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

描述（由申请方提供）：尽管流感疫苗已使用60多年，但目前针对甲型和B型流感病毒的疫苗接种策略易受意外出现与疫苗匹配性差的流行毒株的影响。季节性流感的流行和禽流感病毒亚型的传播增加构成了世界所有地区（包括美国）的重大医疗保健问题。然而，目前许可的疫苗（三价灭活或活的减毒三价病毒疫苗）仅提供针对与疫苗组合物匹配的毒株的保护。没有流感大流行疫苗可供公众使用。此外，目前的疫苗生产基于鸡蛋基质，无法满足大流行爆发期间疫苗接种的激增需求。因此，开发具有改善的针对流感病毒的保护效力的流感疫苗势在必行。Zetra的独特工程化的含灭活剂的病毒纳米颗粒（cVLP）提供了概念验证，即可以通过该公司的专有技术开发具有广泛交叉保护性的非复制型疫苗，该疫苗可能与其他流感亚型A和B交叉反应。由这些cVLP诱导的保护性免疫应答在小鼠中维持在高水平超过14个月。我们疫苗的这种理想质量提供了避免每年更换季节性疫苗配方的可能性。重要的是，单次免疫诱导针对高剂量攻击病毒的保护性免疫。该项目的主要目标是开发和评估针对流感病毒的新型含佐剂流感cVLP疫苗，以增强广泛的交叉保护和持久的免疫力。已知粒细胞-巨噬细胞集落刺激因子（GM-CSF）可增加各种共同施用抗原的免疫原性，并被认为是适合人类使用的佐剂。我们提出了一种新的方法，使用GM-CSF在VLP与流感抗原的膜锚定形式。我们已经开发了掺入GM-CSF的嵌合流感VLP，其显示出理想的疫苗质量。交叉保护以及异亚型保护模型已在我们的实验室建立了良好的季节性流感。在该项目的I期，我们将在完善的小鼠和雪貂模型中确定交叉保护效力，包括由含有免疫刺激分子GM-CSF的嵌合流感VLP诱导的异亚型免疫。细胞因子佐剂和抗原在同一VLP中的物理共定位对于增加我们的新型疫苗的功效是重要的。我们开发安全有效的疫苗，诱导针对流感病毒的广泛交叉保护性免疫的方法将对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的传播增加构成了世界所有地区（包括美国）的重大医疗保健问题。然而，目前许可的疫苗（三价灭活或活的减毒三价病毒疫苗）仅提供针对与疫苗组合物匹配的毒株的保护。该项目的目标是开发一种工程化的含抗菌剂和改进的流感疫苗，该疫苗将诱导广泛的交叉保护和持久的免疫力。

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.