Combined TLR/CD40-agonist vaccine

描述（由申请人提供）：在对自然感染的免疫反应的高峰期，宿主可以产生病原体特异性T细胞反应，占宿主总T细胞库的20-50%。我们现在已经确定了一种疫苗接种策略，能够从纯分子疫苗中产生类似水平的T细胞扩增，这是以前开发的疫苗策略无法实现的结果。这些高水平的CD8+ T细胞扩增可以通过抗原与toll样受体（TLR）和CD40途径的激动剂联合接种宿主来实现（TLR /CD40激动剂联合免疫）。重要的是，我们还确定这种疫苗即使在CD4缺陷宿主中也能成功地产生原发性和记忆性CD8+ T细胞反应。这是这种疫苗接种方法的独特特征（与其他已发表的方法相比），也是疫苗接种成功治疗CD4 T细胞功能严重受损的HIV感染者的必要组成部分。到目前为止，使用这种疫苗接种技术进行的所有研究都要求单独注射抗原、TLR激动剂和CD40激动剂；这构成了将这种疫苗接种方法推广到临床环境的一个并发症。为了简化疫苗生产和临床实施，我们将生产一种疫苗，其中所有三种成分都包含在单一分子实体中；ie。TLR/ cd40激动剂联合疫苗在疫苗生产后，我们将评估对全身和粘膜病毒攻击的保护性免疫诱导。这些可能是成功的疫苗的必要组成部分，以防止病毒，如通过生殖器粘膜传播后产生全身感染的艾滋病毒。这些研究将导致开发一种能够诱导强效细胞免疫的新型疫苗接种策略，并为快速人源化和研究预防和/或治疗艾滋病毒的功效带来重大希望。

DESCRIPTION (provided by applicant): At the peak of an immune responses against a natural infection, a host can generate pathogen-specific T cell responses that comprise 20-50% of the hosts total T cell pool. We have now identified a vaccination strategy that is able to generate a similar level of T cell expansion from a purely molecular based vaccine, a result not possible with previously developed vaccine strategies. These high levels of CD8+ T cell expansion can be achieved by the vaccination of a host with antigen in combination with agonists for both the Toll-Like Receptor (TLR) and CD40 pathways (combined TLR/CD40-agonist immunization). Importantly, we have also determined the success of this vaccine successfully generating primary and memory CD8+ T cell responses even in CD4 deficient hosts. This is a feature unique to this vaccination method (in comparison to other published methods) and is a necessary component for a vaccination to be successful in treating HIV infected individuals where CD4 T cell function is so heavily compromised. All studies conducted up until now using this vaccination technique have required the separate injection of the antigen, the TLR agonist, and the CD40 agonist; this constitutes a complication in the effort to move this vaccination method into a clinical setting. For the purpose of simplifying vaccine production and clinical implementation, we will producing a vaccine in which all three components were contained within a single molecular entity; ie. a combined TLR/CD40-agonist conjugate vaccine. Following production of the vaccine, we will evaluate the induction of protective immunity against both systemic and mucosal viral challenge. These are likely necessary components of a successful vaccine against a virus such as HIV which produces a systemic infection following transmission via the genital mucosa. These studies will result in the development of a novel vaccination strategy capable of inducing potent cellular immunity and which holds significant promise for rapid humanization and investigation for prophylactic and/or therapeutic efficacy against HIV.