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

• 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
• 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; 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

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 该提案的总体目的是使用新的 微分粒子 - 辅助组合产生明显的剂量和稳健免疫 增强效应。流感病毒是对国际关注的反复发生的公共卫生威胁。 当前的流感病毒疫苗由生命减毒病毒，灭活流感疫苗组成 或重组流感蛋白疫苗。后者通常需要佐剂。但是，一个专业 挑战是主要的流感疫苗抗原（如血凝集素）在 不同的流感菌株，因此必须每年生产新的疫苗。有一个 全国推动依靠普遍流感疫苗的替代方法。这种方法 涉及在不同的流感菌株之间共享的常见抗原，但面临一个重大障碍 因为这些抗原通常是弱免疫原性的，并且需要强的佐剂 疗效，迄今尚未实现。微生物病原体相关的分子模式 （PAMP）是由刺激免疫系统的微生物产生的小分子，这些分子 已经成为强大的佐剂。然而 因此提出了交付的挑战。我们使用了一个基于粒子的输送系统 成功地在细胞内部提供大量症状，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 血凝素蛋白，这种微颗粒杆组合增强了比105的特异性抗体反应 折叠在裸抗原上，诱导强烈的T细胞反应，并完全保护感染的小鼠和雪貂。 该提案计划在普遍的流感疫苗中使用该平台。推进这种疫苗 建立预开发的平台，我们有一个监管专家和毒理学家指导我们 在整个提案中。此外，具有颗粒生产专业知识的主要工业合作伙伴和 招募了其他合同研究组织，以帮助我们发展 铅通用疫苗。因此，该提案对RFA-AI-17-042充分响应，并且集中于 关于强大疫苗的临床前开发，该疫苗会引起强烈的T和B细胞 应对最大的公共卫生问题之一的反应和交叉反应抗体。