Division of Viral Products, Center for Biologics Evaluation and Research (CBER), FDA, Silver Spring, MD, 20903, USA.
Sci Rep. 2017 Feb 10;7:42428. doi: 10.1038/srep42428.
In current study, we evaluated the safety and protective efficacy of recombinant unglycosylated RSV G protein ectodomain produced in E. coli (in presence and absence of oil-in-water adjuvant) in a preclinical RSV susceptible cotton rat challenge model compared to formaldehyde inactivated RSV (FI-RSV) and live RSV experimental infection. The adjuvanted G protein vaccine induced robust neutralization antibody responses comparable to those generated by live RSV infection. Importantly, adjuvanted G protein significantly reduced viral loads in both the lungs and nose at early time points following viral challenge. Antibody kinetics determined by Surface Plasmon Resonance showed that adjuvanted G generated 10-fold higher G-binding antibodies compared to non-adjvuanted G vaccine and live RSV infection, which correlated strongly with both neutralization titers and viral load titers in the nose and lungs post-viral challenge. Antibody diversity analysis revealed immunodominant antigenic sites in the N- and C-termini of the RSV-G protein, that were boosted >10-fold by adjuvant and inversely correlated with viral load titers. Enhanced lung pathology was observed only in animals vaccinated with FI-RSV, but not in animals vaccinated with unadjuvanted or adjuvanted RSV-G vaccine after viral challenge. The bacterially produced unglycosylated G protein could be developed as a protective vaccine against RSV disease.
在目前的研究中，我们评估了在临床前 RSV 易感棉鼠挑战模型中，与福尔马林失活 RSV（FI-RSV）和活 RSV 实验感染相比，在大肠杆菌中产生的重组无糖基化 RSV G 蛋白外域（存在和不存在油包水佐剂）的安全性和保护效力。佐剂 G 蛋白疫苗诱导了与活 RSV 感染相当的强大中和抗体反应。重要的是，佐剂 G 在病毒攻击后早期显著降低了肺部和鼻腔中的病毒载量。通过表面等离子体共振测定的抗体动力学表明，与非佐剂 G 疫苗和活 RSV 感染相比，佐剂 G 产生了 10 倍更高的 G 结合抗体，这与病毒攻击后鼻腔和肺部的中和滴度和病毒载量高度相关。抗体多样性分析显示，在 RSV-G 蛋白的 N 和 C 末端存在免疫显性抗原位点，这些位点被佐剂增强了 >10 倍，与病毒载量呈负相关。在病毒攻击后，仅在接种 FI-RSV 的动物中观察到增强的肺部病理学，而在接种未佐剂或佐剂 RSV-G 疫苗的动物中未观察到。这种细菌产生的无糖基化 G 蛋白可开发为针对 RSV 疾病的保护性疫苗。
