Intranasal vaccination of recombinant adeno-associated virus encoding receptor-binding domain of severe acute respiratory syndrome coronavirus (SARS-CoV) spike protein induces strong mucosal immune responses and provides long-term protection against SARS-CoV infection
Intranasal vaccination of recombinant adeno-associated virus encoding receptor-binding domain of severe acute respiratory syndrome coronavirus (SARS-CoV) spike protein induces strong mucosal immune responses and provides long-term protection against SARS-CoV infection
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DOI：
10.4049/jimmunol.180.2.948
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发表时间：
2008-01-15
影响因子：
4.4
通讯作者：
Zheng, Bo-Jian
中科院分区：
文献类型：
--
作者：
Du, Lanying;Zhao, Guangyu;Zheng, Bo-Jian
我们先前报道了基于严重急性呼吸综合征冠状病毒（SARS CoV）刺突蛋白受体结合域（RBD）的亚单位蛋白疫苗和基于重组腺相关病毒（rAAV）的RBD疫苗（RBD rAAV）可以在免疫动物中诱导高度有效的中和抗体应答。在本研究中，在BALB/c小鼠模型中进一步表征了由RBD-rAAV诱导的全身、粘膜和细胞免疫应答以及长期保护性免疫，并比较了RBD-rAAV的i.m.和鼻内（i.n.）给药途径。结果表明：1）i.n.接种诱导的全身体液免疫应答的强度和持续时间与i.m.疫苗接种，但局部不道德免疫反应要强得多; 2）i.n.免疫接种引起比i.m.免疫接种，如肺和脾中产生IL-2和/或IFN-γ的CD 3（+）/CD 8（+）T细胞的更高流行率所证明的; 3）i.n.疫苗接种诱导了与i.m.结果表明：（1）免疫小鼠后血清IgA和血清中和抗体滴度升高，病毒载量降低，肺组织病理损害减轻，但未观察到抗体介导的疾病增强效应;（2）免疫小鼠后血清IgA和血清中和抗体滴度升高，病毒载量降低，肺组织病理损害减轻;（3）免疫小鼠后血清IgA和血清中和抗体滴度升高，病毒载量降低，肺组织病理损害减轻，但未观察到抗体介导的疾病增强效应;（4）免疫小鼠后血清中和抗体滴度升高，病毒载量降低，肺组织病理损害减轻;（5）免疫小鼠后血清中和抗体滴度升高，病毒载量降低，肺组织病理损害减轻。综上所述，我们的研究结果表明，RBD-rAAV可以进一步发展成为预防SARS的候选疫苗，并且i.n.由于疫苗接种能够诱导SARS-CoV特异性的全身和粘膜免疫应答以及其更好的安全性，因此其可能是优选的给药途径。
We have previously reported that a subunit protein vaccine based on the receptor-binding domain (RBD) of severe acute respiratory syndrome corona-virus (SARS-CoV) spike protein and a recombinant adeno-associated virus (rAAV)-based RBD (RBD-rAAV) vaccine could induce highly potent neutralizing Ab responses in immunized animals. In this study, systemic, mucosal, and cellular immune responses and long-term protective immunity induced by RBD-rAAV were further characterized in a BALB/c mouse model, with comparison of the i.m. and intranasal (i.n.) routes of administration. Our results demonstrated that: 1) the i.n. vaccination induced a systemic humoral immune response of comparable strength and shorter duration than the i.m. vaccination, but the local Immoral immune response was much stronger; 2) the i.n. vaccination elicited stronger systemic and local specific cytotoxic T cell responses than the i.m. vaccination, as evidenced by higher prevalence of IL-2 and/or IFN-gamma-producing CD3(+)/CD8(+) T cells in both lungs and spleen; 3) the i.n. vaccination induced similar protection as the i.m. vaccination against SARS-CoV challenge in mice; 4) higher titers of mucosal IgA and serum-neutralizing Ab were associated with lower viral load and less pulmonary pathological damage, while no Ab-mediated disease enhancement effect was observed; and 5) the vaccination could provide long-term protection against SARS-CoV infection. Taken together, our findings suggest that RBD-rAAV can be further developed into a vaccine candidate for prevention of SARS and that i.n. vaccination may be the preferred route of administration due to its ability to induce SARS-CoV-specific systemic and mucosal immune responses and its better safety profile.