Development of Novel Adjuvants LTA and LTA1

 描述（由申请人提供）：疫苗是预防疾病的既定和经证实的方法。作为一个技术平台，它们还扩展到非传统应用，如癌症和阿尔茨海默氏症治疗，但仍然与传染病研究有关，包括控制大流行性流感病毒的策略。佐剂制剂的适当选择和使用可以通过促进持久的保护性免疫、克服高危人群中的免疫力差（即，年轻人、老年人、免疫功能低下的人），和/或简单地增加现有的抗原供应以达到更大数量的人（剂量节省）。 本提案的目的是开发基于大肠杆菌（LT）不耐热肠毒素A亚单位（包括LTA和LTA 1）的下一代佐剂。佐剂的肠毒素家族是强大的粘膜佐剂，但在过去的临床试验中受到主要安全性问题的阻碍，特别是对于鼻内递送。我们的初步研究表明LTA和LTA 1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，而没有亲本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LTA 1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如何（1）通过鼻内或皮内流感疫苗接种改善保护性免疫和对病毒攻击的应答的相关性，（2）提供一种新的、安全和稳定的替代其亲本蛋白或相关的含B亚基的衍生物，（3）通过cAMP介导的树突状细胞活化和Th 17诱导改善疫苗接种效力。在完成这项研究后，我们希望使用候选流感抗原进行鼻内和皮内免疫接种，获得明确的安全性和有效性数据，对于未来在大流行性疾病环境中的人类使用或用于高风险人群特别有价值。基于本提案产生的信息的性质，我们还将为在其他针对细菌和病毒病原体或退行性疾病（如癌症）的独特疫苗制剂中纳入新型LTA和LTA 1佐剂提供明确的理由。

 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.