Messenger RNA immunogens for initiation of HIV V3-glycan neutralizing B cell lineages

开发HIV-1疫苗的一个关键目标是诱导持久的广谱中和抗体(BNAbs)。 可以抑制HIV-1感染的药物。Messenger(M)RNA已经成为一种很有前途的新疫苗模式 可以激发强大的免疫反应，同时避免与以下相关的安全风险和抗媒介免疫 一些活病毒疫苗。诱导bNab的重要靶点是N301、N332糖链 Gp120 V3环路。我们在这项资助中的总体目标是：1)设计一种编码V3-糖链的信使核糖核酸 当表达时，将与V3糖链UCA结合的模拟表位；2)选择并产生mRNA制剂 编码HIV-1 env的非GMP，用于在人源化小鼠和RMS中免疫；以及3)生产 在CGMP条件下连续接种V3-葡聚糖mRNA疫苗，进行毒性研究，并为 在人身上进行I期试验的测试。 总体目标1.为V3-葡聚糖序列环境三聚体开发信使核糖核酸递送载体 BNab B细胞系疫苗接种。 假设：人源化小鼠、猕猴和人类的Messenger RNA疫苗将诱导 长效抗V3糖蛋白bNab表位抗体和mRNA免疫将促进序贯体细胞 以V3-葡聚糖为靶点的B细胞系的超突变和亲和力成熟。 总的特异性目标2。产生CGMP基因的免疫原。 假设：信使RNA可以在以下条件下生产并包裹在有效的纳米颗粒配方中 CGMP用于人类I期试验，将是安全和免疫原性的。此外，信使核糖核酸免疫原 选择用于生产CGMP的细胞在体外和以后的细胞系中将产生稳定的环境三聚体 人源化小鼠体内免疫。 对赛场的期望和影响。信使RNA是目前最有希望的疫苗策略 诱导高滴度和持久的抗体反应。在MAN I期临床试验中首次成功 在这次IPCAVD中产生的临床试验材料将改变这一领域，展示了启动 V3-葡聚糖bNab B细胞系。

A key goal of HIV-1 vaccine development is to induce long-lasting broadly neutralizing antibodies (bnAbs) that can inhibit HIV-1 infection. Messenger (m) RNA has emerged as a promising new vaccine modality that can elicit potent immune responses, while avoiding the safety risks and anti-vector immunity associated with some live virus vaccines. Important targets for bnAb induction are N301, N332 glycans at the base of the gp120 V3 loop. Our overall goals in this grant are 1) To design an mRNA that encodes a V3-glycan mimetope that, when expressed, will bind a V3 glycan UCA; 2) To select and produce mRNA formulations non-GMP that encode HIV-1 Envs for immunization in humanized mice and RMs; and 3) To produce the sequential V3-glycan mRNA vaccine under CGMP conditions, perform toxicity studies, and prepare an IND for testing in a Phase I trial in man. Overall Specific Aim 1. Develop mRNA delivery constructs for sequential Env trimers for V3-glycan bnAb B cell lineage vaccinations. Hypotheses: Messenger RNA vaccination of humanized mice, Rhesus macaques and humans will induce long-lasting anti-V3 glycan bnAb epitope antibodies, and mRNA vaccination will promote sequential somatic hypermutations and affinity maturation in V3-glycan targeted B cell lineages. Overall Specific Aim 2. Produce CGMP mRNA immunogens. Hypotheses: Messenger RNAs can be produced and encapsulated in potent nanoparticle formulations under CGMP for use in human Phase I trials, and will be safe and immunogenic. Moreover, the mRNA immunogens selected for CGMP production will produce stable Env trimers upon transfection of cell lines in vitro and after immunization in vivo in humanized mice. Expectations and Impact on the Field. Messenger RNAs are the current most promising vaccine strategy for inducing high-titered and long-lasting antibody responses. A successful first in man Phase I clinical trial with clinical trials materials produced in this IPCAVD will change the field by showing the plausibility of initiation of V3-glycan bnAb B cell lineages.