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.

摘要概述 我们的IPCAVD项目资助的主要目标是评估人类自我扩增的mRNA （saRNA）疫苗，其表达两种HIV-1 Env衍生的蛋白免疫原，所述免疫原激活并 启动VRC 01类B细胞受体（BCR）的成熟。第一种免疫原， 426c.Mod.Core，被特别设计为以高亲和力结合未突变的（种系， gl）在幼稚B细胞表面上表达的那些BCR的形式。第二 免疫原HxB2.WT.Core虽然不能结合生殖系VRC 01类BCR，但结合 VRC 01类BCR被426c.Mod.Core激活，并积累了一些 体细胞突变。因此，用HxB2.WT.Core的加强免疫促进了免疫应答。 由426c.Mod.Core引发的VRC 01类抗体的成熟。这些观察结果 用这两种免疫原的佐剂化重组（rec）形式制备。作为mRNA- 的疫苗成本更低，更容易GMP生产，重组蛋白，我们 相信他们将加速HIV-1 Env衍生的临床前和临床评价， 免疫原在此，我们建议首先临床前比较VRC 01 B细胞和抗体 当通过saRNA疫苗递送给那些受试者时，这两种Env免疫原引起的应答 由相应的辅助REC蛋白引起。然后，如果结果是有希望的， 表达两种免疫原的saRNA疫苗将通过GMP生产，用于临床 评价由于426c.Mod.Core佐剂化rec蛋白将在临床上进行评价（I期）， 2022年春季（HVTN 301），HxB2.WT.Core rec蛋白目前正在GMP 为2023年的后续I期临床评价而制造，我们将处于独特的地位， 为了比较VRC 01 B细胞和用这些免疫的人引起的抗体应答， 两种HIV-1 Env衍生的免疫原，当作为佐剂化的rec蛋白和作为 由saRNA疫苗表达。为了实现我们在IPCAVD赠款中的目标， 我们在免疫原设计和检测方面的专业知识，在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，我们迅速 使用高通量技术对BCR基因进行测序， 模型、我们在saRNA疫苗技术方面的专业知识、我们在开展临床研究方面的独特专业知识 艾滋病毒-1疫苗的测试，参与团体之间的现有合作， 参与者成功管理复杂计划的书面专业知识。