Department of Biochemistry, University of Washington, Seattle, WA 98195, USA; Institute for Protein Design, University of Washington, Seattle, WA 98195, USA.
Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Cell Rep. 2023 Dec 26;42(12):113553. doi: 10.1016/j.celrep.2023.113553. Epub 2023 Dec 13.
The receptor-binding domain (RBD) of influenza virus hemagglutinin (HA) elicits potently neutralizing yet mostly strain-specific antibodies. Here, we evaluate the ability of several immunofocusing techniques to enhance the functional breadth of vaccine-elicited immune responses against the HA RBD. We present a series of "trihead" nanoparticle immunogens that display native-like closed trimeric RBDs from the HAs of several H1N1 influenza viruses. The series includes hyperglycosylated and hypervariable variants that incorporate natural and designed sequence diversity at key positions in the receptor-binding site periphery. Nanoparticle immunogens displaying triheads or hyperglycosylated triheads elicit higher hemagglutination inhibition (HAI) and neutralizing activity than the corresponding immunogens lacking either trimer-stabilizing mutations or hyperglycosylation. By contrast, mosaic nanoparticle display and antigen hypervariation do not significantly alter the magnitude or breadth of vaccine-elicited antibodies. Our results yield important insights into antibody responses against the RBD and the ability of several structure-based immunofocusing techniques to influence vaccine-elicited antibody responses.
流感病毒血凝素（HA）的受体结合域（RBD）引发了强大的中和作用，但大多数都是针对特定菌株的抗体。在这里，我们评估了几种免疫聚焦技术增强针对 HA RBD 的疫苗诱导免疫反应功能广度的能力。我们提出了一系列“三接头”纳米颗粒免疫原，这些免疫原展示了来自几种 H1N1 流感病毒 HA 的具有天然样封闭三聚体 RBD。该系列包括高糖基化和高可变变体，这些变体在受体结合位点周围的关键位置包含天然和设计的序列多样性。展示三接头或高糖基化三接头的纳米颗粒免疫原比缺乏三聚体稳定突变或高糖基化的相应免疫原引起更高的血凝抑制（HAI）和中和活性。相比之下，嵌合纳米颗粒显示和抗原高变并不显著改变疫苗诱导的抗体的幅度和广度。我们的结果深入了解了针对 RBD 的抗体反应以及几种基于结构的免疫聚焦技术影响疫苗诱导的抗体反应的能力。
