M2-BASED INFLUENZA TYPE A VIRUS VACCINE

描述（由申请人提供）：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抗体（Ab）反应，因为已知这些抗体在血清和呼吸道分泌物中以足够的浓度存在时具有高度保护作用。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与流行病毒株之间的匹配，如果没有预料到出现糖蛋白发生重大改变的流行病毒株，它们的有效性可能很低或微不足道。这种缺陷可以通过最大限度地提高与亚型内和亚型之间的病毒株广泛交叉反应的保护性免疫机制来最小化。实现这一目标的一种可能方法是将抗体定向到跨膜蛋白M2 （M2e）的外畴。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，自然感染在人类中很难诱导这种反应，目前的疫苗也不太可能诱导这种反应。在之前的授权期内，我们已经证明了合成的多抗原肽（MAP）结构可以在小鼠模型中有效地诱导高效价和长时间的m2b特异性抗体反应，对于更新，我们建议：1)优化结构和免疫方案，以在小鼠模型中实现最大的保护；2)建立ELISA定量检测人血清中m2e特异性抗体反应；3)研究流感病毒在体内逃避抗m2e抗体介导的保护的倾向；4)研究m2e特异性免疫对严重嗜肺性和嗜肺性感染小鼠模型的保护作用。这些研究可以更好地说明M2e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.