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Clinical Trials: Infectious Disease/Immune System
IRB No. 20-084-2 (Dr. Zhichao Fan, PI): Mechanisms and Roles of Integrin Activation of Human Blood Leukocytes
Background, Rationale and Significance: Integrins are key mediators of the recruitment of leukocytes which play critical roles in human immunity and inflammatory diseases. Insights about Integrin function hold out the prospect improved inflammatory disease prevention. Blood leukocytes including neutrophils, monocytes, and lymphocytes, all have a recruitment cascade during inflammation and infections. They can first roll on the vascular endothelium, firmly adhere (arrest) on the vascular endothelium, spread on the vascular endothelium, perform intravascular crawling, transmigrate through vascular endothelium, and finally, migrate to the site of inflammation or infections. This cascade is essential for the recruitment and immunological function of leukocytes and involved in many infectious and inflammatory diseases. Integrins, are a group of adhesion molecules vital for the recruitment cascade. Studying the mechanisms and roles of integrin activation will bring new insights into leukocyte recruitment and immune functions and invite discovery of novel treatments for infectious and inflammatory diseases. (See Protocol-Appendix for Leukocyte Recruitment, Integrin Activation Pathways and Super Resolution/ Flow Imaging Graphics- pg.10-16) This protocol is used to develop a continuing supply of fresh blood donations for the Integrin Research Laboratories under the direction of the PI @ UConn Health, Dept of Immunology where the PI recently joined. 2 recent PI authored publications are included for reviewer, explanatory of the Integrin research for which materials are to be utilized in ongoing experiments.
IRB No. 10-273S-2 (Dr. Robert Clark, PI): The Role of Unique Lipids Derived From Common Human Bacteria in Multiple Sclerosis
Study description not available
IRB No. 20-186-1 (Dr. Biree Andemariam, PI): SARS-CoV-2 Serosurveillance in Health Care Workers on COVID-19 patients
Infection with SARS-CoV-2 causes human COVID-19 (HCoV-19). Health care workers are at risk of being exposed to this virus. Since majority of COVID19 patients have been asymptomatic or mildly symptomatic, it is important to identify those who have been exposed, converted to sero-positivity and acquired potential immunity. Finding of seroconversion among healthcare workers will help understand the epidemiology of this infection in the healthcare setting and potentially better inform the workers and their associates
IRB No. 20-192-2.F (Dr. Bruce Liang, PI): A randomized, open-label study of the vascular and microbiologic efficacy of dipyridamole plus standard care vs. standard care in hospitalized COVID19 patients.
Infection with SARS-CoV-2 causes human COVID-19 (HCoV-19). In severe illness, COVID 19 infection results in lymphopenia, elevated D-dimer levels, hypercoagulation, hypertension, acute respiratory distress syndrome (ARDS), and acute cardiac injury. Dipyridamole (DIP) is an FDA- approved drug which inhibits adenosine uptake that leads to increased extracellular adenosine which in turn stimulates adenosine receptor mediated vasodilatory, anti-platelet and anti-inflammatory effects. These effects are also augmented by DIP's inhibition of phosphodiesterase. In addition, DIP appears to bind to the HCoV-19 protease enzyme and also suppresses HCoV-19 proliferation in Vero E6 cells with an IC50 less than or equal to 100 nM. Plasma concentrations in humans from routine dosing regimens (regimen of 50 mg three times per day) exceed this IC50 value for the duration of the dosing interval. In vivo anti-viral effect for DIP, very recently has been demonstrated in vesicular stomatitis virus-induced pneumonia with prolongation of survival (1). There is limited clinical data on dipyridamole in COVID-19 patients. At this writing, the remdesivir and hydroxychloroquine are now approved for investigations, by the FDA to treat these patients. Although the exact mechanism by which these drugs may work in this infection is not known, DIP exerts its potential salutary effect via different mechanism. In a preliminary, un-randomized trial with a small number of COVID19 patients treated with prophylactic anticoagulation therapy (Hubei China, January 2020) --the addition of DIP led to increased platelet and lymphocyte counts with reduced D-dimer level, compared to standard of care patients (1). Additionally, 2 weeks after DIP treatment of 12 patients, 3 of the severe cases and all 4 of the mild-to-moderate cases were discharged from the hospital. One patient died while 3 remaining patients were in remission in the hospital. In the control group, 3 of the 3 mild-to-moderate cases and 1 of 4 severe cases were discharged and only 1 was in remission in the severe group with 1 death. However, the trial was not randomized and was small in size, hence there was no statistical analysis for clinical outcomes. 100 will be enrolled with in an open label, randomized controlled trial with 50 being randomized to receive dipyridamole, 100 mg tid for 7 days being added to Standard Care. (1). Therapeutic effects of dipyridamole on COVID-19 patients with coagulation dysfunction Xiaoyan Liu, Zhou, Hai-Bin Luo, et. al doi: https://doi.org/10.1101/2020.02.27.20027557
IRB No. 21-095J-2 (Dr. George Kuchel, PI): Dynamic assessment of immune system in COVID-19 patients Pilot Study 2: Aging and the Cutaneous Immune System in Young and Older Adults
This prospective, single-site pilot study is designed to determine the feasibility to recruit and enroll COVID-19 convalescent adults into a study that will assess immunity changes associated with aging. To complete a 8-subject pilot study with the following aims: To establish feasibility of conducting a larger trial with the enrollment of adults that have recovered from COVID-19 and healthy adults, we will enroll 4 younger adults (25-50 years) and 4 older adults (>65 years) and collect skin samples using punch biopsy and blood samples. To enumerate and assess functional status of dendritic cells, monocytes, macrophages, T cells and B cells in skin biopsies using multi-marker immunofluorescence and histo-cytometry (10+ markers) as well as image mass spectrometry (IMC) (30+ marker analysis in intact tissues). This is a prospective, single-site pilot study that will use an established and comprehensive approach to cellular and molecular analysis of non-dissociated tissues that will be applied herein to assess tissue immunity and changes associated with COVID-19 and aging. In this study, a total of 8 healthy adult participants who have either recovered from COVID-19 or have had no history of confirmed COVID-19 will be enrolled: four (4) older adults aged 65 years and older and four (4) younger adults aged 25-50 years. Participation in the study will involve two study visits scheduled on two consecutive days and up to three follow-ups via phone or email over three weeks after the biopsies. Subjects will be administered an intradermal injection of saline on one arm and two punch skin biopsies will be performed at the site of injection and adjacent the next day under local anesthesia. The biopsy sites will be closed with an absorbable suture. Peripheral blood specimens (50 mL each) will be collected at both study visits. Self-reported medical history, medication history and demographics information will be collected at Visit 1.
IRB No. 21-149J-1 (Dr. George Kuchel, PI): High-resolution single cell profiling of SARS-CoV-2 vaccine responsiveness in healthy adults
This study is a collaboration between The Jackson Laboratory for Genomic Medicine (JAX) in Farmington, CT and UConn Health in Farmington, CT. All recruitment, enrollment, clinical data, and sample collection will occur at the UConn Center on Aging (COA) or at the Clinical Research Center (CRC), under the direction of Dr. George Kuchel, Professor of Medicine and Director of the UConn COA. This prospective, single-site, multi-cohort observational study is designed to determine how vaccine formulations and subject age affect immunologic responses to SARS-CoV-2 vaccine and to uncover the molecular signatures (genomics) elicited by novel COVID-19 vaccines. Up to 114 SARS-CoV-2 naïve healthy men and women aged 21 years or over, from all races and ethnic backgrounds that receive the Pfizer/Moderna/J&J COVID-19 vaccine will be enrolled to this study over a one-year period. Participation will involve nine (9) study visits for adults receiving the two-dose Pfizer or Moderna vaccine and seven (7) study visits for adults receiving the single-dose J&J vaccine. Blood samples (at all 9/7 visits) and nasal swabs (at three visits) will be collected.
IRB No. 22-179J-1 (Dr. George Kuchel, PI): A deep longitudinal analysis of next generation influenza vaccines in older adults
This study is a collaboration between The Jackson Laboratory for Genomic Medicine (JAX) in Farmington, CT and UConn Health in Farmington, CT. All recruitment, enrollment, clinical data, and sample collection will occur at the UConn Center on Aging (COA), at UConn Health in Farmington, CT under the direction of Dr. George Kuchel, Professor of Medicine and Director of the UConn COA. Coded samples collected at Visits 1-17 will be securely transported to the Jackson Laboratory for Genomic Medicine (JAX), located on the UConn Health campus, for processing, storage, sequencing, and analysis. Dr. Duygu Ucar will oversee sample management and sample and data analysis per protocol. In this study, a total of sixty (60) healthy adults aged 65 years and older who have had no history of confirmed COVID-19 and have not received influenza vaccination for the approaching influenza season will be enrolled in the study and vaccinated with influenza vaccines approved by the U.S Food and Drug Administration (FDA) and recommended by the Centers for Disease Control and Prevention (CDC) for individuals ≥65 years. All participants receive influenza vaccine during the 2022-23, 2023-24, and 2024-25 influenza seasons. Participants will receive Fluzone® Quadrivalent High-Dose vaccine during the 2022-23 and 2024-25 flu seasons and FLUAD® Quadrivalent during the 2023-24 flu season. Blood samples will be collected from the participants at each of the seventeen study visits over three years. Nasal swab and stool samples will also be collected from participants at 7 time-points across the study period. The study is not designed to assess safety or tolerability of the influenza vaccines administered as part of this proposed study. By performing comprehensive profiling of their blood antibodies and immune cells over time, we will be able to associate specific age-related immune alterations with vaccine responder or non-responder status, thus allowing us to pinpoint biological pathways that can be targeted to enhance vaccine efficacy and that can also help us to progress towards developing a universal influenza vaccine.