Novel nanoparticulate adjuvants to enhance HIV-1 Env specific mucosal antibody responses

摘要 开发有效的HIV-1疫苗的关键障碍之一是确定佐剂和免疫原， 诱导高强度持续HIV-1包膜（Env）抗原特异性抗体应答。Alum已经 几乎世纪以来，佐剂的选择用于人类，也用于大多数HIV-1疫苗临床 审判然而，明矾不能诱导适当质量的持续的HIV-1 Env特异性抗体应答 （中和活性或效应子功能）。已知纳米颗粒佐剂可增强免疫应答 通过快速引流和靶向淋巴结中的关键免疫细胞。我们最近完成的研究评估了 来自3 M Pharmaceuticals的新TLR-7/8配体（3 M-052），其本身或与TLR-4激动剂GLA组合 在恒河猴中首次配制了可生物降解的合成聚合物纳米颗粒， 成功地在骨髓中诱导HIV-1 Env特异性长寿命浆细胞（LLPC）。稳健和 在高浓度下也观察到具有结合、中和和ADCC活性的持续抗体应答。 引流淋巴液中除了高频率的生发中心B细胞和滤泡性T辅助细胞外， 结然而，我们的聚合物纳米颗粒在用于人类的可制造性方面面临挑战。 因此，在我们的概念验证研究的基础上，与传染病研究所合作， （IDRI）和3 M制药公司，我们现在建议a）评价一种新型临床相关明矾NanoAlum 与3 M-052分子组合的具有HIV-1 Env免疫原的基于纳米颗粒的佐剂，B） 建立新的方法学，使用新的血清蛋白质组学和BCR测序， 通过定义RM中LLPC的关键子集来评估疫苗诱导的应答，最后c）基于 当将皮下接种与这种新佐剂组合时对病毒攻击的保护效力 鼻内接种（IN）以改善生殖器粘膜的粘膜免疫。

Abstract One of the key obstacles to developing an effective HIV-1 vaccine is identifying adjuvants and immunogens that induce persistent HIV-1 envelope (Env) antigen specific antibody responses of high magnitude. Alum has been the choice of adjuvant for use in humans for almost a century now and also used in most HIV-1 vaccine clinical trials. However, Alum fails to induce persistent HIV-1 Env specific antibody responses of the appropriate quality (neutralizing activity or effector functions). Nanoparticulate adjuvants are known to enhance immune responses by rapidly draining and targeting key immune cells in lymph nodes. Our recently completed studies evaluating a novel TLR-7/8 ligand (3M-052) from 3M Pharmaceuticals by itself or in combination with a TLR-4 agonist GLA formulated in biodegradable synthetic polymer nanoparticles in rhesus macaques has for the first time successfully induced HIV-1 Env specific long-lived plasma cells (LLPCs) in the bone marrow. Robust and persistent antibody responses with binding, neutralizing and ADCC activity were also observed at high magnitude in addition to high frequencies of germinal center B cells and follicular T helper cells in draining lymph nodes. However, our polymer nanoparticles have faced challenges with manufacturability for use in humans. Hence, building on our proof of concept studies, in collaboration with the Infectious Disease Research Institute (IDRI) and 3M Pharmaceuticals, we now propose to a) evaluate a NanoAlum, novel clinically relevant Alum based nanoparticulate adjuvant with HIV-1 Env immunogens in combination with the 3M-052 molecule, b) establish new methodology that uses novel serum proteomics and BCR sequencing to rigorously investigate vaccine induced responses by defining key subsets of LLPCs in RMs and finally c) evaluate vaccine based protective efficacy upon virus challenge when combining sub-cutaneous vaccinations with such new adjuvants with intranasal vaccinations (IN) to improve mucosal immunity at genital mucosa.