Resistance to influenza antibodies Broadly neutralizing human antibodies (bnAbs) to the stem of hemagglutinin (HA), a trimeric glycoprotein found on the surface of influenza viruses, are valuable therapeutics and can guide the development of universal influenza vaccines. For their use in therapy development, it is important to understand the extent to which HA stem variants with resistance to bnAbs can develop. Wu et al. used saturation mutagenesis combined with next-generation sequencing to systematically search for resistance mutations to prototypic bnAbs in two influenza subtypes, H3 and H1. They found that the genetic barrier to resistance to stem bnAbs was low for the H3 subtype but higher for the H1 subtype. The ability of H3 to develop resistance to bnAbs presents a challenge in the development of a universal influenza vaccine. Science, this issue p. 1335 Resistance to broadly neutralizing hemagglutinin stem antibodies varies substantially between influenza subtypes. 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.

中文翻译：

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H3 和 H1 流感病毒对 HA 干抗体耐药的不同遗传障碍


对流感抗体的抗性 针对血凝素 (HA) 茎部的广泛中和人类抗体 (bnAb)（一种在流感病毒表面发现的三聚体糖蛋白）是有价值的治疗方法，可以指导通用流感疫苗的开发。对于其在治疗开发中的应用，了解具有 bnAb 抗性的 HA 干变体的发展程度非常重要。吴等人。使用饱和诱变与下一代测序相结合，系统地寻找两种流感亚型 H3 和 H1 中原型 bnAb 的耐药突变。他们发现，H3 亚型的茎 bnAb 抗性遗传障碍较低，但 H1 亚型的遗传障碍较高。 H3 对 bnAb 产生耐药性的能力对通用流感疫苗的开发提出了挑战。科学，本期第 14 页。第 1335 部分针对高度保守的流感血凝素 (HA) 干区的广泛中和人类抗体 (bnAb) 的发现和表征有助于人们考虑通用流感疫苗。然而，还需要更彻底地评估干 bnAb 的抗性潜力。使用深度突变扫描，重点关注表位残基，我们发现，由于 HA 茎的结构差异，H3 亚型对茎 bnAb 的抗性遗传障碍较低，但 H1 亚型的遗传障碍要高得多。在自然传播的菌株中可以观察到 H3 中的几种强抗性突变，并且不会降低体外病毒适应性和体内致病性。 这项研究凸显了开发真正通用流感疫苗的潜在挑战。