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能够 诱导高强度的HIV-1包膜抗原特异性抗体应答。明矾已经被 人类使用佐剂的选择近一个世纪以来，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久HIV-1环境特异性抗体反应 (中和活动或效应器功能)。已知纳米佐剂可增强免疫反应 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一个 来自3M制药公司的新的TLR-7/8配体(3M-052)或与TLR-4激动剂GLA联合使用 以可生物降解的合成聚合物纳米颗粒配制的恒河猴首次获得 成功地在骨髓中诱导了HIV-1Env特异性长寿浆细胞(LLPC)。健壮且 还观察到具有结合、中和和adcc活性的持久性抗体反应。 引流淋巴中生发中心B细胞和滤泡辅助性T细胞的数量 节点。然而，我们的聚合物纳米颗粒在可制造性方面面临着用于人类的挑战。 因此，在我们概念验证研究的基础上，与传染病研究所合作 (IDRI)和3M制药公司，我们现在建议a)评估一种新的临床相关的纳米明矾 基于HIV-1环境免疫原与3M-052分子结合的纳米颗粒佐剂，b) 建立使用新的血清蛋白质组学和BCR测序的新方法来严格研究 疫苗通过在RMS中定义LLPC的关键子集来诱导应答，并最终c)评估疫苗 皮下接种与新型佐剂联合接种对病毒攻击的保护作用 鼻腔接种(IN)，以提高生殖器粘膜的粘膜免疫力。

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.