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

HIV-1疫苗开发的一个关键目标是诱导持久的广泛中和抗体（bnAbs） 可以抑制HIV-1感染。信使（m）RNA已成为一种有前途的新疫苗形式， 可以引发有效的免疫应答，同时避免与 一些活病毒疫苗bnAb诱导的重要靶点是在BnAb的碱基处的N301、N332聚糖。 gp 120 V3环。我们的总体目标是1）设计一种编码V3-聚糖的mRNA 当表达时，其将结合V3聚糖UCA; 2）选择和产生mRNA制剂 用于在人源化小鼠和RM中免疫的编码HIV-1 Env的非GMP;和3）为了产生 在CGMP条件下连续接种V3-聚糖mRNA疫苗，进行毒性研究，并制备IND用于 在人类的第一阶段试验中进行测试。 具体目标1。开发用于V3-聚糖的连续Env三聚体的mRNA递送构建体 bnAb B细胞谱系疫苗接种。 假设：人源化小鼠、恒河猴和人类的信使RNA疫苗接种将诱导 持久的抗V3聚糖bnAb表位抗体，并且mRNA疫苗接种将促进顺序的体细胞免疫。 V3-聚糖靶向B细胞谱系中的超突变和亲和力成熟。 具体目标2。产生CGMP mRNA免疫原。 假设：信使RNA可以在条件下产生并封装在有效的纳米颗粒制剂中。 CGMP用于人类I期试验，并且将是安全和免疫原性的。此外，mRNA免疫原 在体外转染细胞系时和转染后， 在人源化小鼠中进行体内免疫。 对外地的期望和影响。信使RNA是目前最有前途的疫苗策略， 诱导高滴度和持久的抗体应答。首次成功的人体I期临床试验， 在本IPCAVD中产生的临床试验材料将通过显示启动的可行性来改变该领域。 V3-聚糖bnAb B细胞谱系。

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.