ABSTRACT
The emergence of the SARS-CoV-2 Omicron variant capable of escaping neutralizing antibodies emphasizes the need for prophylactic strategies to complement vaccination in fighting the COVID-19 pandemic. Nasal epithelium is rich in the ACE2 receptor and important for SARS-CoV-2 transmission by supporting early viral replication before seeding to the lung1. Intranasal administration of SARS-CoV-2 neutralizing antibodies or antibody fragments has shown encouraging potential as a protective measure in animal models2-5. However, there remains a need for SARS-CoV-2 blocking agents that are more economical to produce in large scale, while less vulnerable to mutational variation in the neutralization epitopes of the viral Spike glycoprotein. Here we describe TriSb92, a highly manufacturable trimeric human nephrocystin SH3 domain-derived antibody mimetic targeted against a conserved region in the receptor-binding domain of the Spike. TriSb92 potently neutralizes SARS-CoV-2 and its variants of concern, including Delta and Omicron. Intranasal administration of a modest dose of TriSb92 (5 or 50 micrograms) as early as eight hours before the challenge with SARS-CoV-2 B.1.351 efficiently protected mice from infection. The target epitope of TriSb92 was defined by cryo-EM, which revealed triggering of a conformational shift in the Spike trimer rather than competition for ACE2 binding as the molecular basis of its strong inhibitory action. Our results highlight the potential of intranasal inhibitors in protecting susceptible individuals from SARS-CoV-2 infection, and describe a novel type of inhibitor that could be of use in addressing the challenge posed by the Omicron variant.
ABSTRACT
RationaleActivins are inflammatory and tissue-repair-related members of the TGF{beta}-superfamily that have been implicated in the pathogenesis of several immuno-inflammatory disorders including sepsis/acute respiratory distress syndrome (ARDS). We hypothesized that they might be of particular relevance to COVID-19 pathophysiology. ObjectivesTo assess the involvement of the Activin-Follistatin-axis in COVID-19 pathophysiology. MethodsLevels of Activins -A, -B and their physiological inhibitor Follistatin, were retrospectively analyzed in 314 serum samples from 117 COVID-19 patients derived from two independent centers and compared with common demographic, clinical and laboratory parameters. Optimal-scaling with ridge-regression was used to screen variables and establish a prediction model. Main ResultsThe Activin/Follistatin-axis was significantly deregulated during the course of COVID-19 and was independently associated with severity and in-hospital mortality. FACT-CLINYCoD, a novel disease scoring system, adding one point for each of Follistatin >6235 pg/ml, Activin-A >591 pg/ml, Activin-B >249 pg/ml, CRP >10.3 mg/dL, LDH >427 U/L, Intensive Care Unit (ICU) admission, Neutrophil/Lymphocyte-Ratio >5.6, Years of Age >61, Comorbidities >1 and D-dimers >1097 ng/ml, efficiently predicted and monitored fatal outcome independently of multiplicity and timing of sampling (AUC: 0.951{+/-}0.032, p<10-6). Validation in 35 samples derived from a third hospital indicated comparable AUC (0.958{+/-}0.086, p=0.032). ConclusionThis study unravels the link between Activin/Folistatin-axis and COVID-19 mortality and introduces FACT-CLINYCoD, a novel pathophysiology-based tool that copes with the dynamic and heterogeneous nature of COCVID-19, predicts disease outcome and supports clinical decision making. Prospective large-scale validation of this calculator, as well as investigation of the mechanisms linking Activin/Folistatin-axis to COVID-19 pathogenesis is warranted.
