Design Of Immunogens

基于我们对基于棘波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，禁用这些逃避机制。这种抵抗力较弱的修饰免疫原可能会产生更广泛的中和抗体。我们还设计了蛋白质支架技术，作为呈现广泛中和抗体表位的结构模拟的一种手段，以帮助它们重新激发。支架可以是非同源蛋白质，通过对整个蛋白质数据库(PDB)的结构搜索来鉴定。或者，支架可以是结构相似但抗原性不同于HIV-1包膜糖蛋白的同源蛋白。脚手架的另一种替代方法是“重新铺设表面”，即在免疫的“初始”和“增强”阶段之间改变分子的表面，该表面不参与引发所需的反应。我们还开始将表位模拟物与高免疫原性载体蛋白偶联，或在自组装纳米颗粒的背景下展示表位模拟物，其免疫原性远远高于单价甚至三价免疫原。 除了这些“设计者免疫原”，我们还一直在研究广泛中和抗体的B细胞个体发育的见解如何识别免疫可能影响的诱导过程中的困难步骤；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所需的特定发育过程的理解，并通过基于抗体谱系的设计在普通人群中“重新诱导”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.