Self-amplifying mRNA-based vaccines to elicit VRC01-class bnAbs

基于 mRNA 的自我扩增疫苗可引发 VRC01 级 bnAb

• 批准号: 10589641
• 负责人: Leonidas Stamatatos
• 金额: $ 209.98万
• 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/10589641
• 关键词: Acceleration; Adjuvant; Affinity; Animal Model; Antibodies; Antibody Response; Antigens; B-Cell Antigen Receptor; B-Cell Receptor Binding; B-Lymphocytes; Binding; Clinical; Clinical Protocols; Collaborations; Complex; Cyclic GMP; Development; Fred Hutchinson Cancer Research Center; Goals; Grant; HIV Vaccine Trials Network; HIV-1; HIV-1 vaccine; Health; Human; Human immunodeficiency virus test; Immune response; Immunization; Immunize; Individual; Infection; Infectious Diseases Research; Investigation; Lead; Length; Membrane; Messenger RNA; Mutate; Outcome; Participant; Phase; Phase I Clinical Trials; Positioning Attribute; Production; Property; Proteins; Qualifying; RNA vaccine; Receptor Gene; Recombinant Proteins; Recombinants; Research Institute; Research Project Grants; Self-Examination; Somatic Mutation; Surface; Technology; Testing; Vaccination; Vaccines; Virus; cost; design; env Gene Products; first-in-human; follow-up; immunogenic; immunogenicity; improved; manufacture; mouse model; nanoparticle; neutralizing antibody; pre-clinical; preclinical evaluation; programs; research clinical testing; response; safety testing

ABSTRACT OVERALL The main goal of our IPCAVD Program grant is to evaluate in humans self-amplifying mRNA (saRNA) vaccines that express two HIV-1 Env-derived protein immunogens that activate and initiate the maturation of VRC01-class B cell receptors (BCRs). The first immunogen, 426c.Mod.Core, was specifically designed to bind with high affinity to the unmutated (germline, gl) forms of those BCRs as they are expressed on the surface of naïve B cells. The second immunogen, HxB2.WT.Core, although unable to bind germline VRC01-class BCRs, binds the VRC01-class BCRs that became activated by 426c.Mod.Core and have accumulated some somatic mutations. As a result, the boost immunization with HxB2.WT.Core furthers the maturation of the VRC01-class antibodies elicited by the 426c.Mod.Core. These observations were made with the adjuvanted recombinant (rec) forms of these two immunogens. As mRNA- based vaccines are less costly and more easily GMP-manufactured that rec proteins, we believe that they will accelerate the preclinical and clinical evaluation of HIV-1 Env-derived immunogens. Here, we propose to first compare preclinically the VRC01 B cell and antibody responses elicited by these two Env immunogens when delivered by saRNA vaccines to those elicited by the corresponding adjuvanted rec proteins. And then, if the results are promising, the saRNA vaccines expressing the two immunogens will be GMP-manufactured for clinical evaluation. As the 426c.Mod.Core adjuvanted rec protein will be evaluated clinically (phase I) in the spring of 2022 (HVTN301) and the HxB2.WT.Core rec protein is currently being GMP manufactured for a follow-up phase I clinical evaluation in 2023, we will be in a unique position to compare the VRC01 B cell and antibody responses elicited by humans immunized with these two HIV-1 Env-derived immunogens when delivered as adjuvanted rec proteins and as expressed by saRNA vaccines. To accomplish our goals in this IPCAVD grant we will take advantage of our expertise in immunogen-design and testing, expertise in the analysis of B cell and antibody responses elicited by vaccination and during infection, our ability to rapidly sequence BCR genes using high through put technologies, the availability of appropriate animal models, our expertise in saRNA vaccine technology, our unique expertise in conducting clinical testing of HIV-1 vaccines, the existing collaboration among the participating groups and the documented expertise of the participants to successfully manage complex Programs.

摘要总体 我们的 IPCVD 计划资助的主要目标是评估人类自我扩增 mRNA (saRNA) 疫苗表达两种 HIV-1 Env 衍生蛋白免疫原，可激活和 启动 VRC01 类 B 细胞受体 (BCR) 的成熟。第一个免疫原， 426c.Mod.Core，专门设计用于以高亲和力与未突变（种系、 gl) 这些 BCR 的形式，因为它们在幼稚 B 细胞表面表达。第二个 免疫原 HxB2.WT.Core 虽然无法结合种系 VRC01 类 BCR，但可以结合 由 426c.Mod.Core 激活并积累了一些的 VRC01 级 BCR 体细胞突变。因此，HxB2.WT.Core 的加强免疫进一步促进了 426c.Mod.Core 引发 VRC01 类抗体的成熟。这些观察 是用这两种免疫原的佐剂重组（rec）形式制成的。作为 mRNA- 与rec蛋白相比，基于GMP的疫苗成本更低，更容易制造，我们 相信他们将加速HIV-1 Env衍生的临床前和临床评估 免疫原。在这里，我们建议首先对 VRC01 B 细胞和抗体进行临床前比较 当 saRNA 疫苗递送至这些人时，这两种 Env 免疫原引起的反应 由相应的佐剂rec蛋白引发。然后，如果结果是有希望的， 表达这两种免疫原的 saRNA 疫苗将按照 GMP 生产用于临床 评估。由于 426c.Mod.Core 佐剂 rec 蛋白将在以下国家进行临床评估（第一阶段） 2022 年春季 (HVTN301) 和 HxB2.WT.Core rec 蛋白目前正在进行 GMP 认证 为 2023 年后续 I 期临床评估而制造，我们将处于独特的地位 比较 VRC01 B 细胞和接种这些疫苗的人类引发的抗体反应 两种 HIV-1 Env 衍生的免疫原作为佐剂 rec 蛋白和作为 由saRNA疫苗表达。为了实现我们在 IPCVD 赠款中的目标，我们将采取 凭借我们在免疫原设计和测试方面的专业知识以及 B 细胞分析方面的专业知识 以及疫苗接种和感染期间引起的抗体反应，我们快速反应的能力 使用高通量技术对 BCR 基因进行测序，获得适当的动物 模型、我们在 saRNA 疫苗技术方面的专业知识、我们在进行临床方面的独特专业知识 HIV-1 疫苗的测试、参与团体之间的现有合作以及 记录参与者成功管理复杂项目的专业知识。