Moreover, splenocyte activation and proliferation and the number of HA1–2-specific interferon (IFN)-γ- and interleukin (IL)-4-producing splenocytes were markedly increased in the fliC and PEI groups; in the latter, there were more cells secreting IL-4 than IFN-γ, suggesting that fliC induced T helper type (Th)1 and Th2 immune responses, and PEI induced Th2-biased responses, consistent with the serum antibody isotype pattern (IgG1/IgG2a ratio). Furthermore, virus challenge was performed in a chicken model. The results showed that chickens receiving fliC and PEI adjuvant vaccine exhibited robust immune responses leading to a significant reduction in viral loads of throat and cloaca compared to chickens receiving only HA1–2. These findings provide a basis for the development of H7N9 influenza HA1–2 mucosal subunit vaccines.
Highlights
In the spring of 2013, an H7N9 subtype of avian influenza virus infecting humans was discovered in China; initially the virus replicated silently in chickens without causing disease [1], rapid development throughout the country led to an outbreak
Mice were vaccinated intranasally with HA1–2, HA1–2-fliC, or HA1–2 combined with PEI or cholera toxin B subunit (CTB) on days 0, 14, and 28 (Figure 1)
The capacity of these candidate vaccines to induce a humoral immune response was evaluated by detecting the presence of HA1–2-specific antibodies in the serum by enzyme-linked immunosorbent assay (ELISA) at 12 days post the second and third vaccination
Summary
In the spring of 2013, an H7N9 subtype of avian influenza virus infecting humans was discovered in China; initially the virus replicated silently in chickens without causing disease [1], rapid development throughout the country led to an outbreak. There exist no licensed vaccines for H7N9 infection. It is critical to develop a vaccination strategy to protect against H7N9 influenza. The advantage of subunit vaccines is that they provide a safe and specific stimulus for the induction of immunity [3]. The administration of antigen to mucosal surfaces is possibly the best method of inducing mucosal immune responses at distant as well as local sites [4], and efforts are on the way to develop mucosal vaccines for influenza [5, 6]. A main obstacle to mucosal subunit vaccines has been the lack of an appropriate adjuvant; the only one licensed for human use (aluminum) is unsuitable for mucosal applications [3]
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