ABSTRACT
Introduction: Vaccine hesitancy and the continuous emergence of SARS-CoV-2 variants of concern that partially escape vaccine-induced immune responses highlight the urgent need for the development of effective therapeutics for COVID-19 patients. Hypothesis: The Engineered high-affinity ACE2 peptide has a therapeutic effect for SARS-CoV-2 and its variant-induced acute lung vascular injury. Methods: K18-hACE2 transgenic mice were inoculated with SARS-CoV-2 WA-1/2020 or P.1 variant of concerns to induce acute lung injury. The sACE22.v2.4-IgG1 was injected once a day for consecutively 7 days starting from 12 hours at 10 mg/kg/day or 24 hours at 15 mg/kg/day postSARS-CoV-2 inoculation. Results: We demonstrated that the higher binding affinity of sACE22.v2.4-IgG1 to S proteins of the original SARS-CoV-2 WA-1/2020 isolate and the B.1.1.7 (Alpha, UK isolate), B.1.351 (Beta, South Africa isolate), P.1 (Gamma, Brazil isolate), and B.1.617.2 (Delta, India isolate) SARS-CoV-2 variants of concern compared to wild-type soluble ACE2. Using humanized K18-hACE2 mice, we found that both SARS-CoV-2 isolate WA-1/2020 and the P.1 variant of concern induced severe acute lung endothelial injury, which resulted in the severe transvascular leak, lung edema, and death. The P.1 variant induced severe lung vascular leak and death at an earlier time point at Day 5 compared to WA-1 at Day 7, consistent with increased viral entry and replication. Treatment with sACE22.v2.4-IgG1 decoy peptide could be initiated as late as 24h after inoculation with a lethal dose of the SARS-CoV-2 WA-1/2020 isolate and profoundly reduces lung vascular injury and mortality For the P.1 variant of concern, ACE22.v2.4-IgG1 decoy peptide markedly improved survival and reduced lung vascular injury if administered early at 12 hours post-inoculation. Conclusion: sACE22.v2.4-IgG1 has an exceptional therapeutic efficacy to SARS-CoV-2 WA-1/2020 and variant P.1 -induced acute lung vascular injury.