ISS-linked NP vaccine to control pandemic flu outbreak

描述（由申请方提供）：本提案的目的是开发和评价一种新型流感疫苗，该疫苗包含流感病毒的保守内部组分，如核蛋白（NP），具有诱导针对不同和潜在大流行性流感毒株的保护性免疫的潜力。该建议的假设是，流感病毒的核蛋白（NP）连接到免疫刺激寡核苷酸（ISS）将诱导强烈的Th 1和CTL反应，由于核蛋白分子的保守性质，这些反应将与广泛不同的流感病毒株交叉反应。当在疫苗中共同施用时，或当随后在病毒感染期间与NP结合时，由NP-ISS连接的材料诱导的免疫应答可以另外提供交叉帮助以增强对其他病毒抗原如HA的应答。该方案的具体目标是： 1.产生核蛋白免疫刺激性寡核苷酸缀合物（NP-ISS），并证明NP-ISS疫苗在初次感染和先前感染的小鼠中有效诱导Th 1和CTL应答。 2.在小鼠中评价NP-ISS疫苗或NP-ISS与单价灭活全病毒疫苗混合提供的针对同源和不同流感毒株的保护性免疫。 3.在灵长类动物中测试NP-ISS和NP-ISS与标准裂解疫苗组合相比于单独的标准裂解疫苗的免疫原性。 4.使用NP-ISS进行GMP规模扩大生产和IND启用毒理学。 假设每个特定目标都取得成功，该计划旨在生产一种可快速进入临床试验的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.