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. 2007 Apr 12;25(15):2832-8.
doi: 10.1016/j.vaccine.2006.10.031. Epub 2006 Oct 30.

Receptor-binding domain of SARS-CoV spike protein induces long-term protective immunity in an animal model

Lanying Du  1 , Guangyu Zhao, Yuxian He, Yan Guo, Bo-Jian Zheng, Shibo Jiang, Yusen Zhou
Affiliations

Receptor-binding domain of SARS-CoV spike protein induces long-term protective immunity in an animal model

Lanying Du et al. Vaccine. .

Abstract

Development of effective vaccines against severe acute respiratory syndrome (SARS) coronavirus (SARS-CoV) is still a priority in prevention of re-emergence of SARS. Our previous studies have shown that the receptor-binding domain (RBD) of SARS-CoV spike (S) protein elicits highly potent neutralizing antibody responses in the immunized animals. But it is unknown whether RBD can also induce protective immunity in an animal model, a key aspect for vaccine development. In this study, BALB/c mice were vaccinated intramuscularly (i.m.) with 10microg of RBD-Fc (RBD fused with human IgG1 Fc) and boosted twice at 3-week intervals and one more time at 12th month. Humoral immune responses of vaccinated mice were investigated for up to 12 months at a 1-month interval and the neutralizing titers of produced antibodies were reported at months 0, 3, 6 and 12 post-vaccination. Mice were challenged with the homologous strain of SARS-CoV 5 days after the last boost, and sacrificed 5 days after the challenge. Mouse lung tissues were collected for detection of viral load, virus replication and histopathological effects. Our results showed that RBD-Fc vaccination induced high titer of S-specific antibodies with long-term and potent SARS-CoV neutralizing activity. Four of five vaccinated mice were protected from subsequent SARS-CoV challenge because no significant virus replication, and no obvious histopathological changes were found in the lung tissues of the vaccinated mice challenged with SARS-CoV. Only one vaccinated mouse had mild alveolar damage in the lung tissues. In contrast, high copies of SARS-CoV RNA and virus replication were detected, and pathological changes were observed in the lung tissues of the control mice. In conclusion, our findings suggest that RBD, which can induce protective antibodies to SARS-CoV, may be further developed as a safe and effective SARS subunit vaccine.

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Figures

Fig. 1
Fig. 1
Schematics for RBD-Fc vaccination and SARS-CoV challenge. BALB/c mice were i.m. immunized with RBD-Fc fusion protein suspended in PBS plus adjuvant (vaccination group) or PBS only (control group) four times in total. Serum was collected from each mouse at a 1-month interval. The mice in both groups were intranasally challenged with SARS-CoV 5 days after the last vaccination, followed by detection of virus replication and histopathological changes in the mouse lung tissues 5 days after the challenge.
Fig. 2
Fig. 2
Detection of anti-S antibodies and virus neutralizing antibodies in mouse sera. (A) Titers of anti-S antibodies measured by ELISA for 12 months at monthly basis and 5 days after the last boost. Data are presented as the geometric means ± SE of five mouse sera collected at different time points. (B) Titers of the SARS-CoV neutralizing antibody in sera collected at 0, 3, 6 and 12 months post-vaccination and sera collected 5 days after the last boost. The titers of neutralizing antibodies were determined as the highest dilutions of sera that could completely prevent CPE in at least 50% of the wells and are presented as the geometric means ± SE of five mouse sera in each group.
Fig. 3
Fig. 3
RBD-Fc protected vaccinated mice from subsequent challenge with SARS-CoV. Groups of five BALB/c mice vaccinated with RBD-Fc or PBS were intranasally challenged with 106 TCID50 of SARS-CoV 5 days after the last dose of vaccination. The titers of SARS-CoV replicated in the lung tissues of the vaccinated mice and control were detected 5 days after the challenge, and expressed as Log10TCID50/g of tissues. M1–M5 are mice vaccinated with RBD-Fc, and C1–C5 indicate the control mice. The limit of detection was 1.5 Log10TCID50/g.
Fig. 4
Fig. 4
Histopathological examinations of mouse lung tissues. All sections of mouse lung tissues were stained with H&E and examined under microscopy (original magnification 200×). C1–C5 and M1–M5 are control mice and RBD-Fc vaccinated mice, respectively. (A) Histopathological changes of lung tissues from control mice administered with PBS. Obvious histopathological changes were observed in lung tissues from control mice, including diffuse alveolar damages characterized by disruption of alveolar walls and flooding of alveolar lumina with serosanguineous exudates admixed with neutrophils and alveolar macrophages, thickened alveolar walls lined by type 2 pneumocytes, and alveolar macrophages in alveolar lumina. (B) Histological characterization of lung tissues from RBD-Fc vaccinated mice. No significant histopathological changes of lung tissues were observed in four of five RBD-Fc-vaccinated mice (M2–M5). Only M1 mouse exhibited mild histopathological damages in lung tissues. But compared to the control mice, M1 mouse revealed a little damage such as thickened alveolar walls with interstitial mononuclear cells and lymphocytes infiltrates, and with congestion but no markedly hemorrhage or effusion in the alveolar spaces of lung tissues.
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