A prospective study of 3,249 Marine recruits—who were mostly male and between the ages of 18 and 20—shows a significant risk of reinfection among those who have antibodies to SARS-CoV-2, the virus that leads to COVID-19.

The study, posted on MedRxiv, was led by researchers at the Icahn School of Medicine at Mount Sinai working with the Naval Medical Research Center. It found that the risk of reinfection in those with antibodies was 18 percent of the risk of infection in those without antibodies. Most of the reinfected Marines were asymptomatic, and none required hospitalization. The infections were detected by PCR tests.

The findings support the importance of vaccinating all segments of the population, including individuals who have SARS-CoV-2 antibodies but were never actually diagnosed with COVID-19, and those who were diagnosed, recovered, and think they are now safe from another infection. The study also points to the fact that young people, who are typically asymptomatic, may unknowingly spread the disease to others more than once.

“It is important that we don’t neglect this college-age group of the population,” says the study’s lead author, Stuart Sealfon, MD, the Sara B. and Seth M. Glickenhaus Professor of Neurology, Neuroscience, and Pharmacology and Systems Therapeutics at Icahn Mount Sinai. “They are such an important group in spreading the disease. Many young people have this ‘get it and get over it mentality’ and unfortunately they still have a surprisingly high risk of recontracting it and possibly spreading the virus to others.”

The six-week study was highly controlled. It involved two separate periods of quarantine and multiple tests for COVID-19 before the recruits entered basic training at Marine Corps Recruit Depot, Parris Island, in South Carolina. The study found that among those with antibodies, the reinfected individuals had lower antibody levels and more often lacked detectable levels of the virus-neutralizing antibody activity that blocks infection.

According to Dr. Sealfon, the findings should help resolve any concerns over whether people who have already had COVID-19 should receive the vaccine, particularly in light of current vaccine shortages.

Stuart Sealfon, MD,

“That’s an important take-home message,” says Dr. Sealfon. “Certainly we can show from this study that there’s a fairly high risk of reinfection and not everybody who has had infection will generate effective immunity. So you really want to vaccinate everyone and not worry if they’ve had it or not.”

Why some people fail to generate persistent immunity against reinfection from COVID-19 remains unknown. But highly variable responses to any disease are actually beneficial for evolution.

“When a new disease shows up, individual immune responses are variable to ensure survival at a population level,” says Dr. Sealfon. “People have different genetics that make up their immune systems. They have different previous exposure histories that train the immune system in how to respond to new infections. Immunity uses combinatorial systems to hedge its bets to try and generate the best response it can within an individual and to vary what’s happening across individuals. As a result of individual differences, some people generate more effective long-term immune responses than others.”

In the November 11, 2020, issue of The New England Journal of Medicine, Dr. Sealfon published an earlier study of these marine recruits during their initial supervised quarantine period. He showed that strict public health measures including wearing face masks, social distancing, hand washing, and widespread testing did not completely suppress transmission of SARS-CoV-2.

Plitidepsin is derived from Aplidium albicans, a marine organism that typically attaches itself to hard surfaces, such as reefs.

The search for better medical treatments for COVID-19 has led a team of scientists from the Icahn School of Medicine at Mount Sinai, with colleagues in San Francisco, to plitidepsin—a promising small molecule drug derived from a sea organism. When tested in human lung cells, plitidepsin was particularly effective in stopping the replication of SARS-CoV-2, the virus that causes COVID-19. In fact, in pre-clinical trials, plitidepsin was 28-fold more effective than remdesivir—the only antiviral drug currently approved by the U.S. Food and Drug Association (FDA) to treat COVID-19.

Kris M. White, PhD

The research team from Mount Sinai and the University of California at San Francisco recently published their work in Science, revealing one of the most promising efforts to date in identifying an already approved drug that could be successfully repurposed to fight COVID-19. Plitidepsin is approved in Australia—under the name Aplidin—as a treatment for multiple myeloma, a cancer that forms in a group of white blood cells.

One of plitidepsin’s strengths is that it inhibits eEF1A, a host protein within human cells that every variant of SARS-CoV-2 needs to survive. Viruses hijack a human’s cellular machinery in order to thrive and create more copies of themselves, but plitidepsin works by blocking an important pathway that would be used by SARS-CoV-2, its variants, and potentially other respiratory diseases such as respiratory syncytial virus and influenza. In a separate preliminary study in bioRxiv, the research team, and a group of colleagues in England, showed that plitidepsin was effective against b.1.1.7, the newly identified British variant of SARS-CoV-2.

“Aplidin is quite unique in its potency,” says one of the study’s corresponding authors, Kris M. White, PhD, Assistant Professor of Microbiology, and a member of the Global Health and Emerging Pathogens Institute at the Icahn School of Medicine. “It is likely going to be able to work against any variant of SARS-CoV-2 and other coronaviruses, including new pandemics that might happen in the future. eEF1A appears to be a broadly used protein for viruses because it has an important role in protein production, making it important for the host cell and also extremely important for the virus. Now we’re looking to test plitidepsin against these other viruses as well.”

Corresponding study author Adolfo García-Sastre, PhD, Professor of Microbiology and Director of the Emerging Pathogens Institute at the Icahn School of Medicine, says, “The ongoing pandemic created the immediate need for us to find antiviral therapeutics that could be moved into the clinic. This led us to screen clinically approved drugs with established data and safety profiles. We found that plitidepsin was a very promising therapeutic candidate.”

Adolfo García-Sastre, PhD

The decision to pursue plitidepsin resulted from research the team conducted last spring, when they identified 332 different host proteins that SARS-CoV-2 interacted with. The scientists looked to see which ones had FDA-approved drugs that targeted the host protein for cancer or other diseases and began following a trail that ultimately led them to Aplidin. Within a week after publishing their work in Nature, the researchers were contacted by PharmaMar, the drug’s small Madrid-based manufacturer.

In October, PharmaMar released the results of a phase 1,2 clinical trial of Aplidin for use against COVID-19, which showed the drug was safe and effective in helping hospitalized patients recover from the disease. By day seven after taking Aplidin, the patients’ viral load was reduced by 50 percent, and by day 15, viral load was reduced by 70 percent. More than 80 percent of patients had been discharged from the hospital on or before day 15.

The results of the clinical trial also confirmed the tolerability of Aplidin for patients with COVID-19. Tolerability had already been observed in studies of approximately 1,300 cancer patients who actually received higher doses of Aplidin than the COVID-19 patients. PharmaMar is currently establishing phase 3 clinical trials.

“The data has shown that it’s worth trying the drug in a phase 3 clinical trial,” says Dr. White. “There’s a good chance we might see efficacy and that it will be well tolerated by the patients at certain doses.” Like remdesivir, plitidepsin would be given intravenously in a hospital setting.

The researchers have proposed that the drug be tested for use alongside remdesivir and also dexamethasone, an anti-inflammatory authorized for use in severely ill COVID-19 patients. As with other antiviral drugs, plitidepsin would work only if given early in the disease cycle, in the active viral replication stage of COVID-19.

A new study published in the journal Nature by researchers at Mount Sinai in collaboration with two other labs at Rockefeller University and co-investigators from the California Institute of Technology and Weill Cornell Medicine describes for the first time a persistence of SARS-CoV-2 in the intestines long after clinical resolution.

The study, entitled “Evolution of antibody immunity to SARS-Cov-2” and published online January 18, 2021, suggests that the memory B cell response to SARS-Cov-2 evolves between 1.3 and 6.2 months after infection in a manner that is consistent with antigen persistence.

Saurabh Mehandru, MD

The authors studied intestinal biopsies obtained from asymptomatic individuals four months after the onset of COVID-19.

Minami Tokuyama, a medical student at the Icahn School of Medicine at Mount Sinai, and other members of the Mehandru Lab at the School of Medicine discovered that SARS-CoV-2 antigens persisted in the lining cells (epithelium) of the intestines long after (3-4 months post infection) resolution of clinical symptoms. The presence of such sanctuary sites could potentially enable continued maturation of the antibody response as was independently discovered by the Nussenzweig Lab at Rockefeller University.

“This finding is significant because it suggests that the memory B cell response does not wane after six months, providing reassurance that those who have previously been infected with the virus will likely mount a vigorous response if they are exposed a second time,” says study author Saurabh Mehandru, MD, Associate Professor of Gastroenterology at the Icahn School of Medicine and Director of the Mehandru Lab.

“Additionally, the presence of viral sanctuaries within the body needs to be better understood in COVID-19 patients with chronic symptoms, or ‘long haulers,’ which could help in identifying novel opportunities for the treatment of this group of patients,” says Dr. Mehandru.

Valentin Fuster, MD, PhD, Director of Mount Sinai Heart and Physician-in-Chief of The Mount Sinai Hospital.

Building on treatment protocols developed at the height of the COVID-19 pandemic, Mount Sinai Heart has launched the global FREEDOM COVID Anticoagulation Trial to determine the most effective dosage and regimen of anticoagulant therapy in improving the survival rate of hospitalized COVID-19 patients.

“While vaccines are being used and clinical trials are underway, there is an urgent need to determine how to best treat the next hundreds of thousands of COVID-19 patients around the world,” says Valentin Fuster, MD, PhD, Director of Mount Sinai Heart and Physician-in-Chief of The Mount Sinai Hospital, and principal investigator of the FREEDOM trial. “This is a coordinated international effort, launched as an investigator-led trial to speed up the process.”

In March 2020, during the early days of the pandemic, Dr. Fuster closely observed patients with blood clots in their legs who had been admitted with COVID-19. After hearing from colleagues in China of other cases of small, pervasive, and unusual clotting that had triggered myocardial infarctions, strokes, and pulmonary embolisms, he initiated decisive action. “We became one of the first medical centers in the world to treat all COVID-19 patients with anticoagulant medications,” says Dr. Fuster, a pioneer in the study of atherothrombotic disease. “It was a decision that we believe saved many lives.”

That early protocol—based largely on intuition, Dr. Fuster says—led to groundbreaking research and insights by Mount Sinai into the role of anticoagulation in the management of COVID-19-infected patients. That work includes a study published in August 2020 in Journal of the American College of Cardiology that showed a 50 percent higher chance of survival compared to patients given no anticoagulant. The analysis was conducted by the Mount Sinai COVID Informatics Center.

Dr. Fuster says, “While our study was observational, it helped us design the large-scale FREEDOM COVID Anticoagulation Trial in partnership with more than 100 sites in 14 countries in order to reach 3,600 patients.”  The prospective study will be randomized to investigate the effectiveness and safety of the anticoagulants enoxaparin and apixaban in patients age 18 and older who have been hospitalized with confirmed COVID-19, but are not in an ICU or intubated. The trial is currently enrolling and set for completion in June 2021.

Clotting in organs including the lungs, brain, and heart can be a complication of COVID-19, autopsies have shown. And anticoagulation therapies are associated with better outcomes in hospitalized patients with the virus. The FREEDOM clinical trial will evaluate different regimens.

The FREEDOM trial is based on months of clinical observation and pathology work conducted as deaths from the COVID-19 pandemic mounted globally in spring 2020 and thromboembolism emerged as an important disease manifestation. Autopsy studies at Mount Sinai demonstrated a high incidence of macrothrombi and microthrombi, prompting the suggestion that in-hospital use of blood thinners could be beneficial to COVID-19 patients. To help clarify the pivotal questions of anticoagulant choice, dosing, and treatment duration, Mount Sinai began an observational study in May 2020 of 4,389 COVID-19-positive patients who were admitted to five hospitals in the Mount Sinai Health System.

“In this observational study, anticoagulation was associated with improved outcomes, and bleeding rates appeared to be low,” says corresponding author Anu Lala, MD, Assistant Professor of Medicine (Cardiology), and Director of Heart Failure Research at the Icahn School of Medicine at Mount Sinai. “As a clinician who has treated COVID-19 patients on the front lines, the importance of having answers as to what the best treatment for these patients entails is immeasurable. Ultimately, clinical trials are what will inform those answers.”

Researchers looked at six different anticoagulant regimens, including oral and intravenous dosing. They found that both therapeutic and prophylactic doses of anticoagulants were associated with significantly improved in-hospital survival, and with a 30 percent reduced risk of admission to an ICU or intubation. The researchers used a hazard score to estimate risk of death, which took relevant risk factors into account before evaluating the effectiveness of anticoagulation, including age, ethnicity, pre-existing conditions, and whether the patient was already on blood thinners.

Separately, the researchers looked at autopsy results of 26 COVID-19 patients and found that 11 of them (42 percent) had blood clots—pulmonary, brain, and/or heart—that were never suspected in the clinical setting. These findings suggest that treating COVID-19 patients with anticoagulants as a preventive measure may be associated with improved survival.

Researchers were further encouraged by the finding that overall rates of major bleeding were low (3 percent or less), though slightly higher in the therapeutic group compared to the prophylactic and no-blood-thinner groups. This suggested to the team that clinicians should evaluate COVID-19 patients on an individual basis, weighing the risks and benefits of anticoagulant therapy.

“These observational analyses were done with the highest level of statistical rigor and provide important insights into the association of anticoagulation with critical in-hospital outcomes of mortality and intubation,” says first author Girish Nadkarni, MD, Co-Founder and Co-Director of the Mount Sinai COVID Informatics Center, and Clinical Director of the Hasso Plattner Institute for Digital Health at Mount Sinai.

The study also provided a strong rationale for the FREEDOM Trial, says co-author Zahi Fayad, PhD, Professor of Medicine (Cardiology), and Diagnostic, Molecular and Interventional Radiology, and Director of Mount Sinai’s BioMedical Engineering and Imaging Institute. “This work highlights the need to better understand the disease from a diagnostic and therapeutic point of view and the importance of conducting properly designed diagnostic and interventional studies.”