Pathogenicity, immunogenicity, and protective ability of an attenuated SARS-CoV-2 variant with a deletion at the S1/S2 junction of the spike protein

Summary: 

Ca-DelMut is an attenuated SARS-CoV-2 vaccine candidate. Hamsters vaccinated with Ca-DelMut were fully protected from live challenge with two different SARS-CoV-2 strains. Immunization reduced viral titers to undetectable levels in the lungs, induced RBD specific neutralizing antibodies, abrogated weight loss and reduced lung pathology. Infection with Ca-DelMut did not induce the high levels of proinflammatory cytokines (INF-g, CCR4, IL-10, IL-21, TNF-a) seen in WT virus infections. Notably, there was no activation of IL-6, which has been recognized as a biomarker for COVID-19 disease severity. 

Research Highlights  

1. Researchers adapted a variant of SARS-CoV-2 with a deletion in the S1/S2 junction of the spike protein, ‘Ca-DelMut’ 

2. Ca-DelMut replicates efficiently in vitro 

3. Ca-DelMut does not induce elevated levels of proinflammatory cytokines or body weight loss in a hamster model 

4. Ca-DelMut did trigger a neutralizing antibody response in hamsters 

5. Ca-DelMut immunized hamsters challenged with WT SARS-CoV-2 showed no body weight loss and had no signs of viral replication in the respiratory tract  

Impact for COVID-19 research:  

• Develop a vaccine for SARS-CoV2/COVID19   

Methodologies: 

• Study Type: in vitro, in vivo (hamster) 

• Important cell lines/viral models used:  

Cell lines: Vero E6, Calu-3 

Viral models: SARS-CoV-2 WT virus HK-13 and HK-95 for viral challenge, SARS-CoV-2 WT virus HK-001a for neutralization assay, SARS-CoV-2 Cal-DelMut as candidate vaccine 

• Key Techniques: Anti-spike RBD IgG ELISA, intranasal vaccination of hamsters, histopathological assessment of hamster lung and nasal tissue, plaque assay, neutralization assay of sera from hamsters, qRT-PCR for cytokine profiling  

Limitations: 

• N=3 for each sub-group, which is too small to confer statistical significance to the results. 

• No mention of blinding e.g. for the histological analysis. 

• No description of replicates for ELISA data. Would be good to see raw data with CVs calculated in the Supplementary Figures. 

• Done in hamster model, rather than a non-human primate model. This may not translate well to humans. 

• Uses replication in Vero E6 cells to claim that Ca-DelMut replicates more efficiently in vitro than WT virus, but Vero E6 is a limited model and the Calu-3 data is more equivocal. 

• No statistical comparison included for IL-6 and IL-13 in Figure S3. 

• Likely outside scope of study, but no long-term data on antibody titers or protective efficacy. 

• The paper does not discuss potential safety issues with using an attenuated live virus as a vaccine, and potential to revert to a more pathogenic form in vivo.