Modulating durability of HIV-1 env specific humoral immunity with a novel TLR7/8 targeted formulation

开发艾滋病毒疫苗的主要障碍之一是确定可诱导 持续的HIV抗原特异性全身和粘膜高强度体液反应。我们最近 可生物降解3M药物中新型TLR7/8配体(3M052)的评价研究 RMS中的合成聚合物纳米颗粒首次产生了HIV Env特异性长寿命浆细胞 (LLPC)在最后一次接种后近一年的猕猴骨髓中。LLPC的存在 与携带抗体反应的结合、中和和ADCC活性显著相关，这些抗体反应还 持续了一年的高震级。强大而持久的生发中心、滤泡T辅助细胞和 在这些猕猴的引流淋巴结中也观察到了淋巴结浆细胞的存在。最后， 观察到持续反应依赖于新的3M052佐剂的单独存在和 与我们的观察结果相反，与TLR4激动剂联合使用并未进一步增强免疫反应 老鼠。然而，我们在转换我们内部开发的聚合物颗粒方面面临着相当大的挑战 工业中的配方扩大到供人类使用。因此，在我们概念验证研究的基础上，目标是 当前提议的目的是：a)系统评价一种临床制剂(cGMP可缩放油乳剂 基于纳米颗粒)与3M制药公司和传染病研究机构合作开发 研究所(IDRI)有能力在猕猴中诱导这些强大的环境特异性LLPC，以加快翻译速度 在人类中的使用以及b)仔细剖析3M052通过其先天和基于B细胞的分子机制 佐剂能够促进Env特异性LLPC和长寿抗体应答。

One of the major obstacles to developing a HIV vaccine is defining adjuvants and immunogens that induce persistent HIV antigen specific systemic and mucosal humoral responses of high magnitude. Our recent studies evaluating a novel TLR7/8 ligand (3M052) from 3M Pharmaceuticals formulated in biodegradable synthetic polymer nanoparticles in RMs has for the first time yielded HIV Env specific long-lived plasma cells (LLPCs) in the macaque bone marrow for close to one year post final vaccination. The presence of LLPCs correlated significantly with binding, neutralizing and ADCC activity bearing antibody responses that also persisted at high magnitude for a year. Robust and persistent germinal center, follicular t helper cells and lymph node resident plasma cells were also observed in draining lymph nodes in these macaques. Finally, the persistent response was observed to be dependent on the presence of the novel 3M052 adjuvant alone and combining with a TLR4 agonist did not further enhance immune responses in contrast to our observations in mice. However, we have faced considerable challenges in translating our in house developed polymer particle formulations in industrial scale up for human use. Therefore, building on our proof of concept studies, the goal of the current proposal is to: a) systematically evaluate a clinical formulation (cGMP scalable oil emulsion based nanoparticle) developed in partnership with 3M pharmaceuticals and the Infectious Disease Research Institute (IDRI) in its ability to induce these potent Env specific LLPCs in macaques for expedited translation for use in humans and b) carefully dissect the innate and B cell based molecular mechanisms by which the 3M052 adjuvant is capable of promoting Env specific LLPCs and long lived antibody responses.