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

用于通用流感疫苗的有效细胞内佐剂的微粒递送

基本信息

批准号：
10310448
负责人：
Eric Bachelder
金额：
$ 111.09万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-12-14 至 2023-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10310448
关键词：
Address Adjuvant Alpha Particles Animal Model Antibodies Antibody Response Antigen-Presenting Cells Antigens Attenuated B-Lymphocytes Binding Biological Blood Chemical Analysis Blood Circulation CD8-Positive T-Lymphocytes Cells Clinical Cyclic GMP Cytosol Data Development Dextrans Dinucleoside Phosphates Disease Dose Encapsulated Epitopes Evaluation Extracellular Domain Face Ferrets Formulation Gender Genetic Goals Health Hemagglutinin Hematology Hepatotoxicity Human Human Resources Immune Immune system Immunity Immunoglobulin Class Switching Immunologic Receptors In Vitro Industrialization Influenza Influenza Hemagglutinin Influenza prevention Influenza vaccination Intellectual Property Interferon Type I Interferons International Kinetics Lead Life Mammalian Cell Microbe Modeling Molecular Morbidity - disease rate Mus Particle Size Pathology Pattern Peptides Periodicity Polymers Production Proteins Public Health Recombinants Recurrence Research Research Contracts Safety Source Sterilization Stimulator of Interferon Genes Structure of germinal center of lymph node Symptoms System T cell response T-Lymphocyte Testing Toxic effect Vaccinated Vaccination Vaccine Adjuvant Vaccine Antigen Vaccine Production Vaccines Viral Antigens Viral Vaccines Virus Work age group arm base clinically relevant cost cross immunity cross reactivity cytokine efficacy testing head-to-head comparison immune activation immunogenic improved influenza infection influenza virus strain influenza virus vaccine influenzavirus meetings mortality novel novel vaccines off-patent particle pathogen pathogenic microbe preclinical development receptor recruit response small molecule success systemic inflammatory response universal influenza vaccine universal vaccine vaccine candidate vaccine efficacy vaccine evaluation vaccine formulation vaccine platform vaccine response

项目摘要

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.

抽象的该提案的首要目的是使用新的方法生产通用流感疫苗微粒-佐剂组合可产生显着的剂量节约和强大的免疫效果增强效果。流感病毒是国际关注的反复出现的公共卫生威胁。目前的流感病毒疫苗包括减毒活病毒、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，一个主要的挑战在于，主要流感疫苗抗原（例如血凝素）在不同人群中差异很大不同的流感毒株，因此每年必须生产新的疫苗。有一个全国范围内推动采用通用流感疫苗的替代方法。这种做法涉及不同流感毒株之间共享的共同抗原，但面临主要障碍因为这些抗原通常具有弱免疫原性，并且需要强佐剂来发挥其作用功效，至今尚未达到。微生物病原体相关分子模式 (PAMP) 是微生物产生的小分子，可刺激免疫系统，这些已成为强有力的佐剂。然而，许多 PAMP 的受体存在于细胞质中，从而对交付提出了挑战。我们使用了基于粒子的传输系统成功地将 PAMP 递送到细胞内以激活其各自的受体。这会产生一个强大的辅助作用，不会引起毒性或全身炎症。在这样的背景下血凝素，这种微粒-PAMP 组合可将特异性抗体反应增强高达 105 折叠在裸抗原上，诱导强烈的 T 细胞反应并充分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。为了推进这种疫苗面向 IND 前开发的平台，我们有一位监管专家和一位毒理学家指导我们贯穿整个提案。此外，主要工业合作伙伴在颗粒生产和已经招募了其他合同研究组织来协助我们开发领先的通用疫苗。因此，该提案完全响应 RFA-AI-17-042，并且重点关注一种可激发强 T 细胞和 B 细胞的强效候选疫苗的临床前开发反应和交叉反应抗体，以解决最大的公共卫生问题之一。