Flu-BPD, Biopharmaceuticals Development, R&D, AstraZeneca, Liverpool, UK.
J Gen Virol. 2022 Nov;103(11). doi: 10.1099/jgv.0.001811.
The vaccine effectiveness (VE) of the A/H1N1pdm09 component of the 2017-18 quadrivalent live attenuated influenza vaccine (QLAIV) was improved by performing rational haemagglutinin (HA) mutagenesis. Introducing N125D, D127E, D222G and R223Q substitutions into the HA protein of A/Slovenia/2903/2015 (A/SLOV15) enhanced replicative fitness in primary human nasal epithelial cells (hNECs). This allowed A/SLOV15 to overcome inter-strain competition in QLAIV, resulting in improved VE.During strain development for the 2021-22 QLAIV formulation, A/H1N1pdm09 LAIV viruses containing wild-type (WT) HA and neuraminidase (NA) sequences were found to replicate poorly in embryonated eggs and hNECs. We aimed to enhance replicative fitness via the HA mutagenesis approach that was performed previously for A/SLOV15. Therefore, combinations of these four mutations were introduced into the HA protein of representative 6B.1A-5a.2 viruses, A/Victoria/2570/2019 and A/Victoria/1/2020 (A/VIC1). Replicative fitness of A/VIC1 V7 was improved ~30-fold in eggs and ~300-fold in hNECs relative to its parent, without compromising other critical LAIV characteristics.
通过进行合理的血凝素（HA）突变，2017-18 年四价减毒流感活疫苗（QLAIV）中 A/H1N1pdm09 组分的疫苗有效性（VE）得到了提高。在 A/Slovenia/2903/2015（A/SLOV15）的 HA 蛋白中引入 N125D、D127E、D222G 和 R223Q 取代物，增强了其在原代人鼻上皮细胞（hNEC）中的复制适应性。这使得 A/SLOV15 能够克服 QLAIV 中的株间竞争，从而提高了 VE。在 2021-22 年 QLAIV 配方的菌株开发过程中，发现含有野生型（WT）HA 和神经氨酸酶（NA）序列的 A/H1N1pdm09 LAIV 病毒在鸡胚和 hNEC 中复制不良。我们旨在通过之前针对 A/SLOV15 进行的 HA 突变方法来提高复制适应性。因此，将这四个突变的组合引入到代表 6B.1A-5a.2 病毒的 HA 蛋白中，即 A/Victoria/2570/2019 和 A/Victoria/1/2020（A/VIC1）。与亲本相比，A/VIC1 V7 在鸡蛋中的复制适应性提高了约 30 倍，在 hNEC 中的复制适应性提高了约 300 倍，而不影响其他关键的 LAIV 特征。
