Abstract
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.
Highlights
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is single-stranded positive sense enveloped RNA virus.[1,2,3] After its initial outbreak in December 2019, SARS-CoV-2 has infected more than 175 million humans worldwide and caused more than 3.8 million deaths
We developed two replication-competent recombinant Vesicular stomatitis virus (VSV) viruses expressing the S of SARS-CoV-2 WH01 strain[35] with a 21 amino acids deletion at the C-terminus and SARS-CoV BJ01 strain with a 19 aa at the C-terminus[12] (Fig. 1a)
By comparing the immune responses induced by Recombinant VSV (rVSV)-SARS-CoV-2 and rVSV-SARS-CoV, we found the cross-neutralization between SARS-CoV and SARS-CoV-2 is very limited, indicating the difficulty in the development of a universal coronavirus vaccine
Summary
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is single-stranded positive sense enveloped RNA virus.[1,2,3] After its initial outbreak in December 2019, SARS-CoV-2 has infected more than 175 million humans worldwide and caused more than 3.8 million deaths (as of June 2021, covid19.who.it). The S protein, especially the receptor binding domain (RBD), is the major target of neutralizing antibodies.[6] Most vaccine platforms, such as adenovirus-vector, recombinant protein subunit and nucleic acid vaccines, use the S or RBD domain as the immunogen.[7,8,9] Severe acute respiratory syndrome coronavirus (SARS-CoV), a close relative of SARS-CoV2,10,11 shares 75% identical amino acids in the S protein with SARSCoV-2. ACE2 is present in arterial and venous endothelial cells and arterial smooth muscle cells in almost all organs, with low level of ACE2 in the skeletal muscle.[17]
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