ISS-linked NP vaccine to control pandemic flu outbreak

描述(由申请人提供)：这项建议的目标是开发和评估一种新型流感疫苗，该疫苗包含流感病毒保守的内部成分，如核蛋白(NP)，有可能诱导对不同和可能大流行的流感毒株的保护性免疫。这一建议的假设是，流感病毒的核蛋白(NP)与免疫刺激寡核苷酸(ISS)相连，由于核蛋白分子的保守性，它将诱导强大的Th1和CTL反应，从而与差异很大的甲型流感病毒株发生交叉反应。由NP-ISS连接的材料诱导的免疫反应还可以提供交叉帮助，以增强对其他病毒抗原的反应，如在疫苗中联合给药时，或随后在病毒感染期间遇到与NP相关的时。该计划的具体目标是： 1.制备核蛋白免疫刺激性寡核苷酸结合物(NP-ISS)，并证明NP-ISS疫苗在初治和先前感染的小鼠中有效地诱导Th1和CTL反应。 2.评价NP-ISS疫苗或NP-ISS与单价灭活全病毒疫苗混合免疫小鼠对同源和不同亚型流感病毒株的保护性免疫。 3.检测NP-ISS和NP-ISS联合标准裂解疫苗在灵长类动物体内的免疫原性，并与单独使用标准裂解疫苗进行比较。 4.使用NP-ISS进行GMP规模化生产和支持IND的毒理学。 假设每个特定目标都取得成功，该计划旨在生产一种可以迅速进入临床测试的IND就绪产品。

DESCRIPTION (provided by applicant): The goal of this proposal is to develop and evaluate a novel influenza vaccine that incorporates conserved internal components of influenza virus such as the nucleoprotein (NP) with a potential to induce protective immunity against divergent and potentially pandemic influenza strains. The hypothesis of this proposal is that the nucleoprotein (NP) of influenza virus linked to an immunostimulatory oligonucleotide (ISS) will induce strong Th1 and CTL responses that will cross-react with widely divergent influenza A strains due to the conserved nature of the nucleoprotein molecule. The immune response induced by the NP-ISS linked material may additionally provide cross-help to enhance the response to other viral antigens such as HA, when co-administered in a vaccine, or when subsequently encountered in association with NP during viral infection. The Specific Aims of the program are: 1. Produce a nucleoprotein immunostimulatory oligonucleotide conjugate (NP-ISS) and demonstrate potent induction of Th1 and CTL responses by the NP-ISS vaccine in naive and previously infected mice. 2. Evaluate the protective immunity provided by the NP-ISS vaccine, or NP-ISS mixed with monovalent inactivated whole virus vaccine against homologous and divergent influenza strains in mice. 3. Test the immunogenicity of NP-ISS, and NP-ISS combined with standard split vaccine in primates compared to standard split vaccine alone. 4. Perform GMP scale-up manufacture and IND-enabling toxicology with NP-ISS. Assuming success in each Specific Aim, this program is intended to produce an IND-ready product that could rapidly move into clinical testing.