An adjuvanted influenza vaccine platform for dose sparing, multiplexing, and rapid deployment

用于节省剂量、多重使用和快速部署的佐剂流感疫苗平台

• 批准号: 9909457
• 负责人: Bruce A. Davidson
• 金额: $ 22.38万
• 依托单位: POP BIOTECHNOLOGIES, INC
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-02-10 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9909457
• 关键词: Adjuvant; Antibodies; Antigens; Attenuated; Binding; Biotechnology; Body Weight decreased; Buffaloes; Cessation of life; Chickens; Clinical; Clinical Trials; Cobalt; Contracts; Development; Disease; Dose; Effectiveness; Elderly; Epitopes; Ferrets; Formulation; Goals; Grant; Hemagglutinin; Histidine; Immune response; Immunization; Infant; Influenza; Influenza Hemagglutinin; Laboratories; Lead; Lipid A; Lipid Bilayers; Liposomes; Modeling; Molecular Biology Techniques; Morbidity - disease rate; Mus; Mutate; Mutation; Phase; Phospholipids; Population; Porphyrins; Preparation; Probability; Process; Production; Property; Recombinants; Risk; Site; Small Business Technology Transfer Research; Surface; TLR4 gene; Testing; Time; Toxic effect; Universities; Vaccination; Vaccine Adjuvant; Vaccine Antigen; Vaccines; Vial device; Virus; base; chemical property; design; egg; flu; immunogenic; influenza virus vaccine; influenzavirus; lung injury; mortality; mouse model; nanoliposome; novel; pandemic influenza; particle; physical property; pregnant; prevent; prophylactic; response; seasonal influenza; vaccine development; vaccine efficacy; young woman

Abstract Influenza is the cause of considerable morbidity and mortality globally. Certain groups, i.e., infants, pregnant young women, and older adults are especially at risk for severe disease. Despite immunization being the most effective and economical prophylactic approach, vaccines often provide less than optimal defense against an influenza illness, with efficacies ranging from 10-60%. This inadequate vaccine efficacy is mainly due to the high mutation rate (antigenic drift), or reassortment (antigenic shift) of the surface influenza molecule hemagglutinin (HA) which is the primary target of influenza vaccines. As a result, circulating influenza strains may evade the body’s protective antibodies induced by vaccination because the influenza’s targeted epitope may have mutated and no longer be recognized by the antibodies. The vast majority of influenza vaccine doses made today are produced in chicken eggs. This process takes 6-8 months which increases the probability of influenza mutation and the associated decreased in efficacy of the vaccine. This STTR Phase 1 proposal involves the development and characterization of a unique vaccine platform that has been developed by the company POP BIO. This platform consists of fabricating lipid bilayer nanoliposomes with a cobalt-porphyrin moiety intercalated into the bilayer (CoPoP) along with the synthetic monophosphoryl lipid A (PHAD®), a TLR4-based vaccine adjuvant. This prep is then combined with his-tagged recombinant influenza HA. The his-tag stably inserts into the bilayer by association with the cobalt producing nanoliposomes decorated with the immunogenic influenza antigen. The CoPoP/PHAD can be mass produced and stockpiled and the production of the influenza HA antigens can be performed rapidly using standard molecular biology techniques (avoiding the long duration of egg production). At the time of vaccination, the recently produced HA antigens can be added on-site to the CoPoP/PHAD vial to produce the vaccine dose. Shortening the time from HA antigen design to time of vaccination will reduce the probability of virus mutation and thus be more effective. In addition, it has been shown that this platform allows for the use of much less antigen in the vaccine (antigen sparing) and has the capacity for multiplexing with numerous antigens from different influenza strains (expanding its breadth). This study will involve POP BIO producing and characterizing the physical and chemical properties of the CoPoP/PHAD-influenza antigen formulations. The University at Buffalo sub-contracting laboratory will then test them in mice to assess the level of protection against challenge with mouse-adapted strains of influenza. The amount of antigen-sparing will be determined in comparison with other influenza vaccine formulations. In addition, the ability of the CoPoP/PHAD nanoliposomes to accommodate multiple different influenza antigens with associated protection against influenza infection in mice will be assessed. The subsequent STTR Phase 2 proposal will expand development of this platform to novel influenza antigen designs and testing in ferrets in preparation for an IND application.

摘要 流感是全球发病率和死亡率相当高的原因。某些群体，即，婴儿，怀孕 年轻妇女和老年人特别容易患上严重疾病。尽管免疫是最重要的 作为有效和经济的预防方法，疫苗通常不能提供最佳的防御， 流感疾病，疗效范围为10- 60%。疫苗效力不足主要是由于 表面流感分子血凝素的突变率（抗原漂移）或重配（抗原转变） (HA)这是流感疫苗的主要目标。因此，流行的流感病毒株可能会逃避 由于流感的靶向表位可能发生了突变， 不再被抗体识别。目前生产的绝大多数流感疫苗都是 产于鸡蛋中。这个过程需要6-8个月，这增加了流感突变的可能性 以及相关的疫苗效力降低。本STTR第1阶段提案涉及开发 以及POP BIO公司开发的独特疫苗平台的特性。这 该平台由制造脂质双层纳米脂质体组成，其中钴-卟啉部分插入到脂质双层纳米脂质体中。 双层（CoPoP）与合成的单磷酰脂质A（PHAD®）（一种基于TLR 4的疫苗佐剂）一起沿着。 然后将该制备物与his标记的重组流感HA组合。His标签稳定地插入双分子层 通过与修饰有免疫原性流感抗原的产生钴的纳米脂质体结合。的 CoPoP/PHAD可以大规模生产和储存，并且流感HA抗原的生产可以通过以下方式进行： 使用标准分子生物学技术快速进行（避免长时间的产蛋）。 在接种疫苗时，可以将最近生产的HA抗原现场添加到CoPoP/PHAD小瓶中， 生产疫苗剂量。缩短从HA抗原设计到接种疫苗的时间将减少 病毒变异的可能性，从而更有效。此外，还表明该平台允许 用于在疫苗中使用少得多的抗原（抗原保留），并且具有与 来自不同流感病毒株的多种抗原（扩展其广度）。本研究将涉及POP BIO CoPoP/PHAD-流感抗原的制备和表征 制剂。然后，布法罗大学的分包实验室将在老鼠身上进行测试，以评估它们的水平 保护免受小鼠适应性流感病毒株的攻击。保留抗原的量将是 与其他流感疫苗制剂相比，此外， CoPoP/PHAD纳米脂质体以容纳多种不同的流感抗原并具有相关保护 将评估小鼠中抗流感感染的能力。随后的STTR第2阶段提案将扩大 开发该平台，用于新型流感抗原设计和雪貂试验，为IND做准备 应用程序.