Gamma-ray inactivated influenza A virus vaccine for cross-protective T cell immunity

虽然有新的抗病毒药物似乎对流感病毒有效，但更具成本效益和效率的对抗流感大流行的方法是接种疫苗。目前的流感疫苗使用通过化学处理灭活的病毒制剂。灭活疫苗主要通过诱导抗病毒抗体发挥作用，几乎每年都必须重新配制，以考虑到不断变化的病毒，因为抗体识别易于突变的病毒表面。因此，就威胁性的H5 N1禽流感大流行而言，如果病毒变异以适应在人群中有效生长和传播，则不知道基于流行的H5 N1毒株的灭活疫苗是否有效。与针对流感病毒的抗体应答相反，细胞毒性T细胞应答在异源流感病毒株之间广泛地交叉反应。活病毒感染有效地诱导细胞毒性T细胞免疫，其在降低第二种异源流感病毒感染后的疾病严重程度和死亡率方面起重要作用，尽管感染本身不能被预防。因此，引发细胞毒性T细胞记忆的疫苗接种策略应在预防流感大流行中给予紧急考虑。我们已经发现，使用γ-照射（与化学处理相反）制备针对流感和其他病毒的灭活实验疫苗不会破坏疫苗引发细胞毒性T细胞免疫的能力。γ射线灭活疫苗在小鼠中赋予针对异源流感病毒株的致死性攻击的保护。该建议旨在将这一新发现扩展到禽流感病毒，并揭示γ射线灭活疫苗的细胞毒性T细胞免疫原性所涉及的机制。

Although there are new antiviral drugs that appear to be effective against influenza virus, the far more costeffective and efficient means to combat an influenza pandemic would be by vaccination. Current influenza vaccines employ virus preparations that are inactivated by chemical treatment. The inactivated vaccines, which function mostly by inducing antibody against the virus, have to be reformulated almost every year to take account of the changing virus because the antibodies recognize the viral surface which is prone to mutation. Accordingly, in terms of the threatening H5N1 avian influenza pandemic, it is not known if an inactivated vaccine based on the circulating H5N1 strain will be effective if the virus mutates to adapt to efficient growth and spread in the human population. In contrast to the antibody response against influenza virus, the cytotoxic T cell response is broadly crossreactive between heterologous influenza virus strains. Live virus infection efficiently induces cytotoxic T cell immunity which plays an important role in reducing disease severity and mortality following infection with a second, heterologous influenza virus, although infection per se is not prevented. Accordingly, vaccination strategies that elicit cytotoxic T cell memory should be given urgent consideration in the preparation against an influenza pandemic. We have found that the use of gamma-irradiation (in contrast to chemical treatment) for the preparation of inactivated experimental vaccines against influenza and other viruses does not destroy the ability of the vaccines to elicit cytotoxic T cell immunity. The gamma-ray inactivated vaccines conferred protection against lethal challenge with heterologous influenza virus strains in mice. This proposal is aimed at extending this novel finding to avian influenza viruses and to uncover the mechanisms involved in the cytotoxic T cell immunogenicity of gamma-ray inactivated vaccines.