Mucosal delivery of inactivated influenza vaccine induces B-cell-dependent heterosubtypic cross-protection against lethal influenza a H5N1 virus infection
Mucosal delivery of inactivated influenza vaccine induces B-cell-dependent heterosubtypic cross-protection against lethal influenza a H5N1 virus infection
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DOI：
10.1128/jvi.75.11.5141-5150.2001
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发表时间：
2001-06-01
影响因子：
5.4
通讯作者：
Katz, JM
中科院分区：
文献类型：
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作者：
Tumpey, TM;Renshaw, M;Katz, JM
诱导更强的交叉反应性或异亚型免疫（Het-L）的流感疫苗可以克服甲型流感病毒抗原变异性对疫苗效力的限制。我们比较了灭活流感疫苗粘膜与传统胃肠外给药在BALB/c小鼠中诱导Het-I的能力，并评价了改良的大肠杆菌不耐热肠毒素佐剂LT（R192 G），来增强海特一号接受三次鼻内（i.n.）在LT（R192 G）存在下的H3 N2疫苗的免疫完全保护免受高致病性人H5 N1病毒的致死性攻击，并且具有比仅接受LT（R192 G）的对照小鼠低至少2，500倍的鼻和肺病毒滴度。相比之下，在LT（R192 G）或不完全弗氏佐剂存在或不存在的情况下皮下接受H3 N2疫苗的三次接种的小鼠不被保护免于致死性攻击，并且在H5 N1病毒攻击后第5天观察到组织病毒滴度没有显著降低。显示对异亚型攻击的部分保护。研究了Het-1的免疫介质。分别使用基因靶向B细胞（IgH-6（-/-））或β 2-微球蛋白（β 2 m（-/-））缺陷小鼠评价B和CD 8（+）T细胞在Het-I中的功能作用。β 2 m（-/-）而不是IgH-6（-/-）接种的小鼠受到Het-I的保护，并且在H5 N1的致死感染中存活，这表明B细胞而不是CD 8（+）T细胞对于保护小鼠免受异亚型攻击至关重要。然而，CD 8（+）T细胞有助于异型免疫小鼠肺和脑组织中的病毒清除。粘液而不是肠胃外疫苗接种诱导亚型交叉反应性肺免疫球蛋白G（IgG），伊加和血清IgG抗血凝素抗体，这表明H3和H5的血凝素中存在共同的交叉反应表位。这些结果表明，粘膜疫苗接种策略可刺激针对多种流感病毒亚型（包括具有大流行潜力的病毒）的交叉保护。
Influenza vaccines that induce greater cross-reactive or heterosubtypic immunity (Het-L) may overcome limitations in vaccine efficacy imposed by the antigenic variability of influenza A viruses, We have compared mucosal versus traditional parenteral administration of inactivated influenza vaccine for the ability to induce Het-I in BALB/c mice and evaluated a modified Escherichia coli heat-labile enterotoxin adjuvant, LT(R192G), for augmentation of Het-I. Mice that received three intranasal (i.n.) immunizations of H3N2 vaccine in the presence of LT(R192G) were completely protected against lethal challenge with a highly pathogenic human H5N1 virus and had nasal and lung viral titers that were at least 2,500-fold lower than those of control mice receiving LT(R192G) alone. In contrast, mice that received three vaccinations of H3N2 vaccine subcutaneously in the presence or absence of LT(R192G) or incomplete Freund's adjuvant were not protected against lethal challenge and had no significant reductions in tissue virus titers observed on day 5 post-H5N1 virus challenge, Mice that were i.n, administered H3N2 vaccine alone, without LT(R192G), displayed partial protection against heterosubtypic challenge. The immune mediators of Het-I were investigated. The functional role of B and CD8(+) T cells in Het-I were evaluated by using gene-targeted B-cell (IgH-6(-/-))- or beta2-microglobulin (beta 2m(-/-))-deficient mice, respectively. beta 2m(-/-) but not IgH-6(-/-) vaccinated mice were protected by Het-I and survived a lethal infection with H5N1, suggesting that B cells, but not CD8(+) T cells, were vital for protection of mice against heterosubtypic challenge. Nevertheless, CD8(+) T cells contributed to viral clearance in the lungs and brain tissues of heterotypically immune mice. Mucosal but not parenteral vaccination induced subtype cross-reactive lung immunoglobulin G (IgG), IgA, and serum IgG anti-hemagglutinin antibodies, suggesting the presence of a common cross-reactive epitope in the hemagglutinins of H3 and H5. These results suggest a strategy of mucosal vaccination that stimulates cross-protection against multiple Influenza virus subtypes, including viruses with pandemic potential.