M2-BASED INFLUENZA TYPE A VIRUS VACCINE

描述(申请人提供)：流感病毒仍然是对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烈抗体反应，因为已知当血清和呼吸道分泌物中存在足够浓度的抗体时，这些抗体具有高度的保护性。这些疫苗固有的主要问题是，它们针对的是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病毒株之间的匹配，如果没有预料到出现其糖蛋白发生重大变化的流行病毒株，其有效性可能很低或不显著。这一缺陷可以通过最大限度地利用保护性免疫机制来最小化，这些机制与亚型内和亚型之间的病毒株广泛交叉反应。一种可能的方法是通过针对跨膜蛋白M2(M2e)的胞外域的抗体来实现这一点。自1918年至今，M2E在人类流行毒株中保持高度保守。在小鼠模型中，M2e特异性抗体已被证明具有保护作用。最重要的是，有限的证据表明，这种反应在人类中由自然感染诱导得很差，目前的疫苗也不太可能诱导这种反应。在之前的授权期内，我们已经证明合成的多重抗原肽(MAP)构建物在小鼠模型中诱导高滴度和长时间的M2e特异性抗体反应是有效的，为了更新，我们建议：1)优化构建和免疫方案以实现对小鼠模型的最大保护；2)建立定量检测人血清中M2e特异性抗体反应的ELISA法；3)研究流感病毒在体内逃避抗M2e抗体介导的保护的倾向；以及4)研究M2e特异性免疫在严重肺炎和泛热性感染小鼠模型中的保护活性。这些研究可能为M2E在人类疫苗接种中的潜力提供更好的图景。

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.