Benhur Lee, MD, Professor of Microbiology and Ward-Coleman Chair in Microbiology

As governments make plans to reopen their economies and seek reliable ways to ensure their populations can get back to work safely, high-quality antibody testing has emerged as the only way to truly determine which individuals may be protected against the SARS-CoV-2 virus that causes COVID-19. Microbiologists at the Icahn School of Medicine at Mount Sinai have created tests that are answering that need.

A team of scientists led by Benhur Lee, MD, Professor of Microbiology and Ward-Coleman Chair in Microbiology, has developed an assay that tests the quality of an individual’s antibodies to see whether they strongly neutralize the SARS-CoV-2 virus.

Using technology that differs from the more commonly used ELISA method of testing for antibodies, Dr. Lee’s lab has built an identical replica of the outer portion of the SARS-CoV-2 virus, or a pseudo virus. This replica allows researchers to see how well the antibodies from recovered patients actually block SARS-CoV-2 from entering into cells and effectively stop the infection in its tracks. Such neutralizing action provides confirmation that an individual is protected against the virus.

Using the ELISA test and the pseudo virus test together shows how well antibodies that bind to the spike protein also correlate with virus neutralization, says Dr. Lee. The two-step process can provide governments and institutions with a critically important starting point in effectively determining which individuals have been exposed to the virus and carry neutralizing protection.

There are still many unknowns. While the scientific community at large agrees that immunity to the SARS-CoV-2 virus offers protection from re-infection, there is no firm understanding of how long that immunity will last. In addition, researchers do not know whether there is a threshold or level at which antibodies correlate with immunity.

“The gold standard in determining whether someone carries neutralizing antibodies is by using a live virus to test their serum after it has been drawn,” says Dr. Lee. “But this is not scalable for the hundreds of thousands of samples that will need to be tested. So what we developed is a safe surrogate that represents the real virus and can be automated with high-throughput testing in scientific facilities used by many governments and universities around the world.”

Dr. Lee says his pseudo virus assay is essentially a bridge between the binding capability of the ELISA test and the “gold standard” of live-virus neutralization, which requires laboratories to carry a higher, biosafety-level-3 (BSL 3) designation, allowing them to work with dangerous or potentially lethal agents. The pseudo virus can be handled in more commonplace biosafety-level-2 (BSL 2) laboratories that are designated for working with milder agents.

The new pseudo virus can serve as a platform for creating and optimizing potential vaccine designs, generating monoclonal antibodies, and screening anti-viral peptides—all of which would be used to treat or prevent COVID-19.

Government health agencies and universities in the United States and around the world have been sending formal requests to use Dr. Lee’s assay, and he says he will look to them for feedback on how well it is working. “We’re spending time investing in quality control,” he says. “It is important that when we send out this test it works the way we say it works.”

A renowned team of virologists, pathologists, and clinicians at the Mount Sinai Health System developed, validated, and launched a blood test for COVID-19 antibodies that received the U.S. Food and Drug Administration’s (FDA) emergency use authorization late Wednesday.

The blood test determines whether individuals have antibodies to the SARS-CoV-2 virus that causes COVID-19. It is used for the qualitative detection of human IgG antibodies in serum and plasma that is collected from individuals suspected of having been infected with SARS-CoV-2.

Early development of the assay, led by Florian Krammer, PhD, Professor of Microbiology at the Icahn School of Medicine at Mount Sinai, enabled Mount Sinai to become the first health system in the nation to undertake a convalescent plasma program that transfers the antibody-rich plasma from recovered COVID-19 patients into those who are critically ill.

To date, Mount Sinai has identified more than 1,900 donors who are eligible to provide their antibodies. A total of 141 patients have received the protocol, and the results are being evaluated clinically.

Under the leadership of Peter Palese, PhD, Horace W. Goldsmith Professor and Chair of the Department of Microbiology, Mount Sinai has built one of the world’s leading academic institutions for the study of viruses and emerging pathogens. “The COVID-19 antibody test is not only helpful in identifying individuals who could be donors for the convalescent plasma program but also identifies persons who can safely go back to work now that they are immune to the virus,” Dr. Palese says. This important step would allow the nation to return to economic productivity.

“We are grateful to the FDA for granting this expanded authorization so that we can deploy this vital test to the community at large,” says Carlos Cordon-Cardo, MD, PhD, Irene Heinz Given and John LaPorte Given Professor and Chair of Pathology, Molecular and Cell-Based Medicine. Dr. Cordon-Cardo oversaw the validation of the test that is produced by the Mount Sinai Laboratory, Center for Clinical Laboratories. The Mount Sinai Hospital’s Clinical Laboratories are certified by the Clinical Laboratory Improvement Amendments and accredited by the College of American Pathologists.

According to Dr. Krammer, the antibody test can, in some cases, pick up the body’s response to infection as early as three days post-symptom onset and is highly specific and sensitive. “We have shared the toolkit needed to set up the test with more than 200 research laboratories worldwide to help mitigate this global crisis,” Dr. Krammer says.

David L. Reich, MD, President of The Mount Sinai Hospital, and Judith A. Aberg, MD, Chief of the Division of Infectious Diseases and Immunology in the Department of Medicine, have led Mount Sinai’s convalescent plasma program. “The exchange of ideas between clinicians and scientists and our intense drive to innovate is the catalyst that led to this achievement,” says Dr. Reich. “Mount Sinai will continue to advance the science and medicine in the fight against COVID-19.”

Hooman D. Poor, MD, Assistant Professor of Medicine (Pulmonology, Critical Care and Sleep Medicine, and Cardiology)

A small, preliminary case series led by physicians at the Icahn School of Medicine at Mount Sinai found that five severely ill patients with the SARS-CoV-2 virus responded to the blood-clot-busting drug tPA when it was introduced as a life-saving measure. This response, and the large number of critically ill COVID-19 patients who have blood clots in their lungs, have raised new questions concerning the course of the disease and may present new possibilities for treating it.

“This case series pushes us to consider avenues of clinical investigation that are different from what they are now,” says the paper’s first author, Hooman D. Poor, MD, Assistant Professor of Medicine (Pulmonology, Critical Care and Sleep Medicine, and Cardiology). “Perhaps we should be looking at the disease from the standpoint of clots that form in the blood vessels and travel to the lungs.”

Dr. Poor says that more testing will be needed to determine whether the clots are the “inciting events in a subset of patients,” and not a complication that develops after these patients develop acute respiratory distress syndrome (ARDS). “ARDS looks the same, but it’s not,” he says. It requires “dramatically different treatments.”

According to the paper, the critically ill COVID-19 patients had relatively well-preserved lung mechanics, and did not develop stiffness of the lungs, despite severe gas exchange abnormalities. This feature is more consistent with pulmonary vascular disease and not with classic ARDS. The COVID-19 patients also demonstrated markedly abnormal coagulation with elevated D-dimers—small protein fragments present in the blood after a blood clot—and higher rates of venous thromboembolism, a condition where blood clots that form in the deep veins of the legs or groin travel and become lodged in the lungs.

Mount Sinai’s paper cited autopsy studies from the SARS outbreak in the early 2000s, which revealed that patients had “pulmonary thrombi, pulmonary infarcts, and microthrombi in other organs.” SARS-CoV-1, the virus that caused SARS, and SARS-CoV-2, which causes COVID-19, belong to the same family of coronaviruses.

With mounting evidence that a consistent pattern of COVID-19 patients are presenting with blood clots, front-line clinicians at the Mount Sinai Health System and throughout the United States are reassessing and modifying existing guidelines that incorporate anticoagulation therapies.

Mount Sinai has provided treatment guidelines for its eight hospitals that address the significant role microthrombi—tiny clots composed of platelets—may play in patients with severe cases of COVID-19. The new guidelines help to inform clinical decision-making on administering anti-coagulation therapy for critically ill patients throughout the Health System. They call for patients who require hospitalization to be assessed for blood clots in their lungs by measuring their oxygen levels, testing for markers of clotting in their blood, and assessing their difficulty breathing or shortness of breath. Patients in intensive care units may also be eligible for a clinical trial at Mount Sinai that will examine the use of thrombolysis in respiratory failure due to COVID-19.

The recommendation was made by a panel of expert clinicians within Mount Sinai, and was based on published and rapidly emerging data, international and local experience, and autopsy reports.

Recently, the International Society on Thrombosis and Haemostatis recommended that all hospitalized COVID-19 patients, even those not in intensive care units, should receive prophylactic-dose low molecular weight heparin—a blood thinner—unless they have contraindications, such as active bleeding.

“If patients with COVID-19 show a small problem with their lungs, perhaps we should start them on blood thinners to prevent the clots from reaching the point where we have to administer tPA,” says Dr. Poor. “However, this treatment paradigm with early anticoagulation will need to be evaluated with well-designed clinical trials.”

Members of the Mount Sinai team that created the ventilator prototype seen here, included, from left, Drew Copeland, RPSGT; Thomas Tolbert, MD; Brian Mayrsohn, MD; and Hooman Poor, MD.

A team of pulmonologists, anesthesiologists, sleep and critical care specialists, and medical students at the Mount Sinai Health System are reconfiguring hundreds of donated machines that are typically used at home for sleep apnea and deploying them as ventilators to be used for severely ill patients who are hospitalized with COVID-19. Mount Sinai has shared the protocols and instructions with the Greater New York Hospital Association and the American Thoracic Society, as well as with other hospitals that are dealing with a national shortage of invasive ventilators during this pandemic. COVID-19 affects the respiratory system and has greatly increased the number of patients who are entering intensive care units and require assisted breathing.

When Mount Sinai received a shipment of 200 ResMed VPAP ST machines as a donation from Elon Musk, Chief Executive Officer of Tesla, Inc., in late March, a Health System task force was immediately organized to repurpose them. Within several days, the team put together a prototype that was tested in the Simulation HELPS Center at Mount Sinai, a unique laboratory run by the Department of Anesthesia that enables clinicians to simulate human responses to innovative technologies and procedures.

Three important modifications were made by the Mount Sinai team. First, a connection to an endotracheal tube replaced the typical mask that can present a risk of COVID-19 aerosolization; second, alarms that can alert clinicians if there is a problem with air flow were included; and third, the team enabled doctors and respiratory therapists to view and control the machine’s settings from outside the patient’s room, so they do not need to enter the room to make minor adjustments.

These VPAP machines will be used as an option under the current circumstances at Mount Sinai to prevent a shortage of invasive ventilators needed to serve the ongoing surge of patients. They are preferable to splitting invasive ventilators that serve two patients at the same time, a move that many hospitals are concerned they may have to pursue as a last resort.

Among the clinicians leading the effort at Mount Sinai is Charles A. Powell, MD, Janice and Coleman Rabin Professor of Medicine, Chief of the Division of Pulmonary, Critical Care, and Sleep Medicine, and Chief Executive Officer of the Mount Sinai – National Jewish Health Respiratory Institute. Dr. Powell says the machines can be used “in patients who do not require all the power of a regular ventilator, freeing up those conventional devices for the acutely ill.” He adds, “Our objective is to share our protocols widely with our colleagues around the globe facing this crisis. This project is a demonstration of the success of the team science collaborative research infrastructure at Mount Sinai that allowed us to make these innovations quickly.”

Any type of high-performing sleep device that delivers a comparable level of pressure to the ResMed VPAP ST model can work as a repurposed ventilator, according to Drew Copeland, Director of Operations for the Sleep Program at the Mount Sinai Health System. He says, “For many patients, this can save their life. We are not yet at a critical mass for ventilators but we may be getting there. This is a moving target. Hopefully, we can keep pace.”

After the first prototype was developed, Mr. Copeland enlisted a team of medical students from the Icahn School of Medicine at Mount Sinai to write the instructional user manual. They completed it in one day.

The students are now assembling the machines to be used throughout the Health System’s eight hospitals in the event of a shortage of invasive ventilators. Two floors of the medical school’s library have been set up as a staging area for the makeshift assembly line. The goal is to have all of the machines ready to be deployed by the end of this week.