A novel broad-spectrum influenza vaccine

一种新型广谱流感疫苗

• 批准号: 8920473
• 负责人: Yawei Ni
• 金额: $ 29.06万
• 依托单位: KJ BIOSCIENCES, LLC
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-05 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8920473
• 关键词: Adjuvant; Animals; Antibody Response; Antigens; Blood Circulation; Clinical; Cross Reactions; Development; Disease Outbreaks; Effectiveness; Emergency Situation; Epidemic; Event; Foundations; Future; Generations; Goals; Health; Hemagglutinin; Immune response; Immunization Programs; Inactivated Vaccines; Influenza; Influenza A virus; Left; Light; Measures; Monoclonal Antibodies; Phylogenetic Analysis; Safety; Solutions; Temperature; Time; Vaccines; Variant; Virus; base; cold temperature; cross reactivity; falls; immunogenicity; influenza epidemic; influenza virus vaccine; influenzavirus; manufacturing process; meetings; new technology; novel; novel vaccines; pandemic disease; pandemic influenza; pre-clinical; protective effect; seasonal influenza; vaccine development

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.

描述（由申请人提供）：流感病毒不断发生抗原变化，这对流感大流行和大流行疫苗的开发构成了巨大挑战。已知甲型流感病毒至少有16种亚型，可分为两大系统发育群。目前用于季节性流感的三价灭活疫苗（TIV； H1、H3和B）不适合用于控制大流行，因为它们具有毒株特异性，必须每年进行毒株交换以匹配流行毒株。迫切需要一种广谱流感疫苗，这种疫苗至少对对流行病很重要的主要亚型有效，而且更有可能引起未来的大流行，以满足当前和眼前的需要。KJ生物科学公司提出了一种新颖和高度实用的解决方案来满足这一迫切的未满足需求——一种基于在适当的低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增加的交叉反应性抗体反应和针对相同或不同亚型的异源病毒的交叉保护。特别是，我们发现，在轻度低pH条件下处理的失活抗原（低温下的低pH）具有部分效价损失，可以独特地诱导与HA更大的交叉反应，HA更保守的部分和交叉保护。因此，这种抗原可用于新型广谱流感疫苗。新疫苗可以很容易地生产，以满足毒株特异性效力标准，因此它不仅可以提供与现有灭活疫苗相同水平的毒株特异性保护，还可以提供对疫苗中不含病毒的交叉保护，包括可能的大流行病毒和季节性变异病毒。尤其考虑到H1和H3亚型分别属于两个不同的系统发育群，它特别适合于TIV，因为对所有三种菌株使用处理过的抗原可以获得更广泛的交叉反应性。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规划。目前灭活疫苗的有效性和生产工艺已得到很好的确立。因此，基于抗原在适当的低pH条件下处理的新型灭活疫苗可以更快地开发出来，为可能发生的大流行提供及时有效的应对措施，并更好地控制季节性流感。此外，在适当条件下的低pH值处理还可能用于在给药之前转化流通或储存的现有疫苗，以便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疫情。鉴于这些有希望的新发现和显著的潜在益处，KJ生物科学公司建议继续开发这种基于抗原在适当的低pH条件下处理的新型灭活流感疫苗。我们提出的研究包括两个特定目标：特异性目标1 -低pH处理抗原的表征和优化，特异性目标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条件下处理抗原的交叉反应免疫应答和交叉保护增加。成功完成这两个特定目标将为未来的开发活动奠定基础，包括与FDA的ind前会议，以制定新疫苗的开发路径以及随后的临床前和临床安全性和免疫原性研究。