Graduate Program in Biomaterials Science and Engineering, College of Life Science and Biotechnology, Yonsei University, Seoul, South Korea.
Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul, South Korea.
Front Immunol. 2021 Dec 2;12:779223. doi: 10.3389/fimmu.2021.779223. eCollection 2021.
Influenza virus infections can cause a broad range of symptoms, form mild respiratory problems to severe and fatal complications. While influenza virus poses a global health threat, the frequent antigenic change often significantly compromises the protective efficacy of seasonal vaccines, further increasing the vulnerability to viral infection. Therefore, it is in great need to employ strategies for the development of universal influenza vaccines (UIVs) which can elicit broad protection against diverse influenza viruses. Using a mouse infection model, we examined the breadth of protection of the caspase-triggered live attenuated influenza vaccine (ctLAIV), which was self-attenuated by the host caspase-dependent cleavage of internal viral proteins. A single vaccination in mice induced a broad reactive antibody response against four different influenza viruses, H1 and rH5 (HA group 1) and H3 and rH7 subtypes (HA group 2). Notably, despite the lack of detectable neutralizing antibodies, the vaccination provided heterosubtypic protection against the lethal challenge with the viruses. Sterile protection was confirmed by the complete absence of viral titers in the lungs and nasal turbinates after the challenge. Antibody-dependent cellular cytotoxicity (ADCC) activities of non-neutralizing antibodies contributed to cross-protection. The cross-protection remained robust even after depletion of T cells or NK cells, reflecting the strength and breadth of the antibody-dependent effector function. The robust mucosal secretion of sIgA reflects an additional level of cross-protection. Our data show that the host-restricted designer vaccine serves an option for developing a UIV, providing pan-influenza A protection against both group 1 and 2 influenza viruses. The present results of potency and breadth of protection from wild type and reassortant viruses addressed in the mouse model by single immunization merits further confirmation and validation, preferably in clinically relevant ferret models with wild type challenges.
流感病毒感染可引起广泛的症状，从轻微的呼吸道问题到严重和致命的并发症。虽然流感病毒对全球健康构成威胁，但频繁的抗原变化常常显著降低季节性疫苗的保护效果，进一步增加了病毒感染的易感性。因此，迫切需要采用策略来开发通用流感疫苗（UIV），以针对多种流感病毒产生广泛的保护作用。我们使用小鼠感染模型研究了 caspase 触发的减毒活流感疫苗（ctLAIV）的保护广度，该疫苗通过宿主 caspase 依赖性切割内部病毒蛋白而自我减弱。单次接种疫苗可诱导针对四种不同流感病毒（H1 和 rH5（HA 组 1）和 H3 和 rH7 亚型（HA 组 2）的广泛反应性抗体应答。值得注意的是，尽管未检测到中和抗体，但疫苗接种提供了针对病毒致死性挑战的异型保护。通过挑战后肺部和鼻甲骨中完全不存在病毒滴度来确认无菌保护。非中和抗体的抗体依赖性细胞毒性（ADCC）活性有助于交叉保护。即使耗尽 T 细胞或 NK 细胞后，交叉保护仍然强大，这反映了抗体依赖性效应功能的强度和广度。黏膜分泌的 sIgA 的大量分泌反映了额外的交叉保护水平。我们的数据表明，宿主受限的设计疫苗是开发 UIV 的一种选择，可针对 1 型和 2 型流感病毒提供泛流感 A 保护。通过单次免疫在小鼠模型中针对野生型和重组病毒进行的效力和保护广度的研究结果需要进一步确认和验证，最好在具有野生型挑战的临床相关雪貂模型中进行。
