Durable Antibody Mediated Protection Against HIV

 描述（由申请人提供）：对预防性艾滋病疫苗的探索正在进行中，成功的疫苗很可能必须引起保护性抗体反应。不管抗体介导的保护机制如何，抗体持久性和适当的T细胞帮助正在成为艾滋病疫苗开发中的重要问题。抗体持久性的问题在RV 144试验中清楚地看到。第一年的保护作用最高，但与抗V2抗体（与感染风险降低相关）平行，迅速减弱至背景水平。抗体持久性差并非RV 144所独有。它发生在VAX 003/VAX 004有效性试验中，也使用了gp 120免疫原，并且在人类和非人灵长类动物的gp 120疫苗试验中反复观察到。对gp 120的抗体持久性差是第二个主要问题。如何引起必要的CD 4 + T细胞的帮助，而不建立肥沃的领域增加艾滋病毒复制在暴露的网站，钝化保护，或增加收购。在使用Ad 5 Hu- HIV“T细胞疫苗”作为免疫原的Step/Phambili试验中，疫苗引发的CD 4 + T细胞和先天性免疫应答似乎与获得增加相关。有报道称，在非人灵长类动物（NHP）模型中，使用除AdHu 5之外的其他载体和免疫原，疫苗相关的获得增加。总之，抗体持久性和T细胞“平衡”的联合问题必须解决任何基于抗体的HIV疫苗是有效的。这一要求为基于实现“平衡的”T细胞和体液应答的HIV疫苗开发引入了一个新的概念，与当前专注于一个臂或另一个臂或寻求并行最大化两个臂的方法形成鲜明对比。对这一概念的探索形成了拟议计划的基础，该计划将测试中心假设，即HIV候选疫苗可以引起持久的抗体应答，该抗体应答由有利于保护的平衡的CD 4 + T细胞谱支持。这一假设是基于研究者发表的研究成果和RM模型中可靠的初步数据。这一假设将通过三个高度互动的项目进行检验。罗伯特·C博士Gallo（IHV）将领导该计划。Anthony L.博士DeVico（IHV）将领导项目1，该项目利用DNA/蛋白质联合免疫方案来测试有关浆细胞亚群分布的假设，以及它们如何确定抗gp 120抗体应答的持久性异常差。乔治博士K.刘易斯（IHV）将领导项目2，以确定疫苗诱导的CD 4 + T细胞如何减弱抗体介导的保护作用。Guido Silvestri博士（埃默里大学）将领导项目3，以确定疫苗诱导的CD 4 + T细胞的表型和有利于持久保护的先天免疫特征。就主要成果而言，这项工作有望完全确定抗Env抗体持久性差的机制，并克服这一问题，同时保持CD 4 + T细胞的“安全”水平，不会削弱保护作用。这些结果有望从根本上推动艾滋病疫苗的开发，而广泛持久的保护是艾滋病疫苗的圣杯。

 DESCRIPTION (provided by applicant): The quest for a prophylactic AIDS vaccine is ongoing and it is probable that the successful vaccine must elicit protective antibody responses. Regardless of the mechanism of antibody-mediated protection, antibody persistence and appropriate T cell help are emerging as significant problems in AIDS vaccine development. The problem of antibody persistence is seen clearly in the RV144 trial. Protection was as highest in the first year but waned rapidly to background in parallel with anti-V2 antibodies that were associated with reduced risk of infection. Poor antibody persistence is not unique to RV144. It occurred in the VAX003/VAX004 efficacy trials, also using gp120 immunogens, and it has been observed repeatedly in gp120 vaccine trials in humans and non-human primates. Poor antibody persistence to gp120 is entwined with a second major problem. How to elicit necessary CD4+ T cell help without establishing fertile fields for increased HIV replication at sites of exposure, blunting protection, or increasing acquisition. It appears that vaccine-elicited CD4+ T cell and innate immune responses are associated with increased acquisition in the Step/Phambili trials that used an Ad5Hu- HIV "T-cell vaccine" as the immunogen. There are reports of vaccine-associated increased acquisition in non- human primate (NHP) models using other vectors and immunogens in addition to AdHu5. Taken together, the conjoint problems of antibody persistence and T cell "balance" must be solved for any antibody-based HIV vaccine to be effective. This requirement introduces a new concept for HIV vaccine development based on achieving "balanced" T cell and humoral responses, contrasting sharply with current approaches that focus on one arm or the other, or that seek to maximize both arms in parallel. Exploration of this concept forms the foundation of the proposed program that will test the central hypothesis that an HIV vaccine candidate can elicit durable antibody responses supported by a balanced CD4+ T cell profile that favors protection. This hypothesis is based on published work from the investigators and on solid preliminary data in RM models. This hypothesis will be tested via three highly interactive projects. Dr. Robert C. Gallo (IHV) will lead the program. Dr. Anthony L. DeVico (IHV) will lead Project 1 that exploits DNA/Protein co-immunization protocols to test hypotheses regarding the disposition of plasma cell subsets and how they determine the unusually poor durability of anti-gp120 antibody responses. Dr. George K. Lewis (IHV) will lead Project 2 to determine how vaccine elicited CD4+ T cells attenuate antibody-mediated protection. Dr. Guido Silvestri (Emory) will lead Project 3 to determine the phenotypes of vaccine-elicited CD4+ T cells and innate immune signatures that favor durable protection. In terms of major outcomes, this work is expected to fully identify the mechanism of poor anti-Env antibody persistence and to overcome this problem while maintaining "safe" levels of CD4+ T cells that don't blunt protection. These results are expected to fundamentally advance AIDS vaccine development for which broad durable protection is the Holy Grail.