The adaptive immune response, consisting of antiviral T and B cells, is critical for providing protection against viruses such as SARS-CoV-2, both during an active infection and later following a subsequent exposure. They can both also potentially contribute to pathogenesis if they are overstimulated. Despite these advances in knowledge, there are still significant gaps in understanding of what constitutes a protective or immunopathologic immune response and its durability. Significant knowledge gaps also remain pertaining to the early recognition of COVID patients with increased risk of clinical deterioration who require continued hospitalization and the use of more intensive treatments designed to improve outcomes. Data from non-COVID patients with MI show that platelet surface expression of FcγRIIa, the low-affinity receptor for the Fc fragment of immunoglobulin (Ig) G, identifies patients at high and low risk of subsequent cardiovascular events. Platelet expression of FcγRIIa is increased by interferon γ20 that is significantly elevated in severe COVID-19 infections. The high prevalence of arterial thrombosis among COVID-19 patients and the central role of thrombosis in respiratory failure support the hypothesis that elevated platelet expression of FcγRIIa will identify COVID patients at increased risk of thrombotic complications and clinical deterioration. In addition to the potential role of platelet activation in thrombosis associated with COIVD-19, the endothelium may also play a significant role. The investigators hypothesize that elevated EMPs in plasma will identify patients at high risk of thrombosis and clinical deterioration. To begin to address the knowledge gaps above and obtain preliminary data for future large grant submission, the investigators propose a small, prospective, single-center cohort study that will enroll patients hospitalized for COVID-19 infection and exhibiting a range of disease severity. Biosamples will be obtained and used to study T and B cells, antibody repertoire, and durability of protective immunity, and also to quantify platelet expression of FcγRIIa and circulating EMPs, as described in the protocol.
Since December 2019, the novel coronavirus (SARS-CoV-2) and associated COVID-19 illness has spread worldwide. Globally, there are \>86 million infections and over 1.8 million confirmed deaths, with the pandemic continuing at record levels throughout the USA. While new data on COVID-19 are emerging daily, several knowledge gaps remain, including understanding of the adaptive immune response to infection, the propensity for infected patients to experience thrombotic events, and identification of biomarkers that might predict clinical deterioration. The adaptive immune response, consisting of antiviral T and B cells, is critical for providing protection against viruses such as SARS-CoV-2, both during an active infection and later following a subsequent exposure. They can both also potentially contribute to pathogenesis if they are overstimulated. Much has been learned about the T and B cell responses to SARS-CoV-2 since the beginning of the COVID-19 pandemic. The most comprehensive study to date shows that most individuals make a balanced T and B cell response that persists for at least 8 months. Despite these advances in knowledge, there are still significant gaps in understanding of what constitutes a protective or immunopathologic immune response and their durability. Significant knowledge gaps also remain pertaining to the early recognition of COVID patients with increased risk of clinical deterioration who require continued hospitalization and the use of more intensive treatments designed to improve outcomes. In addition, the identification of low risk patients who can be discharged from the hospital would reduce the use of potentially scarce medical resources, particularly during a surge. Among patients with thrombosis, 49% required critical care and 43% died. Data from non-COVID patients with MI show that platelet surface expression of FcγRIIa, the low-affinity receptor for the Fc fragment of immunoglobulin (Ig) G, identifies patients at high and low risk of subsequent cardiovascular events. Platelet expression of FcγRIIa is increased by interferon γ20 that is significantly elevated in severe COVID-19 infections. Because FcγRIIa amplifies platelet activation, greater expression of FcγRIIa on the surface of the platelet increases platelet reactivity. The high prevalence of arterial thrombosis among COVID-19 patients and the central role of thrombosis in respiratory failure support the hypothesis that elevated platelet expression of FcγRIIa will identify COVID patients at increased risk of thrombotic complications and clinical deterioration. In addition to the potential role of platelet activation in thrombosis associated with COIVD-19, the endothelium may also play a significant role. The endothelium is a key site of entry for COVID-19 infection and endothelial injury contributes to thrombotic events that increase morbidity and mortality. Endothelial microparticles (EMPs), submicron membranous vesicles indicating endothelial activation and injury, are released by the endothelium into blood and reflect the competency of endothelial function by identifying endothelial activation and injury, which promote thrombosis. Circulating EMPs can be quantified with the use of flow cytometry. The investigators hypothesize that elevated EMPs in plasma will identify patients at high risk of thrombosis and clinical deterioration. To begin to address the knowledge gaps above and obtain preliminary data for future large grant submission, the investigators propose a small, prospective, single-center cohort study that will enroll patients hospitalized for COVID-19 infection and exhibiting a range of disease severity. Blood will be obtained on study days 1, 3±1, 7±1 (and every 7±1 days thereafter up to day 28 while hospitalized), and again at 12 months of follow up. Nasopharyngeal (NP) swabs will be collected on these same study days through day 28, but not at 12 months. These biosamples will be used to study T and B cells, antibody repertoire, and durability of protective immunity, and also to quantify platelet expression of FcγRIIa and circulating EMPs, as described in the protocol.
Study Type
OBSERVATIONAL
Enrollment
16
This is observational--there is no intervention
University of Vermont
Burlington, Vermont, United States
To compare the polyfunctionality and frequency of antiviral CD4 and CD8 T cells.
The investigators hypothesize patients with severe disease will have higher frequencies of antiviral T cells that contribute to the cytokine storm observed in the most severe cases of COVID-19.
Time frame: Four weeks (while hospitalized)
To compare the polyfunctionality and frequency of antiviral CD4 and CD8 T cells.
The investigators hypothesize patients with severe disease will have higher frequencies of antiviral T cells that contribute to the cytokine storm observed in the most severe cases of COVID-19.
Time frame: 12 months after hospital admission
To compare the frequency of plasmablasts (early B cells that produce antiviral antibodies) and plasma antiviral antibody titer during acute infection.
The investigators predict that patients with severe disease will have greater numbers of antiviral plasmablasts and plasma antiviral antibody levels compared to those with mild disease.
Time frame: Four weeks (while hospitalized)
To compare the frequency of plasmablasts (early B cells that produce antiviral antibodies) and plasma antiviral antibody titer during acute infection.
The investigators predict that patients with severe disease will have greater numbers of antiviral plasmablasts and plasma antiviral antibody levels compared to those with mild disease.
Time frame: 12 months after hospital admission
The number of virus specific CD4 T cells will be measured using flow cytometry.
The investigators hypothesize that severe disease will result in the formation of higher magnitude antiviral B and T cell CHRMS (Medical) #STUDY00001369 Approved: 1/25/2021 4Human subjects protocol form 7/19/19responses during acute disease due to increased viral load and antigen in these patients. The investigators further predict that higher frequency T and B cells during acute disease will correlate with more robust durability of these responses during convalescence.
Time frame: Four weeks (while hospitalized)
The number of virus specific CD8 T cells will be measured using flow cytometry.
The investigators hypothesize that severe disease will result in the formation of higher magnitude antiviral B and T cell CHRMS (Medical) #STUDY00001369 Approved: 1/25/2021 4Human subjects protocol form 7/19/19responses during acute disease due to increased viral load and antigen in these patients. The investigators further predict that higher frequency T and B cells during acute disease will correlate with more robust durability of these responses during convalescence.
Time frame: Four weeks (while hospitalized)
The number of virus specific CD4 T cells will be measured using flow cytometry.
The investigators hypothesize that severe disease will result in the formation of higher magnitude antiviral B and T cell CHRMS (Medical) #STUDY00001369 Approved: 1/25/2021 4 Human subjects protocol form 7/19/19 responses during acute disease due to increased viral load and antigen in these patients. The investigators further predict that higher frequency T and B cells during acute disease will correlate with more robust durability of these responses during convalescence.
Time frame: 12 months after hospital admission
The number of virus specific CD8 T cells will be measured using flow cytometry.
The investigators hypothesize that severe disease will result in the formation of higher magnitude antiviral B and T cell CHRMS (Medical) #STUDY00001369 Approved: 1/25/2021 4Human subjects protocol form 7/19/19responses during acute disease due to increased viral load and antigen in these patients. The investigators further predict that higher frequency T and B cells during acute disease will correlate with more robust durability of these responses during convalescence.
Time frame: 12 months after hospital admission
To obtain preliminary data on platelet activation in patients hospitalized with COVID-19
To compare platelet activation, measured by platelet surface FcγRIIa while in hospital and 12 months after infection, in patients with severe (i.e., mechanical ventilation in ICU) vs. non-severe (hospitalized, but not in an ICU) COVID-19 disease.
Time frame: Four weeks (while hospitalized)
To obtain preliminary data on platelet activation in patients hospitalized with COVID-19
To compare platelet activation, measured by platelet surface FcγRIIa while in hospital and 12 months after infection, in patients with severe (i.e., mechanical ventilation in ICU) vs. non-severe (hospitalized, but not in an ICU) COVID-19 disease.
Time frame: 12 months after hospital admission
To obtain preliminary data on endothelial activation in patients hospitalized with COVID-19
To compare endothelial activation, measured by circulating EMPs while in hospital and 12 months after infection, in patients with severe (i.e., mechanical ventilation in ICU) vs. non-severe (hospitalized, but not in an ICU) COVID-19 disease.
Time frame: Four weeks (while hospitalized)
To obtain preliminary data on endothelial activation in patients hospitalized with COVID-19
To compare endothelial activation, measured by circulating EMPs while in hospital and 12 months after infection, in patients with severe (i.e., mechanical ventilation in ICU) vs. non-severe (hospitalized, but not in an ICU) COVID-19 disease.
Time frame: 12 months after hospital admission
Preliminarily determine if the FcγRIIa and EMPs have utility as biomarkers
To preliminarily determine if the FcγRIIa and EMPs have utility as biomarkers for prediction of thrombotic events and clinical deterioration in hospitalized patients with COVID-19.
Time frame: Four weeks (while hospitalized)
Preliminarily determine if the FcγRIIa and EMPs have utility as biomarkers
To preliminarily determine if the FcγRIIa and EMPs have utility as biomarkers for prediction of thrombotic events and clinical deterioration in hospitalized patients with COVID-19.
Time frame: 12 months after hospital admission
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