Design Of Immunogens

基于我们对基于刺突或刺突的体液逃避机制的理解，我们正在努力设计基于刺突的免疫原，这些逃避机制被禁用。这种具有减弱的防御的修饰的免疫原可以引发更广泛的中和抗体。我们还设计了蛋白质支架技术，作为呈现广泛中和抗体的表位的结构模拟物以帮助其重新引发的手段。支架可以是非同源蛋白质，通过整个蛋白质数据库（PDB）的结构搜索进行鉴定。或者，支架可以是同源蛋白，其结构相似，但抗原性不同于HIV-1包膜糖蛋白。支架的替代方案涉及“表面重塑”，其中不参与引发所需应答的分子的表面在免疫的“初免”和“加强”阶段之间改变。我们还开始将表位模拟物偶联到高免疫原性载体蛋白或在自组装纳米颗粒的背景下展示表位模拟物，其具有比单价甚至三价免疫原高得多的免疫原性。 除了这种“设计免疫原”，我们还一直在研究如何从广泛中和抗体的B细胞个体发育中获得见解，以确定可能受免疫影响的激发过程中的困难步骤;这种基于抗体谱系的设计旨在利用我们对目标谱系实现中和和“重新引发”所需的特定发育过程的理解通过基于抗体谱系的设计在一般人群中产生类似的抗体。

Based on our understanding of spike- or envelope-based mechanisms of humoral evasion, we are working to design envelope-based immunogens with these evading mechanisms disabled. Such modified immunogens with weakened defenses may elicit more broadly neutralizing antibodies. We have also devised protein scaffolding technologies, as a means of presenting structural mimics of the epitopes of broadly neutralizing antibodies to assist in their re-elicitation. Scaffolds can be non-homologous proteins, identified through structural searches of the entire Protein Data Bank (PDB). Alternatively, scaffolds can be homologous proteins, which are structurally similar, but antigenically distinct from the HIV-1 envelope glycoproteins. An alternative to scaffolding involves "resurfacing", where the surface of a molecule, not involved in eliciting a desired response, is altered between "prime" and "boost" phases of immunization. We have also begun to couple epitope mimics to highly immunogenic carrier proteins or to display epitope mimics in the context of self-assembling nanoparticles, which have substantially higher immunogenicity than monovalent or even trivalent immunogens. In addition to such "designer immunogens", we have also been investigating how insights from B cell ontogeny of broadly neutralizing antibodies can identify difficult steps in the elicitation process, which might be influenced by immunization; such antibody-lineage based design seeks to exploit our understanding of the specific developmental processes that a target lineage requires to achieve neutralization - and to "re-elicit" similar antibodies in the general population through antibody-lineage based design.