Oral immunization against HIV/AIDS with prime-boost strategies

描述(申请人提供)：粘膜传播是全球艾滋病毒感染的主要方式。经口传播是罕见的。然而，它确实发生在成人和婴儿身上，后者很可能是通过摄入感染艾滋病毒的母亲的牛奶而发生的。如果能够配制一种有效的口服疫苗，它不仅可能预防口腔和其他粘膜传播，而且还可以通过其易于接种而增加疫苗的获得，从而提供一种具有成本效益的艾滋病毒/艾滋病预防方法。在过去的二十年里，我们的实验室已经证明了使用痘病毒主/蛋白增强策略进行肠外免疫的可行性，从而对猕猴的黏膜SIV或SIV攻击产生完全或部分保护。在这一应用中，我们建议扩展这些发现，并利用天然Toll样受体(TLR)配体和口服制剂技术的最新发展来探索将这种免疫方法应用于口服艾滋病毒/艾滋病疫苗的可能性。我们提出的总体假设是，在主要增强免疫策略中，有效的口服痘病毒和蛋白质疫苗将比非肠道免疫产生更大的口腔和粘膜反应，从而保护免受粘膜攻击。具体目的是：(1)评估具有复制能力的减毒痘病毒疫苗口服给药的安全性和免疫原性；(2)评估以天然TLR配基为佐剂的蛋白质疫苗口服给药的安全性和免疫原性；(3)比较不同口服和非肠道给药方案中痘病毒初级和蛋白质增强途径的免疫原性；(4)在非人类灵长类动物模型中评价口服优质/增强疫苗对黏膜攻击的保护作用。这些研究的结果可能有助于阐明对艾滋病毒/艾滋病的保护机制，并为痘病毒初级/蛋白质增强免疫概念的临床发展提供信息。

DESCRIPTION (provided by applicant): Mucosal transmission represents the predominant mode of global HIV acquisition. Oral transmission is rare. However, it does occur, in adults and in infants, with the latter occurring most likely through ingestion of milk from HIV-infected mothers. If an effective vaccine can be formulated for orally delivery, it is likely to protect not only against oral and other mucosal transmission, but also enhance vaccine access through its ease of administration, thus providing a cost-effective preventive approach against HIV/AIDS. Over the past two decades, our lab has demonstrated the feasibility of parenteral immunization with a poxvirus prime/protein boost strategy, resulting in complete or partial protection against mucosal SIV or SHIV challenge in macaques. In this application, we propose to extend these findings and to leverage recent developments in natural Toll-like receptor (TLR) ligands and oral formulation technologies to explore the possibility of adapting this immunization approach for oral vaccination against HIV/AIDS. The overall hypothesis we propose is that effective oral delivery of poxvirus and protein vaccines in a prime-boost immunization strategy will generate greater oral and mucosal responses than parenteral immunizations, resulting in protection against mucosal challenge. The Specific Aims are: (1) To evaluate the safety and immunogenicity of oral delivery of a replication competent, attenuated poxvirus vaccine; (2) To evaluate the safety and immunogenicity of protein vaccines adjuvanted with a natural TLR ligand and formulated for oral delivery; (3) To compare the immunogenicity of poxvirus prime and protein boost approach in different oral and parenteral delivery regimens; (4) To evaluate the protective efficacy of oral delivered prime/boost vaccines against mucosal challenge in non-human primate models. Results from these studies are likely to help elucidate the protective mechanisms against HIV/AIDS and inform the clinical development of the poxvirus prime/protein boost immunization concept.