AIDS Prevention: Mucosally-Targeted Plant Based Vaccines

描述（由申请人提供）：尽管广泛的艾滋病预防计划和强大的抗逆转录病毒药物在限制HIV-1在高收入国家的传播方面取得了成功，但人们普遍认为，对于发展中国家来说，这些努力必须与有效的疫苗相结合，但此类疫苗的设计和测试已被证明是复杂的。已经表明，粘膜抗体在防止HIV-1穿过上皮屏障并最终提供免受感染的保护方面具有重要作用。我们建议利用融合蛋白工程和转基因植物作为疫苗生产平台，以开发一种粘膜靶向亚单位疫苗，激发局部和全身免疫反应，对广泛的HIV-1亚型，以防止无创伤性的性传播的病毒。该提议的主要目的集中在基于融合蛋白的这种候选疫苗的开发，所述融合蛋白由霍乱毒素的粘膜靶向B亚基（CT B）和保守的β-D-半乳糖苷（GalCer）结合结构域（包括ELDKWA中和表位，a.a. 649-681，“P1”肽），其介导HIV-1穿过粘膜上皮的转胞吞作用。CTB-P1嵌合体将在细菌和植物细胞中表达。然后，我们将测试其在小鼠中引发针对HIV-1的粘膜和全身免疫应答的潜力，并测定抗体中和转胞吞和感染的能力。我们认为，这种结合免疫学和植物基因工程的植物衍生（“可食用”）疫苗新技术有可能在提供有效、成本效益高和安全（无针）疫苗方面对艾滋病毒/艾滋病疫苗开发领域产生重大影响。虽然单一形式的疫苗接种在孤立的情况下可能不会有效，但植物疫苗可以与其他类型的疫苗结合使用，采用初免/加强策略。

DESCRIPTION (provided by applicant): Despite the success of extensive AIDS prevention programs and powerful anti-retroviral drugs in limiting the spread of HIV-1 in high-income countries, it is generally agreed that for the developing world, these efforts will have to be combined with effective vaccines, but the design and testing of such vaccines have proven to be complex. It has been suggested that mucosal antibodies have an important role in preventing HIV-1 from crossing the epithelial barrier and ultimately in providing protection from infection. We propose to utilize fusion protein engineering and transgenic plants as a vaccine production platform in order to develop a mucosally-targeted subunit vaccine that provoke local and systemic immune responses against a broad range of HIV-1 subtypes to prevent the atraumatic sexual transmission of the virus. The main objective of this proposal centers on the development of such a candidate vaccine based on a fusion protein consisting of the mucosal-targeting B subunit of cholera toxin (CTB) and the conserved cerebroside (GalCer) binding domain (including the ELDKWA neutralizing epitope, a.a. 649-681, the "P1" peptide) of the HIV-1 gp41 envelope protein, which mediates the transcytosis of HIV-1 across the mucosal epithelia. The CTB-P1 chimera will be expressed in bacteria and in plant cells. We will then test its potential to elicit mucosal and systemic immune responses against HIV-1 in mice and assay the antibodies' capacity to neutralize transcytosis and infection. We believe that this new technology of plant-derived ("edible") vaccines emerging from the combination of immunology and plant genetic engineering has the potential to significantly impact the field of HIV/AIDS vaccine development in providing efficacious, cost-effective and safe (needle-free) vaccines. While it is probable that a single form of vaccination would not be effective in isolation, the plant-based vaccine may be combined with other types of vaccines in a prime/boost strategy.