中科院武漢病毒所肖庚富組在呼吸道合胞病毒疫苗研究方面取得重要進展

2019年5月，中國科學院武漢病毒研究所/病毒學國家重點實驗室肖庚富研究組在呼吸道合胞病毒疫苗研究方面取得重要進展，相關工作以「A novel RSV F-Fc fusion protein vaccine reduces lung injury induced by respiratory syncytial virus infection」（一種新的呼吸道合胞病毒F-Fc融合蛋白疫苗減少病毒感染引起的肺損傷）為題正式刊印於國際學術期刊《抗病毒研究》（Antiviral Research）。

呼吸道合胞病毒（Respiratory syncytial virus，RSV）是嬰幼兒肺炎和支氣管炎的首要病毒病因。常規的福爾馬林滅活疫苗（FI-RSV）在2-7月齡嬰兒引起疫苗依賴的感染增強，被認為是由於滅活苗誘發的中和性抗體活性過低、誘發過激的Th2型細胞因子造成免疫損傷。F（Fusion）蛋白是RSV囊膜蛋白之一，在病毒感染過程中發揮膜融合作用，是最有希望的RSV抗原。它存在融合前（Pre-fusion）和融合後（Post-fusion）兩種構象。美國國立衛生研究院（NIH）Peter D. Kwong團隊基於結構設計和蛋白質工程改造，構建了穩定構象的融合前F蛋白疫苗，保留重要抗原表位site，在小鼠和猴中產生高滴度中和性抗體，是2013年科學十大進展之一。

在本項研究中，肖庚富研究組將RSV F蛋白基因與小鼠IgG2a抗體Fc段基因融合併在哺乳動物細胞中表達，其產物F-Fc為六聚體形式，能夠與識別融合前表位site的抗體高效結合。F-Fc滴鼻免疫，通過FcRn傳遞，在小鼠肺部誘發高滴度抗體；通過與FcγR結合和抗原遞呈，產生偏向Th1型的細胞免疫。攻毒保護試驗證實F-Fc免疫顯著降低小鼠肺部病理損傷並清除病毒，為最終研製抗RSV疫苗並防控嬰幼兒肺炎等提供了新的思路。發明專利「呼吸道合胞病毒F蛋白與Fc的融合蛋白及其用途」已獲國家知識產權局授權。

博士研究生張艷君為該論文第一作者，肖庚富研究員為通訊作者。該研究得到武漢大學/病毒學國家重點實驗室潘茲書教授、美國Peter D. Kwong等的大力支持，並受到「生物安全關鍵技術研發」國家重點研發計劃和國家自然科學基金的資助。

Highlights

Generated RSV F and IgG Fc fusion protein F-Fc that can be recognized by pre-fusion F specific mAb D25.

F-Fc immunized mouse induced RSV protective Th1-biased cellular immune response.

None of the mice immunized with the F-Fc protein had detectable virus in their lungs after RSV infection.

F-Fc reduced the lung injury in immunized mouse after RSV challenge.

Abstract

Respiratory syncytial virus (RSV) infection causes significant disease in the lower respiratory tract of young children, and there is currently no licensed vaccine to prevent RSV infection. The F glycoprotein is considered a major antigenic target for RSV vaccine development. Recent evidence indicates that the pre-fusion F state, compared with the post-fusion F state, is a superior antigen for generation of neutralizing antibodies. In this study, we developed a novel vaccine antigen, RSV glycoprotein F fused with an IgG Fc fragment (F-Fc). The F-Fc fusion protein is predominantly a hexamer and could be recognized by the pre-fusion F-specific monoclonal antibody D25. Intranasal immunization with the F-Fc fusion protein promoted a protective Th1-biased cellular immune response relative to that promoted by immunization with the F protein. This immunization strategy significantly reduced the lung viral load in mice. Furthermore, immunization with F-Fc reduced lung pathology and the production of pro-inflammatory cytokines and chemokines in the lung after RSV infection. These results suggest that the F-Fc protein may be a safe and effective RSV vaccine candidate.

本期編輯：Tony

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