Enhanced protective immunity against SARS-CoV-2 elicited by a VSV vector expressing a chimeric spike protein

• Published in: Signal transduction and targeted therapy 2021-11, Vol.6 (1), p.389-12, Article 389
• Main Authors: Li, Hongyue, Zhang, Yuhang, Li, Dong, Deng, Yong-Qiang, Xu, Hongde, Zhao, Chaoyue, Liu, Jiandong, Wen, Dan, Zhao, Jianguo, Li, Yongchun, Wu, Yong, Liu, Shujun, Liu, Jiankai, Hao, Junfeng, Yuan, Fei, Duo, Shuguang, Qin, Cheng-Feng, Zheng, Aihua
• Format: Article
• Language: English
• Subjects: 631/250/590; 631/326/590; ACE2; Angiotensin-converting enzyme 2; Animal models; Animals; Antibodies, Neutralizing - blood; Antibodies, Viral - blood; Antigens; Cancer Research; Cell Biology; Chimeras; Coronaviruses; COVID-19; COVID-19 - prevention & control; COVID-19 vaccines; COVID-19 Vaccines - immunology; Cross-reactivity; Gene Knock-In Techniques; HEK293 Cells; Humans; Immune response (humoral); Immunization; Internal Medicine; Lymphocytes T; Medicine; Medicine & Public Health; Mice; Mice, Inbred C57BL; Neutralization Tests; Oncology; Pathology; Recombinant Fusion Proteins - immunology; SARS-CoV-2; Severe acute respiratory syndrome coronavirus 2; Spike Glycoprotein, Coronavirus - genetics; Spike Glycoprotein, Coronavirus - immunology; Spike protein; Transplantation
• ISSN: 2059-3635; 2095-9907; 2059-3635
• DOI: 10.1038/s41392-021-00797-9

SARS-CoV-2 and SARS-CoV are genetically related coronavirus and share the same cellular receptor ACE2. By replacing the VSV glycoprotein with the spikes (S) of SARS-CoV-2 and SARS-CoV, we generated two replication-competent recombinant viruses, rVSV-SARS-CoV-2 and rVSV-SARS-CoV. Using wild-type and human ACE2 (hACE2) knock-in mouse models, we found a single dose of rVSV-SARS-CoV could elicit strong humoral immune response via both intranasal (i.n.) and intramuscular (i.m.) routes. Despite the high genetic similarity between SARS-CoV-2 and SARS-CoV, no obvious cross-neutralizing activity was observed in the immunized mice sera. In macaques, neutralizing antibody (NAb) titers induced by one i.n. dose of rVSV-SARS-CoV-2 were eight-fold higher than those by a single i.m. dose. Thus, our data indicates that rVSV-SARS-CoV-2 might be suitable for i.n. administration instead of the traditional i.m. immunization in human. Because rVSV-SARS-CoV elicited significantly stronger NAb responses than rVSV-SARS-CoV-2 in a route-independent manner, we generated a chimeric antigen by replacing the receptor binding domain (RBD) of SARS-CoV S with that from the SARS-CoV-2. rVSV expressing the chimera (rVSV-SARS-CoV/2-RBD) induced significantly increased NAbs against SARS-CoV-2 in mice and macaques than rVSV-SARS-CoV-2, with a safe Th1-biased response. Serum immunized with rVSV-SARS-CoV/2-RBD showed no cross-reactivity with SARS-CoV. hACE2 mice receiving a single i.m. dose of either rVSV-SARS-CoV-2 or rVSV-SARS-CoV/2-RBD were fully protected against SARS-CoV-2 challenge without obvious lesions in the lungs. Our results suggest that transplantation of SARS-CoV-2 RBD into the S protein of SARS-CoV might be a promising antigen design for COVID-19 vaccines.