Yang Leerang, Van Beek Matthew, Wang Zijun, Muecksch Frauke, Canis Marie, Hatziioannou Theodora, Bieniasz Paul D, Nussenzweig Michel C, Chakraborty Arup K
Departments of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139.
Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065, USA.
bioRxiv. 2022 Aug 25:2022.08.24.505127. doi: 10.1101/2022.08.24.505127.
The Omicron variant of SARS-CoV-2 evades neutralization by most serum antibodies elicited by two doses of mRNA vaccines, but a third dose of the same vaccine increases anti-Omicron neutralizing antibodies. By combining computational modeling with data from vaccinated humans we reveal mechanisms underlying this observation. After the first dose, limited antigen availability in germinal centers results in a response dominated by B cells with high germline affinities for immunodominant epitopes that are significantly mutated in an Omicron-like variant. After the second dose, expansion of these memory cells and differentiation into plasma cells shape antibody responses that are thus ineffective for such variants. However, in secondary germinal centers, pre-existing higher affinity antibodies mediate enhanced antigen presentation and they can also partially mask dominant epitopes. These effects generate memory B cells that target subdominant epitopes that are less mutated in Omicron. The third dose expands these cells and boosts anti-variant neutralizing antibodies.
严重急性呼吸综合征冠状病毒2（SARS-CoV-2）的奥密克戎变种能够逃避两剂mRNA疫苗所引发的大多数血清抗体的中和作用，但同一疫苗的第三剂可增加抗奥密克戎中和抗体。通过将计算模型与接种疫苗的人类数据相结合，我们揭示了这一观察结果背后的机制。首剂接种后，生发中心有限的抗原可用性导致反应主要由对免疫显性表位具有高胚系亲和力的B细胞主导，这些表位在类似奥密克戎的变种中发生了显著突变。第二剂接种后，这些记忆细胞的扩增以及向浆细胞的分化塑造了对这类变种无效的抗体反应。然而，在次级生发中心，预先存在的高亲和力抗体介导增强的抗原呈递，并且它们还可以部分掩盖显性表位。这些效应产生了靶向奥密克戎中突变较少的亚显性表位的记忆B细胞。第三剂扩大了这些细胞并增强了抗变种中和抗体。
