Comprehensive Evaluation of ACE2-Fc Combination with Neutralization Antibody on Broad Protection against SARS-CoV-2 and Its Variants

Abstract

Emerging SARS-CoV-2 variants are threatening the efficacy of antibody therapies. Combination treatments including ACE2-Fc have been developed to overcome the evasion of neutralizing antibodies (NAbs) in individual cases. Here we conducted a comprehensive evaluation of this strategy by combining ACE2-Fc with NAbs of diverse epitopes on the RBD. NAb+ACE2-Fc combinations efficiently neutralized HIV-based pseudovirus carrying the spike protein of the Delta or Omicron variants, achieving a balance between efficacy and breadth. In an antibody escape assay using replication-competent VSV-SARS-CoV-2-S, all the combinations had no escape after fifteen passages. By comparison, all the NAbs without combo with ACE2-Fc had escaped within six passages. Further, the VSV-S variants escaped from NAbs were neutralized by ACE2-Fc, revealing the mechanism of NAb+ACE2-Fc combinations survived after fifteen passages. We finally examined ACE2-Fc neutralization against pseudovirus variants resistant to the therapeutic antibodies that have currently been in clinic. Our results suggest ACE2-Fc is a universal combination partner to combat SARS-CoV-2 variants including Delta and Omicron.

Elucidating Design Principles for Engineering Cell‐Derived Vesicles to Inhibit SARS‐CoV‐2 Infection

“…[8,10] Although untested here, we hypothesize that variants such as Omicron would be similarly inhibited by decoy vesicles because this variant requires ACE2 for entry, [63] the Omicron Spike-ACE2 affinity is similar in strength to that of the Beta strain [9] evaluated here, and ACE2-based soluble protein inhibitors confer neutralization of Omicron. [64] We speculate that avidity is largely responsible for the efficacy of decoy nanoparticles and confers advantages in terms of potency and robustness to drug resistance compared to soluble receptor protein decoys. Given our estimated levels of ACE2 loading (Figure S3A,B, Supporting Information), our decoy particles contain approximately one ACE2 molecule per 100-500 nm 2 area of exposed outer membrane, on average.…”

Turning point: A new global COVID‐19 wave or a signal of the beginning of the end of the global COVID‐19 pandemic?

“…It binds to protein antigens as an adjuvant to induce significantly stronger humoral and cellular responses. A comprehensive evaluation was conducted on the extensive protective effect of ACE2‐FC combined neutralizing antibodies against SARS‐CoV‐2 and its variants 55–57 . Until specific Omicron vaccines are available, new universal vaccines and booster shots tailored to Omicron have been successful.…”