Quantitative regulation of the thermal stability of enveloped virus vaccines by surface charge engineering to prevent the self-aggregation of attachment glycoproteins.
Quantitative regulation of the thermal stability of enveloped virus vaccines by surface charge engineering to prevent the self-aggregation of attachment glycoproteins.
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通过表面电荷工程定量调节包膜病毒疫苗的热稳定性以防止附着糖蛋白的自聚集
DOI：
10.1371/journal.ppat.1010564
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发表时间：
2022-06
期刊：
影响因子：
6.7
通讯作者：
中科院分区：
文献类型：
--
作者：
热稳定性疫苗的开发可以缓解现有疫苗因热不稳定性和随后效力差而造成的瓶颈，这是疫苗可预防疾病造成数百万人死亡的主要原因之一。对病毒热稳定性机制的研究可能为开发热稳定性疫苗提供策略。以新城疫病毒（NDV）为模型，我们发现附着糖蛋白的负表面电荷是病毒热稳定性的新决定因素。它阻止了温度诱导的糖蛋白聚集以及随后从病毒颗粒表面的脱离。热处理后病毒颗粒表面的结构稳定性得到改善，病毒可以有效地结合并感染细胞。采用表面电荷工程方法，成功提高了NDV和甲型流感病毒（IAV）疫苗的热稳定性。疫苗热稳定性水平的提高由附着糖蛋白的负表面电荷的增值决定。工程化活疫苗和灭活疫苗分别在37°C下储存至少10天和60天后可以有效使用。因此，我们的结果揭示了 HN 蛋白和 NDV 热稳定性之间新的表面电荷介导的联系，可用于合理设计热稳定的 NDV 和 IAV 疫苗。热稳定疫苗的开发可以帮助全球免疫计划的执行和扩大，因为它们减少了对运输和储存冷链的依赖。对病毒热稳定性机制的研究可能为开发热稳定性疫苗提供策略。然而，人们对包膜病毒继承其热稳定性的机制知之甚少。此前，我们发现附着糖蛋白（血凝素神经氨酸酶，HN）负责新城疫病毒（NDV）的热稳定性。在本研究中，我们进一步证明HN蛋白的负表面电荷通过阻止HN蛋白的聚集来正调节NDV的热稳定性。通过对包膜病毒疫苗株的附着糖蛋白表面进行基因工程改造，将电荷相关氨基酸突变到包膜病毒疫苗株的附着糖蛋白表面，显着提高了新城疫病毒和流感病毒疫苗的热稳定性和效力。基于这些数据，我们提出了 HN 蛋白和 NDV 热稳定性之间新的表面电荷介导的联系，并为合理设计热稳定包膜病毒疫苗提供了新策略。
The development of thermostable vaccines can relieve the bottleneck of existing vaccines caused by thermal instability and subsequent poor efficacy, which is one of the predominant reasons for the millions of deaths caused by vaccine-preventable diseases. Research into the mechanism of viral thermostability may provide strategies for developing thermostable vaccines. Using Newcastle disease virus (NDV) as model, we identified the negative surface charge of attachment glycoprotein as a novel determinant of viral thermostability. It prevented the temperature-induced aggregation of glycoprotein and subsequent detachment from virion surface. Then structural stability of virion surface was improved and virus could bind to and infect cells efficiently after heat-treatment. Employing the approach of surface charge engineering, thermal stability of NDV and influenza A virus (IAV) vaccines was successfully improved. The increase in the level of vaccine thermal stability was determined by the value-added in the negative surface charge of the attachment glycoprotein. The engineered live and inactivated vaccines could be used efficiently after storage at 37°C for at least 10 and 60 days, respectively. Thus, our results revealed a novel surface-charge-mediated link between HN protein and NDV thermostability, which could be used to design thermal stable NDV and IAV vaccines rationally. The development of thermal stable vaccines can assist in the execution and expansion of global immunization programs, due to their decreased dependence on the cold chain for transport and storage. Research into the mechanism of viral thermostability may provide strategies for developing thermal stable vaccines. However, the mechanism by which an enveloped virus inherits its thermostability is poorly understood. Previously, we identified that the attachment glycoprotein (hemagglutinin-neuraminidase, HN) was responsible for the thermostability of Newcastle disease virus (NDV). In the present study, we further demonstrated that negative surface charge of HN protein positively regulated the thermostability of NDV through preventing the aggregation of HN protein. By genetically engineering charge-associated amino acid mutations onto the surface of the attachment glycoprotein of an enveloped virus vaccine strain, we remarkably improved the NDV and influenza virus vaccine’s thermal stability and potency. Based on these data, we proposed a novel surface-charge-mediated link between HN protein and NDV thermostability, and provided a novel strategy for rational design of thermal stable enveloped virus vaccines.
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影响因子：
64.8
作者：
Kostyuchenko, Victor A.;Lim, Elisa X. Y.;Lok, Shee-Mei
通讯作者：
Lok, Shee-Mei
影响因子：
3.8
作者：
Liu, J;Nguyen, MDH;Shire, SJ
通讯作者：
Shire, SJ
影响因子：
64.8
作者：
Imai, Masaki;Watanabe, Tokiko;Hatta, Masato;Das, Subash C.;Ozawa, Makoto;Shinya, Kyoko;Zhong, Gongxun;Hanson, Anthony;Katsura, Hiroaki;Watanabe, Shinji;Li, Chengjun;Kawakami, Eiryo;Yamada, Shinya;Kiso, Maki;Suzuki, Yasuo;Maher, Eileen A.;Neumann, Gabriele;Kawaoka, Yoshihiro
通讯作者：
Kawaoka, Yoshihiro
影响因子：
4.9
作者：
Laber JR;Dear BJ;Martins ML;Jackson DE;DiVenere A;Gollihar JD;Ellington AD;Truskett TM;Johnston KP;Maynard JA
通讯作者：
Maynard JA
影响因子：
30.5
作者：
Clemens, John;Holmgren, Jan;Mantovani, Alberto
通讯作者：
Mantovani, Alberto