Novel Respiratory Syncytial Virus-Like Particle Vaccine Composed of the Postfusion and Prefusion Conformations of the F Glycoprotein.
Novel Respiratory Syncytial Virus-Like Particle Vaccine Composed of the Postfusion and Prefusion Conformations of the F Glycoprotein.
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DOI：
10.1128/cvi.00720-15
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发表时间：
2016-06
期刊：
影响因子：
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通讯作者：
Galarza JM
中科院分区：
文献类型：
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作者：
Cimica V;Boigard H;Bhatia B;Fallon JT;Alimova A;Gottlieb P;Galarza JM
呼吸道合胞病毒(RSV)是导致婴幼儿严重呼吸道疾病的主要原因，是全球老年人和免疫功能低下者的重要健康负担。尽管进行了几十年的研究，但目前还没有获得许可的RSV疫苗。我们以人偏肺病毒(HMPV)基质蛋白(M)为结构支架，以融合后或融合前的RSV融合糖蛋白(F)为主要表面抗原，研制了基于病毒样颗粒(VLP)的RSV疫苗。疫苗由融合后F、融合前F或两种构象的组合组成，并以角鲨烯为基础的油乳剂作为佐剂配制。这些VLP疫苗的免疫提供了对RSV感染的完全保护，并防止了攻击后小鼠肺内可检测到的病毒复制。对肺细胞因子和趋化因子的分析表明，VLP疫苗主要诱导产生干扰素(干扰素-γ)，这是Th1介导的免疫反应的标志，而Th1介导的免疫反应主要是病毒保护所必需的。相反，福尔马林灭活呼吸道合胞病毒(FI-RSV)疫苗免疫可诱导高水平的炎性趋化因子和Th2和Th17介导的免疫反应类型的细胞因子，以及严重的肺部炎症和组织病理学。VLP疫苗显示这些免疫介质的产生受到限制，并且没有像FI-RSV疫苗那样引起严重的毛细支气管炎或血管周围浸润。值得注意的是，对免疫小鼠的血清分析表明，融合后和融合前F组合制成的VLP疫苗诱导了最高水平的中和抗体，并增强了Th1介导的免疫应答。
Respiratory syncytial virus (RSV) is the leading cause of severe respiratory disease in infants and children and represents an important global health burden for the elderly and the immunocompromised. Despite decades of research efforts, no licensed vaccine for RSV is available. We have developed virus-like particle (VLP)-based RSV vaccines assembled with the human metapneumovirus (hMPV) matrix protein (M) as the structural scaffold and the RSV fusion glycoprotein (F) in either the postfusion or prefusion conformation as its prime surface immunogen. Vaccines were composed of postfusion F, prefusion F, or a combination of the two conformations and formulated with a squalene-based oil emulsion as adjuvant. Immunization with these VLP vaccines afforded full protection against RSV infection and prevented detectable viral replication in the mouse lung after challenge. Analyses of lung cytokines and chemokines showed that VLP vaccination mostly induced the production of gamma interferon (IFN-γ), a marker of the Th1-mediated immune response, which is predominantly required for viral protection. Conversely, immunization with a formalin-inactivated RSV (FI-RSV) vaccine induced high levels of inflammatory chemokines and cytokines of the Th2- and Th17-mediated types of immune responses, as well as severe lung inflammation and histopathology. The VLP vaccines showed restricted production of these immune mediators and did not induce severe bronchiolitis or perivascular infiltration as seen with the FI-RSV vaccine. Remarkably, analysis of the serum from immunized mice showed that the VLP vaccine formulated using a combination of postfusion and prefusion F elicited the highest level of neutralizing antibody and enhanced the Th1-mediated immune response.