Immunization with recombinant accessory protein-deficient SARS-CoV-2 protects against lethal challenge and viral transmission

Ye, C.; Park, J.-G.; Chiem, K.; Dravid, P.; Allue Guardia, A.; Garcia-Vilanova, A.; kapoor, A.; Walter, M. R.; Kobie, J.; Plemper, R. K.; Torrelles, J. B.; Martinez-Sobrido, L.

doi:10.1101/2022.03.13.484172

bioRxiv · 10.1101/2022.03.13.484172

Immunization with recombinant accessory protein-deficient SARS-CoV-2 protects against lethal challenge and viral transmission

Ye, C.·Park, J.-G.·Chiem, K.·Dravid, P.·Allue Guardia, A.·Garcia-Vilanova, A.·kapoor, A.·Walter, M. R.·Kobie, J.·Plemper, R. K.·Torrelles, J. B.·Martinez-Sobrido, L.

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Abstract

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has led to a worldwide Coronavirus Disease 2019 (COVID-19) pandemic. Despite high efficacy of the authorized vaccines, protection against the surging variants of concern (VoC) was less robust. Live-attenuated vaccines (LAV) have been shown to elicit robust and long-term protection by induction of host innate and adaptive immune responses. We sought to develop a COVID-19 LAV by generating 3 double open reading frame (ORF)-deficient recombinant (r)SARS-CoV-2 simultaneously lacking two accessory open reading frame (ORF) proteins (ORF3a/ORF6, ORF3a/ORF7a, and ORF3a/ORF7b). Here, we report that these double ORF-deficient rSARS-CoV-2 have slower replication kinetics and reduced fitness in cultured cells as compared to their parental wild-type (WT) counterpart. Importantly, these double ORF-deficient rSARS-CoV-2 showed attenuation in both K18 hACE2 transgenic mice and golden Syrian hamsters. A single intranasal dose vaccination induced high levels of neutralizing antibodies against different SARS-CoV-2 VoC, and also activated viral component-specific T-cell responses. Notably, the double ORF-deficient rSARS-CoV-2 were able to protect, as determined by inhibition of viral replication, shedding, and transmission, against challenge with SARS-CoV-2. Collectively, our results demonstrate the feasibility to implement these double ORF-deficient rSARS-CoV-2 as safe, stable, immunogenic and protective LAV for the prevention of SARS-CoV-2 infection and associated COVID-19 disease.

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Ye, C., Park, J.-G., Chiem, K., Dravid, P., Allue Guardia, A., Garcia-Vilanova, A., kapoor, A., Walter, M. R., Kobie, J., Plemper, R. K., Torrelles, J. B., Martinez-Sobrido, L.. 2022-03-14. Immunization with recombinant accessory protein-deficient SARS-CoV-2 protects against lethal challenge and viral transmission. https://doi.org/10.1101/2022.03.13.484172

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