Investigation into the activation of multiple bnAb precursors using structure-designed immunogens and Ig knock-in mice

项目摘要 能够诱导广谱中和抗体(BNAbs)的HIV-1疫苗是一个主要目标。到目前为止，它已经 证明了单一的bNab谱系(VRC01类)可以在人体试验中被特异性激活。抗体 从这项试验中不能中和HIV-1，并且异种顺序免疫被认为是需要的 发展bNAbs。异源序贯免疫已经在临床前被用来产生bNAbs 模特们。虽然从感染者身上分离出的VRC01类抗体可能相当广泛，但其广度限制 对于VRC01类抗体由这些类型的疫苗在人群中诱导的接种策略尚不清楚。因此， 我们正在通过高级蛋白质开发一种替代的bNab血统靶向疫苗(VH1-46类) 新生人免疫球蛋白基因敲入小鼠的工程化方法及评价 VH1-46生殖系抗体。此外，我们正在寻求创新的方法来开发双bNab谱系 靶向疫苗，可以与目前的VRC01类疫苗协同作用。个体血统定位 疫苗可能不能使这些血统完全成熟，因此严重限制了中和的广度。 以及这些疫苗的最终有效性。双谱系靶向可能是第一个bNab成功的关键- 研制出HIV-1疫苗。

Project Summary HIV-1 vaccines that can elicit broadly neutralizing antibodies (bnAbs) are a primary goal. To date, it has been demonstrated that a single bnAb lineage (VRC01-class) can be specifically activated in human trials. Antibodies from this trial do not neutralize HIV-1 and heterologous sequential immunization is thought to be required to develop bnAbs. Heterologous sequential immunization has been employed to generate bnAbs in pre-clinical models. While VRC01-class antibodies isolated from infected individuals can be quite broad, the limit of breadth for VRC01-class antibodies induced by these types of vaccination strategies in people is unknown. Therefore, we are developing an alternative bnAb lineage targeting vaccine (VH1-46 class) through advanced protein engineering approaches and assessment in newly generated human immunoglobulin knock-in mice harboring VH1-46 germline antibodies. Further, we are pursuing innovative approaches to develop a dual bnAb lineage targeting vaccine which could synergize with current VRC01-class vaccines. Individual lineage targeting vaccines may not succeed at fully maturating these lineages, thus severely limiting the neutralization breadth and ultimate effectiveness of these vaccines. Dual lineage targeting may be critical for success of the first bnAb- eliciting HIV-1 vaccine.