Supinda Bunyavanich, MD, MPH, and post-doctoral fellow Scott Tyler, PhD. File photo.

On Saturday, March, 14,  as the U.S. economy was beginning to shut down due to the COVID-19 pandemic, Supinda Bunyavanich, MD, MPH, a mother of two young children and a Professor of Genetics and Genomic Sciences, and Pediatrics, at the Icahn School of Medicine at Mount Sinai, had a “eureka” moment.

“I was at home thinking about the world and how New York City was being hit, and I realized so much is unknown about this virus,” Dr. Bunyavanich recalls. As a parent, Dr. Bunyavanich says she was relieved to read that children appeared to be less susceptible to catching COVID-19 than the rest of the population based on reports from China, although no one knew precisely why.

Dr. Bunyavanich was on the phone that day with Alfin Vicencio, MD, Chief of Pediatric Pulmonology at the Icahn School of Medicine at Mount Sinai. They discussed how the SARS-CoV-2 virus, which causes COVID-19, might enter the body through ACE2 receptors—proteins on the surface of many cells, including those found in the lining of the nose. At that moment, she realized she had important data that connected both lines of research.

“I thought, ‘wait a minute,’ ” Dr. Bunyavanich says. “COVID-19 is a respiratory condition. I have data on what’s happening in the noses of people of many ages from my studies of asthma. Could it be that kids have fewer access points for the virus to enter?’”

In May, JAMA published the novel findings from Dr. Bunyavanich’s data, which showed that lower ACE2 expression in children relative to adults may help explain why the disease is less prevalent in young children.

“The degree to which we express ACE2 may play into how susceptible we are to the SARS-CoV-2 virus,” Dr. Bunyavanich says. “Our finding that there are age-related differences in the level of ACE2 is consistent with epidemiologic data from around the world that children suffer less from COVID-19. Lower nasal expression of ACE2 in children is a concrete finding from our study that might explain why children are less affected by SARS-CoV-2.”

Interestingly, Dr. Bunyavanich’s data are from a Mount Sinai study she has been leading for a few years that looks for nasal biomarkers for asthma. The data, part of a study of 305 individuals between the ages of 4 and 60, includes “an atlas of genes that a person expresses in their nose,” she says. “The original project wasn’t targeted to ACE2, but we had this library of information on hand, so we homed in on ACE2 given its potential role in COVID-19.”

The researchers found that young children have the least expression of ACE2 in their nasal passages and that the quantity increases with age, so that children 10 to 17 years of age have more than younger children, but less than young adults age 18 to 24. The highest level was found in individuals 25 and older.

It is possible, she says, that young children have plenty of virus particles in their noses, but perhaps they are less likely to enter the body. “Think of ACE2 as a doorknob that SARS-CoV-2 uses to get in. There might be plenty of virus waiting to get through the door, but it has a harder time compared to adults,” she says. “The virus won’t cause illness if it can’t get in.”

According to Diana W. Bianchi, MD, Director of the National Institute of Child Health and Human Development, young children tend to be mildly affected by COVID-19, and relatively few end up in intensive care units. Their symptoms also present differently than those in adults, with diarrhea, abdominal pain, and other gastrointestinal problems.

Many questions surrounding children and COVID-19 continue to be the focus of widespread debate, particularly as communities consider whether to reopen schools in the fall.

“In-person learning versus virtual learning is such a complicated topic,” says Dr. Bunyavanich. “For every family it’s going to require a different set of considerations about risk versus benefits and what their preferences are. Even though children are less susceptible overall, susceptibility might vary between individual children, and it’s still possible for children to carry the virus. You have to think of the whole web of complex interactions children have. That’s what makes it so hard.”

Daniel Stadlbauer, PhD, a postdoctoral fellow in Florian Krammer’s laboratory, adds a substrate to an ELISA plate that indicates whether antibodies binding to the spike protein of the SARS-CoV-2 virus are present in a human serum sample. The deep yellow color indicates antibodies are present. No color means that antibodies are not present.

The majority of individuals with COVID-19—including those with mild infections—mount a robust antibody response that is stable for at least three months, according to a new study by researchers at the Icahn School of Medicine at Mount Sinai. This antibody response correlates with the body’s ability to neutralize or actually kill the SARS-CoV-2 virus.

Mount Sinai’s findings concur with studies conducted by major academic institutions elsewhere. Scientists have now had more than three months to track the levels of antibodies produced by individuals since the SARS-Co-V2 virus began to infect populations around the world.

“There were messages about the antibodies going away quickly. That’s not the case,” says Florian Krammer, PhD, Professor of Microbiology, Icahn School of Medicine at Mount Sinai, a senior author on the recent preprint study. “The take-home message is that it looks like a pretty normal immune response.” Dr. Krammer developed one of the first effective SARS-CoV-2 antibody tests, which received emergency use authorization from the U.S. Food and Drug Administration at Mount Sinai’s clinical laboratory.

Additional time will be needed to determine how protective those antibodies are and how long-lived they are beyond three months. So far, Dr. Krammer says, animal models show that antibodies to COVID-19 behave like typical antibody responses to other diseases, meaning they protect from reinfection. The same scenario is likely for the vast majority of individuals, he says. If people become infected again their symptoms would likely be less severe.

“You need to follow people to see how long the antibodies are stable. These studies require time and there will be more data as researchers look at antibodies after 3 months, after 6 months and then again after a year,” Dr. Krammer says. He and his colleague, Viviana Simon, MD, PhD, Professor of Microbiology, and Medicine (Infectious Diseases), at the Icahn School of Medicine at Mount Sinai, are doing exactly that. In a study called Protection Associated with Rapid Immunity to SARS-CoV-2 (PARIS), they are tracking the antibody levels of, approximately, 140 individuals over 12 months. “We examine the participants every two weeks so we get a very granular look at how the antibodies are moving,” Dr. Krammer says.

Within the human body there are several levels of defense. In a typical response, acute plasmablast B cells are generated within days of an infection. These first responders serve as the infantry and coalesce to make an initial bolus of antibody, but their strength soon wanes. Then the body’s immune system kicks in with long-lived plasma B cells, which provide antibodies over a long period of time, and memory B cells, which can respond quickly if the virus attacks again. COVID-19’s relatively long incubation period of upwards of 7 days, likely gives the body ample time to create antibodies quickly if a reinfection would occur.

In addition to these B cell antibodies, the human body makes memory T cells, which appear to be helpful in fighting off the SARS-CoV-2 virus. In fact, blood samples taken from individuals who survived the first SARS virus in 2002-2003—a coronavirus cousin of SARS-CoV-2—showed they still had active memory T cells 17 years later, according to the National Institutes of Health (NIH). Interestingly, the NIH reported that these memory T cells now also recognized part of the SARS-CoV-2 virus.

“There’s a lot of evidence that we see a normal immune response,” Dr. Krammer says. “Now that doesn’t mean we will all be protected forever. And it doesn’t mean that it’s impossible to get re-infected, specifically if someone is immune suppressed. We just don’t have that data yet. We will generate that data as we move forward.”

The Mount Sinai Health System in July will begin collecting high levels of blood-based antibodies from people who have recovered from COVID-19 as part of a $34.6 million clinical trial to create and test a hyperimmune globulin drug that would be used to treat early COVID-19 disease and to prevent specific at-risk populations from developing the disease.

Hyperimmune globulin is derived from pooled blood-plasma donations from many people with high levels of antibodies to COVID-19, as opposed to convalescent plasma, which uses just one donor per recipient. The pooled plasma is then then purified into a product that can be used as a treatment or prophylactic drug administered by injection or intravenously, conferring temporary immunity to the disease from the antibodies. The same process is used to prevent people from developing diseases such as hepatitis B and rabies.

To conduct clinical research trials, one of which is funded by the U.S. Department of Defense, Mount Sinai will work with two companies, Emergent BioSolutions and ImmunoTek Bio Centers, to produce the drug. It is expected to be given to patients with early disease, to front-line medical workers, and to military personnel who are unable to avoid close contact while training and conducting missions.

Jeffrey Bander, MD, Medical Director of Network Development for the Mount Sinai Health System, is assisting in recruiting donors for the clinical trial. “We’re not helpless against COVID-19,” Dr. Bander says. “People can fight back by donating antibodies.” While experts are not certain how long antibodies last, Dr. Bander says, “we do know that people who had the strongest antibody response still seem to have it three months later.”

To create the drug, Mount Sinai will rely on blood-plasma donations from people who recovered from COVID-19 during the spring surge of cases in New York City. People may donate twice a week for multiple weeks. A new collection center that can process 12 donors at a time has been established on The Mount Sinai Hospital campus. 

ImmunoTek Bio Centers is assisting Mount Sinai in the blood-plasma collection. The plasma will be frozen on site and then transported to Emergent BioSolutions to pool it and create the hyperimmune globulin. Then the product will be sent back to Mount Sinai and other sites to be used in clinical trials.

“It is imperative that we have more options to prevent this terrible disease in front-line workers and other high-risk populations and to potentially decrease the severity of illness in those infected,” says David L. Reich, MD, President of The Mount Sinai Hospital and Mount Sinai Queens.

Suzanne Arinsburg, DO, Associate Professor of Pathology, Molecular and Cell Based Medicine, who is overseeing Mount Sinai’s blood-banking and donation process, says that monthly administration of hyperimmune globulin may also serve as a prophylactic treatment for people who would not be medically eligible to receive a vaccine.

The regulations surrounding blood-plasma donations that are used for hyperimmune globulin are stricter than for convalescent plasma, according to Dr. Arinsburg. Donors are carefully screened and participate by appointment only.

With convalescent plasma, “every patient is getting plasma from a different donor and every donor has a different amount of antibody, and there are always differences between donors that we may not understand,” says Dr. Arinsburg. “With hyperimmune globulin, the plasma is pooled from many donors and fractionated to highly concentrate the antibodies so that every patient gets the same amount. That removes the issue of differences between donors.”