Micro-Particle Delivery of a Potent Intracellular Adjuvant for a Universal Flu Vaccine

摘要 该提案的首要目的是使用新的流感疫苗生产通用流感疫苗。 微粒-佐剂组合，产生显著的剂量节省和强大的免疫 增强效应流感病毒是国际关注的经常性公共卫生威胁。 目前流行的流感病毒疫苗包括减毒活病毒、灭活流感疫苗、灭活疫苗等。 或重组流感蛋白疫苗。后者通常需要佐剂。然而一个主要 挑战在于，主要的流感疫苗抗原如血凝素在 不同的流感病毒株，因此必须每年生产新的疫苗。有一个 国家推动依赖通用流感疫苗的替代方法。这种方法 涉及不同流感病毒株共有的共同抗原，但面临一个主要障碍， 因为这些抗原通常是弱免疫原性的，并且需要强佐剂用于其免疫原性。 这是迄今为止还没有达到的效果。微生物病原体相关分子模式 PAMP是由微生物产生的小分子，可以刺激免疫系统， 已经成为强有力的辅助剂。然而，许多PAMP的受体存在于胞质溶胶中， 因此对递送提出了挑战。我们使用了一种基于颗粒的输送系统， 成功地将PAMP递送到细胞内以激活它们各自的受体。这产生 强大的佐剂作用，不会引起毒性或全身炎症。背景下 血凝素，这种微粒-PAMP组合增强特异性抗体反应高达105 在裸抗原上折叠，诱导强烈的T细胞应答，并完全保护受感染的小鼠和雪貂。 该提案计划在通用流感疫苗中使用该平台。为了推进这种疫苗 作为IND前开发的平台，我们有一位监管专家和毒理学家指导我们 整个提案。此外，一个主要的工业合作伙伴，在颗粒生产和 我们已聘请其他合约研究机构协助我们发展 领先的通用疫苗。因此，本提案完全响应RFA-AI-17-042并且重点突出 在临床前开发一种强大的候选疫苗， 反应和交叉反应抗体，以解决最大的公共卫生问题之一。

Abstract The overarching purpose of this proposal is to produce a universal influenza vaccine using a new micro-particle-adjuvant combination that generates dramatic dose-sparing and robust immune enhancement effects. Influenza virus is a recurrent public health threat of international concern. Current influenza viral vaccines are comprised of life attenuated virus, inactivated influenza vaccine or recombinant influenza protein vaccine. The latter usually requires an adjuvant. However, a major challenge is that dominant flu vaccine antigens such as hemagglutinin are highly variable among different influenza strains, and hence new vaccines have to be produced annually. There is a national push for an alternative approach relying on a universal influenza vaccine. This approach involves common antigens that are shared among different influenza strains, but faces a major hurdle in that these antigens are typically weakly immunogenic and requires a strong adjuvant for their efficacy, which has not been achieved to date. Microbial pathogen-associated molecular patterns (PAMP) are small molecules produced by microbes that stimulate the immune system, and these have emerged as strong adjuvants. However the receptors for many PAMPs reside in the cytosol, thus presenting a challenge for delivery. We have used a particle-based delivery system that successfully delivers PAMPs inside the cell to activate their respective receptors. This produces a robust adjuvant effect that does not cause toxicity or systemic inflammation. In the context of hemagglutinin, this microparticle-PAMP combination enhances specific antibody response up to 105 fold over bare antigen, induces a strong T cell response and fully protects infected mice and ferrets. This proposal plans to use this platform in a universal influenza vaccine. To advance this vaccine platform towards pre-IND development, we have a regulatory expert and a toxicologist guiding us throughout the proposal. In addition, a main industrial partner with expertise in particle production and other contract research organizations have been recruited to assist us towards the development of a lead universal vaccine. Thus, this proposal is fully responsive to the RFA-AI-17-042 and is focused on the preclinical development of a robust vaccine candidate that elicits strong T and B cell responses and cross-reacting antibodies to address one of the greatest public health concerns.