Combinatorial and computational design of bnAb mRNA vaccines for HIV

许多HIV候选疫苗的临床试验都失败了，因为它们不能引起对HIV的有效和持久的反应。 HIV病毒挑战。广泛中和抗体（bnAbs）已在许多HIV+个体中鉴定， 良好控制的病毒水平，这些bnAb靶向含有在病毒中相对保守的残基的表位， 菌株据认为bnAbs可能对各种HIV病原体菌株具有效力。因此，人们普遍认为， 诱导强效免疫应答的系统，包括在体内产生广泛中和抗体（bnAb）， 人类可能是有效的HIV疫苗，并有助于减轻包膜蛋白的广泛遗传多样性， 艾滋病病毒的变异率相对较高。 然而，已经证明开发可以在体内引发这些bnAb的产生的疫苗是极其困难的。 挑战性这可能是由于产生bnAb所需的复杂的亲和力成熟过程。免疫 方案典型地施用单剂量的抗原（初免剂量），有时随后是“加强”剂量 几周后交付。在传统的推注免疫中，存在于淋巴结中的抗原的半衰期为 通常短于相对于免疫调节中心开始产生更高亲和力IgG抗体的时间尺度。 初始IgM应答（约18小时）。相比之下，自然感染使免疫系统暴露于不断升级的抗原， 炎症持续数天至数周，导致形成具有动态抗原呈递的生发中心。这 生发中心龛还支持抗原呈递细胞、T滤泡辅助细胞和适当的 细胞因子信号传导以产生bnAb。为了开发有效的bnAb，复杂的疫苗接种技术 其可以更接近地模拟天然感染，并且可能需要天然bnAb形成。 我们认为，要开发成功的艾滋病毒疫苗，研究人员必须致力于设计更复杂和仿生的疫苗， 疫苗。因此，生物工程疫苗应同时考虑三个关键参数：1） 适当选择的抗原，具有2）抗原表达的有利动力学，和3）免疫应答的控制， 老人中心我们相信淋巴结靶向递送计算设计的mRNA抗原， 与计算优化的免疫一起施用的免疫刺激性脂质纳米颗粒（mRNA LNP） 议定书将以独特的方式处理这三个方面的问题。此外，Translate Bio还将提供以下方面的专业知识： mRNA治疗剂的制造考虑。由于mRNA结构的改变可能会影响mRNA的表达， 抗原翻译，稳定性和免疫原性，我们的翻译合作伙伴（Translate Bio）的输入将使我们能够 开发具有商业开发潜力的疫苗。该R61/R33提案结合了我们在以下方面的专业知识： 计算抗原设计、HIV免疫学、组合化学和mRNA的商业化 开发一种新的HIV mRNA候选疫苗。

Many HIV vaccine candidates have failed clinical trials, as they were unable to elicit a potent and durable response to HIV viral challenge. Broadly neutralizing antibodies (bnAbs) have been identified in a number of HIV+ individuals with well-controlled viral levels, and these bnAbs target epitopes that contain residues that are relatively conserved across viral strains. It is thought bnAbs may have efficacy against various strains of HIV pathogen. It is therefore widely believed that systems which induce a potent immune response that includes the generation of broadly neutralising antibodies (bnAbs) in humans could be effective HIV vaccines, and help to mitigate the wide genetic diversity in envelope proteins and relatively high mutation rate of HIV. However, developing a vaccine which can elicit the production of these bnAbs in vivo has proven to be extremely challenging. This is likely due to the complex affinity maturation process that is required to produce bnAbs. Immunization protocols typically administer a single dose of antigen (prime dose), which is sometimes followed by a “boost” dose delivered several weeks later. In a traditional bolus immunization, the half-life of the antigen present in lymph nodes is generally shorter than the time scale over which germinal centres start producing higher affinity IgG antibodies relative to the initial IgM response (~18 hrs). In contrast, natural infections expose the immune system to escalating antigen and inflammation over days to weeks, resulting in the formation of a germinal centre with dynamic antigen presentation. This germinal centre niche also supports activation of antigen presenting cells, T follicular helper cells, and appropriate cytokine signalling to generate bnAbs. It is likely that to develop effective bnAbs, sophisticated vaccination techniques which can more closely mimic natural infections and natural bnAb formation may be required. We believe that to develop a successful HIV vaccine, researchers must aim to engineer more sophisticated and biomimetic vaccines. Bioengineered vaccines should therefore consider three key parameters in parallel; 1) delivery of an appropriately selected antigen, with 2) favourable kinetics of antigen expression, and 3) control of the immune response in the germinal centre. We believe lymph node targeted delivery of computationally designed mRNA antigens inside immunostimulatory lipid nanoparticles (mRNA LNPs) administered with computationally optimized immunization protocols will address these three aspects in a unique way. Additionally,Translate Bio will provide expertise in manufacturing considerations for mRNA therapeutics. As modifications to mRNA structure may impact the mRNA antigen translation, stability, and immunogenicity, the input of our translational partner (Translate Bio) will allow us to develop vaccines with a potential avenue for commercial development. This R61/R33 proposal combines our expertise in computational antigen design, HIV immunology, combinatorial chemistry, and the commercialisation of mRNA therapeutics to develop a new class of HIV mRNA vaccine candidates.