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* Department of Microbiology,
Department of Biochemistry, University of Hong Kong, Pokfulam, Hong Kong Special Administrative Region, China;
State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing, China;
Lindsley F. Kimball Research Institute, New York Blood Center, New York, NY 10021; and
¶ Department of Immunology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
We have previously reported that a subunit protein vaccine based on the receptor-binding domain (RBD) of severe acute respiratory syndrome coronavirus (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 humoral 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-
-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.
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1 This work was supported by the Research Fund for the Control of Infectious Diseases, the Health, Welfare and Food Bureau of the Hong Kong Special Administrative Region government; by the National 973 Basic Research Program of China (2005CB523001); and by the National Institutes of Health of the United States (RO1 AI68002).
2 Address correspondence and reprint requests to Dr. Bo-Jian Zheng, Department of Microbiology, University of Hong Kong, Pokfulam, Hong Kong SAR, China. E-mail address: bzheng{at}hkucc.hku.hk or Dr. Yusen Zhou, State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing 100071, China. E-mail address: yszhou{at}nic.bmi.ac.cn
3 Abbreviations used in this paper: SARS, severe acute respiratory syndrome; SARS-CoV, SARS coronavirus; S protein, spike protein; NA, neutralizing Ab; RBD, receptor-binding domain; rAAV, recombinant adeno-associated virus; i.n., intranasal; TCID50, 50% tissue culture infectious dose; VP, viral particle; CPE, cytopathic effect; SFC, spot-forming cell; Q-RT-PCR, quantitative RT-PCR; ADE, Ab-mediated disease enhancement.
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