To rapidly identify a human monoclonal antibody that potently neutralizes SARS-CoV-2 and that is suitable for clinical development for prevention and treatment of COVID-19 based on convalescent serum screening.
To scale up protein production in order to compare and advance antibody therapeutics against COVID-19 around the world through our international consortium.
To identify the cellular and molecular basis for durable immunity to SARS-CoV-2, with a focus on the identification of T cell receptor and antibody sequences that are shared among virus controllers and the identification of immune dysfunction in COVID-19 that could be treated with existing FDA-approved drugs.
For evaluating the use of cardiac CT angiography (CCTA) to study myocardial injury in COVID-19 patients.
Dr. Julia Schaletzky, Prof. Sarah Stanley and their team at the UCB Drug Discovery center work on a repurposing approach, discovering if compounds with existing safety data in humans can be used to combat COVID-19 infection.
The Seley-Radtke group has developed a series of flexible nucleoside analogues ("fleximers") that have exhibited potent activity against epidemic (i.e. SARS and MERS), and endemic (i.e., NL63) human coronaviruses (CoVs). The Fast Grant will help advance our synthetic efforts as well as to fastrack our preclinical animal studies against SARS-CoV-2 and CoVID-19.
To transcriptionally and serologically profile blood from COVID-19 patients to determine the molecular signatures associated with a spectrum of disease severities. These studies will expand our knowledge of COVID-19 pathogenesis and biomarkers of disease.
For the discovery of human antibodies blocking ACE2 binding by the viral S protein through screening of libraries of billions of human antibodies and their further validation to move them towards clinical trials as an antiviral drug to fight COVID-19 directly.
For discerning immune cell signaling states associated with disease escalation in COVID-19 based on prospective patient samples in order to identify therapeutic targets to modulate inflammation in COVID-19 patients.
For testing of repurposed antiviral compounds in an in-vivo disease model.
To create a COVID-19 vaccine through a novel immunotherapeutic platform.
For the development of non-PCR point-of-care tests for COVID-19 infection, based on engineered peroxidase reporters.
To characterize monoclonal antibodies to Spike protein of SARS-CoV-2 from convalescent human donors for their binding, neutralization and structural properties.
To develop novel COVID-19 therapeutics that target SARS-CoV-2 spike glycoprotein in collaboration with the Baker lab.
To accelerate structure based drug discovery (including biologics) by bringing atomic details to host-viral complexes through the QCRG Structural Biology Consortium.
Clinical trials to determine whether prazosin, a drug already widely used for common medical conditions, can prevent cytokine storms and severe disease in COVID-19 patients when given early after infection.
To investigate ACE-I, ARB and type 5 PDE-I drugs in the context of ARDS and microvascular dysfunction in Covid-19 patients.
To generate a single cell resolution spatial atlas of SARS-CoV-2 infection across multiple tissues in patients with severe COVID-19.
Wang and her group are studying molecules that correlate with immunity against COVID-19. Their studies focus on defining a protective antibody response, and they will investigate whether antibodies have a role in determining the severity of COVID-19. The overarching goal of this work is to guide the development of vaccines and monoclonal antibody therapeutics against SARS-CoV-2.
To investigate the the diversity and longevity of T cell immunity to SARS-COV2 through longitudinal study of Covid-19 patients.
For the discovery of drugs that inhibit macrophage activation for use in severe cases of COVID-19. These drugs may suppress cytokine storm, hyperinflammation, and pulmonary infiltration to prevent respiratory failure.
To use state-of-the-art technologies including organoid culture and single-cell sequencing to identify the cell types infected by SARS-CoV2 and to reveal how the virus disturbs these cells to cause disease.
For developing an isothermal point of care diagnostic test to detect Sars-CoV2.
To investigate the relationship between systemic exposure to hydroxychloroquine and therapeutic efficacy as well as side effects in COVID-19 patients.
For the global COVID Human Genetic Effort, to search for monogenic etiologies for rare individuals naturally resistant to SARS-CoV-2 infections, as well as young and previously healthy individuals who suffered from life-threatening COVID-19.
Abstract
Coronaviruses are prone to emergence into new host species most recently evidenced by SARSCoV-2, the causative agent of the COVID-19 pandemic. Small animal models that recapitulate SARS-CoV-2 disease are desperately needed to rapidly evaluate medical countermeasures (MCMs). SARS-CoV-2 cannot infect wildtype laboratory mice due to inefficient interactions between the viral spike (S) protein and the murine ortholog of the human receptor, ACE2. We used reverse genetics to remodel the S and mACE2 binding interface resulting in a recombinant virus (SARS-CoV-2 MA) that could utilize mACE2 for entry. SARS-CoV-2 MA replicated in both the upper and lower airways of both young adult and aged BALB/c mice. Importantly, disease was more severe in aged mice, and showed more clinically relevant phenotypes than those seen in hACE2 transgenic mice. We then demonstrated the utility of this model through vaccine challenge studies in immune competent mice with native expression of mACE2. Lastly, we show that clinical candidate interferon (IFN) lambda-1a can potently inhibit SARS-CoV-2 replication in primary human airway epithelial cells in vitro, and both prophylactic and therapeutic administration diminished replication in mice. Our mouse-adapted SARS-CoV-2 model demonstrates age-related disease pathogenesis and supports the clinical use of IFN lambda-1a treatment in human COVID-19 infections
Abstract
The novel coronavirus SARS-CoV-2, the causative agent of COVID-19 respiratory disease, has infected over 2.3 million people, killed over 160,000, and caused worldwide social and economic disruption1,2. There are currently no antiviral drugs with proven clinical efficacy, nor are there vaccines for its prevention, and these efforts are hampered by limited knowledge of the molecular details of SARS-CoV-2 infection. To address this, we cloned, tagged and expressed 26 of the 29 SARS-CoV-2 proteins in human cells and identified the human proteins physically associated with each using affinity-purification mass spectrometry (AP-MS), identifying 332 high-confidence SARS-CoV-2-human protein-protein interactions (PPIs). Among these, we identify 66 druggable human proteins or host factors targeted by 69 compounds (29 FDA-approved drugs, 12 drugs in clinical trials, and 28 preclinical compounds). Screening a subset of these in multiple viral assays identified two sets of pharmacological agents that displayed antiviral activity: inhibitors of mRNA translation and predicted regulators of the Sigma1 and Sigma2 receptors. Further studies of these host factor targeting agents, including their combination with drugs that directly target viral enzymes, could lead to a therapeutic regimen to treat COVID-19.
Abstract
The novel coronavirus SARS-CoV-2, the causative agent of COVID-19 respiratory disease, has infected over 2.3 million people, killed over 160,000, and caused worldwide social and economic disruption1,2. There are currently no antiviral drugs with proven clinical efficacy, nor are there vaccines for its prevention, and these efforts are hampered by limited knowledge of the molecular details of SARS-CoV-2 infection. To address this, we cloned, tagged and expressed 26 of the 29 SARS-CoV-2 proteins in human cells and identified the human proteins physically associated with each using affinity-purification mass spectrometry (AP-MS), identifying 332 high-confidence SARS-CoV-2-human protein-protein interactions (PPIs). Among these, we identify 66 druggable human proteins or host factors targeted by 69 compounds (29 FDA-approved drugs, 12 drugs in clinical trials, and 28 preclinical compounds). Screening a subset of these in multiple viral assays identified two sets of pharmacological agents that displayed antiviral activity: inhibitors of mRNA translation and predicted regulators of the Sigma1 and Sigma2 receptors. Further studies of these host factor targeting agents, including their combination with drugs that directly target viral enzymes, could lead to a therapeutic regimen to treat COVID-19.
Abstract
With the first reports on coronavirus disease 2019 (COVID-19), which is caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the scientific community working in the field of type III IFNs (IFN-λ) realized that this class of IFNs could play an important role in this and other emerging viral infections. In this Viewpoint, we present our opinion on the benefits and potential limitations of using IFN-λ to prevent, limit, and treat these dangerous viral infections.
Abstract
Rapid and accurate SARS-CoV-2 diagnostic testing is essential for controlling the ongoing COVID-19 pandemic. The current gold standard for COVID-19 diagnosis is real-time RT-PCR detection of SARS-CoV-2 from nasopharyngeal swabs. Low sensitivity, exposure risks to healthcare workers, and global shortages of swabs and personal protective equipment, however, necessitate the validation of new diagnostic approaches. Saliva is a promising candidate for SARS-CoV-2 diagnostics because (1) collection is minimally invasive and can reliably be self-administered and (2) saliva has exhibited comparable sensitivity to nasopharyngeal swabs in detection of other respiratory pathogens, including endemic human coronaviruses, in previous studies. To validate the use of saliva for SARS-CoV-2 detection, we tested nasopharyngeal and saliva samples from confirmed COVID-19 patients and self-collected samples from healthcare workers on COVID-19 wards. When we compared SARS-CoV-2 detection from patient-matched nasopharyngeal and saliva samples, we found that saliva yielded greater detection sensitivity and consistency throughout the course of infection. Furthermore, we report less variability in self-sample collection of saliva. Taken together, our findings demonstrate that saliva is a viable and more sensitive alternative to nasopharyngeal swabs and could enable at-home self-administered sample collection for accurate large-scale SARS-CoV-2 testing.
Abstract
Rapid and accurate SARS-CoV-2 diagnostic testing is essential for controlling the ongoing COVID-19 pandemic. The current gold standard for COVID-19 diagnosis is real-time RT-PCR detection of SARS-CoV-2 from nasopharyngeal swabs. Low sensitivity, exposure risks to healthcare workers, and global shortages of swabs and personal protective equipment, however, necessitate the validation of new diagnostic approaches. Saliva is a promising candidate for SARS-CoV-2 diagnostics because (1) collection is minimally invasive and can reliably be self-administered and (2) saliva has exhibited comparable sensitivity to nasopharyngeal swabs in detection of other respiratory pathogens, including endemic human coronaviruses, in previous studies. To validate the use of saliva for SARS-CoV-2 detection, we tested nasopharyngeal and saliva samples from confirmed COVID-19 patients and self-collected samples from healthcare workers on COVID-19 wards. When we compared SARS-CoV-2 detection from patient-matched nasopharyngeal and saliva samples, we found that saliva yielded greater detection sensitivity and consistency throughout the course of infection. Furthermore, we report less variability in self-sample collection of saliva. Taken together, our findings demonstrate that saliva is a viable and more sensitive alternative to nasopharyngeal swabs and could enable at-home self-administered sample collection for accurate large-scale SARS-CoV-2 testing.