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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 Infection¹

Lanying Du^*,, Guangyu Zhao, Yongping Lin^*, Hongyan Sui^*, Chris Chan^*, Selene Ma^*, Yuxian He, Shibo Jiang, Changyou Wu^¶, Kwok-Yung Yuen^*, Dong-Yan Jin, Yusen Zhou^2, and Bo-Jian Zheng^2,*

^* 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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

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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