Development of Novel Adjuvants LTA and LTA1

新型佐剂LTA和LTA1的开发

• 批准号: 9207427
• 负责人: Elizabeth B Norton
• 金额: $ 37.63万
• 依托单位: TULANE UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-01 至 2020-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9207427
• 关键词: Adjuvant; Adjuvanticity; Adverse effects; Alzheimer' s Disease; Animals; Antibodies; Antigens; Bell Palsy; Binding; Brain; Cell Maturation; Cell surface; Cholera; Cholera Toxin; Clinical; Clinical Trials; Communicable Diseases; Cyclic AMP; Data; Degenerative Disorder; Dendritic Cells; Dendritic cell activation; Development; Disease; Dose; Effectiveness; Elderly; Elements; Enterotoxins; Erythema; Escherichia coli; Excipients; Facial paralysis; Family; Fluzone; Formulation; Future; Gangliosides; Human; Immune response; Immunity; Immunization; Immunocompromised Host; In Vitro; Induration; Infectious Diseases Research; Inflammatory Response; Influenza; Influenza vaccination; Injection of therapeutic agent; Investigation; Laboratories; Life; Link; Malignant Neoplasms; Mediating; Memory; Methods; Modeling; Mucosal Immunity; Nature; Neurons; Parents; Preparation; Procedures; Property; Proteins; Publishing; Reaction; Recombinants; Reporting; Risk; Safety; Signal Transduction; Site; Skin; Stretching; Surface; Tertiary Protein Structure; Testing; Toxin; Vaccination; Vaccines; Viral; base; biophysical properties; cancer therapy; cost effective; design; high risk population; holotoxins; immunogenicity; improved; in vivo; influenza virus vaccine; influenzavirus; intradermal injection; irritation; liquid formulation; mucosal vaccine; mutant; next generation; novel; novel vaccines; olfactory bulb; pandemic disease; pandemic influenza; pathogen; prevent; protective efficacy; public health relevance; receptor binding; response; vaccine development; vaccine efficacy; vaccine trial

 DESCRIPTION (provided by applicant): Vaccines are the established and proven method to prevent diseases. As a technological platform they are also expanding into nontraditional applications such as cancer and Alzheimer's therapy, but continue to be relevant in infectious diseases research, including strategies for controlling pandemic Influenza virus. Proper selection and use of adjuvant formulations can overcome barriers to vaccine efficacy by promoting long-lasting protective immunity, overcoming poor immunity in high-risk populations (i.e., young, elderly, immunocompromised), and/or simply augmenting the existing antigen supply to reach a greater number of people (dose-sparing). The objective of this proposal is to develop next generation adjuvants based on the A-subunit of the heat-labile enterotoxin from Escherichia coli (LT), including LTA and LTA1. The enterotoxin family of adjuvants are powerful mucosal adjuvants, but have been hindered by major safety concerns in past clinical trials, particularly for intranasal delivery. Our preliminary studies indicate LTA and LTA1 proteins are safe and effective mucosal adjuvants because they can achieve broad mucosal and systemic immunity without the potential safety risks of the parent proteins and high levels of immunogenicity (i.e., anti-LT antibodies). In this proposal, we will critically evaluate LTA and LTA1 as adjuvants in combination with inactivated, pandemic influenza antigen. In our studies, we will determine how these adjuvants (1) improve correlates of protective immunity and responses to viral challenge by intranasal or intradermal influenza vaccination, (2) provide a new, safe and stable alternative to their parent protein or related B-subunit containing derivatives, (3) improve vaccination efficacy through cAMP-mediated dendritic cell activation and Th17 induction. Upon completion of this investigation, we expect to generate clear safety and efficacy data using a candidate influenza antigen for intranasal and intradermal immunization, specifically valuable for future human use in a pandemic disease setting or for use in high-risk populations. Based on the nature of the information generated by this proposal, we will also provide clear rational for novel LTA and LTA1 adjuvant inclusion in other unique vaccine formulations targeting bacterial and viral pathogens or degenerative disease like cancer.

 描述（由申请人提供）：疫苗是预防疾病的既定且行之有效的方法，作为一种技术平台，它们还扩展到癌症和阿尔茨海默病治疗等非传统应用，但仍然与传染病研究相关，包括控制策略。大流行性流感病毒。适当选择和使用佐剂制剂可以通过促进持久的保护性免疫力来克服疫苗功效的障碍，克服高危人群（即年轻人、老年人、免疫功能低下），和/或简单地增加现有抗原供应以覆盖更多人（节省剂量） 该提案的目的是开发基于大肠杆菌不耐热肠毒素 A 亚基的下一代佐剂。大肠杆菌 (LT)，包括 LTA 和 LTA1 肠毒素家族佐剂是强大的粘膜佐剂，但在过去的临床试验中受到重大安全问题的阻碍。我们的初步研究表明，LTA 和 LTA1 蛋白是安全有效的粘膜佐剂，因为它们可以实现广泛的粘膜和全身免疫，而没有母体蛋白的潜在安全风险和高水平的免疫原性（即抗 LT 抗体）。在本提案中，我们将严格评估 LTA 和 LTA1 作为佐剂与灭活的大流行性流感抗原的组合。在我们的研究中，我们将确定这些佐剂 (1) 如何改善。通过鼻内或皮内流感疫苗接种保护性免疫和对病毒攻击的反应的相关性，(2) 为其母体蛋白或含有衍生物的相关 B 亚基提供新的、安全和稳定的替代品，(3) 通过 cAMP 介导的树突提高疫苗接种效力完成这项研究后，我们期望使用候选流感抗原进行鼻内和皮内免疫产生明确的安全性和有效性数据，这对于未来人类在大流行性疾病中的使用或在流感中使用特别有价值。根据该提案产生的信息的性质，我们还将为将新型 LTA 和 LTA1 佐剂纳入其他针对细菌和病毒病原体或癌症等退行性疾病的独特疫苗配方中提供明确的理由。