As the frequency and geographic distribution of COVID-19 progressed, so did the concern for the safety of all persons engaged in research activities and in turn the impact of the virus on public health. A comprehensive review of research in the department resulted in cessation of all nonessential research in wet/dry laboratories across campus. Research was shut down in mid-March 2020. These efforts were organized by the Vice Chair of Basic Research, Lloyd Cantley, MD, and the Vice Chair of Clinical Research, Robert Soufer, MD.
Labs Shuttered Across the School of Medicine
The process of shutting down the laboratories required tremendous collaboration by all laboratory personnel. With limited notice, laboratories were able to suspend nearly all in-person experiments while following environmental and safety standards.
Personnel prepared their work spaces for shutdown by ramping down all operations. Laboratories ceased all functions without knowing when experiments would resume. From inspecting equipment to halting shipping, receiving, and management of materials, to more complicated issues like waste management and decontamination, procedures were followed to minimize safety issues. For research involving animals, veterinary care and husbandry was provided primarily through the Yale Animal Resource Center (YARC).
Since most on-campus research efforts were paused, laboratory personnel were encouraged to be productive and challenge themselves intellectually by working from home, including analyzing data, writing grants, and planning experiments. Many found themselves holding virtual meetings with colleagues and becoming creative with remote work.
The restrictions put in place had a significant effect on the department’s traditional research projects. While some research was disrupted entirely, other projects were repurposed to confront the current health crisis: research on SARS-CoV-2. In late March, the Yale Center for Clinical Investigation (YCCI) implemented resources to assist researchers who wanted to pursue this work. Yale’s Research, Clinical and Data Driven Responses to COVID-19 website began tracking data repositories, biorepositories, and other resources to assist in research efforts.
For many junior investigators, the pandemic had the potential to derail their career progression. In academia, milestones are set for faculty members depending on their rank and chosen track. Faculty also have a specified amount of time to fulfill research requirements. For example, an assistant professor in the Traditional, Investigator, and Clinician-Scientist tracks may devote between 50-80% of their time to research. But as the clinical demands of the pandemic required more of their time and research was halted across Yale, these faculty members were at risk of failing to meet these requirements in the allotted amount of time.
Yale University and Yale School of Medicine (YSM) made some programmatic changes to support the faculty during the pandemic. In March 2020, Provost Scott Strobel announced that Yale would grant tenure-track faculty a one-year extension to their current appointment. YSM partnered with departments across the school to offer gap funding to support junior investigators who needed additional financial support. The program was announced in August 2020. A new section on the CV supplement was also added to note COVID-19 clinical work.
Eligible faculty for the gap funding were assistant professors on the Traditional, Investigator, and Clinician-Scientist tracks with 50% or more effort dedicated to research. Of the 33 members of the department who applied for the funding, 100% received it.
Advanced Therapeutics Group ![]()
The department formed the Advanced Therapeutics Group, an interdisciplinary group of departmental and basic science faculty that met weekly through July 2020 to discuss features of the disease; review the scientific basis of such candidate therapies as convalescent plasma; and make connections for members to obtain more information. Fifty-one members from the department participated in the group, which led to numerous clinical trials and key observations of the disease. The team was led by Rick Bucala, MD, PhD, the Waldemar Von Zedtwitz Professor of Medicine (Rheumatology) and professor of pathology and of epidemiology (microbial diseases); and chief of rheumatology, allergy and immunology; and Naftali Kaminski, MD, the Boehringer-Ingelheim Endowed Professor of Internal Medicine and chief of pulmonary, critical care, and sleep medicine.
Reactivation of Research
A three-phase reactivation of in-person research began in early June 2020. The purpose of the phased approach was to allow for the gradual reopening of research activity, while maintaining the health and safety of all staff members. The reactivation phases followed strict procedures and guidelines from both the State of Connecticut and Yale University to decrease the spread of COVID-19.
In order to mitigate the possibility of an outbreak, specific procedures were set down for those whose research qualified them to return to campus. The procedures included training on safety, daily health checks and symptom monitoring, and the required use of PPE; and physical and temporal distancing as well as rigorous cleaning standards.
Each phase granted more access to on-campus research with the flexibility of shifting between phases based on federal, state, and local public health guidance in a rapidly evolving and changing situation. As was the case at YSM, research was shut down at VACHS. For research to start again, each area had to submit a plan to the local research office that had to be cleared by both Hospital Epidemiology and the research group leadership.
Equitable Access to COVID Data for Research: Yale DOM COVID Explorer
In mid-July, in order to provide equitable access to COVID-related hospital data for research purposes, the Department of Internal Medicine launched the Yale DOM COVID Explorer (DOM-COVX).
Created by F. Perry Wilson, MD, MSCE, and his team at the Clinical and Translational Research Accelerator, the DOM-COVX tool is an open-access dataset with clinical data from more than 3000 COVID-19-positive patients across Yale New Haven Health. This resource is available to the Department of Internal Medicine and can be used to generate hypotheses; to support research projects; to provide preliminary data for grant applications; and to foster inquisitiveness among department faculty. This project highlights the faculty’s commitment to an expansion of the department’s intellectual culture and the vision of continued research development within the department. To date, 20 data engagement groups are working with this information, and several papers and grant submissions have been published or submitted as a result.
Phase 3 Vaccine Trials ![]()
In August 2020, Yale School of Medicine and Yale New Haven Hospital announced the start of Phase 3 of the Pfizer vaccine trial at the hospital. This groundbreaking study was one of several vaccine trials to be undertaken in hope of finding a scientifically validated vaccine in the shortest amount of time. The study is a collaboration between BioNTech SE and Pfizer using modified RNA and is a novel way to create a vaccine for use in humans. Rather than using the part or whole of the actual virus in an inactive form to create immunity, this vaccine candidate uses a genetic code (modified RNA) to make the body generate proteins that resemble the SARS CoV-2 virus spike protein, thereby stimulating development of antibodies against it. Antibodies against the spike protein, a projection from the COVID virus that allows it to attack cells and infect a person, may block the infection from taking hold if the body comes in contact with the virus. In Phases 1 and 2 of the trial, this novel vaccine has proven safe and effective in generating an appropriate immune response. This third phase hopes to show that it can prevent infection. Onyema Ogbuagu, MBBCh, is the principal investigator on the study.
COVID-Related Research
Many COVID-related research projects emerged as a result of the department’s commitment to innovation, creativity, and scientific rigor.
Internal Medicine has many active research projects investigating complications of the disease on various organ systems; overall health disparities across different populations; and operational and logistical challenges posed by the pandemic. *Current projects include:
- Abnormal blood clotting and platelet dysfunction in patients with COVID-19
- Anti-rheumatic disease therapies for the treatment of COVID-19
- Decreased plasma renalase associated with worse outcomes in COVID-19
- Mechanism of acute kidney injury in SARS-CoV-2 and therapeutic utility of renalase agonists
- Cardiovascular complications stratified by age and outcomes for patients with cardiac conditions
- COVID-19’s effects on vulnerable populations and health disparities across different populations
- COVID-19’s effects on patients with cancer and hematologic malignancies
- COVID-19’s effects on children
- COVID-19-induced collateral damage in limited resource settings
- COVID-19’s interaction with insulin signaling and obesity-associated insulin resistance in a genetically modified mouse model
- Evaluation of volatile organic compounds as diagnostic markers of COVID-19
- Fatty acid metabolism and its impact on T-cell immune response
- Functional assays involving humoral response
- Genetic predisposition to severe COVID-19 disease
- Identification of cytokine profiles associated with BMI in patients with COVID-19
- Immunologic responses
- Impact of COVID-19 on the liver
- Interactions among diabetes, obesity, and hyperglycemia in older patients with COVID-19
- Mask adherence among health care workers
- Mouse modeling of COVID-19 disease
- New-onset diabetes as a result of COVID-19
- Neurological complications and neuroinvasive potential of the disease
- NLRP3 activation
- Outcomes of COVID-19 infection in patients with HIV and opioid use disorder
- Provider satisfaction with e-consults during the pandemic
- Rates of new-onset type 1 diabetes and diabetic ketoacidosis in COVID-19 versus influenza infections
- Restructuring residencies for a possible second wave
- SARS-CoV-2 interaction with host cells
- SARS-CoV-2 viral load correlation with clinical severity in immunocompromised patients
- Self-replicating RNA vaccine against SARS-CoV-2 and novel pandemic viruses
- Targeted goals of care for older patients with COVID-19
- Transition of in-person clinics to telehealth
- Use of tocilizumab for COVID-19 patients
- VALIANT project to track the outcome of older adults admitted with COVID-19
- Viral proteins in urine and other biospecimens for use as biomarkers of kidney injury and the virus’ impact on kidney transplant recipients
Department researchers are also working on the following clinical trials:*
- Camostat mesylate in COVID-19 outpatients
- Convalescent plasma
- MIF antagonism
- Immunophenotyping assessment in a COVID-19 cohort (IMPACC)
- Pfizer vaccine trial
- Remdesivir
- SARS-CoV-2 recombinant spike protein nanoparticle vaccine (SARS-CoV-2 rS) with Matrix-M1 adjuvant
- Targeting TMPRSS2 in early COVID-19
Other clinical research projects quickly developed with the support of YCCI and the Smilow Clinical Trials office teams led by Roy Decker, MD/PhD, Joyce Tull, MSN, RN, CCRP, and Patricia LoRusso, DO. The clinical trial enrollments were quickly resumed after the teams developed new workflows for remote operations.
One unsolved mystery for doctors and patients is the long-term effects of COVID-19. Alfred Lee, MD, PhD, partnered with Hyung Chun, MD, to examine blood samples of 68 patients with COVID-19. They found that injury to endothelial cells may be a key indicator of COVID-19 severity.
Samit Shah, MD, PhD, and Alan Enriquez, MD, contacted national training program leaders of their respective subspecialties to assess the impact of COVID-19 on their training programs. They each published their findings:
- Shah S, Castro-Domingez Y, et al. “Impact of the COVID-19 pandemic on interventional cardiology training in the United States.” Catheterization and Cardiovascular Interventions, August 2020: doi:10.1002/ccd.29198.
This paper concluded that the COVID-19 pandemic has substantially affected interventional CV training in the United States, with many fellows at risk of failing to satisfy current program procedural requirements.
- Singla VK, Jain S, Ganeshan R, Rosenfeld LE, Enriquez AD. “The Impact of the COVID-19 Pandemic on Cardiac Electrophysiology Training: A Survey Study.” Journal of Cardiovascular Electrophysiology, November 4, 2020. doi: 10.1111/jce.14805.
This study found that while nearly all fellows and programs experienced an interruption in procedural volume, only a minority felt unprepared for independent practice.
In July, Amy Justice, MD, PhD, was chosen to participate in the COVID-19 Insights Partnership, a joint initiative between the U.S. Department of Veterans Affairs (VA) and the Departments of Energy (DOE) and Health and Human Services (HHS). As VA-DOE Scientific Liaison and Head of the Data/Analytics Group, Justice will work closely with VA and DOE scientists to maximize the clinical effectiveness of their joint research. She has served in a similar role for another research initiative between VA and DOE for the past two years. The COVID-19 Insights Partnership will focus on increasing knowledge of COVID-19, including vaccines, treatments, virology, and other critical topics.
Research on COVID-19 and Health Disparities
Under the leadership of Marcella Nunez-Smith, MD, MHS, from the Section of General Internal Medicine, the Yale Equity Research and Innovation Center (ERIC) has partnered with collaborators across Yale, the City of New Haven, the region, and nationally to respond to the COVID-19 crisis. A team of over 50 YSM researchers has met regularly since April to investigate disparities in access to testing, outcomes, and effects of the pandemic on non-COVID ambulatory service delivery across Yale New Haven Health. ERIC partnered with the African American Research Council and the NAACP to conduct a first-of-its-kind national survey assessing African Americans’ COVID knowledge, attitudes, and behaviors. They are working with colleagues at the Yale School of Public Health to evaluate the State of Connecticut Department of Public Health Contact Tracing Program. Thanks to a generous donor gift, ERIC launched a project to examine supportive services for self-quarantine or isolation at the local, regional, and national levels. Finally, with an NIMHD-funded RADx-UP award, ERIC researchers will enhance and amplify the COVID-19 diagnostic testing cascade in the U.S. Virgin Islands and Puerto Rico by using community-based assets— Federally Qualified Health Centers (FQHCs) and their community-based organization (CBO) partners—to address barriers to full participation in the testing continuum from diagnosis through to self-isolation and quarantine.
Yale-Led medRxiv Leading Source of COVID-19 Discoveries
A site co-founded by Harlan Krumholz, MD, SM, and Joseph Ross, MD, MHS, for sharing preliminary medical research called medRxiv (pronounced “med archive”) has become a leading source of scientific discovery related to the COVID-19 pandemic. Known as a preprint server—an online archive of scholarly papers that have not yet been peer-reviewed— medRxiv allows scientists to share new discoveries and research findings in the clinical and health sciences as rapidly as possible in order to accelerate possible treatments.
The researchers launched medRxiv in June 2019 in a partnership with the Long Island-based Cold Spring Harbor Laboratory and with The BMJ, a global medical journal. The site received a $2 million award from the Chan Zuckerberg Initiative in May 2020 to support its operations. Krumholz and Ross recently reported on the submissions, downloads, and experience over the first year of medRxiv in the November 10, 2020 issue of JAMA. Sharing scientific data is especially critical during a pandemic. As of November 18, 2020, there were over 13,400 articles posted on medRxiv for the scientific community to view, including over 8,300 reports of COVID-19 research from around the globe. These included studies of the impact of so-called super spreaders on disseminating COVID-19; the estimation of the true infection rate of COVID-19 in each country; and a novel antimicrobial coating that has been found to be effective against the virus for hours after application.
* At the time of publication, the projects and clinical trials were underway.