New Vaccine against Influenza

描述（由申请人提供）：流感是主要的公共卫生威胁之一，也是NIH生物防御研究的重点。H5 N1流感病毒从禽类传播到人类，迫切需要开发有效的流感疫苗。本研究的目的是利用相对保守的H5 N1禽流感A病毒基质蛋白2（M2）作为抗原，通过脱毒的炭疽水肿毒素来开发有效的流感疫苗。由于炭疽毒素能够通过主要组织相容性复合体（MHC）I类和II类途径进入宿主细胞进行抗原递送，因此所提出的疫苗可能引发针对流感抗原的有效细胞介导的免疫。我们假设，拟议的疫苗是能够交叉保护对H5 N1和其他类型的甲型流感病毒。重要的是，所提出的疫苗可以通过非侵入性鼻粘膜途径给药，这便于给药，并且可能更有效地引发粘膜免疫以保护免受可能的大流行性流感。为了评价这些假设，我们将在小鼠模型中评价鼻内递送拟定疫苗的有效性。本项目的具体目标是：具体目标#1：生产重组融合炭疽水肿因子N片段与M2。具体目标#2：目的研究融合基因EFn/M2与炭疽保护性抗原联合滴鼻免疫小鼠后对流感病毒的全身和粘膜免疫力。具体目的#3：确定拟定疫苗在小鼠模型中针对H5和其他甲型流感病毒株的保护效力。具体目的#4：评估接种后拟定疫苗在动物中的毒性。这项研究的成功不仅将提供一种新的、易于接种的流感疫苗，还将为开发针对其他传染病的粘膜疫苗提供一个平台。 公共卫生相关性：流感既是一个主要的公共卫生威胁，也是NIAID生物防御研究的重点。H5 N1流感病毒从禽类向人类的传播表明，研制有效的流感病毒疫苗迫在眉睫。我们建议开发一种可以通过非侵入性鼻粘膜途径给药的疫苗，并且可能更有效地引发粘膜和全身免疫，以保护免受可能的大流行性流感。这将满足公共卫生的迫切需要。

DESCRIPTION (provided by applicant): Influenza is one of the major public health threats and NIH biodefense research priorities. Transmission of H5N1 influenza virus from the avian species to human shows great urgency for the development of an effective vaccine against influenza. The objective of this research is to develop an effective influenza vaccine using the relatively conserved matrix protein 2 (M2) of H5N1 avian influenza A virus as an antigen delivered by a detoxified anthrax edema toxin. Since the anthrax toxins are capable of entering host cells for antigen delivery through the major histocompatibility complex (MHC) class I and class II pathways, the proposed vaccine may elicit potent cell-mediated immunity against influenza antigens. We hypothesize that the proposed vaccine is able to cross-protect against H5N1 and other types of influenza A viruses. Importantly, the proposed vaccine could be administrated through a noninvasive nasal mucosal route which is convenient for administration and maybe more efficient to elicit mucosal immunity for protection against a possible pandemic influenza. In order to evaluate these hypotheses, we will evaluate the efficacy of intranasal delivery of the proposed vaccine in a mouse model. The specific aims of this project are: Specific Aim #1: To produce recombinant fusion N-fragment of anthrax edema factor with M2. Specific Aim #2: To study the systemic and mucosal immunity against influenza viruses after intranasal vaccination in mice with the fusion EFn/M2 in combination with the anthrax protective antigen. Specific Aim #3: To determine the efficacy of the proposed vaccine for protection against H5 and other influenza A virus strains in a mouse model. Specific Aim #4: To assess toxicity of the proposed vaccine in animals after vaccination. The success of the proposed research will provide not only a new and easily administered influenza vaccine but also a platform for development of mucosal vaccines against other infectious diseases. PUBLIC HEALTH RELEVANCE: Influenza is both a major public health threat and a NIAID biodefense research priority. Transmission of H5N1 influenza virus from the avian species to human shows great urgency for the development of an effective vaccine against influenza viruses. We propose to develop a vaccine which could be administrated through a noninvasive nasal mucosal route and maybe more efficient to elicit mucosal and systemic immunity for protection against a possible pandemic influenza. This will meet the urgent need for public health.