Genetic adjuvants to elicit neutralizing antibodies against HIV

该项目将测试T滤泡辅助细胞（Tfh）靶向“遗传佐剂”改善 晚期HIV包膜（Env）三聚体的免疫原性。激发抗以下疾病的中和抗体（nAb）： 艾滋病毒可能需要创造有效的治疗疫苗，减缓艾滋病毒疾病的进展， 减少艾滋病毒的传染性，甚至在没有每日抗逆转录病毒药物的情况下实现持续缓解 疗法然而，引发这种抗体是一个挑战，在B细胞免疫中的多个步骤中可能会遇到挫折。 特别是在艾滋病毒感染者中。与本申请最相关的是，低亲和力种系 对中和表位有反应性的B细胞可能不能成功地与结合非中和表位的细胞竞争。 抗原的表位，或者获得的抗原的量可能不足以刺激Tfh细胞提供抗原表位。 需要帮助。 Tendel Therapies Inc开发B细胞佐剂技术，增强Tfh细胞， 使用载体疫苗。我们的初步数据表明，佐剂作用于Tfh和B细胞，以促进Tfh和B细胞之间的相互作用。 独特的强烈和持久的抗体反应。我们建议将这些佐剂与两种 有希望的B细胞免疫原，以可靠地引发2级中和抗体在猕猴：（i）先进的 BG 505 SOSIP样三聚体，旨在促进对nAb靶标的集中应答，并最大限度地降低 非中和Env表位，例如V3环或非中和CD 4结合位点亚区，和（ii） 噬菌体VLP以高度多聚体形式展示HIV融合肽（FP）。 我们假设新型Tfh靶向佐剂促进了对晚期HIV Env的更广泛的nAb应答， 免疫原通过包括民主幼稚B细胞募集和刺激Tfh反应的机制。 目标1.评估nAb、Tfh和生发中心B细胞对免疫应答的强度和持久性。 晚期HIV包膜三聚体，在有或没有Tendel佐剂的情况下递送，作为脂质中的mRNA 纳米粒子目的是（i）测试Tendel佐剂是否具有类似的增强抗体的效力 对针对天然样HIV Env三聚体的mRNA载体疫苗接种的应答，如先前所示， 增强针对SARS-CoV-2受体结合域的应答;以及（ii）选择一种方案 用于融合肽引发后的目的2中的评价。 目标2.评价用HIV Env融合肽FP 8引发免疫对HIV感染的影响。 通过Tendel佐剂和HIV Env天然样三聚体实现的中和宽度。这种启动 方案旨在为nAb应答提供额外的表位焦点。由于抗- FP nAb与由三聚体免疫提供的其他nAb，FP 8引发的方案应产生产生由三聚体免疫提供的nAb。 反应的广度增加，也许更高的滴度。

This project will test the ability of T follicular helper (Tfh) cell-targeting “genetic adjuvants” to improve immunogenicity of an advanced HIV envelope (Env) trimer. Eliciting neutralizing antibodies (nAb) against HIV will likely be required to create effective therapeutic vaccines that attenuate HIV disease progression, reduce HIV infectiousness, or even effect sustained remission in the absence of daily antiretroviral drug therapy. However, eliciting such antibodies is a challenge that can be frustrated at multiple steps in B-cell development, particularly in HIV-infected people. Of greatest relevance to this application, low-affinity germline B cells reactive to neutralizing epitopes may not successfully compete with cells binding non-neutralizing epitopes for antigen, or the amount of antigen acquired may be insufficient to stimulate Tfh cells to provide the required help. Tendel Therapies Inc. developed B-cell adjuvant technology that augments Tfh cells and is designed for use with vectored vaccines. Our preliminary data show that the adjuvant acts on both Tfh and B cells to promote uniquely intense and durable antibody responses. We propose to use these adjuvants in combination with two promising B-cell immunogens to reliably elicit tier-2 neutralizing antibodies in macaques: (i) an advanced BG505 SOSIP-like trimer designed to promote focused responses to nAb targets and minimize reactivity of non-neutralizing Env epitopes such as the V3 loop or non-neutralizing CD4 binding site sub-regions, and (ii) bacteriophage VLPs displaying the HIV fusion peptide (FP) in highly multimeric form. We hypothesize that novel Tfh-targeting adjuvants promote broader nAb responses to an advanced HIV Env immunogen via mechanisms including democratic naïve B-cell recruitment and stimulation of Tfh responses. Aim 1. Assess the intensity and durability of nAb, Tfh, and germinal center B-cell responses to an advanced HIV envelope trimer, delivered with or without Tendel adjuvants, as mRNA in lipid nanoparticles. The goals are (i) to test if Tendel adjuvants have similar potency for augmentation of antibody responses to mRNA-vectored vaccination against native-like HIV Env trimers, as previously shown for augmentation of responses against the SARS-CoV-2 receptor binding domain; and (ii) to select one regimen for evaluation in Aim 2 subsequent to fusion-peptide priming. Aim 2. Evaluate the effect of priming immunization with the HIV Env fusion peptide, FP8, on neutralization breadth achieved by Tendel adjuvants and HIV Env native-like trimers. This priming regimen is intended to provide an additional epitopic focus for nAb responses. Due to the combination of anti- FP nAbs with other nAbs provided by trimer immunization, the FP8-primed regimen should result in nAb responses of increased breadth and perhaps higher titer.