| Budget Amount *help |
¥18,460,000 (Direct Cost: ¥14,200,000、Indirect Cost: ¥4,260,000)
Fiscal Year 2011: ¥5,980,000 (Direct Cost: ¥4,600,000、Indirect Cost: ¥1,380,000)
Fiscal Year 2010: ¥5,980,000 (Direct Cost: ¥4,600,000、Indirect Cost: ¥1,380,000)
Fiscal Year 2009: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000)
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| Research Abstract |
Optimal vaccine efficacy requires not only a protective antigen, but also a strong immune activator as an adjuvant. Most viral vaccines, such as influenza vaccines and non-viral genetic vaccines(e. g., DNA vaccines), contain nucleic acids, which appear to act as essential "built-in" adjuvants. Specific receptors, including toll-like receptors(TLR), retinoic-acid-inducible protein I(RIG-I)-like receptors(RLR), and nucleotide-binding oligomerization domain(NOD)-like receptors(NLR), can detect specific nucleic acid patterns, such as sequence, structure and modification, which are also influenced by the immunized tissue, cell type, and intracellular localization. The resultant immune activation is uniquely regulated by intra-and inter-cellular signaling pathways, which are indispensable for the ensuing vaccine immunogenicity, such as antigen-specific T-and B-cell responses.
A variety of vaccine compositions for H1N1 influenza A virus infections are available ; however, the key innate immune
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mechanisms controlling their immunogenicity remain unclear. Here we identified that plasmacytoid dendritic cells(pDC) and their type-I IFN-mediated intra-and inter-cellular signalling were essential for the induction of virus specific CD4 T and B cells following killed virion vaccination. While Toll-like receptor(TLR) 7, but not RIG-I-like-or NOD-like-receptors, mediated immunogenicity of both live and killed virion vaccines, a commonly used split vaccine failed to activate TLR7, resulting in no efficacy in naive mice. PDC-activating adjuvant restored split vaccine immunogenicity in mice, but split vaccine alone was sufficient to recall memory responses in humans, underscoring the importance of the pDC-TLR7/9-type-I axis for priming, but not secondary immunization.
Aluminum-based adjuvants(alum) are widely used in human vaccination, although little is understood of their mechanisms of action. Here, we report that, in mice, alum causes the release of host cell DNA, which acts as a potent endogenous immunostimulatory signal mediating alum adjuvant activity. Furthermore, we show that host DNA signaling differentially regulates IgE and IgG1 production upon alum immunization. Indeed, we show support that host DNA induces primary B cell responses, including IgG1 production, through IRF-3 independent mechanisms, and inflammatory'canonical' type 2 T cell responses associated with IgE isotype switching and effector tissue responses through IRF-3 dependent mechanisms. The finding that host cell DNA is a damage-associated molecular pattern relaying alum adjuvant activity may thus help in the comprehension of the mechanisms of action of current vaccines and in the design of novel adjuvants.
1.Aoshi T et al. Innate and adaptive immune responses to viral infection and vaccination. Curr Opin Virol. 2011, 1(4): 226-232.
2.Marichal T et al. DNA released from dying host cells mediates aluminum adjuvant activity. Nat. Med. 2011 17(8): 996-1002
3.Koyama S, et al. Plasmacytoid dendritic cells delineate immunogenicity of influenza vaccine subtypes. Sci Transl Med. 2010 2(25): 25ra24. Less
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