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诱导免疫应答的佐剂和免疫原。 持续的高强度HIV抗原特异性全身和粘膜体液应答。我们最近 研究评价了来自3 M Pharmaceuticals的新型TLR 7/8配体（3 M052）， RM中的合成聚合物纳米颗粒首次产生了HIV Env特异性长寿浆细胞 在最后一次接种后近一年，猕猴骨髓中的LLPC。LLPC的存在 与结合、中和和携带ADCC活性的抗体应答显著相关， 持续了一年的高强度。强大和持久的生发中心，滤泡t辅助细胞和 在这些猕猴的引流淋巴结中也观察到淋巴结驻留浆细胞。最后 观察到持续应答依赖于单独的新型3 M052佐剂的存在， 结合TLR 4激动剂并没有进一步增强免疫应答，这与我们在 小鼠然而，我们在翻译我们内部开发的聚合物颗粒方面面临着相当大的挑战。 用于人类使用的工业规模的制剂。因此，基于我们的概念验证研究， a）系统地评价临床制剂（cGMP可缩放的油乳剂 基于纳米粒子）与3 M制药公司和传染病研究合作开发 研究所（IDRI）在猕猴中诱导这些有效的Env特异性LLPC的能力，以加速翻译， 和B）仔细剖析3 M052在人中使用的先天性和基于B细胞的分子机制 佐剂能够促进Env特异性LLPC和长寿命抗体应答。

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.