A novel broad-spectrum influenza vaccine

一种新型广谱流感疫苗

• 批准号: 8647750
• 负责人: Yawei Ni
• 金额: $ 30.03万
• 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 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8647750
• 关键词: Adjuvant; Animals; Antibody Formation; Antigens; Blood Circulation; Clinical; Cross Reactions; Development; Disease Outbreaks; Effectiveness; Emergency Situation; Epidemic; Event; Foundations; Future; Generations; Goals; 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; public health relevance; seasonal influenza; vaccine development

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.

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挑战 预防流感和流行病的疫苗。至少有16种已知的亚型， 甲型流感病毒分为两大系统发生组。目前的三价灭活疫苗（TIV; H1、H3和B）季节性流感不适合控制大流行，因为它们具有毒株特异性， 必须每年进行菌株交换，以匹配流通的菌株。一种广谱流感 至少对流行病重要的主要亚型有效并且具有更大的 为了满足当前和眼前的需要，非常需要消除可能造成未来大流行病的危险。 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 该策略基于新的发现，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，我们发现在温和条件下处理的灭活抗原， 低pH值条件（低温下的低pH值），部分效力损失，可独特地诱导更大的 与HA的保守部分HA 2的交叉反应和交叉保护。因此，这些抗原可以是 用于新型广谱流感疫苗。新的疫苗可以很容易地生产出来，以满足菌株- 特异性效价标准，使其不仅提供相同水平的菌株特异性保护， 疫苗中所含的病毒与目前的灭活疫苗一样，还能对病毒产生交叉保护作用 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。显得尤为 非常适合于TIV，因为通过使用处理的抗原可以获得更广泛的交叉反应性， 三种菌株，特别是当考虑到H1和H3亚型分别属于两种不同的菌株时， 系统发生群重要的是，新的TIV可以容易地并入当前的免疫接种中。 预防季节性流感的计划。当前灭活疫苗的有效性和生产工艺 疫苗已经很成熟了。因此，基于适当低pH处理的抗原的新灭活疫苗， 条件可以更快地发展，提供及时有效的应对措施， 流行病以及更好地控制季节性流感。此外，在适当的pH值下， 条件也可用于转换流通中的现有疫苗或库存， 在紧急情况下，例如由新的流感病毒引起的大流行爆发， 出现变异病毒。鉴于这些有前途的新发现和重大的潜在利益，KJ 生物科学公司建议继续开发这种基于抗原处理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处理抗原的表征和优化，以及特定目标2-免疫原性和交叉免疫原性 低pH处理的抗原的保护作用，以证明交叉反应性免疫应答增加 和与在最佳低pH条件下处理的抗原的交叉保护。 成功地完成这两个具体目标将成为未来发展的基础 活动包括与FDA的IND前会议，以制定这种新疫苗的开发路径， 随后的临床前和临床安全性和免疫原性研究。