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Adv Mater ; 33(51): e2104362, 2021 Dec.
Article in English | MEDLINE | ID: covidwho-1469404


The development of effective vaccines that can be rapidly manufactured and distributed worldwide is necessary to mitigate the devastating health and economic impacts of pandemics like COVID-19. The receptor-binding domain (RBD) of the SARS-CoV-2 spike protein, which mediates host cell entry of the virus, is an appealing antigen for subunit vaccines because it is efficient to manufacture, highly stable, and a target for neutralizing antibodies. Unfortunately, RBD is poorly immunogenic. While most subunit vaccines are commonly formulated with adjuvants to enhance their immunogenicity, clinically-relevant adjuvants Alum, AddaVax, and CpG/Alum are found unable to elicit neutralizing responses following a prime-boost immunization. Here, it has been shown that sustained delivery of an RBD subunit vaccine comprising CpG/Alum adjuvant in an injectable polymer-nanoparticle (PNP) hydrogel elicited potent anti-RBD and anti-spike antibody titers, providing broader protection against SARS-CoV-2 variants of concern compared to bolus administration of the same vaccine and vaccines comprising other clinically-relevant adjuvant systems. Notably, a SARS-CoV-2 spike-pseudotyped lentivirus neutralization assay revealed that hydrogel-based vaccines elicited potent neutralizing responses when bolus vaccines did not. Together, these results suggest that slow delivery of RBD subunit vaccines with PNP hydrogels can significantly enhance the immunogenicity of RBD and induce neutralizing humoral immunity.

Antibodies, Neutralizing/immunology , Hydrogels/chemistry , Spike Glycoprotein, Coronavirus/immunology , Vaccines, Subunit/immunology , Adjuvants, Immunologic/chemistry , Animals , Antibodies, Neutralizing/blood , Antibodies, Viral/blood , Antibodies, Viral/immunology , COVID-19/prevention & control , COVID-19/virology , CpG Islands/genetics , Female , Humans , Immunity, Humoral , Mice , Mice, Inbred C57BL , Nanoparticles/chemistry , Polymers/chemistry , Protein Domains/immunology , SARS-CoV-2/chemistry , SARS-CoV-2/immunology , SARS-CoV-2/isolation & purification , SARS-CoV-2/metabolism , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/isolation & purification , Vaccines, Subunit/chemistry , Vaccines, Subunit/metabolism
J Thromb Thrombolysis ; 53(3): 567-575, 2022 Apr.
Article in English | MEDLINE | ID: covidwho-1432598


Although certain risk factors have been associated with morbidity and mortality, validated emergency department (ED) derived risk prediction models specific to coronavirus disease 2019 (COVID-19) are lacking. The objective of this study is to describe and externally validate the COVID-19 risk index (CRI). A large retrospective longitudinal cohort study was performed to analyze consecutively hospitalized patients with COVID-19. Multivariate regression using clinical data elements from the ED was used to create the CRI. The results were validated with an external cohort of 1799 patients from the MI-COVID19 database. The primary outcome was the composite of the need for mechanical ventilation or inpatient mortality, and the secondary outcome was inpatient mortality. A total of 1020 patients were included in the derivation cohort. A total of 236 (23%) patients in the derivation cohort required mechanical ventilation or died. Variables independently associated with the primary outcome were age ≥ 65 years, chronic obstructive pulmonary disease, chronic kidney disease, cerebrovascular disease, initial D-dimer > 1.1 µg/mL, platelet count < 150 K/µL, and severity of SpO2:FiO2 ratio. The derivation cohort had an area under the receiver operator characteristic curve (AUC) of 0.83, and 0.74 in the external validation cohort Calibration shows close adherence between the observed and expected primary outcomes within the validation cohort. The CRI is a novel disease-specific tool that assesses the risk for mechanical ventilation or death in hospitalized patients with COVID-19. Discrimination of the score may change given continuous updates in contemporary COVID-19 management and outcomes.

COVID-19 , Aged , COVID-19/therapy , Emergency Service, Hospital , Hospitalization , Humans , Longitudinal Studies , Respiration, Artificial , Retrospective Studies , Risk Assessment/methods , Risk Factors , SARS-CoV-2
Am J Cardiol ; 133: 154-161, 2020 10 15.
Article in English | MEDLINE | ID: covidwho-671381


Although certain risk factors have been associated with increased morbidity and mortality in patients admitted with Coronavirus Disease 2019 (COVID-19), the impact of cardiac injury and high-sensitivity troponin-I (hs-cTnI) concentrations are not well described. In this large retrospective longitudinal cohort study, we analyzed the cases of 1,044 consecutively admitted patients with COVID-19 from March 9 until April 15. Cardiac injury was defined by hs-cTnI concentration >99th percentile. Patient characteristics, laboratory data, and outcomes were described in patients with cardiac injury and different hs-cTnI cut-offs. The primary outcome was mortality, and the secondary outcomes were length of stay, need for intensive care unit care or mechanical ventilation, and their different composites. The final analyzed cohort included 1,020 patients. The median age was 63 years, 511 (50% patients were female, and 403 (40% were white. 390 (38%) patients had cardiac injury on presentation. These patients were older (median age 70 years), had a higher cardiovascular disease burden, in addition to higher serum concentrations of inflammatory markers. They also exhibited an increased risk for our primary and secondary outcomes, with the risk increasing with higher hs-cTnI concentrations. Peak hs-cTnI concentrations continued to be significantly associated with mortality after a multivariate regression controlling for comorbid conditions, inflammatory markers, acute kidney injury, and acute respiratory distress syndrome. Within the same multivariate regression model, presenting hs-cTnI concentrations were not significantly associated with outcomes, and undetectable hs-cTnI concentrations on presentation did not completely rule out the risk for mechanical ventilation or death. In conclusion, cardiac injury was common in patients admitted with COVID-19. The extent of cardiac injury and peak hs-cTnI concentrations were associated with worse outcomes.

Betacoronavirus , Coronavirus Infections/complications , Heart Diseases/etiology , Inpatients , Pneumonia, Viral/complications , Troponin I/blood , Adult , Aged , Biomarkers/blood , COVID-19 , Coronavirus Infections/epidemiology , Female , Follow-Up Studies , Heart Diseases/blood , Heart Diseases/epidemiology , Humans , Incidence , Intensive Care Units , Male , Michigan/epidemiology , Middle Aged , Pandemics , Pneumonia, Viral/epidemiology , Prognosis , Retrospective Studies , SARS-CoV-2 , Survival Rate/trends