Preclinical evaluation of bacterially produced RSV-G protein vaccine: Strong protection against RSV challenge in cotton rat model
Preclinical evaluation of bacterially produced RSV-G protein vaccine: Strong protection against RSV challenge in cotton rat model
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DOI：
10.1038/srep42428
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发表时间：
2017-02-10
影响因子：
4.6
通讯作者：
Khurana, Surender
中科院分区：
文献类型：
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作者：
Fuentes, Sandra;Klenow, Laura;Khurana, Surender
在本研究中，我们评价了在大肠杆菌中产生的重组非糖基化RSVG蛋白胞外域（存在和不存在水包油佐剂）在临床前RSV易感棉鼠攻击模型中与甲醛灭活RSV（FI-RSV）和活RSV实验感染相比的安全性和保护功效。含佐剂的G蛋白疫苗诱导与活RSV感染产生的中和抗体应答相当的稳健中和抗体应答。重要的是，在病毒攻击后的早期时间点，佐剂化的G蛋白显著降低了肺和鼻中的病毒载量。通过表面等离子体共振测定的抗体动力学显示，与未加佐剂的G疫苗和活RSV感染相比，加佐剂的G产生高10倍的G结合抗体，这与病毒攻击后鼻和肺中的中和滴度和病毒载量滴度两者强烈相关。抗体多样性分析揭示了RSV-G蛋白的N-和C-末端中的免疫显性抗原位点，其通过佐剂增强> 10倍，并且与病毒载量滴度负相关。仅在接种FI-RSV的动物中观察到肺病理学增强，但在病毒攻毒后接种无佐剂或有佐剂RSV-G疫苗的动物中未观察到。细菌产生的非糖基化G蛋白可被开发为针对RSV疾病的保护性疫苗。
In current study, we evaluated the safety and protective efficacy of recombinant unglycosylated RSVG 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.