A Novel Immune Modulator/ Adjuvant for HIV Vaccines

描述(由申请人提供)：在过去二十年的艾滋病毒疫苗开发过程中，人们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显示出一些希望，尽管它们存在局限性。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性记录，以及在需要时易于制造、储存和交付大规模免疫。此外，DNA疫苗提供了一种有效的方法来传递代表单个或几个病原体的多个免疫原/表位。DNA疫苗的效力可以通过在疫苗配方中添加CpG基序或免疫调节细胞因子等佐剂来增强。这些观察结果有力地表明，带有免疫刺激佐剂的DNA疫苗可能是新一代新出现的传染病疫苗。 我们开发了一种由腺病毒载体的空衣壳组成的新型佐剂，称为CAP，并将其用作DNA疫苗的免疫学佐剂。我们的初步研究表明，CAP在体外激活了脾APC，在体内和体外都能诱导包括IL-12在内的促炎细胞因子。此外，CAP和编码GAG抗原的质粒DNA共同作用，可显著增加GAG特异性的CD4和CD8T细胞的增殖和Th1细胞因子的产生。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Th1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(NL4-3支链B)Gag、pol、Tat和rev的质粒DNA，以及2)重组Gag和Tat蛋白(rGag和rTat)与CAP一起使用，并在Prime-Boost方案中评估其效力。这笔赠款的具体目的是评估CAP作为DNA或蛋白质HIV疫苗的佐剂，并确定Prime-Boost组合在NAIVE以及已有抗Ad免疫的小鼠中的有效性。公共卫生相关性：艾滋病疫情是一种全球紧急情况，艾滋病预防和治疗性疫苗是结束这一流行病的最大希望。我们正在评估使用一种从已经批准用于人类使用的产品中提取的制剂来增强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，这种增强不仅是因为更强的免疫反应，而且是因为反应的类型转变为更适合预防艾滋病毒的反应。

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.