Development of Novel Adjuvants LTA and LTA1

 说明(申请人提供)：疫苗是公认的预防疾病的有效方法。作为一个技术平台，它们也在扩展到癌症和阿尔茨海默氏症治疗等非传统应用领域，但仍在传染病研究中发挥重要作用，包括控制大流行性流感病毒的策略。适当选择和使用佐剂配方可通过促进长期保护性免疫、克服高危人群(即年轻人、老年人、免疫缺陷人群)免疫力差和/或只是增加现有抗原供应以惠及更多人(节省剂量)来克服疫苗效力的障碍。这项建议的目的是开发基于大肠杆菌(LT)不耐热肠毒素A亚单位的下一代佐剂，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，特别是在鼻腔给药方面，由于主要的安全性问题而受到阻碍。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系统免疫，而不存在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)。在这项提案中，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相结合的作用。在我们的研究中，我们将确定这些佐剂如何(1)通过鼻内或皮内接种流感疫苗来提高保护性免疫和对病毒攻击的反应的相关性，(2)提供一种新的、安全和稳定的替代其母蛋白或相关B亚单位的衍生物，(3)通过cAMP介导的树突状细胞激活和Th17诱导来提高疫苗接种效率。在这项研究完成后，我们预计将使用候选流感抗原进行鼻腔和皮内免疫，以产生明确的安全性和有效性数据，这对未来人类在大流行疾病环境中的使用或在高危人群中使用特别有价值。基于这项建议产生的信息的性质，我们还将为新的LTA和LTA1佐剂包含在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。

 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.