A Novel Immune Modulator/ Adjuvant for HIV Vaccines

描述（由申请人提供）：在过去二十年的HIV疫苗开发中，已经探索了各种各样的艾滋病疫苗策略。在许多测试中，基于DNA和病毒载体的疫苗激活细胞免疫反应，尽管有其局限性，但已显示出一些前景。基于质粒DNA的疫苗是理想的候选疫苗，因为它们在各种临床试验中的安全记录以及在需要时易于制造、储存和运送用于大规模免疫。此外，DNA疫苗提供了递送代表单一或几种病原体的多个免疫原/表位的有效方法。DNA疫苗的效力可以通过向疫苗配方中添加佐剂如CpG基序或免疫调节细胞因子来增强。这些观察结果有力地表明，与免疫刺激佐剂一起递送的DNA疫苗可能是用于新兴传染病的新一代疫苗。 我们开发了一种新的佐剂组成的空衣壳的腺病毒载体，称为CAP，并使用它作为免疫佐剂的DNA疫苗。我们的初步研究表明CAP在体外激活脾APC，并在体内和体外诱导包括IL-12在内的促炎细胞因子。此外，CAP和编码gag抗原的质粒DNA的共同施用导致gag特异性CD 4和CD 8 T细胞增殖和Th 1细胞因子产生的急剧增加。这些数据表明，CAP可以作为一种免疫调节佐剂，具有增强免疫原特异性Th 1细胞因子产生的能力。为了验证我们的假设，我们建议进一步评估CAP作为HIV疫苗的免疫佐剂，以促进HIV特异性细胞和体液反应。我们将使用两种类型的免疫原1）编码HIV-1（NL 4 -3进化枝B）gag、pol、tat和rev的质粒DNA和2）重组gag和tat蛋白（rGag和r达特）沿着CAP，并评估其在初免-加强方案中的效力。该补助金的具体目的是评估CAP作为DNA或蛋白质为基础的艾滋病毒疫苗的佐剂，并确定初免-加强组合在幼稚以及预先存在抗Ad免疫的小鼠中的有效性。公共卫生相关性：艾滋病流行是全球性的紧急情况，艾滋病预防和治疗疫苗为结束这一流行病提供了最大的希望。我们正在评估使用一种从已批准用于人类的产品中提取的制剂来提高艾滋病毒疫苗的效力。我们计划在这项研究中扩展的初步结果表明，这种增强不仅是由于更大的免疫反应，而且是反应类型向更适合预防艾滋病毒的反应类型的转变。

DESCRIPTION (provided by applicant): During the past two decades of HIV vaccine development, a wide variety of AIDS vaccine strategies have been explored. Among the many tested, DNA and viral vector-based vaccines that activate cellular immune responses have shown some promise despite their limitations. Vaccines based on plasmid DNA are ideal candidates as vaccines due to their safety record in various clinical trials as well as ease of manufacturing, storage and delivery for mass immunization when the need arises. Furthermore, DNA vaccines offer an effective method of delivering multiple immunogens/epitopes representing a single or several pathogens. The efficacy of the DNA vaccines can be enhanced by the addition of adjuvants such as CpG motifs or immunomodulatory cytokines to the vaccine formula. These observations strongly indicate that DNA vaccines delivered with immunostimulatory adjuvants could be the new generation of vaccines for emerging infectious diseases. We developed a novel adjuvant consisting of an empty capsid of an adenoviral vector, termed CAP and used it as an immunological adjuvant to a DNA vaccine. Our preliminary studies indicate that CAP activated splenic APC in vitro and induced pro-inflammatory cytokines including IL-12 both in vivo and in vitro. In addition, coadministration of CAP and plasmid DNA coding for gag antigen, resulted in a dramatic increase in gag-specific CD4 and CD8 T cell proliferation and Th1 cytokine production. These data suggest that CAP can function as an immunomodulatory adjuvant with the ability to enhance immunogen-specific Th1 cytokine production. To test our hypothesis, we propose to further evaluate CAP as an immunological adjuvant to HIV vaccines to promote HIV-specific cellular and humoral responses. We will use two types of immunogens 1) plasmid DNA encoding HIV-1 (NL4-3 Clade B) gag, pol, tat and rev and 2) recombinant gag and tat proteins (rGag and rTat) along with CAP and evaluate its potency in prime-boost protocols. The specific aims of the grant are to evaluate CAP as an adjuvant to DNA or protein-based HIV vaccines and to determine the effectiveness of prime-boost combinations in naive as well as mice with pre-existing anti-Ad immunity. PUBLIC HEALTH RELEVANCE: The AIDS epidemic is a global emergency and preventive and therapeutic vaccines for AIDS offer the best hope of ending the pandemic. We are evaluating the use of a preparation derived from a product already approved for human use to enhance the potency of HIV vaccines. The initial results which we plan to extend in this study, show the enhancement is not only due to greater immune responses but also a shift of the type of response to one better suited to protect against HIV.