A novel broad-spectrum influenza vaccine

项目摘要 流感病毒不断发生抗原性变化，这给发展带来了巨大的挑战 针对流感流行和大流行的疫苗。至少有16个已知的亚型 甲型流感病毒分为两个广泛的系统发育组。目前的三价灭活疫苗(TIV； 用于季节性流感的H1、H3和B)不适合控制大流行，因为它们是特定于菌株的，并且 必须进行每年一次的菌株交换，以匹配正在传播的菌株。一种广谱流感 至少对对流行病重要的主要亚型有效的疫苗，并具有更大的 为满足当前和迫在眉睫的需求，极需要有可能导致未来的大流行。 KJ生物科学公司提出了一种新颖且高度实用的解决方案，以满足这一迫切的未得到满足的需求--a 广谱流感疫苗，以灭活抗原为基础，在适当的低pH条件下处理。我们的 该策略基于一项新的发现，即在适当的低pH条件下处理的灭活抗原可以 诱导更强的交叉反应抗体反应和对异源病毒的交叉保护 相同或不同的子类型。特别是，我们发现它是在温和的情况下处理的灭活抗原 低pH值条件(低温下的低pH值)，具有部分效力丧失，可独特地诱导 与HA更保守的部分HA2发生交叉反应，并进行交叉保护。因此，这种抗原可以是 用于新型广谱流感疫苗。新疫苗可以很容易地生产出来，以满足毒株- 特定效力标准，这样它不仅会提供相同水平的菌株特定保护，以防止 疫苗中含有的病毒与目前的灭活疫苗一样，还能交叉保护免受病毒的侵害 没有包含在疫苗中，包括可能的大流行以及季节性变异病毒。它特别是 非常适合TIV，因为使用针对ALL的处理过的抗原可以获得更广泛的交叉反应 三个毒株，特别是考虑到H1和H3亚型分别属于两个不同的 系统发育类群。重要的是，新的TIV可以很容易地纳入目前的免疫接种。 针对季节性流感的计划。电流灭活剂的有效性和制造工艺 疫苗已经得到了很好的证实。因此，基于适当低pH处理的抗原的新型灭活疫苗 条件可以发展得更快，为可能的情况提供及时和有效的对策 以及更好地控制季节性流感。此外，适当的低pH处理 条件也可能被用来转换流通中或库存中的现有疫苗 政府在紧急情况下提供交叉保护，例如由新的 出现变异病毒。鉴于这些有希望的新发现和显著的潜在好处，KJ 生物科学公司建议继续开发这种基于已治疗抗原的新型灭活流感疫苗 在适当的低pH条件下。我们建议的研究包括两个具体目标：具体目标1- 低pH处理抗原的特性和优化及其特异性目标2--免疫原性和交叉反应 低pH处理抗原对增强交叉反应免疫反应的保护作用 和在最佳低pH条件下处理的抗原的交叉保护。 这两个具体目标的圆满完成将为今后的发展奠定基础 活动包括与FDA的IND前会议，以制定这种新疫苗的开发路径，并 随后的临床前和临床安全性和免疫原性研究。

Project Summary Influenza viruses constantly undergo antigenic changes which pose great challenges for development of vaccines against influenza epidemics as well as pandemics. There are at least 16 known subtypes of influenza A viruses which fall into two broad phylogenetic groups. Current trivalent inactivated vaccines (TIV; H1, H3, and B) for seasonal influenza are not suited for controlling pandemics as they are strain-specific and have to undergo annual strain exchange in order to match circulating strains. A broad-spectrum influenza vaccine which is at least effective against major subtypes important to epidemics and having a greater potential to cause future pandemics is greatly needed to meet the current and immediate needs. KJ Biosciences proposes a novel and highly practical solution to meet this urgent unmet need - a broad-spectrum influenza vaccine based on inactivated antigens treated at proper low pH conditions. Our strategy is based on the novel finding that inactivated antigens treated at appropriate low pH conditions can induce increased cross-reactive antibody responses and cross protection against heterologous viruses of the same or different subtypes. In particular, we have found that it is the inactivated antigens treated at the mild low pH conditions (low pH at low temperatures) with a partial potency loss that can uniquely induce the greater cross reaction with HA2, the more conserved part of HA, and cross protection. Such antigens can therefore be used for a novel broad-spectrum influenza vaccine. The new vaccine can be readily produced to meet strain- specific potency standard so that it will not only provide the same level of the strain-specific protection against viruses contained in the vaccine as the current inactivated vaccines, but also cross protection against viruses not contained in the vaccine, including possible pandemic as well as seasonal variant viruses. It is particularly well suited for TIV since an even broader cross-reactivity could be obtained by using treated antigens for all three strains, especially when considering that H1 and H3 subtypes belong separately to the two different phylogenetic groups. Importantly, the new TIV can be readily incorporated into the current immunization programs against seasonal influenza. The effectiveness and manufacturing processes for current inactivated vaccines are well established. Thus, the new inactivated vaccines based on antigens treated at proper low pH conditions could be developed much faster, providing a timely and effective counter measure for possible pandemics as well as better control of seasonal influenza. In addition, the low pH treatment at proper conditions can also be potentially used to convert existing vaccines in circulation or stockpiles just prior to administration to provide cross protection in emergencies such as a pandemic outbreak caused by a newly emerged variant virus. In light of these promising novel findings and significant potential benefits, KJ Biosciences propose to continue developing this new inactivated influenza vaccine based on antigens treated at proper low pH conditions. Our proposed studies include two specific aims: Specific Aim 1 - Characterization and optimization of low pH-treated antigens, and Specific Aim 2 - Immunogenicity and cross- protective effect of low pH-treated antigens to demonstrate the increased cross-reactive immune responses and cross protection with antigens treated at the optimal low pH conditions. Successful completion of these two specific aims will form the foundation for future development activities including the pre-IND meeting with the FDA to lay out the development path for this new vaccine and subsequent preclinical and clinical safety and immunogenicity studies.