Improved HIV-Adenoviral Vector Vaccine for Re-immunization

描述（由申请人提供）：该项目的目标是研制一种抗艾滋病毒的腺病毒载体疫苗，该疫苗能有效地刺激先前对腺病毒免疫的动物的细胞介导免疫。艾滋病毒疫苗将用于预防感染和治疗感染者。Gag、Pol和Nef是据报道对疫苗开发有用的HIV蛋白。证据表明，需要广泛的细胞介导免疫（CMI）反应来治疗或预防HIV感染。腺病毒（Ad）载体疫苗可诱导CMI反应，并已成为用作疫苗递送平台的主要候选疫苗。第一代Ad疫苗已被证明不如预期有效，不良反应值得怀疑。此外，大多数人的预先存在的Ad免疫导致有效性降低。为了解决这些问题，我们开发了一种先进的基于Ad的载体，它缺乏早期基因E1， E3和E2B。与第一代Ad载体相比，“e2b缺失”载体的聚合酶和前端蛋白基因缺失，克隆能力增强，病毒晚期基因表达量大大降低。多种Ad病毒基因表达的减少对疫苗开发是有利的，原因包括抗原竞争减少、表达时间延长，从而提供更大的免疫刺激和减少不良反应。这种优势在存在预先存在的Ad免疫的情况下是重要的，因为Ad载体需要是隐形的。该公司获得了密歇根大学新的Ad载体系统和支持载体生产的E.C7细胞系的独家许可。基于新的e2b缺失Ad载体系统的拟议疫苗将携带融合的Ad-gag-pol、融合的Ad-gag-pol-nef和Clade C环境基因。这些HIV疫苗将测试其诱导CMI的潜力，以及它们在Ad-naive和Ad-immune小鼠中的再免疫（增强）潜力。该项目完成后，我们将开发一个新的平台，提供有效、安全、稳定、具有成本效益、易于分发和使用的艾滋病毒疫苗。我们的目标是在临床前数据允许的情况下，在2至3年内启动非人类灵长类动物II期SBIR研究，并使用这些或类似疫苗产品进行I期临床试验。

DESCRIPTION (provided by applicant): The objective of this project is to develop an adenoviral vector vaccine against HIV that is effective in stimulating cell-mediated immunity in animals previously immune to adenovirus The HIV vaccine will be used to protect against infection and to treat the infected. Gag, Pol, and Nef are HIV proteins that have been reported to be useful for vaccine development. Evidence indicates that a broad cell-mediated immune (CMI) response is needed to treat or prevent HIV infection. Adenovirus (Ad) vector vaccines induce CMI responses and have emerged as a leading candidate to be used as a vaccine delivery platform. First Generation Ad vaccines have proven less effective than anticipated and adverse reactions are in question. Furthermore, pre-existing Ad immunity of most humans causes decreased effectiveness. To address these issues, we have developed an advanced Ad based vector that is devoid of early genes E1, E3, and E2B. "E2B-deleted" vectors, with deletions in the polymerase and preterminal protein genes, have an expanded cloning capacity and greatly reduced expression of viral late genes as compared to First Generation Ad vectors. Reduced expression of multiple Ad viral genes is advantageous for vaccine development for reasons such as reduced antigenic competition, greater longevity of expression that provides greater immunologic stimulus and reduced adverse effects. Such advantages are important in the presence of pre-existing Ad immunity since the Ad vector needs to be stealth-like. The Company has exclusive license from the U of M for the new Ad vector system and the E.C7 cell line, which supports vector production. The proposed vaccines based on the new E2B-deleted Ad vector system will carry fused Ad-gag-pol, fused Ad-gag-pol-nef and Clade C env genes. The HIV vaccines will be tested for their potential to induce CMI as a prime and for their re-immunization (boost) potential in Ad-naive and Ad-immune mice. Upon completion of this project, we will have developed a new platform for the delivery of HIV vaccines that is effective, safe, stable, cost effective, easy to distribute and use. Our goal is to initiate non-human primate studies in the Phase II SBIR and a Phase I clinical trial using these or like vaccine product within 2 to 3 years of funding as pre-clinical data allows.