ABSTRACT
Understanding who is at risk of progression to severe COVID-19 is key to effective treatment. We studied correlates of disease severity in the COMET-ICE clinical trial that randomized 1:1 to placebo or to sotrovimab, a monoclonal antibody for the treatment of SARS-CoV-2 infection. Several laboratory parameters identified study participants at greater risk of severe disease, including a high neutrophil-lymphocyte ratio (NLR), a negative SARS-CoV-2 serologic test and whole blood transcriptome profiles. Sotrovimab treatment in these groups was associated with normalization of NLR and the transcriptomic profile, and with a decrease of viral RNA in nasopharyngeal samples. Transcriptomics provided the most sensitive detection of participants who would go on to be hospitalized or die. To facilitate timely measurement, we identified a 10-gene signature with similar predictive accuracy. In summary, we identified markers of risk for disease progression and demonstrated that normalization of these parameters occurs with antibody treatment of established infection.
Subject(s)
COVID-19ABSTRACT
VIR-7831 and VIR-7832 are dual action monoclonal antibodies (mAbs) targeting the spike glycoprotein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). VIR-7831 and VIR-7832 were derived from a parent antibody (S309) isolated from memory B cells of a 2003 severe acute respiratory syndrome coronavirus (SARS-CoV) survivor. Both mAbs contain an LS mutation in the Fc region to prolong serum half-life and potentially enhance distribution to the respiratory mucosa. In addition, VIR-7832 encodes an Fc GAALIE mutation that has been shown previously to evoke CD8+ T-cells in the context of an in vivo viral respiratory infection. VIR-7831 and VIR-7832 potently neutralize live wild-type SARS-CoV-2 in vitro as well as pseudotyped viruses encoding spike protein from the B.1.1.7, B.1.351 and P.1 variants. In addition, they retain activity against monoclonal antibody resistance mutations that confer reduced susceptibility to currently authorized mAbs. The VIR-7831/VIR-7832 epitope does not overlap with mutational sites in the current variants of concern and continues to be highly conserved among circulating sequences consistent with the high barrier to resistance observed in vitro. Furthermore, both mAbs can recruit effector mechanisms in vitro that may contribute to clinical efficacy via elimination of infected host cells. In vitro studies with these mAbs demonstrated no enhancement of infection. In a Syrian Golden hamster proof-of concept concept wildtype SARS-CoV-2 infection model, animals treated with VIR-7831 had less weight loss, and significantly decreased total viral load and infectious virus levels in the lung compared to a control mAb. Taken together, these data indicate that VIR-7831 and VIR-7832 are promising new agents in the fight against COVID-19.