Combinatorial and computational design of bnAb mRNA vaccines for HIV

HIV bnAb mRNA 疫苗的组合和计算设计

• 批准号: 10386924
• 负责人: DANIEL G ANDERSON
• 金额: $ 79万
• 依托单位: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-07 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10386924
• 关键词: Address; Adjuvant; Affinity; Animal Model; Antibodies; Antigen Presentation; Antigen Targeting; Antigen-Presenting Cells; Antigens; B-Lymphocytes; Belief; Biomedical Engineering; Biomimetics; Bolus Infusion; CD8-Positive T-Lymphocytes; CD8B1 gene; Cells; Chemicals; Clinic; Clinical Trials; Clonal Expansion; Collaborations; Complex; Computer Models; Cytokine Signaling; Developing Countries; Development; Dose; Engineering; Epitopes; Evaluation; Formulation; Future; Generations; Genetic Variation; HIV; HIV Antigens; HIV vaccine; HIV-1; HLA-A gene; Half-Life; Helper-Inducer T-Lymphocyte; Human; Immune; Immune response; Immune system; Immunity; Immunization; Immunoglobulin G; Immunoglobulin M; Immunologic Tests; Immunology; Individual; Infection; Inflammation; Kinetics; Knock-in Mouse; Laboratories; Lipids; Machine Learning; Membrane Proteins; Messenger RNA; Methods; Modeling; Modification; Mus; Mutation; Pathway interactions; Pattern; Process; Production; Property; Protocols documentation; RNA vaccination; RNA vaccine; Research Personnel; Scheme; Signal Transduction; Structure; Structure of germinal center of lymph node; System; T cell response; T-Lymphocyte; Tail; Techniques; Testing; Therapeutic; Time; Toxic effect; Transgenic Mice; Translating; Translations; Vaccination; Vaccines; Variant; Viral; adoptive B cell transfer; cell behavior; clinical development; clinical translation; combinatorial; combinatorial chemistry; cross reactivity; design; efficacy validation; env Gene Products; humanized mouse; immune activation; immunogenicity; improved; in vivo; lipid nanoparticle; lymph nodes; mRNA delivery; models and simulation; molecular dynamics; mouse model; nanoformulation; nanoparticle delivery; nanotherapeutic; nanovaccine; neutralizing antibody; next generation; novel; pandemic disease; pathogen; response; targeted delivery; vaccination protocol; vaccine candidate; vaccine development; vaccine efficacy; vaccine evaluation

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.

许多候选艾滋病毒疫苗都失败了临床试验，因为它们无法引起有效和持久的反应 HIV 病毒攻击已在许多 HIV + 患者中发现了广泛中和抗体 (bnAb)。 病毒水平得到良好控制，并且这些 bnAb 靶向的表位含有在病毒中相对保守的残基 人们认为 bnAb 可能对多种 HIV 病原体具有功效。 诱导有效免疫反应的系统，包括在体内产生广泛中和抗体（bnAb） 人类可以成为有效的艾滋病毒疫苗，并有助于减少蛋白质和药物中广泛的遗传多样性。 HIV突变率相对较高。 然而，事实证明，开发一种能够在体内诱导产生这些 bnAb 的疫苗是极其困难的。 这可能是由于生产 bnAb 所需的复杂的亲和力成熟过程。 方案通常施用单剂量抗原（初始剂量），有时随后是“加强”剂量 在传统的推注免疫中，淋巴结中存在的抗原的半衰期是几周后。 通常比生发中心开始产生更高亲和力 IgG 抗体的时间尺度要短 最初的 IgM 反应（约 18 小时）相反，自然感染使免疫系统暴露于不断增加的抗原和 数天至数周的炎症，导致形成具有动态抗原呈递的生发中心。 生发中心生态位还支持抗原呈递细胞、滤泡辅助 T 细胞和适当的抗原呈递细胞的激活 产生 bnAb 的细胞因子信号传导 开发有效的 bnAb 可能需要复杂的疫苗接种技术。 它可以更接近地模拟自然感染，并且可能需要自然的 bnAb 形成。 我们相信，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 因此，生物工程疫苗应同时考虑三个关键参数：1）疫苗的交付； 适当选择的抗原，具有 2) 有利的抗原表达动力学，以及 3) 控制免疫反应 我们相信淋巴结内有计算设计的 mRNA 抗原的靶向传递。 通过计算优化免疫进行免疫刺激脂质纳米粒子（mRNA LNP） 协议将以独特的方式解决这三个方面的问题，Translate Bio 将提供以下方面的专业知识。 mRNA 疗法的生产注意事项。 mRNA 结构的修饰可能会影响 mRNA。 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 该 R61/R33 提案结合了我们在以下领域的专业知识：开发具有潜在商业开发途径的疫苗。 计算抗原设计、HIV 免疫学、组合化学和 mRNA 商业化 开发一类新型 HIV mRNA 候选疫苗的疗法。