Oral immunization against HIV/AIDS with prime-boost strategies

描述（由申请方提供）：粘液传播代表了全球HIV感染的主要模式。口腔传播是罕见的。然而，它确实发生在成人和婴儿中，后者最有可能通过摄入感染艾滋病毒的母亲的乳汁而发生。如果能够配制有效的口服疫苗，不仅可以防止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预防艾滋病毒/艾滋病的方法。在过去的二十年中，我们的实验室已经证明了用痘病毒初免/蛋白加强策略进行胃肠外免疫的可行性，从而在猕猴中完全或部分保护粘膜SIV或SHIV攻击。在本申请中，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，探索适应这种免疫方法口服疫苗接种艾滋病毒/艾滋病的可能性。我们提出的总体假设是，在初免-加强免疫策略中，痘病毒和蛋白疫苗的有效口服递送将产生比肠胃外免疫更大的口腔和粘膜应答，从而保护免受粘膜攻击。具体目标是：（1）评价口服递送具有复制能力的减毒痘病毒疫苗的安全性和免疫原性;（2）评价以天然TLR配体为佐剂并配制用于口服递送的蛋白疫苗的安全性和免疫原性;（3）比较痘病毒初免和蛋白加强方法在不同口服和胃肠外递送方案中的免疫原性;（4）在非人灵长类动物模型中评价口服递送的初免/加强疫苗对粘膜攻击的保护效力。这些研究的结果可能有助于阐明艾滋病毒/艾滋病的保护机制，并为痘病毒初免/蛋白加强免疫概念的临床开发提供信息。

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.