Combinatorial and computational design of bnAb mRNA vaccines for HIV

HIV bnAb mRNA 疫苗的组合和计算设计

基本信息

批准号：
10592273
负责人：
DANIEL G ANDERSON
金额：
$ 78.54万
依托单位：
MASSACHUSETTS INSTITUTE OF TECHNOLOGY
依托单位国家：
美国
项目类别：
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/10592273
关键词：
Address Adjuvant Affinity Animal Model Antibodies Antibody Formation Antibody titer measurement 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 Transcription 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 Stimulation 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 manufacture 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

Address Adjuvant Affinity Animal Model Antibodies Antibody Formation Antibody titer measurement 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 Transcription 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 Stimulation 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 manufacture 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

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项目摘要

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.

许多艾滋病毒疫苗候选者的临床试验失败了，因为它们无法引起对艾滋病毒挑战。在许多HIV+个体中已经确定了广泛中和抗体（BNAB）控制良好的病毒水平，这些BNAB靶向含有相对构成病毒的保留的表位菌株。人们认为，针对各种HIV病原体的BNAB可能具有有效的效率。因此，人们普遍认为诱导有效免疫响应的系统，包括在人类可能是有效的艾滋病毒疫苗，并有助于减轻包膜蛋白质中广泛的遗传多样性和艾滋病毒相关的高突变率。但是，开发一种可以在体内产生这些bnabs生产的疫苗已被证明是极其的具有挑战性的。这可能是由于产生BNAB所需的复杂亲和力成熟过程。免疫方案通常会施用单剂量的抗原（素剂量），有时会进行“增强”剂量几周后交付。在传统的推注免疫中，淋巴结中存在的抗原的半衰期是通常比生发中心开始产生较高亲和力IgG抗体的时间尺度短初始IgM响应（〜18小时）。相比之下，自然感染暴露于免疫系统升级的抗原和几天到几周的炎症，导致形成具有动态抗原表现的生发中心。这生发中心的生态位还支持抗原呈现细胞的激活，T卵泡辅助细胞以及适当的细胞因子信号传导产生BNAB。开发有效的BNAB，复杂的疫苗接种技术很可能可能需要更紧密地模拟自然感染和自然BNAB形成。我们认为，要开发成功的艾滋病毒疫苗，研究人员必须旨在设计更精致和仿生的疫苗疫苗。因此，生物工程疫苗应同时考虑三个关键参数。 1）交付适当选择的抗原，2）有利的抗原表达动力学，3）控制免疫激素生发中心。我们相信淋巴结针对计算设计的mRNA抗原的目标输送通过计算优化免疫化给药的免疫刺激性脂质纳米颗粒（mRNA LNP）协议将以独特的方式解决这三个方面。此外，Translate Bio将提供专业知识 mRNA治疗的制造考虑因素。由于对mRNA结构的修改可能会影响mRNA 抗原翻译，稳定性和免疫原性，我们的翻译合作伙伴的输入（翻译生物）将使我们能够开发具有潜在商业开发途径的疫苗。该R61/R33提案结合了我们的专业知识计算抗原设计，HIV免疫学，联合化学和mRNA的商业化疗法开发新的HIV mRNA疫苗候选者。