Adjuvant-containing chimeric virus-like particles as improved influenza vaccines

说明(申请人提供)：虽然流感疫苗已经使用了60多年，但目前针对甲型和乙型流感病毒的疫苗接种策略容易受到与疫苗匹配不佳的流行病株的意外出现的影响。季节性流感的流行和禽流感病毒亚型传播的增加构成了包括美国在内的世界所有地区的一个重大医疗问题。每年推荐的疫苗接种是控制流感流行的主要手段。然而，目前获得许可的疫苗(三价灭活或三价减毒活病毒疫苗)只能针对与疫苗成分匹配的毒株提供保护。目前还没有流感大流行疫苗可供普通公众使用。此外，目前的疫苗生产是以鸡蛋为基础的，不能满足大流行期间疫苗接种的激增需求。因此，开发对流感病毒具有更好保护效果的流感疫苗势在必行。Zetra独特设计的含有佐剂的病毒纳米粒(CVLP)提供了概念证明，即可以通过该公司的专有技术开发一种广泛交叉保护、不可复制、可能与其他流感A和B亚型发生交叉反应的疫苗。这些cVLPs在小鼠体内诱导的保护性免疫反应已维持在高水平超过14个月。我们疫苗的这种令人满意的质量提供了避免每年改变季节性疫苗配方的需要。重要的是，单一免疫诱导了对高剂量挑战病毒的保护性免疫。本项目的一个主要目标是开发和评价针对流感病毒的新型佐剂流感cVLP疫苗，以增强广泛的交叉保护性和持久的免疫力。粒细胞-巨噬细胞集落刺激因子(GM-CSF)被认为是一种适合人类使用的佐剂，可提高多种联合给药抗原的免疫原性。我们提出了一种新的方法，在带有流感抗原的VLP中以膜锚定的形式使用GM-CSF。我们已经开发出含有GM-CSF的嵌合流感VLP，显示出令人满意的疫苗质量。我们实验室已经很好地建立了季节性流感的交叉保护和异型保护模式。在这个项目的第一阶段，我们将确定含有免疫刺激分子GM-CSF的嵌合流感病毒脂蛋白在成熟的小鼠和雪貂模型中诱导的交叉保护效果，包括异型免疫。细胞因子佐剂和抗原在同一VLP中的物理共定位对于提高我们的新型疫苗的效力非常重要。我们开发一种安全有效的疫苗，以诱导对流感病毒的广泛交叉保护性免疫，这将对一般公众健康产生重大影响。公共卫生相关性：季节性流感的流行和禽流感病毒亚型传播的增加构成了包括美国在内的世界所有地区的一个重大医疗问题。每年推荐的疫苗接种是控制流感流行的主要手段。然而，目前获得许可的疫苗(三价灭活或三价减毒活病毒疫苗)只能针对与疫苗成分匹配的毒株提供保护。该项目的目标是开发一种含有佐剂和改进的工程流感疫苗，它将诱导广泛的交叉保护和持久的免疫。

DESCRIPTION (provided by applicant): Although the influenza vaccine has been used for over 60 years, the current vaccination strategy against influenza A and B viruses is vulnerable to the unanticipated emergence of epidemic strains that are poorly matched by the vaccine. Epidemics of seasonal influenza and increased circulation of avian influenza virus subtypes constitute a significant healthcare problem in all regions of the world, including the U.S. The annually recommended vaccination is the principal means of controlling influenza epidemics. However, the current licensed vaccines (trivalent inactivated or live, attenuated trivalent virus vaccines) provide protection only against the strains that are matched with the vaccine composition. There is no influenza pandemic vaccine available to the general public. In addition, the current vaccine production is based on egg substrates and would not meet the surge demand in vaccination during a pandemic outbreak. Therefore, development of influenza vaccines with improved protective efficacy against influenza virus is an imperative. Zetra's uniquely engineered adjuvant-containing viral nanoparticles (cVLPs) provided proof-of-concept that a broadly cross-protective, non-replicating vaccine with the possibility of cross reactivity with other influenza subtypes A and B, can be developed by the company's proprietary technology. The protective immune responses induced by these cVLPs have been maintained at high levels in mice for over 14-months. This desirable quality of our vaccines provides a potential to avoid the need to change the seasonal vaccine formulation every year. Importantly, a single immunization induced protective immunity against a high dose of challenge virus. A major goal of this project is to develop and evaluate novel adjuvant-containing influenza cVLPs vaccines against influenza virus in order to enhance broadly cross protective and long-lasting immunity. Granulocyte-macrophage colony-stimulating factor (GM-CSF) is known to increase the immunogenicity of various co-administered antigens and is considered as an adjuvant appropriate for human use. We propose the novel approach to use GM-CSF in a membrane-anchored form in VLPs with influenza antigens. We have already developed chimeric influenza VLPs incorporating GM-CSF which show desirable vaccine qualities. Cross-protection as well as heterosubtypic protection models have been well established in our laboratory for seasonal influenza. In Phase I of this project, we will determine the cross-protective efficacy including heterosubtypic immunity induced by chimeric influenza VLPs containing the immunostimulatory molecule, GM-CSF, in well-established mouse and ferret models. The physical co-localization of the cytokine adjuvant and antigen in the same VLP is important to increase the efficacy of our novel vaccines. Our approach to development of a safe and effective vaccine that induces broadly cross protective immunity against influenza viruses will have a significant impact on public health in general. PUBLIC HEALTH RELEVANCE: Epidemics of seasonal influenza and increased circulation of avian influenza virus subtypes constitute a significant healthcare problem in all regions of the world, including the U.S. The annually recommended vaccination is the principal means of controlling influenza epidemics. However, the current licensed vaccines (trivalent inactivated or live, attenuated trivalent virus vaccines) provide protection only against the strains that are matched with the vaccine composition. The goal of this project is the development of an engineered adjuvant-containing and improved influenza vaccine that will induce broadly cross-protective and long-lasting immunity.