Modified mRNA/lipid nanoparticle-based vaccines expressing respiratory syncytial virus F protein variants are immunogenic and protective in rodent models of RSV infection
Modified mRNA/lipid nanoparticle-based vaccines expressing respiratory syncytial virus F protein variants are immunogenic and protective in rodent models of RSV infection
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DOI：
10.1038/s41541-020-0163-z
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发表时间：
2020-02-14
期刊：
影响因子：
9.2
通讯作者：
Bett, Andrew J.
中科院分区：
文献类型：
--
作者：
Espeseth, Amy S.;Cejas, Pedro J.;Bett, Andrew J.
RSV融合(F)蛋白是中和抗体反应的靶标，也是疫苗开发的重点；然而，RSV进入的过程需要F采用亚稳定的预融合形式，并过渡到更稳定的融合后形式，后者显示出更弱的中和表位。mRNA疫苗编码抗原，疫苗接种后由宿主细胞翻译，这可能允许类似于自然感染期间观察到的构象转变发生。在这里，我们评估了一组表达不同形式RSV F蛋白的化学修饰mRNA疫苗，包括分泌型、膜相关型、预渗稳定型和非稳定型结构，在啮齿动物模型中的构象、免疫原性、保护和安全性。用编码天然RSV F的mRNA接种疫苗可引起抗体对融合前和融合后特异性表位的反应，这表明该抗原在体内可能采用两种构象。纳入预融合稳定突变进一步将免疫反应转向预融合特异性表位，但不影响中和抗体滴度。表达预融合稳定或天然形式RSV F蛋白的mRNA候选疫苗在小鼠和棉花大鼠中均可引起强大的中和抗体反应，其水平与相当剂量的佐剂预融合稳定RSV F蛋白观察到的水平相似。与蛋白质亚单位疫苗相比，基于mrna的疫苗在小鼠中引发了强大的CD4+和CD8+ t细胞反应，这突出了需要细胞免疫反应才能发挥功效的疫苗技术的潜在优势。
The RSV Fusion (F) protein is a target for neutralizing antibody responses and is a focus for vaccine discovery; however, the process of RSV entry requires F to adopt a metastable prefusion form and transition to a more stable postfusion form, which displays less potent neutralizing epitopes. mRNA vaccines encode antigens that are translated by host cells following vaccination, which may allow conformational transitions similar to those observed during natural infection to occur. Here we evaluate a panel of chemically modified mRNA vaccines expressing different forms of the RSV F protein, including secreted, membrane associated, prefusion-stabilized, and non-stabilized structures, for conformation, immunogenicity, protection, and safety in rodent models. Vaccination with mRNA encoding native RSV F elicited antibody responses to both prefusion- and postfusion-specific epitopes, suggesting that this antigen may adopt both conformations in vivo. Incorporating prefusion stabilizing mutations further shifts the immune response toward prefusion-specific epitopes, but does not impact neutralizing antibody titer. mRNA vaccine candidates expressing either prefusion stabilized or native forms of RSV F protein elicit robust neutralizing antibody responses in both mice and cotton rats, similar to levels observed with a comparable dose of adjuvanted prefusion stabilized RSV F protein. In contrast to the protein subunit vaccine, mRNA-based vaccines elicited robust CD4+ and CD8+ T-cell responses in mice, highlighting a potential advantage of the technology for vaccines requiring a cellular immune response for efficacy.