A Peptide Nanoparticle Nicotine Vaccine

肽纳米颗粒尼古丁疫苗

• 批准号: 8723795
• 负责人: PETER BURKHARD
• 金额: $ 79万
• 依托单位: UNIVERSITY OF CONNECTICUT STORRS
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-30 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8723795
• 关键词: Adjuvant; Adverse effects; Animal Model; Antibodies; B-Lymphocytes; Binding; Blood; Clinical Research; Clinical Trials; Coupled; Drug Formulations; Engineering; Epitopes; Freeze Drying; Goals; Haplotypes; Haptens; Human; Immune response; Immunization; Intramuscular Injections; Mus; Nicotine; Nicotine Dependence; Pain; Patients; Peptides; Phase I Clinical Trials; Price; Property; Proteins; Protocols documentation; Route; Safety; Stream; Testing; Toxic effect; Translations; Vaccines; Work; addiction; density; design; immunogenic; immunogenicity; large scale production; nanoparticle; novel; peptide A; phase 1 study; polypeptide; scaffold

We have recently developed a novel type of vaccine platform, so-called self-assembling polypeptide nanoparticles (SAPNs). We have demonstrated that these SAPNs are highly immunogenic and induce a strong B cell immune response characterized by high antibody titers without the ned of adjuvant. We have engineered and biophysically characterized SAPNs to which activated nicotine hapten molecules can be coupled. Antibodies induced upon immunization with these SAPNs will bind nicotine in the blood stream and hence counteract the addiction-causing effect of nicotine. The overarching goal of the project is to demonstrate safety, tolerability and immunogenicity of the SAPN nicotine vaccine in a clinical trials phase I study. To achieve this goal we propose to first establish the immunogenicity of these nicotine-SAPNs in mice and to optimize their design with respect to the density of the hapten molecules, the SAPN concentration, and the route of immunization to obtain the highest possible antibody titer. Next, we will optimize the SAPNs for human use by engineering pan-DR binding epitopes that are specific for the human haplotypes into the SAPN scaffold. The immunogenicity of the SAPNs will then be verified in a second animal model followed by toxicity testings that will establish a safety profile of the SAPNs. The translation path will then include protein formulation and lyophilization studies to optimize the long-term storage properties of the SAPNs. Along with the application for Swissmedic approval for clinical studies we will work on a large-scale production protocol of the final vaccine. The vaccine of the present project is adjuvant-free. This will eliminate all adjuvant induced side effects and reduce the price as it will allow a simple galenic formulation of the vaccine. Since the SAPN-vaccines can be applied intranasally their patient acceptance is expected to be higher than for curent vaccine approaches which require painful intramuscular injections.

我们最近开发了一种新型的疫苗平台，即所谓的自组装多肽 纳米颗粒(SAPN)。我们已经证明，这些SAPN具有高度的免疫原性，并诱导强烈的 B细胞免疫应答，以高抗体滴度为特征，不需要佐剂。我们有 经工程设计并具有生物物理特性的活化尼古丁半抗原分子可与之结合的SAPN 结合在一起。免疫这些SAPN后产生的抗体将结合血流中的尼古丁和 从而抵消尼古丁的成瘾作用。 该项目的首要目标是证明SAPN的安全性、耐受性和免疫原性。 尼古丁疫苗处于临床试验第一阶段研究。为达致这个目标，我们建议首先设立 这些尼古丁-SAPN在小鼠中的免疫原性以及根据尼古丁-SAPN的密度优化它们的设计 半抗原分子、SAPN浓度和免疫途径，以获得尽可能高的 抗体效价。接下来，我们将通过设计泛DR结合表位来优化SAPN供人类使用 是人类特有的单倍型进入SAPN支架。然后，SAPN的免疫原性将是 在第二个动物模型中进行了验证，随后进行了毒性测试，以确定SAPN的安全性。 翻译路径随后将包括蛋白质配方和冷冻干燥研究，以优化长期 SAPN的存储属性。在申请瑞士医疗集团批准进行临床研究的同时，我们将 致力于最终疫苗的大规模生产方案。 本项目的疫苗是无佐剂的。这将消除所有佐剂引起的副作用和 降低价格，因为它将允许简单的Galen疫苗配方。由于SAPN疫苗可以 鼻腔应用它们的患者接受度预计将高于目前的疫苗方法。 这需要痛苦的肌肉注射。