Flu-BPD, AstraZeneca, Liverpool, UK.
Flu-BPD, AstraZeneca, Liverpool, UK.
Vaccine. 2019 Jul 26;37(32):4543-4550. doi: 10.1016/j.vaccine.2019.06.016. Epub 2019 Jul 3.
During the 2013-2014 influenza season, the quadrivalent live attenuated influenza vaccine (QLAIV), had lower than expected vaccine effectiveness (VE) against circulating A/H1N1pdm09 viruses in the USA. The underlying reason proposed for this was that the A/H1N1pdm09 vaccine strain, A/California/07/2009 (A/CA09), had a thermally unstable haemagglutinin (HA) protein. Consequently, a new A/H1N1pdm09 candidate strain, A/Bolivia/559/2013 (A/BOL13), was developed for inclusion in the 2015-2016 QLAIV. A key parameter for selection of A/BOL13 was its more thermostable HA phenotype compared with A/CA09. During the 2015-2016 season, QLAIV containing A/BOL13 was found in some studies to have improved, but still with suboptimal, VE against circulating A/H1N1pdm09 viruses and was not recommended for use by the CDC in the US market in the 2016-2017 influenza season. This suggested that improved HA thermostability had not entirely resolved the reduced VE observed. One hypothesis for this was that, by improving thermostability, the A/BOL13 HA protein had been over-stabilised, compromising its activation at the low endosomal pH required for successful viral entry. Here we demonstrate that, while the A/BOL13 HA protein is more stable than that of A/CA09, its thermal and pH stability were comparable with historically efficacious LAIV strains, suggesting that the HA had not been over-stabilised. Furthermore, studies simulating potential heat exposure during distribution by exposing QLAIV nasal sprayers to 33 °C for 4 h showed that, while remaining within product specification, A/CA09 viral potency was statistically decreased after 12 weeks at 2-8 °C. These data suggest that although unfavourable HA protein stability may have contributed to the reduced VE of A/CA09 in 2013-2014, it was unlikely to have affected A/BOL13 in 2015-2016. We conclude that HA stability was not the primary cause of the reduced effectiveness of LAIV against A/H1N1pdm09 viruses in the 2013-2014 and 2015-2016 seasons.
在 2013-2014 年流感季节，四价流感减毒活疫苗（QLAIV）对美国流行的 A/H1N1pdm09 病毒的疫苗有效性（VE）低于预期。提出的根本原因是 A/H1N1pdm09 疫苗株 A/加利福尼亚/07/2009（A/CA09）的血凝素（HA）蛋白具有不稳定的热稳定性。因此，开发了新的 A/H1N1pdm09 候选株 A/玻利维亚/559/2013（A/BOL13），用于 2015-2016 年 QLAIV。选择 A/BOL13 的一个关键参数是与 A/CA09 相比，其具有更稳定的热 HA 表型。在 2015-2016 季节，一些研究发现含有 A/BOL13 的 QLAIV 对循环的 A/H1N1pdm09 病毒的 VE 有所提高，但仍不理想，因此美国疾病预防控制中心不建议在美国市场 2016-2017 流感季节使用。这表明，HA 热稳定性的提高并没有完全解决观察到的 VE 降低的问题。对此的一个假设是，通过提高热稳定性，A/BOL13 HA 蛋白被过度稳定化，从而破坏了其在成功进入病毒所需的低内体 pH 下的激活。在这里，我们证明虽然 A/BOL13 HA 蛋白比 A/CA09 更稳定，但它的热稳定性和 pH 稳定性与历史上有效的 LAIV 株相当，这表明 HA 没有被过度稳定。此外，通过将 QLAIV 鼻喷雾剂暴露于 33°C 4 小时来模拟分配过程中潜在的热暴露的研究表明，尽管仍在产品规格范围内，但在 2-8°C 下放置 12 周后，A/CA09 病毒效价具有统计学意义降低。这些数据表明，尽管不利的 HA 蛋白稳定性可能导致 2013-2014 年 A/CA09 的 VE 降低，但在 2015-2016 年不太可能影响 A/BOL13。我们得出的结论是，HA 稳定性不是 LAIV 对 2013-2014 年和 2015-2016 年 A/H1N1pdm09 病毒有效性降低的主要原因。
