Development of an Adenovirus-Based Respiratory Syncytial Virus Vaccine: Preclinical Evaluation of Efficacy, Immunogenicity, and Enhanced Disease in a Cotton Rat Model
Development of an Adenovirus-Based Respiratory Syncytial Virus Vaccine: Preclinical Evaluation of Efficacy, Immunogenicity, and Enhanced Disease in a Cotton Rat Model
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DOI：
10.1128/jvi.03194-13
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发表时间：
2014-05-01
影响因子：
5.4
通讯作者：
Gambotto, Andrea
中科院分区：
文献类型：
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作者：
Kim, Eun;Okada, Kaori;Gambotto, Andrea
缺乏针对呼吸道合胞病毒（RSV）的疫苗是预防医学中一个具有挑战性的严重差距。在此，我们表征了编码融合（F）蛋白（Ad 5. RSV-F）和用Ad 5免疫后提供的保护。RSV-F，并评估其在棉鼠（CR）模型中产生增强疾病的潜力。将动物鼻内（i. n.）和/或肌内（i.m.）并随后用RSV/A/Tracy（i. n.）评估保护。在用Ad 5接种的CR中观察到稳健的免疫应答。RSV-F i.m.或i.n.，这些反应与攻击后鼻和肺中病毒复制减少有关。用单剂量的Ad 5免疫后的中和抗体应答。RSV-F，1 x 10（11）个病毒颗粒（v. p.）引发的抗体滴度比自然感染后的抗体滴度高64至256倍。用Ad 5提高CR。RSV-F i.n. 28天后，一个i.m.剂量也具有中和抗体滴度的显著增加。不同的F-蛋白抗原位点的抗体亲和力揭示了由Ad 5引起的抗体之间的实质性差异。RSV-F和RSV感染后观察到的抗体谱;在给予Ad 5的CR之间也观察到抗体谱的差异。RSV-F i.m.和给予Ad 5的CR。RSV-F i.n. Ad5。与福尔马林灭活RSV/A/Burnett疫苗CR中观察到的组织病理学相反，RSV-F初免在活病毒攻毒后未导致疾病增强。
The lack of a vaccine against respiratory syncytial virus (RSV) is a challenging and serious gap in preventive medicine. Herein, we characterize the immunogenicity of an adenovirus serotype 5-based RSV vaccine encoding the fusion (F) protein (Ad5. RSV-F) and the protection provided following immunization with Ad5. RSV-F and assess its potential for producing enhanced disease in a cotton rat (CR) model. Animals were immunized intranasally (i.n.) and/or intramuscularly (i.m.) and subsequently challenged with RSV/A/Tracy (i.n.) to assess protection. Robust immune responses were seen in CRs vaccinated with Ad5. RSV-F given i.m. or i.n., and these responses correlated with reduced replication of the virus in noses and lungs after challenge. Neutralizing antibody responses following immunization with a single dose of Ad5. RSV-F at 1 x 10(11) viral particles (v.p.) elicited antibody titers 64-to 256-fold greater than those seen after natural infection. CRs boosted with Ad5. RSV-F i.n. 28 days after an i.m. dose also had significant increases in neutralizing antibody titers. Antibody affinity for different F-protein antigenic sites revealed substantial differences between antibodies elicited by Ad5. RSV-F and those seen after RSV infection; differences in antibody profiles were also seen between CRs given Ad5. RSV-F i.m. and CRs given Ad5. RSV-F i.n. Ad5. RSV-F priming did not result in enhanced disease following live-virus challenge, in contrast to the histopathology seen in CRs given the formalin-inactivated RSV/A/Burnett vaccine.