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.

摘要项目一 我们报道了一种种系靶向重组 (rec) HIV-1 Env 衍生免疫原的设计， 426c.Mod.Core-C4b，激活表达种系 VRC01 类 BCR 的幼稚 B 细胞，并处于“增强剂”状态 rec 蛋白免疫原 HxB2.WT.Core-C4b，可促进 VRC01 类抗体的成熟 然而，这种成熟是由 426c.Mod.Core-C4b 引起的，并且是不完全的和额外的免疫。 尚未确定的异源环境将是完成成熟过程所必需的，从而导致 生产广泛中和 VRC01 类抗体需要鉴定此类 Env。 为了加快这一过程，我们正在探索替代疫苗接种方法。 rec 蛋白质免疫，例如自扩增 RNA (saRNA) 疫苗平台提供的 RNA 疫苗。 与rec蛋白免疫原相比有几个优点，因为RNA免疫原序列可以很容易地修改， 它们更容易生产，并且不需要大量的纯化步骤，而且数量较少。 它们价格昂贵且符合 GMP 生产速度更快，而且不需要佐剂，但到目前为止，情况并不多。 已知 saRNA 疫苗和疫苗如何引发抗 Env B 细胞和抗体反应的质量 为了解决这一点，在这个科学项目一中，我们将比较佐剂化的rec Env蛋白免疫原。 表征 426c.Mod.Core-C4b 种系靶向引起的 VRC01 B 细胞和抗体反应 当通过 saRNA 疫苗递送时，Env 和 HxB2.WT.Core-C4b 会增强 Env。我们将比较这些疫苗。 我们还将对相应的佐剂rec蛋白纳米颗粒产生的反应进行研究。 检查 saRNA 疫苗表达的免疫原的形式（无论是分泌蛋白还是 纳米粒子或膜锚定蛋白）影响 VRC01 B 细胞和抗体的质量 此外，VRC01 B 细胞和抗体反应的质量将在 以下三种初免-加强模式：（a）saRNA初免和saRNA加强；（b）saRNA初免和rec蛋白 加强；和（c）rec 蛋白初免和 saRNA 加强。 我们依靠我们在 VRC01 类抗体、Env 免疫原设计、BCR 分析和抗体方面的专业知识 表征以及我们在 saRNA 疫苗模式方面的专业知识对于我们的研究至关重要。 IPCVD 赠款的目标。