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.

项目概要 一种有效的 HIV-1 疫苗将能够引发多种抗病毒免疫反应，包括广泛的免疫反应 中和抗体（bnAb）。我们专注于抗 CD4 结合位点 (CD4-BS) bnAb 的诱导， 包括 VRC01 级 bnAb，通过专门设计的 Env 衍生的引导免疫方法 蛋白质免疫原。我们之前报道了 C 进化枝 Env 衍生的免疫原的设计，该免疫原可激活 体内表达 VRC01 类抗体的 bnAb 前体的幼稚 B 细胞。我们还报道了 设计源自进化枝 B Env 的第二种免疫原，当作为第一次加强施用时，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 使用稳定的可溶性三聚体环境 (SOSIP) 混合物进行第二次加强免疫的观察结果 这些 VRC01 B 细胞的成熟接近完全成熟，因此引发的抗体显示 与某些异源 2 级病毒相比，大大提高了交叉中和潜力 第一次加强后产生的抗体。然而，这个成熟过程仍然不完整，抗体 由第二次增强引起的中和反应与完全成熟的人类 VRC01 不表现出相同的中和气息- 从 HIV+ 受试者中分离出的类抗体。我们期望并建议通过实验验证他们的 通过使用这种稳定的环境三聚体混合物进行额外的免疫来完成成熟 (SOSIP)，或这些 SOSIP 的特定子集。我们提案的一个重要方面是我们将比较 VRC01 B 细胞的成熟和抗体反应如何受到免疫原方式的影响 被呈现给免疫系统。具体来说，我们将比较体细胞突变的类型和比率—— 当免疫原施用时，相应抗体的积累和质量 佐剂重组蛋白或通过自我扩增平台（saRNA）在体内表达。其他 我们建议的一个重要方面是，我们不会将我们的工作限制在良好控制的敲入小鼠上，而是 也表达人类 VH/VL 基因的转基因小鼠。因为这些小鼠的 B 细胞功能更好 反映人类的情况，我们期望我们优化的免疫方案不仅会激活更广泛的免疫接种方案 VRC01类抗体的范围比敲入小鼠模型中的要多，但额外类别的抗 CD4-BS 抗体反应也将被引发。