M2-BASED INFLUENZA TYPE A VIRUS VACCINE

描述（由申请人提供）：流感病毒仍然是人类健康的主要威胁。目前的流感病毒疫苗旨在诱导对病毒糖蛋白的强抗体（Ab）应答，因为已知这些Ab在以足够浓度存在于血清和呼吸道分泌物中时具有高度保护性。这些疫苗固有的主要问题是它们针对高度可变的病毒结构。因此，它们的有效性在很大程度上取决于疫苗和流行性病毒株之间的匹配，如果没有预料到糖蛋白发生重大改变的流行性病毒株的出现，它们的有效性可能很低或不显著。这种缺陷可以通过最大化保护性免疫机制来最小化，这些免疫机制与亚型内和亚型之间的病毒株广泛交叉反应。实现这一点的可能方式是通过针对跨膜蛋白M2（M2 e）的胞外域的Ab。自1918年至今，M2 e在人类流行毒株中保持高度保守。在小鼠模型中，M2 e特异性Ab已显示出保护性。最重要的是，有限的证据表明，这种反应在自然感染的人类中诱导效果很差，目前的疫苗也不太可能诱导这种反应。在之前的授权期间，我们已经证明合成的多抗原肽（MAP）构建体在小鼠模型中有效诱导高滴度和长持续时间的M2 e特异性Ab应答，并且为了更新，我们建议：1）优化构建体和免疫方案以在小鼠模型中实现最大保护; 2）开发用于定量测量人血清中M2 e特异性Ab应答的ELISA; 3）研究流感病毒逃避抗M2 e Ab介导的体内保护的倾向;（4）研究M2 e特异性免疫在严重嗜肺性和泛嗜性感染小鼠模型中的保护活性。这些研究可以更好地了解M2 e用于人类疫苗接种的潜力。

DESCRIPTION (provided by applicant): Influenza virus continues to be a major threat to human health. Current influenza virus vaccines aim to induce a strong antibody (Ab) response to the viral glycoproteins as these Abs are known to be highly protective when present at sufficient concentration in serum and respiratory tract secretions. The main problem inherent in these vaccines is that they target viral structures that are highly variable. Therefore, their effectiveness depends largely on the match between vaccine and epidemic virus strain and may be low or insignificant if the emergence of an epidemic virus strain with major alterations in its glycoproteins was not anticipated. This deficiency could be minimized by maximizing protective immune mechanisms that are broadly cross-reactive with virus strains within and between subtypes. A possible way to achieve this is through Abs directed to the ectodomain of the transmembrane protein M2 (M2e). M2e has remained highly conserved amongst human epidemic strains since 1918 to present. In the mouse model, M2e-specific Abs have been shown to be protective. Most importantly, limited evidence indicates that this response is poorly induced in humans by natural infection and current vaccines are not likely to induce it either. During the preceding granting period, we have shown that a synthetic multiple antigenic peptide (MAP) construct is effective in inducing M2e-specific Ab responses of high titer and long duration in the mouse model and for renewal, we propose to: 1) optimize the construct and immunization protocol to achieve maximum protection in the mouse model; 2) develop an ELISA for quantitative measurement of the M2e-specific Ab response in human sera; 3) investigate the propensity of influenza virus to escape anti-M2e Ab-mediated protection in vivo; and 4) study the protective activity of M2e-specific immunity in mouse models of severe pneumotropic and pantropic infections. These studies may provide better picture of the potential of M2e for human vaccination.