Guiding the maturation of anti-CD4-BS bnAbs through sequential heterologous Env immunization

通过序贯异源 Env 免疫指导抗 CD4-BS bnAb 的成熟

• 批准号: 10849963
• 负责人: Leonidas Stamatatos
• 金额: $ 58.93万
• 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: 2023-09-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10849963
• 关键词: Adjuvant; Affect; Antibodies; Antibody Binding Sites; Antibody Response; Antigens; B cell repertoire; B-Cell Activation; B-Cell Antigen Receptor; B-Lymphocytes; Binding; Binding Sites; Development; Genes; Growth; HIV; HIV-1; HIV-1 vaccine; Human; Immune; Immune response; Immune system; Immunization; Immunologics; Infection; Knock-in Mouse; Light; Messenger RNA; Methodology; Mus; Mutate; Pathway interactions; Process; Proteins; Protocols documentation; Recombinant Proteins; Reporting; Secondary Immunization; Somatic Mutation; Surface; Transgenic Mice; Vaccines; Viral; Virus; Work; design; improved; in vivo; mouse model; neutralizing antibody; response

PROJECT SUMMARY An effective HIV-1 vaccine will be one that elicits diverse anti-viral immune responses, including broadly neutralizing antibodies (bnAbs). We are focused on the elicitation of anti-CD4-binding site (CD4-BS) bnAbs, including VRC01-class bnAbs, through a guided immunization approach with specifically designed Env-derived protein immunogens. We previously reported on the design of a clade C Env-derived immunogen that activates naïve B cells expressing the bnAb precursors of VRC01-class antibodies in vivo. We also reported on the design of a second immunogen derived from a clade B Env that, when administered as a 1st boost, increases the maturation of the emerging VRC01 B cell responses. Our current proposal is based on our very recent observations that a 2nd booster immunization with a cocktail of stabilized soluble trimeric Envs (SOSIPs) drives the maturation of these VRC01 B cells closer to their full maturation, so that the elicited antibodies display vastly improved cross-neutralizing potentials against certain heterologous, tier 2 viruses as compared to the antibodies elicited after the 1st boost. However, this maturation process is still incomplete, and the antibodies elicited by the 2nd boost do not display the same breath of neutralization as the fully matured human VRC01- class antibodies isolated from HIV+ subjects. We expect, and propose to validate experimentally, that their maturation will be completed with additional immunizations with this cocktail of stabilized Env trimers (SOSIPs), or a specific subset of these SOSIPs. An important aspect of our proposal is that we will compare how the maturation of the VRC01 B cell and antibody responses may be affected by the way the immunogens are presented to the immune system. Specifically, we will compare the type and rates of somatic mutation- accumulation and the quality of the corresponding antibodies, when the immunogens are administered as adjuvanted recombinant proteins or expressed in vivo by a self-amplifying platform (saRNA). Another important aspect of our proposal is that we will not limit our work to well-controlled knock-in mice, but transgenic mice that express human VH/VL genes, as well. Because the B cell repertoire of these mice better reflect that of humans, we expect that our optimized immunization schema will not only activate a broader range of VRC01-class antibodies than it does in the knock-in mouse models, but that additional classes of anti- CD4-BS antibody responses will also be elicited.

项目摘要 有效的HIV-1疫苗将是引起潜水员抗病毒免疫调查的一种疫苗，包括广泛 中和抗体（BNAB）。我们专注于抗CD4结合位点（CD4-BS）BNAB的启发， 包括VRC01级的BNAB，通过带有特定设计的Env衍生的指导免疫抑制方法 蛋白质免疫原。我们以前报道了激活的进化枝C源性免疫原的设计 幼稚的B细胞表达体内VRC01类抗体的BNAB前体。我们还报告了 从进化枝B env中得出的第二次免疫原的设计，当作为第一个提升时给药时，会增加 新兴VRC01 B细胞反应的成熟。我们当前的建议是基于我们最近的 观察到第二次助推器免疫，并用稳定的固体三聚合物Envs（SOSIP）驱动器鸡尾酒进行免疫接种 这些VRC01 B细胞的成熟度更接近它们的完整成熟，以使引起的抗体显示 与某些异源，第2层病毒相比 第一个提升后引起的抗体。但是，这种成熟过程仍然不完整，抗体 第二次提升引起的没有表现出与完全成熟的人VRC01-相同的神经化呼吸 从HIV+受试者分离的类抗体。我们期望并建议通过实验验证他们的 这款稳定的Env Trimers鸡尾酒将通过其他免疫接种完成成熟 （SOSIPS），或这些SOSIP的特定子集。提案的一个重要方面是我们将比较 VRC01 B细胞和抗体反应的成熟如何受到免疫原子的影响 呈现给免疫系统。具体而言，我们将比较体细胞突变的类型和速率 - 当免疫原施用为相应抗体的积累和质量 调整后的重组蛋白或通过自我扩增平台（SARNA）在体内表达。其他 提案的重要方面是，我们不会将工作限制在控制良好的敲入小鼠中，而是 表达人VH/VL基因的转基因小鼠。因为这些小鼠的B细胞曲目更好 反映人类的反映，我们期望我们优化的免疫策略不仅会激活更广泛的 VRC01级抗体的范围比在敲击小鼠模型中所含量比 CD4-BS抗体反应也将引起。