Oral Delivery of Nanoparticles encapsulated with HIV-DNA Vaccine

描述(申请人提供)：研制针对艾滋病毒的疫苗是控制艾滋病大流行的唯一希望。然而，尽管细胞免疫(CMI)反应已被证明对控制感染者的病毒很重要，但能够诱导这些反应的疫苗的识别和成功仍然难以捉摸。DNA疫苗能够诱导CMI反应，其安全性使其成为传统疫苗的一种有吸引力的替代品。然而，尽管通过肌肉注射途径的DNA免疫取得了一些成功，但它的免疫原性很差，特别是在非人类灵长类动物&人类中。最近的研究强调，肠道粘膜是艾滋病毒感染的主要部位，因此疫苗策略应以诱导粘膜免疫为目标。因此，我们预计口服DNA疫苗将是预防艾滋病毒的最有效方法。本项目提出了两个具体目标。在第一个目标中，我们将制备和表征靶向特异性的聚丙交酯-乙交酯(PLGA)纳米颗粒，并将其包裹在广谱猿猴HIV(SIV)DNA疫苗中，然后筛选HIV-1蛋白在细胞培养中的表达。这将使鉴定有效的基因递送载体(S)能够在小鼠体内口服DNA疫苗。在第二个目的中，我们将研究口服纳米粒在胃肠道APC中表达基因的能力，然后在小鼠身上测试针对Shiv-DNA疫苗产生的免疫应答。我们预计，这种方法将通过口服相对较小剂量的DNA疫苗一次就能产生强烈的粘膜和全身免疫反应。这项提议的长期目标是开发包裹纳米颗粒的DNA疫苗，作为一种有效的预防艾滋病毒感染的口服疫苗策略。公共卫生相关性：拟议的研究将加强目前开发有效的艾滋病毒预防性疫苗的努力，这是控制艾滋病大流行的唯一希望，从而直接解决国家卫生研究院通过多学科努力预防传染病来改善人类健康的目标。

DESCRIPTION (provided by applicant): Development of a vaccine against HIV is the only hope of controlling the AIDS pandemic. However, although cell mediated immune (CMI) responses have been shown to be important for controlling the virus in infected persons, identification and success of a vaccine that could induce these responses has remained elusive. The ability of DNA vaccine to elicit CMI response and its safe profile makes plasmid DNA an attractive alternative to traditional vaccines. However, despite some success of DNA based immunization through intramuscular route, it shows poor immunogenicity especially in nonhuman primates & humans. Recent studies have highlighted the intestinal mucosa as the primary site of HIV-infection and therefore vaccine strategies should be aimed at induction of mucosal immunity. We expect that oral DNA vaccination will, thus, be the most effective approach in providing protection against HIV. Two specific aims are proposed in this project. In the first aim we will fabricate and characterize target specific poly (lactide-co-glycolide) (PLGA) nanoparticles encapsulated with broad spectrum simian-HIV (SHIV) DNA vaccine followed by screening for the expression of HIV-1 proteins in cell culture. This will allow identification of viable gene delivery vector(s) for oral delivery of DNA vaccine in mice. In the second aim we will investigate the ability of the orally administered nanoparticles to express genes in the APCs of gastrointestinal tract and then test the immune responses generated against the SHIV-DNA vaccine in mice. We expect that this approach will strongly generate both mucosal and systemic immune responses with a single oral immunization of a relatively small dose of DNA vaccine. The long term goal of this proposal is to develop DNA vaccine encapsulated nanoparticles, as an effective oral vaccination strategy against HIV-infection. PUBLIC HEALTH RELEVANCE: The proposed research will augment current efforts to develop an effective prophylactic vaccine against HIV, the only hope of controlling the AIDS pandemic, thus, directly addressing the goals of the NIH for improving human health through a multidisciplinary effort to prevent infectious disease.