Messenger RNA Immunogens for initiation of protective HIV non-neutralizing antibodies

虽然HIV-1广谱中和抗体(BNAbs)提供了对HIV-1的有效保护，但到目前为止，它们已经 在接种疫苗的背景下很难诱导。第二类HIV-1包膜(Env)抗体是 容易诱发的抗体被称为非中和抗体(NNAbs)(因为它们不是bNAbs)，或称为 效应器抗体，因为它们介导了无数潜在的保护性抗HIV-1效应器机制。 5期IIb HIV-1疫苗疗效试验之一(RV144中的ALVAC/AIDSVAX)显示出估计的 疫苗有效率为31%，与降低多功能抗体传播风险相关 介导FCR-抗HIV-1活性，包括针对C1和V2的ADCC。目前有两种疫苗 正在进行的有效性试验，以测试ALVAC-C，二价C/C gp120 Boost(HVTN 702)和rAd26的能力 Prime，gp140蛋白Boost(HVTN 705)，希望诱导保护性NNAb。HVTN 702有两个野生型 (WT)gp120环境作为助推器，而HVTN 705有一个WT环境作为助推器。然而，这两个试验都没有利用 通过增强环境设计来诱导更广泛的NNAb的策略。因此，当前HIV-1的一个关键目标 疫苗的开发是开发最简单和最有效的疫苗，诱导多功能的NNAbs 如果目前的两项疗效试验中有一项未能改善RV144的疗效。 我们的总体目标是1)开发一种遵循ALVAC-C的ADCC马赛克多价环境免疫原 2)根据当前良好的制造规范(CGMP)生产ADCC马赛克环境gp120 条件，执行毒性研究，并准备研究新药应用(IND)以在 HVTN在MAN的I期临床试验。 总的具体目标1.研制并生产一种能够 遵循ALVAC-C质数并在动物核心中测试它们在ADCC中介导的NNAB-未突变 共同祖先(UCA)VH+VL小鼠模型和在传代/创始(Tf)第2级、R5Shiv中 恒河猴研究(RMS)(Drew Weissman，项目负责人；Barton Haynes，Co-I) 总的特异性目标2.制备CGMP三价ADCC马赛克mRNAgp120免疫原。(托马斯) Denny项目负责人；Maureen Maughan，Project Co-I) 。

While HIV-1 broadly neutralizing antibodies (bnAbs) provide potent protection from HIV-1, to date they have been difficult to induce in the setting of vaccination. A second type of HIV-1 envelope (Env) antibodies that are easy to induce are termed non-neutralizing antibodies (NNAbs) (because they are not bnAbs), or called effector antibodies, because they mediate a myriad of potentially protective anti-HIV-1 effector mechanisms. One of the 5 Phase IIb HIV-1 vaccine efficacy trials (ALVAC/AIDSVAX in RV144) showed an estimated vaccine efficacy of 31%, with a correlate of decreased transmission risk of polyfunctional antibodies that mediate FcR-anti-HIV-1 activities including C1 and V2-targeted ADCC. Currently there are two vaccine efficacy trials ongoing to test the ability of an ALVAC-C, bivalent C/C gp120 boost (HVTN 702) and rAd26 prime, gp140 protein boost (HVTN 705) with hopes of inducing protective NNAbs. HVTN 702 has two wildtype (WT) gp120 Envs as boosts, and HVTN 705 has one WT Env as boost. However, neither trial utilitize strategies for inducing a breadth of NNAbs with boosting Env design. Thus, a key goal of current HIV-1 vaccine development is to develop the simplest and most effective vaccine that induces polyfunctional NNAbs should either of the current efficacy trials fail to improve on RV144. Our overall goals are 1) to develop an ADCC mosaic multivalent Env immunogen to follow an ALVAC-C prime; and 2) to produce ADCC mosaic Env gp120s under current good manufacturing practices (CGMP) conditions, perform toxicity studies, and prepare an investigational new drug application (IND) for testing in an HVTN Phase I clinical trial in man. Overall Specific Aim 1. Develop and produce a trivalent ADCC mosaic Env immunogen that can follow an ALVAC-C prime and test them in the Animal Core in an ADCC mediating NNAb-unmutated common ancestor (UCA) VH + VL mouse model and in a transmitted/founder (TF) tier 2, R5 SHIV rhesus macaque study (RMs) (Drew Weissman, Project Lead; Barton Haynes, Co-I) Overall Specific Aim 2. Produce CGMP trivalent ADCC mosaic mRNA gp120 immunogens. (Thomas Denny Project Lead; Maureen Maughan, Project Co-I) .