Design Of Immunogens

基于我们对基于刺突或包膜的体液逃避机制的理解，我们正在努力设计基于包膜的免疫原，使这些逃避机制失效。这种防御能力减弱的免疫原可以引起更广泛的中和抗体。我们还设计了蛋白质支架技术，作为一种呈现广泛中和抗体表位的结构模拟的手段，以协助它们的再激发。支架可以是非同源蛋白，通过整个蛋白质数据库（PDB）的结构搜索确定。或者，支架可以是同源蛋白，其结构相似，但在抗原性上与HIV-1包膜糖蛋白不同。另一种替代支架的方法是“重新表面处理”，即在免疫的“启动”和“增强”阶段之间改变分子表面，而不涉及引发预期反应。我们也开始将表位模拟物偶联到高免疫原性载体蛋白上，或者在自组装纳米颗粒的背景下展示表位模拟物，这比单价甚至三价免疫原具有更高的免疫原性。

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.