Abstract
Parenteral administration of killed/inactivated swine influenza A virus (SwIAV) vaccine in weaned piglets provides variable levels of immunity due to the presence of preexisting virus specific maternal derived antibodies (MDA). To overcome the effect of MDA on SwIAV vaccine in piglets, we developed an intranasal deliverable killed SwIAV antigen (KAg) encapsulated chitosan nanoparticles called chitosan-based NPs encapsulating KAg (CS NPs-KAg) vaccine. Further, to target the candidate vaccine to dendritic cells and macrophages which express mannose receptor, we conjugated mannose to chitosan (mCS) and formulated KAg encapsulated mCS nanoparticles called mannosylated chitosan-based NPs encapsulating KAg (mCS NPs-KAg) vaccine. In MDA-positive piglets, prime-boost intranasal inoculation of mCS NPs-KAg vaccine elicited enhanced homologous (H1N2-OH10), heterologous (H1N1-OH7), and heterosubtypic (H3N2-OH4) influenza virus-specific secretory IgA (sIgA) antibody response in nasal passage compared to CS NPs-KAg vaccinates. In vaccinated upon challenged with a heterologous SwIAV H1N1, both mCS NPs-KAg and CS NPs-KAg vaccinates augmented H1N2-OH10, H1N1-OH7, and H3N2-OH4 virus-specific sIgA antibody responses in nasal swab, lung lysate, and bronchoalveolar lavage (BAL) fluid; and IgG antibody levels in lung lysate and BAL fluid samples. Whereas, the multivalent commercial inactivated SwIAV vaccine delivered intramuscularly increased serum IgG antibody response. In mCS NPs-KAg and CS NPs-KAg vaccinates increased H1N2-OH10 but not H1N1-OH7 and H3N2-OH4-specific serum hemagglutination inhibition titers were observed. Additionally, mCS NPs-KAg vaccine increased specific recall lymphocyte proliferation and cytokines IL-4, IL-10, and IFNγ gene expression compared to CS NPs-KAg and commercial SwIAV vaccinates in tracheobronchial lymph nodes. Consistent with the immune response both mCS NPs-KAg and CS NPs-KAg vaccinates cleared the challenge H1N1-OH7 virus load in upper and lower respiratory tract more efficiently when compared to commercial vaccine. The virus clearance was associated with reduced gross lung lesions. Overall, mCS NP-KAg vaccine intranasal immunization in MDA-positive pigs induced a robust cross-reactive immunity and offered protection against influenza virus.
Highlights
Swine influenza is an acute respiratory disease of pigs caused by swine influenza A virus (SwIAV) [1]
All the weaned piglets born to vaccinated mothers used in this experimental trial had high levels of SwIAV specific maternally-derived antibodies (MDA) in serum, with no significant difference between the groups (Supplementary Figure 1)
Compared to commercial SwIAV vaccine, both mannose ligand with chitosan (mCS) NPs-killed SwIAV antigen (KAg) and chitosan nanoparticles (CS NPs)-KAg vaccinates increased H1N2OH10 virus-specific sIgA antibody levels in nasal swabs, while mCS NPs-KAg vaccine increased level was significantly (p < 0.05) higher (Figure 1A). mCS NPs-KAg and commercial vaccinates had significantly (p < 0.05) increased H1N1-OH7 and H3N2-OH4 viruses-specific sIgA antibody levels in nasal swab compared to mock pigs (Figures 1B,C)
Summary
Swine influenza is an acute respiratory disease of pigs caused by swine influenza A virus (SwIAV) [1]. Triple reassortant SwIAVs have been isolated from pigs [5], and its association with human infections have been documented [6, 7]. Vaccination of pigs is a common practice to reduce the influenza burden in swine industry and to avoid the risk of zoonotic transmission to humans [10]. The SwIAV vaccine inoculated into sows protects the herd from infection and heightens the transfer of maternally-derived antibodies (MDA) to offspring through colostrum [11, 12]. MDA interferes with parenteral administered killed/inactivated influenza virus vaccines, resulting in poor induction of antibody responses and documented evidence of vaccine-associated enhanced respiratory disease [2, 13,14,15]
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