Combinatorial and computational design of bnAb mRNA vaccines for HIV

许多候选艾滋病毒疫苗都没有通过临床试验，因为他们无法引起对 艾滋病毒病毒挑战。广谱中和抗体(BNAbs)已在一些HIV+患者中被发现 病毒水平得到很好的控制，这些bNAbs针对的是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病原体有疗效。因此，人们普遍认为 诱导包括产生广谱中和抗体(BNAbs)在内的有效免疫反应的系统 人类可以成为有效的艾滋病毒疫苗，并有助于减轻包膜蛋白和 HIV的变异率相对较高。 然而，开发一种能够在体内诱导产生这些bNAbs的疫苗已被证明是极其困难的。 很有挑战性。这可能是由于产生bNAbs所需的复杂亲和力成熟过程所致。免疫接种 治疗方案通常只注射一剂抗原(主要剂量)，有时还会进行一次“强化”注射 几周后交付。在传统的团注免疫中，存在于淋巴结中的抗原的半衰期为 通常比生发中心开始产生高亲和力抗体的时间范围短 初始免疫球蛋白M应答(~18小时)。相比之下，自然感染使免疫系统暴露在不断升级的抗原和 炎症持续数天至数周，导致生发中心的形成，具有动态的抗原递呈。这 生发中心利基还支持抗原提呈细胞、T滤泡辅助细胞和适当的 细胞因子信号转导产生bNAbs。很可能开发出有效的bNAbs，复杂的疫苗接种技术 它可以更接近地模拟自然感染，可能需要自然形成bNab。 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出更复杂、更仿生的疫苗。 疫苗。因此，生物工程疫苗应同时考虑三个关键参数：1)提供 选择适当的抗原，2)有利的抗原表达动力学，3)控制免疫反应 生发中心。我们相信通过计算设计的mrna抗原在体内的淋巴结靶向递送 免疫刺激脂质纳米粒(MRNALNPs)与计算优化免疫 协议将以独特的方式解决这三个方面的问题。此外，Translate Bio将在以下方面提供专业知识 信使核糖核酸疗法的制造考虑。因为对信使核糖核酸结构的修改可能会影响信使核糖核酸 抗原翻译、稳定性和免疫原性，我们翻译伙伴(翻译生物)的投入将使我们能够 开发具有潜在商业开发途径的疫苗。这份R61/R33建议书结合了我们在 计算抗原设计、艾滋病毒免疫学、组合化学和信使核糖核酸的商业化 治疗公司将开发一种新的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.