Scientific Project One

科学项目一

• 批准号: 10589645
• 负责人: Leonidas Stamatatos
• 金额: $ 107.65万
• 依托单位: FRED HUTCHINSON CANCER CENTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-30 至 2027-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10589645
• 关键词: Acceleration; Address; Adjuvant; Affinity; Antibodies; Antibody Response; Antigens; Autologous; B-Cell Antigen Receptor; B-Lymphocytes; Binding; Bypass; Clinical Trials; Complement 4b; Goals; Grant; HIV-1; HIV-1 vaccine; Immunization; Immunization Schedule; Light; Membrane; Methodology; Modality; Monoclonal Antibodies; Mutate; Predisposition; Process; Production; Protein Secretion; Proteins; RNA; RNA amplification; RNA vaccine; Recombinant Proteins; Recombinants; Reporting; Somatic Mutation; Specificity; Vaccination; Virus; design; env Gene Products; improved; manufacture; nanoparticle; neutralizing antibody; prevent; research clinical testing; response; self assembly; vaccination strategy; vaccine delivery; vaccine platform

ABSTRACT PROJECT ONE We have reported on the design of a germline-targeting recombinant (rec) HIV-1 Env-derived immunogen, 426c.Mod.Core-C4b, that activates naïve B cells that express germline VRC01-class BCRs and on “booster” rec protein immunogen, HxB2.WT.Core-C4b, that improves the maturation of the VRC01-class antibodies elicited by 426c.Mod.Core-C4b. This maturation is, however, incomplete and additional immunizations with heterologous Envs, yet to be identified, will be necessary to complete the maturation process that leads to the production of broadly neutralizing VRC01-class antibodies. The identification of such Envs will require extensive experimentation. To expedite this process, we are exploring alternative vaccination methodologies to rec protein immunizations, such as self-amplifying RNA (saRNA) vaccine platforms. RNA vaccines offer several advantages over rec protein immunogens as the RNA immunogen sequences can easily be modified, they are more easily produced, and they do not require extensive purification steps. Also, they are less expensive and faster to GMP-manufacture and they do not require adjuvants. So far however, not much is known on how the quality of anti-Env B cell and antibody responses elicited by saRNA vaccines and by adjuvanted rec Env protein immunogens compare. To address this point, in this Scientific Project One, we will characterize the VRC01 B cell and antibody responses elicited by the 426c.Mod.Core-C4b germline-targeting Env and the HxB2.WT.Core-C4b boost Env when delivered by saRNA vaccines. We will compare these responses to those generated by the corresponding adjuvanted rec protein nanoparticles. We will also examine whether the form of the immunogen expressed by the saRNA vaccines (either as secreted protein nanoparticles or as membrane-anchored proteins) influences the quality of the VRC01 B cell and antibody responses. In addition, the qualities of the VRC01 B cell and antibody responses will be evaluated in the following three prime-boost modalities: (a) saRNA prime and saRNA boost; (b) saRNA prime and rec protein boost; and (c) rec protein prime and saRNA boost. We propose an accelerated immunization schedule that relies on our expertise on VRC01-class antibodies, Env-immunogen-design, BCR analysis and antibody characterization, as well as our expertise with saRNA vaccine modalities. Our proposed studies are central to the goals of this IPCAVD grant.

抽象项目一 我们已经报道了一种种系靶向重组(Rec)HIV-1env来源免疫原的设计， 426c.Mo.Core-C4b，激活表达种系VRC01类BCR的幼稚B细胞，并在“助推器”上 REC蛋白免疫原HxB2.WT.Core-C4b，可促进VRC01类抗体的成熟 由426c.Mo.Core-C4b激发。然而，这种成熟是不完整的，需要额外的免疫接种。 异源环境尚待鉴定，这将是完成成熟过程所必需的，这将导致 生产广谱中和VRC01类抗体。识别这类环境将需要 广泛的实验。为了加快这一进程，我们正在探索其他疫苗接种方法，以 REC蛋白免疫，如自扩增RNA(SARNA)疫苗平台。RNA疫苗提供了 与REC蛋白免疫原相比有几个优点因为RNA免疫原序列可以容易地被修改， 它们更容易生产，而且不需要大量的提纯步骤。此外，它们也更少 GMP生产成本高、速度快，而且不需要佐剂。然而，到目前为止，还没有多少 已知如何由Sarna疫苗和通过 佐剂rec env蛋白免疫原比较。为了解决这一点，在这个科学项目一中，我们将 426c.Mo.Core-C4b种系靶向诱导的VRC01 B细胞和抗体反应的特征 当通过Sarna疫苗递送时，Env和HxB2.WT.Core-C4b增强了Env。我们将对这些进行比较 对相应佐剂的rec蛋白纳米粒产生的反应。我们还将 检查SARNA疫苗表达的免疫原的形式(无论是作为分泌蛋白 纳米颗粒或作为膜锚定蛋白)影响VRC01B细胞和抗体的质量 回应。此外，VRC01 B细胞的质量和抗体反应将在 以下三种质数-增强模式：(A)Sarna Prime和Sarna Boost；(B)Sarna Prime和rec蛋白质 Boost；和(C)rec蛋白质数和Sarna Boost。我们提出了一个加速免疫时间表， 依靠我们在VRC01类抗体、环境免疫原设计、BCR分析和抗体方面的专业知识 特性，以及我们在SARNA疫苗模式方面的专业知识。我们建议的研究是 这笔IPCAVD赠款的目标。