Discovery and intranasal administration of a SARS-CoV-2 broadly acting neutralizing antibody with activity against multiple Omicron subvariants.

BACKGROUND: The continual emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern, in particular the newly emerged Omicron (B.1.1.529) variant and its BA.X lineages, has rendered ineffective a number of previously FDA emergency use authorized SARS-CoV-2 neutralizing antibody therapies. Furthermore, those approved antibodies with neutralizing activity against Omicron BA.1 are reportedly ineffective against the subset of Omicron subvariants that contain a R346K substitution, BA.1.1, and the more recently emergent BA.2, demonstrating the continued need for discovery and characterization of candidate therapeutic antibodies with the breadth and potency of neutralizing activity required to treat newly diagnosed COVID-19 linked to recently emerged variants of concern. METHODS: Following a campaign of antibody discovery based on the vaccination of Harbor H2L2 mice with defined SARS-CoV-2 spike domains, we have characterized the activity of a large collection of spike-binding antibodies and identified a lead neutralizing human IgG1 LALA antibody, STI-9167. FINDINGS: STI-9167 has potent, broad-spectrum neutralizing activity against the current SARS-COV-2 variants of concern and retained activity against each of the tested Omicron subvariants in both pseudotype and live virus neutralization assays. Furthermore, STI-9167 nAb administered intranasally or intravenously provided protection against weight loss and reduced virus lung titers to levels below the limit of quantitation in Omicron-infected K18-hACE2 transgenic mice. CONCLUSIONS: With this established activity profile, a cGMP cell line has been developed and used to produce cGMP drug product intended for intravenous or intranasal use in human clinical trials. FUNDING: Funded by CRIPT (no. 75N93021R00014), DARPA (HR0011-19-2-0020), and NCI Seronet (U54CA260560).

Unbiased approach to identify and assess efficacy of human SARS-CoV-2 neutralizing antibodies.

Coronavirus disease 2019 (COVID-19) continues to significantly impact the global population, thus countermeasure platforms that enable rapid development of therapeutics against variants of SARS-CoV-2 are essential. We report use of a phage display human antibody library approach to rapidly identify neutralizing antibodies (nAbs) against SARS-CoV-2. We demonstrate the binding and neutralization capability of two nAbs, STI-2020 and STI-5041, against the SARS-CoV-2 WA-1 strain as well as the Alpha and Beta variants. STI-2020 and STI-5041 were protective when administered intravenously or intranasally in the golden (Syrian) hamster model of COVID-19 challenged with the WA-1 strain or Beta variant. The ability to administer nAbs intravenously and intranasally may have important therapeutic implications and Phase 1 healthy subjects clinical trials are ongoing.

Characteristics of Liver Function in Patients With SARS-CoV-2 and Chronic HBV Coinfection.

BACKGROUND & AIMS: Coronavirus disease 2019 (COVID-19) is a major global health threat. We aimed to describe the characteristics of liver function in patients with SARS-CoV-2 and chronic hepatitis B virus (HBV) coinfection. METHODS: We enrolled all adult patients with SARS-CoV-2 and chronic HBV coinfection admitted to Tongji Hospital from February 1 to February 29, 2020. Data of demographic, clinical characteristics, laboratory tests, treatments, and clinical outcomes were collected. The characteristics of liver function and its association with the severity and prognosis of disease were described. RESULTS: Of the 105 patients with SARS-CoV-2 and chronic HBV coinfection, elevated levels of liver test were observed in several patients at admission, including elevated levels of alanine aminotransferase (22, 20.95%), aspartate aminotransferase (29, 27.62%), total bilirubin (7, 6.67%), gamma-glutamyl transferase (7, 6.67%), and alkaline phosphatase (1, 0.95%). The levels of the indicators mentioned above increased substantially during hospitalization (all P < .05). Fourteen (13.33%) patients developed liver injury. Most of them (10, 71.43%) recovered after 8 (range 6-21) days. Notably the other, 4 (28.57%) patients rapidly progressed to acute-on-chronic liver failure. The proportion of severe COVID-19 was higher in patients with liver injury (P = .042). Complications including acute-on-chronic liver failure, acute cardiac injury and shock happened more frequently in patients with liver injury (all P < .05). The mortality was higher in individuals with liver injury (28.57% vs 3.30%, P = .004). CONCLUSION: Liver injury in patients with SARS-CoV-2 and chronic HBV coinfection was associated with severity and poor prognosis of disease. During the treatment of COVID-19 in chronic HBV-infected patients, liver function should be taken seriously and evaluated frequently.

Coagulopathy of Patients with COVID-19 is Associated with Infectious and Inflammatory Markers.

BACKGROUND: SARS-CoV-2 infection activates coagulation and stimulates innate immune system. Little is known about coagulopathy and response of inflammation and infection in ICU patients with COVID-19. Derangement of coagulation and markers of infection and inflammation induced by SARS-CoV-2 infection, as well as their correlations were elucidated. METHODS: One hundred eight ICU patients with COVID-19 (28 survivors and 80 non-survivors) in Tongji hospital and Wuhan Jinyintan hospital, in Wuhan, China were included. Coagulation parameters, infectious and inflammatory markers were dynamically analysed. The correlation between coagulopathy of patients and infectious and inflammatory markers was verified. RESULTS: SARS-CoV-2-associated coagulopathy occurred in most cases of critical illness. Raised values of d-dimer and FDP were measured in all patients, especially in non-survivors, who had longer PT, APTT, INR, as well as TT, and lower PTA and AT compared to survivors. SIC and DIC mostly occurred in non-survivors. CRP, ESR, serum ferritin, IL-8, and IL-2R increased in all patients, and were much higher in non-survivors who had significantly higher levels of IL-6 and IL-10. D-dimer was positively associated with CRP, serum ferritin (p = 0.02), PCT (p < 0.001), and IL-2R (p = 0.007). SIC scores were positively correlated with CRP (p = 0.006), PCT (p = 0.0007), IL-1ß (p = 0.048), and IL-6 (p = 0.009). DIC scores were positively associated with CRP (p < 0.0001), ESR (p = 0.02), PCT (p < 0.0001), serum ferritin (p < 0.0001), IL-10 (p = 0.02), and IL-2R (p = 0.0005). CONCLUSION: Prothrombotic state, SIC, and DIC are the characteristics of coagulation in ICU patients with COVID-19. CRP, ESR, serum ferritin, IL-8, IL-2R, IL-6, and PCT were stimulated by SARS-CoV-2 infection. CRP, PCT, serum ferritin, and IL-2R indicate the coagulopathy severity of patients with COVID-19.

Acute Physiology and Chronic Health Evaluation II Score as a Predictor of Hospital Mortality in Patients of Coronavirus Disease 2019.

OBJECTIVES: Coronavirus disease 2019 has emerged as a major global health threat with a great number of deaths in China. We aimed to assess the association between Acute Physiology and Chronic Health Evaluation II score and hospital mortality in patients with coronavirus disease 2019, and to compare the predictive ability of Acute Physiology and Chronic Health Evaluation II score, with Sequential Organ Failure Assessment score and Confusion, Urea, Respiratory rate, Blood pressure, Age 65 (CURB65) score. DESIGN: Retrospective observational cohort. SETTING: Tongji Hospital in Wuhan, China. SUBJECTS: Confirmed patients with coronavirus disease 2019 hospitalized in the ICU of Tongji hospital from January 10, 2020, to February 10, 2020. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Of 178 potentially eligible patients with symptoms of coronavirus disease 2019, 23 patients (12.92%) were diagnosed as suspected cases, and one patient (0.56%) suffered from cardiac arrest immediately after admission. Ultimately, 154 patients were enrolled in the analysis and 52 patients (33.77%) died. Mean Acute Physiology and Chronic Health Evaluation II score (23.23 ± 6.05) was much higher in deaths compared with the mean Acute Physiology and Chronic Health Evaluation II score of 10.87 ± 4.40 in survivors (p < 0.001). Acute Physiology and Chronic Health Evaluation II score was independently associated with hospital mortality (adjusted hazard ratio, 1.07; 95% CI, 1.01-1.13). In predicting hospital mortality, Acute Physiology and Chronic Health Evaluation II score demonstrated better discriminative ability (area under the curve, 0.966; 95% CI, 0.942-0.990) than Sequential Organ Failure Assessment score (area under the curve, 0.867; 95% CI, 0.808-0.926) and CURB65 score (area under the curve, 0.844; 95% CI, 0.784-0.905). Based on the cut-off value of 17, Acute Physiology and Chronic Health Evaluation II score could predict the death of patients with coronavirus disease 2019 with a sensitivity of 96.15% and a specificity of 86.27%. Kaplan-Meier analysis showed that the survivor probability of patients with coronavirus disease 2019 with Acute Physiology and Chronic Health Evaluation II score less than 17 was notably higher than that of patients with Acute Physiology and Chronic Health Evaluation II score greater than or equal to 17 (p < 0.001). CONCLUSIONS: Acute Physiology and Chronic Health Evaluation II score was an effective clinical tool to predict hospital mortality in patients with coronavirus disease 2019 compared with Sequential Organ Failure Assessment score and CURB65 score. Acute Physiology and Chronic Health Evaluation II score greater than or equal to 17 serves as an early warning indicator of death and may provide guidance to make further clinical decisions.