Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.
Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA 92037, USA.
Science. 2020 Jun 19;368(6497):1335-1340. doi: 10.1126/science.aaz5143.
The discovery and characterization of broadly neutralizing human antibodies (bnAbs) to the highly conserved stem region of influenza hemagglutinin (HA) have contributed to considerations of a universal influenza vaccine. However, the potential for resistance to stem bnAbs also needs to be more thoroughly evaluated. Using deep mutational scanning, with a focus on epitope residues, we found that the genetic barrier to resistance to stem bnAbs is low for the H3 subtype but substantially higher for the H1 subtype owing to structural differences in the HA stem. Several strong resistance mutations in H3 can be observed in naturally circulating strains and do not reduce in vitro viral fitness and in vivo pathogenicity. This study highlights a potential challenge for development of a truly universal influenza vaccine.
广谱中和人类抗体（bnAbs）对流感血凝素（HA）高度保守茎区的发现和鉴定，推动了对通用流感疫苗的考虑。然而，对茎部 bnAbs 产生耐药性的可能性也需要更彻底的评估。通过深度突变扫描，重点是表位残基，我们发现 H3 亚型对茎部 bnAbs 的耐药性遗传障碍较低，而由于 HA 茎部结构的差异，H1 亚型的耐药性遗传障碍则大大增加。在自然循环株中可以观察到几个 H3 中的强耐药突变，并且不会降低体外病毒适应性和体内致病性。本研究突出了开发真正通用流感疫苗的一个潜在挑战。
