A novel broad-spectrum influenza vaccine

描述（由申请方提供）：流感病毒不断发生抗原变化，这对开发针对流感流行和大流行的疫苗构成了巨大挑战。至少有16种已知的甲型流感病毒亚型，分为两个广泛的系统发育组。目前用于季节性流感的三价灭活疫苗（TIV; H1、H3和B）不适合控制大流行，因为它们是毒株特异性的，并且必须进行年度毒株交换以匹配流行毒株。为了满足当前和眼前的需求，非常需要一种广谱流感疫苗，其至少对流行病的主要亚型有效，并且具有引起未来大流行病的更大潜力。 KJ Biosciences提出了一种新颖且高度实用的解决方案来满足这一迫切的未满足的需求-基于在适当的低pH条件下处理的灭活抗原的广谱流感疫苗。我们的策略是基于新的发现，即在适当的低pH条件下处理的灭活抗原可以诱导增加的交叉反应性抗体应答和针对相同或不同亚型的异源病毒的交叉保护。特别地，我们已经发现，在温和的低pH条件（低温下的低pH）下处理的具有部分效力损失的灭活抗原可以独特地诱导与HA的更保守部分HA 2的更大交叉反应和交叉保护。因此，此类抗原可用于新型广谱流感疫苗。新疫苗易于生产，以符合毒株特异性效力标准，因此，它不仅能提供与现有灭活疫苗相同水平的毒株特异性保护，以对抗疫苗中所含的病毒，而且还能对疫苗中不含的病毒（包括可能的大流行病毒和季节性变异病毒）提供交叉保护。它特别适用于TIV，因为通过使用所有三种毒株的处理抗原可以获得更广泛的交叉反应性，特别是当考虑到H1和H3亚型分别属于两个不同的系统发生组时。重要的是，新的TIV可以很容易地纳入目前针对季节性流感的免疫接种计划。目前灭活疫苗的有效性和生产工艺已得到充分确立。因此，基于在适当的低pH条件下处理的抗原的新型灭活疫苗可以更快地开发，为可能的大流行提供及时有效的对策，以及更好地控制季节性流感。此外，在适当条件下的低pH值处理也可潜在地用于在施用前转化流通中或库存中的现有疫苗，以在紧急情况下提供交叉保护，例如由新出现的变异病毒引起的大流行爆发。鉴于这些有希望的新发现和显著的潜在益处，KJ Biosciences建议继续开发这种基于在适当的低pH条件下处理的抗原的新型灭活流感疫苗。我们提出的研究包括两个具体目标：具体目标1 -低pH处理抗原的表征和优化，以及具体目标2 -低pH处理抗原的免疫原性和交叉保护作用，以证明在最佳低pH条件下处理的抗原的交叉反应性免疫应答和交叉保护增加。 这两个具体目标的成功完成将为未来的开发活动奠定基础，包括与FDA的IND前会议，以制定这种新疫苗的开发路径以及后续的临床前和临床安全性和免疫原性研究。

DESCRIPTION (provided by applicant): 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.