Pandemic H5N1 vaccine containing recombinant H5 and a synthetic TLR4 agonist, GLA

含有重组 H5 和合成 TLR4 激动剂 GLA 的大流行 H5N1 疫苗

• 批准号: 7748082
• 负责人: Christopher H Clegg
• 金额: $ 44.02万
• 依托单位: TRIA BIOSCIENCE CORPORATION
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-25 至 2011-03-01
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7748082
• 关键词: Address; Adjuvant; Agonist; Animals; Antibodies; Antibody Formation; Antigens; Avian Influenza; Avian Influenza A Virus; Baculoviruses; Biological; Biological Assay; Birds; CD8B1 gene; Cell physiology; Cessation of life; Clinical Trials; Cytotoxic T-Lymphocytes; Dendritic Cells; Dendritic cell activation; Disease; Disease Progression; Dose; Drug Formulations; Emulsions; Enzyme-Linked Immunosorbent Assay; Ferrets; Goals; Gold; H5 hemagglutinin; Hemagglutination; Human; Immune response; Indonesia; Infection; Infection prevention; Influenza A Virus, H5N1 Subtype; Injection of therapeutic agent; International; Lead; Life; Lipid A; Liposomes; Measures; Mediating; Methods; Modeling; Monitor; Mus; Oils; Phase; Plasma Cells; Population; Production; Proteins; Receptor Cell; Recombinants; Relative (related person); Research; Risk; Science; Stretching; T-Lymphocyte; TLR4 gene; Technology; Testing; Titrations; Vaccinated; Vaccine Production; Vaccines; Vietnam; Viral; Viral Load result; Virus; Virus Diseases; Water; Work; anti-influenza; base; combat; cytokine; egg; immunogenicity; improved; innovation; meetings; mouse model; nonhuman primate; novel; novel vaccines; pandemic disease; particle; prevent; public health relevance; research study; response; toll-like receptor 4; transmission process; vaccine effectiveness; vaccine efficacy

DESCRIPTION (provided by applicant): H5N1 is a highly pathogenic avian influenza virus that can cause severe disease and death in humans. H5N1 is spreading rapidly in bird populations world-wide and there is great concern that this virus will begin to transmit between people and cause a global pandemic catastrophe. Vaccines are the cornerstone strategy for combating avian flu but there are numerous challenges in producing the vast numbers of safe and effective doses that are needed to prevent infection and to save millions of lives. One previous effort to eliminate traditional egg-based vaccine production involved a clinical trial that tested baculovirus-derived recombinant H5 Hemagglutinin (rH5). The results showed that rH5 was safe but could only stimulate "protective" antibodies in ~50% of subjects after 2 injections. We believe the relative ease in manufacturing rH5 protein could be a very important strategy for addressing the world's vaccine stockpiling efforts if rH5 immunogenicity was improved. We also believe this is possible by combining rH5 with an innovative adjuvant that targets dendritic cell function. Here we describe straightforward proof of concept experiments where rH5 will be formulated with an oil-in-water emulsion and Glucopyranosyl Lipid A (GLA), a synthetic Toll-Like Receptor-4 (TLR-4) agonist. Collectively, these components augment antibody responses needed for preventing viral infection, as well as stimulate T cells that limit disease progression within the host and reduce viral transmission within the population. The improved immunogenicity of this pandemic vaccine will be established following completion of three specific aims. We will produce, characterize and optimize vaccine formulations for physical integrity, stability, and GLA potency using mouse and human DC activation assays. Improvements in vaccine immunogenicity will be established in mice by measuring antigen-specific antibody responses, including those that can cross-react and neutralize H5N1 virus from different strains. Identification of a lead formulation for subsequent work will require that the GLA adjuvant can; (1) mediate a significant dose-sparing effect and maintain maximal antibody responses following a 10-fold reduction in rH5 concentration, and (2), induce long- lasting CD4+ and CD8+ T cell responses in mice. If successful, then rH5+GLA adjuvant will be tested in virus challenge models by inoculating mice and ferrets with two strains of H5N1. Viral load, disease progression and survival will be monitored, as well as adjuvant dose-sparing activity and induction of cross-reactive antibodies. Our criteria for vaccine efficacy is that GLA adjuvant will stimulate 100% survival at 1/10 the rH5 dose compared to nonadjuvanted rH5 vaccine. Moreover, the adjuvant will be cross-protective and stimulate significant survival in animals challenged with a different H5N1 virus. Successful completion of these studies will establish a method for enhancing the immunogenicity of a previously tested pandemic vaccine. This new vaccine should significantly improve stockpiling capacity and provide an important degree of protection against any newly emerging strains of H5N1. PUBLIC HEALTH RELEVANCE: There is great international concern that the highly pathogenic H5N1 avian influenza virus will cause a pandemic infection resulting in millions of deaths. New vaccine technologies are need if we are to successfully prevent H5N1 infection and avert a global catastrophe. Adjuvants that stimulate dendritic cells can be used to increase vaccine potency, thereby stretching vital manufacturing capacity and protecting against newly emerging strains of H5N1 virus.

描述（由申请人提供）：H5N1 是一种高致病性禽流感病毒，可导致人类严重疾病和死亡。 H5N1 病毒正在世界各地的鸟类中迅速传播，人们非常担心这种病毒将开始在人与人之间传播并导致全球大流行灾难。疫苗是对抗禽流感的基石战略，但在生产预防感染和拯救数百万人生命所需的大量安全有效剂量方面面临着许多挑战。此前一项旨在消除传统鸡蛋疫苗生产的努力涉及一项测试杆状病毒衍生的重组 H5 血凝素 (rH5) 的临床试验。结果表明，rH5 是安全的，但在注射 2 次后只能在约 50% 的受试者中刺激“保护性”抗体。我们相信，如果 rH5 免疫原性得到改善，rH5 蛋白的制造相对容易可能成为解决世界疫苗储存工作的一个非常重要的策略。我们还相信，通过将 rH5 与针对树突状细胞功能的创新佐剂相结合，这是可能的。在这里，我们描述了简单的概念验证实验，其中 rH5 将由水包油乳液和吡喃葡萄糖脂 A (GLA)（一种合成的 Toll 样受体 4 (TLR-4) 激动剂）配制而成。总的来说，这些成分增强了预防病毒感染所需的抗体反应，并刺激 T 细胞，限制宿主内的疾病进展并减少人群内的病毒传播。在完成三个具体目标后，将确定这种大流行疫苗的免疫原性得到改善。我们将使用小鼠和人类 DC 激活测定来生产、表征和优化疫苗配方，以实现物理完整性、稳定性和 GLA 效力。通过测量抗原特异性抗体反应，包括可以交叉反应和中和不同毒株的 H5N1 病毒的抗体反应，将在小鼠中建立疫苗免疫原性的改进。确定后续工作的先导制剂需要 GLA 佐剂： (1) 在 rH5 浓度降低 10 倍后介导显着的剂量节约效应并维持最大抗体反应，以及 (2) 在小鼠中诱导持久的 CD4+ 和 CD8+ T 细胞反应。如果成功，则将通过给小鼠和雪貂接种两种 H5N1 毒株，在病毒攻击模型中测试 rH5+GLA 佐剂。将监测病毒载量、疾病进展和存活率，以及佐剂剂量节约活性和交叉反应抗体的诱导。我们的疫苗功效标准是，与无佐剂的 rH5 疫苗相比，GLA 佐剂在 1/10 的 rH5 剂量下即可刺激 100% 的存活。此外，该佐剂将具有交叉保护作用，并能刺激受到不同 H5N1 病毒攻击的动物的显着存活。这些研究的成功完成将建立一种增强先前测试的大流行疫苗免疫原性的方法。这种新疫苗应能显着提高储存能力，并针对任何新出现的 H5N1 毒株提供重要程度的保护。公共卫生相关性：国际社会非常担心高致病性 H5N1 禽流感病毒将引起大流行感染，导致数百万人死亡。如果我们要成功预防 H5N1 感染并避免全球灾难，就需要新的疫苗技术。刺激树突状细胞的佐剂可用于提高疫苗效力，从而扩展重要的生产能力并预防新出现的 H5N1 病毒株。