A replication-incompetent virus possessing an uncleavable hemagglutinin as an influenza vaccine.
A replication-incompetent virus possessing an uncleavable hemagglutinin as an influenza vaccine.
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DOI：
10.1016/j.vaccine.2012.07.059
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发表时间：
2012-09-14
期刊：
影响因子：
5.5
通讯作者：
Kawaoka Y
中科院分区：
文献类型：
--
作者：
Katsura H;Iwatsuki-Horimoto K;Fukuyama S;Watanabe S;Sakabe S;Hatta Y;Murakami S;Shimojima M;Horimoto T;Kawaoka Y
接种疫苗是预防流感病毒感染的最有效措施之一。可获得流感灭活疫苗和减毒活疫苗；然而，它们的功效并不理想。为了开发一种安全且更具免疫原性的疫苗，我们生产了一种具有不可切割血凝素（HA）的新型复制无能流感病毒，并测试了其疫苗潜力。通过用苏氨酸取代HA1 c末端的精氨酸，构建了不可切割的HA，从而阻止了HA分裂成HA1和HA2亚基，从而阻止了宿主和病毒膜之间的融合。虽然这种具有不可切割HA的融合缺陷HA流感病毒（不可切割HA病毒）只能在表达HA的野生型细胞中进行多个复制周期，但它可以感染正常细胞并在感染细胞中表达病毒蛋白，但由于HA不可切割，不能从感染细胞中产生感染性病毒。C57BL/6小鼠经鼻内免疫后，在鼻洗液、支气管肺泡灌洗液和血清中检测到流感特异性IgG和IgA抗体。此外，流感特异性CD8+ T细胞在这些小鼠的肺部积聚。此外，与用福尔马林灭活病毒免疫的小鼠不同，用不可切割的HA病毒免疫的小鼠免受致命剂量流感病毒的攻击。这些发现表明，这种融合缺陷病毒具有不可切割的HA，是一种合适的流感疫苗候选者。
Vaccination is one of the most effective measures to protect against influenza virus infection. Inactivated and live-attenuated influenza vaccines are available; however, their efficacy is suboptimal. To develop a safe and more immunogenic vaccine, we produced a novel replication-incompetent influenza virus that possesses uncleavable hemagglutinin (HA) and tested its vaccine potential. The uncleavable HA was engineered by substituting the arginine at the C-terminus of HA1 with threonine, which prevents cleavage of HA into its HA1 and HA2 subunits, preventing fusion between the host and viral membranes. Although this fusion-deficient HA influenza virus that possesses uncleavable HA (uncleavable HA virus) could undergo multiple cycles of replication in only wild-type HA-expressing cells, it could infect normal cells and express viral proteins in infected cells, but could not generate infectious virus from infected cells due to the uncleavable HA. When C57BL/6 mice were intranasally immunized with the uncleavable HA virus, influenza-specific IgG and IgA antibodies were detected in nasal wash and bronchoalveolar lavage samples and in serum. In addition, influenza-specific CD8+ T cells accumulated in the lungs of these mice. Moreover, mice immunized with the uncleavable HA virus were protected against a challenge of lethal doses of influenza virus, unlike mice immunized with a formalin-inactivated virus. These findings demonstrate that this fusion-deficient virus, which possesses uncleavable HA, is a suitable influenza vaccine candidate.
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