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

尽管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抗击流感大流行的方法是接种疫苗。目前的流感疫苗使用的是通过化学处理灭活的病毒制剂。灭活疫苗主要通过诱导针对病毒的抗体发挥作用，几乎每年都必须重新配制疫苗，以考虑到不断变化的病毒，因为抗体识别容易发生变异的病毒表面。因此，就具有威胁性的H5N1禽流感大流行而言，如果病毒发生变异以适应在人类人口中的有效生长和传播，尚不清楚基于流行的H5N1毒株的灭活疫苗是否有效。与针对流感病毒的抗体反应不同，细胞毒性T细胞反应在异种流感病毒株之间具有广泛的交叉反应。活病毒感染有效地诱导细胞毒性T细胞免疫，在感染第二种异源流感病毒后，这在降低疾病严重程度和死亡率方面发挥着重要作用，尽管感染本身并不能预防。因此，在应对流感大流行的准备工作中，应紧急考虑激发细胞毒性T细胞记忆的疫苗接种策略。我们发现，使用伽马辐射(与化学处理相反)来制备针对流感和其他病毒的灭活实验疫苗并不会破坏疫苗诱导细胞毒性T细胞免疫的能力。伽马射线灭活疫苗在小鼠中对异种流感病毒株的致命攻击具有保护作用。这项建议旨在将这一新发现推广到禽流感病毒，并揭示伽马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.