An Adenoviral-Based Mucosal Vaccine for AIDS

描述（由申请人提供）：艾滋病是一个全球性的健康问题，有3600万人感染艾滋病毒，估计每年有500万新感染者。这些数字表明，需要一种预防性疫苗，以防止疾病的进一步传播。尽管在艾滋病疫苗研究方面做出了巨大努力，但传统的疫苗开发方法未能生产出有效的艾滋病毒感染疫苗。最近的疫苗工作集中在引发针对HIV结构蛋白的细胞免疫应答，而不是/除了靶向对包膜的体液免疫应答之外。通过这种方法，基于腺病毒载体的疫苗已经显示出作为人类HIV疫苗的巨大潜力。腺病毒载体引发强烈的先天免疫应答，这极大地有助于诱导强烈的细胞免疫应答。此外，腺病毒作为粘膜疫苗是极好的。然而，腺病毒疫苗的一个主要缺点是人类对腺病毒的免疫力，这可能限制其功效。 我们建议利用PEG化技术来掩盖我们的基于腺病毒的艾滋病疫苗载体Ad/HIV，并在体内测试其功效。我们建议评估由PEG化的Ad/HIV（通过鼻内途径）的粘膜施用诱导的先天免疫应答和针对HIV免疫原的细胞免疫应答（CTL和细胞因子谱）;腺病毒载体编码的gag。此外，我们还将确定对PEG化Ad/HIV产生的全身和粘膜免疫应答。我们将测试PEG化的Ad/HIV在幼稚小鼠和对腺病毒具有预先存在的免疫力的小鼠中的功效。 这项研究的结果将为开发一种高效的粘膜艾滋病疫苗提供基础，这种疫苗可以重复给患者使用，具有很高的疗效。

DESCRIPTION (provided by applicant): AIDS is a worldwide health problem with 36 million people infected with HIV and estimated 5 million new infections occurring per year. These numbers indicate the need for a prophylactic vaccine to prevent the further spread of the disease. Despite tremendous efforts in AIDS vaccine research, traditional methods of vaccine development have failed to produce an effective vaccine for HIV infection. Recent vaccine efforts have focused on eliciting cellular immune responses directed against structural proteins of HIV instead/in addition to targeting humoral immune responses to the envelope. With that approach, adenoviral vector based vaccines have shown a great potential as vaccines for HIV in humans. Adenoviral vectors elicit strong innate immune responses, which greatly aid in inducing strong cellular immune responses. Moreover, adenoviruses are excellent as mucosal vaccines. However, one major drawback of adenoviral vaccines is prior immunity to adenoviruses in human, which could limit their efficacy. We propose to utilize a PEGylation technique to mask our Adeno-based AIDS vaccine vector, Ad/HIV, and test its efficacy in vivo. We propose to evaluate innate immune responses induced by the mucosal administration of PEGylated Ad/HIV (via intranasal route) and cellular immune responses (CTL and cytokine profiles) directed to HIV immunogen; gag encoded by the adenovector. In addition, we will determine both systemic and mucosal immune responses generated to PEGylated Ad/HIV. We will test the efficacy of PEGylated Ad/HIV both in naive mice and in mice with pre-existing immunity to adenoviruses. The results from this study will provide the groundwork for the development of a highly effective mucosal AIDS vaccine that can be repeatedly administered to patients with high efficacy.