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.