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

摘要 这项提议的主要目的是用一种新的 微粒子-佐剂组合，产生显著的节省剂量和强大的免疫 增强效果。流感病毒是一种反复出现的国际关注的公共卫生威胁。 目前的流感病毒疫苗包括减毒活疫苗、灭活流感疫苗 或重组流感蛋白疫苗。后者通常需要佐剂。然而，一个主要的 挑战是，主要的流感疫苗抗原，如血凝素，在 不同的流感毒株，因此必须每年生产新的疫苗。有一个 国家推动一种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，需要强佐剂才能使其 功效，这是迄今尚未实现的。微生物病原体相关分子图谱 (PAMP)是由刺激免疫系统的微生物产生的小分子，这些 已经成为强有力的佐剂。然而，许多PAMP的受体驻留在细胞质中， 因此对交付提出了挑战。我们使用了一种基于粒子的递送系统， 成功地将PAMP输送到细胞内，以激活它们各自的受体。这会产生一个 强健的佐剂作用，不会引起毒性或全身炎症。在…的背景下 血凝素，这种微粒-PAMP组合将特异性抗体反应提高到105 折叠裸露的抗原，诱导强烈的T细胞反应，充分保护感染的小鼠和雪貂。 这项提案计划将这一平台用于通用流感疫苗。为了推进这一疫苗 开发IND前的平台，我们有监管专家和毒理学家指导我们 贯穿整个提案。此外，一个主要的工业合作伙伴，在颗粒生产和专业知识 我们亦已聘请其他合约研究机构，协助我们发展 引领万能疫苗。因此，本提案完全响应RFA-AI-17-042，并重点 诱导强T和B细胞的强效候选疫苗的临床前研究进展 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.