Oral immunization against HIV/AIDS with prime-boost strategies

描述（由申请人提供）：粘膜传播是全球HIV感染的主要方式。口腔传播是罕见的。然而，它确实发生在成人和婴儿身上，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。如果能够研制出一种有效的口服疫苗，它不仅可能防止口服和其他粘膜传播，而且还可能通过其易于给药而增加疫苗的获取，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。在过去的二十年里，我们的实验室已经证明了用痘病毒原质/蛋白增强策略进行肠外免疫的可行性，从而在猕猴中对粘膜SIV或SHIV攻击产生完全或部分保护。在这项应用中，我们建议扩展这些发现，并利用天然toll样受体（TLR）配体和口服配方技术的最新发展，探索将这种免疫方法应用于口服HIV/AIDS疫苗接种的可能性。我们提出的总体假设是，在初始-增强免疫策略中，有效口服痘病毒和蛋白质疫苗将产生比肠外免疫更大的口腔和粘膜反应，从而保护粘膜免受攻击。具体目的是：(1)评估口服可复制的减毒痘病毒疫苗的安全性和免疫原性；(2)评价以天然TLR配体为佐剂的口服蛋白疫苗的安全性和免疫原性；(3)比较不同口服和肠外给药方案中痘病毒原体和蛋白增强方式的免疫原性；(4)在非人灵长类动物模型中评估口服初级/加强疫苗对粘膜攻击的保护效果。这些研究结果可能有助于阐明抗艾滋病毒/艾滋病的保护机制，并为痘病毒启动物/蛋白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. PUBLIC HEALTH RELEVANCE: Most HIV infections result from mucosal transmission, including transmissions through the oral mucosa. Orally delivered vaccines are easy to administer and are likely to induce immunity at mucosal sites. In this proposal, we will examine oral formulations and delivery of a prime-boost vaccination strategy for its potential to generate protective immunity in macaque models.