ABSTRACT
The ongoing COVID-19 pandemic and the frequent emergence of new SARS-CoV-2 variants of concern (VOCs), requires continued development of fast and effective therapeutics. Recently, we identified high-affinity neutralizing nanobodies (Nb) specific for the receptor-binding domain (RBD) of SARS-CoV-2, which are now being used as biparatopic Nbs (bipNbs) to investigate their potential as future drug candidates. Following detailed in vitro characterization, we chose NM1267 as the most promising candidate showing high affinity binding to several recently described SARS-CoV-2 VOCs and strong neutralizing capacity against a patient isolate of B.1.351 (Beta). To assess if bipNb NM1267 confers protection against SARS-CoV-2 infection in vivo, human ACE2 transgenic mice were treated by intranasal route before infection with a lethal dose of SARS-CoV-2. NM1267-treated mice showed significantly reduced disease progression, increased survival rates and secreted less infectious virus via their nostrils. Histopathological analyses and in situ hybridization further revealed a drastically reduced viral load and inflammatory response in lungs of NM1267-treated mice. These data suggest, that bipNb NM1267 is a broadly active and easily applicable drug candidate against a variety of emerging SARS-CoV-2 VOCs.
ABSTRACT
SummaryO_ST_ABSBackgroundC_ST_ABSPatients infected with SARS-CoV-2 exhibit a highly variable clinical course, varying from barely discernible signs of disease, to moderate flu-like symptoms and, occasionally, with life-threatening pneumonia and/or cytokine storm. The relationship between the nasopharyngeal virus load, IgA and IgG antibodies to both the S1-RBD-protein and the N-protein as well the neutralizing activity (NAbs) against SARS-CoV-2 in the blood of moderately afflicted COVID-19 patients has not been investigated longitudinally so far. MethodsSeveral new serological methods to examine these parameters were developed and validated for the longitudinal investigation in three patients of a family which underwent a mild course of COVID-19. FindingsWe observed that the virus load had almost completely disappeared after about four weeks, whereas serum antibodies showed a contrasting course. IgA levels to S1-RBD-protein and, to a lesser extent, to the N-protein, peaked about three weeks after clinical disease onset but declined soon thereafter. IgG levels rose continuously, reaching a plateau approximately six weeks after disease onset. NAbs in serum reached a peak about four weeks after disease onset but dropped to a lower level about six weeks later. InterpretationOur data establishes associations of virus neutralization and a serological immune response foremost against Sars-CoV-2 S1-RDB-protein in a longitudinal manner.
ABSTRACT
Males develop more severe SARS-CoV-2 infection related disease outcome than females. Herein, sex hormones were repeatedly proposed to play an important role in Covid-19 pathophysiology and immunity. However, it is yet unclear whether sex hormones are associated with Covid-19 outcome in males and females. In this study, we analyzed sex hormones, cytokine and chemokine responses as well as performed a large profile analysis of 600 metabolites in critically-ill male and female Covid-19 patients in comparison to healthy controls and patients with coronary heart diseases as a prime Covid-19 comorbidity. We here show that dysregulated sex hormones, IFN-{gamma} levels and unique metabolic signatures are associated with critical illness in Covid-19 patients. Both, male and female Covid-19 patients, present elevated estradiol levels which positively correlates with IFN-{gamma} levels. Male Covid-19 patients additionally display severe testosterone and triglyceride deficiencies as compared to female patients and healthy controls. Our results suggest that male Covid-19 patients suffer from multiple metabolic disorders, which may lead to higher risk for fatal outcome. These findings will help to understand molecular pathways involved in Covid-19 pathophysiology.
