OPTIMIZE THE IMMUNOGENICITY OF MVA-BASED AIDS VACCINES

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 只有开发出安全、有效、负担得起和足够简单的疫苗，才可能控制艾滋病大流行造成的无休止的破坏，以便在艾滋病最严重的发展中国家实施。为了实现这一重要目标，Emory IPCAVD计划将在改良安卡拉疫苗(MVA)的更高免疫原性变体的背景下，对表达共识的多亚型、多基因HIV-1抗原的艾滋病疫苗进行一系列补充研究。我们努力改进现有MVA疫苗的良好实用特性，但免疫原性不令人满意，这取决于我们合作的HIVRAD研究工作中出现的一系列技术进步和基本见解。这些进展包括：开发产生MVA独特遗传变异的新方法；定义MVA对树突状细胞的优先取向；以及阐明病毒感染对这些关键抗原提呈细胞(APC)的影响。在这些进展的基础上，我们开发了MVA的遗传变体，它可以更有效地促进APC的招募、成熟和抗原呈递的有效性，并产生具有更大免疫原性潜力的疫苗载体。 我们现在将这些发现扩展到(1)开发更具免疫原性的基于MVA的艾滋病候选疫苗；(2)开发更简单、但比传统疫苗管理方法更有效的疫苗方案，通过特定靶向易于获得但具有免疫效力的APC；以及(3)更好地定义通过接种疫苗可能引发有效记忆T细胞反应的发育过程，以及这些过程与自然艾滋病毒感染后的特征有何不同。随着开发时间表的加快，我们建议将我们领先的基于MVA的艾滋病毒候选疫苗推进到人类志愿者的第一阶段临床试验，同时我们继续进一步改进基于MVA的疫苗的免疫原性和递送方法。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The unremitting devastation wrought by the AIDS pandemic will likely only be controlled when a vaccine is developed that is safe, effective, affordable, and simple enough to permit implementation in developing countries where AIDS is most severe. To address this essential goal, the Emory IPCAVD Program will pursue a complementary series of studies of AIDS vaccines that express consensus multi-subtype, multigene HIV-1 antigens in the context of more highly immunogenic variants of modified vaccinia Ankara (MVA). Our efforts to improve upon the favorable practical properties but unsatisfactory immunogenicity of available MVA-based vaccines rest on a series of technical advances and basic insights emerging from our collaborative HIVRAD research efforts. These advances include: development of novel methods to generate unique genetic variants of MVA; the definition of the preferential tropism of MVA for dendritic cells; and elucidation of the consequences of virus infection on these key antigen-presenting cells (APCs). Based on these advances, we developed genetic variants of MVA that more effectively promote APC recruitment, maturation and the effectiveness of antigen presentation, and that yield vaccine vectors with substantially greater immunogenic potential. We now extend these findings to (1) develop even more immunogenic MVA-based AIDS vaccine candidates; (2) to develop vaccine regimens that are simpler, yet more effective than traditional methods of vaccine administration via specific targeting of easily accessible, but immunologically potent APCs; and (3) to better define the developmental processes by which effective memory T cell responses may be elicited by vaccination and how these differ in character from those that follow natural HIV infections. Following an accelerated developmental timeline, we propose to advance our lead MVA-based HIV vaccine candidates into Phase I clinical trials in human volunteers, while we continue to further improve upon the immunogenic properties of and methods of delivery for MVA-based vaccines.