The Race to Rein in Renegade RNA

From the Fall 2020 edition of Vanderbilt Medicine Magazine

Illustration by Woody Harrington

How is it that an encapsulated, single strand of genetic material called SARS-CoV-2 can cause so much havoc?

By the middle of September, nine months after an outbreak of viral pneumonia was first reported by health authorities in Wuhan, China, the RNA virus that causes COVID-19 had infected more than 29 million people worldwide and killed 936,000 of them.

Throughout most of the natural world, RNA — ribonucleic acid — is a workhorse. It translates the genome DNA into the proteins that build and do the work of the cell.

But RNA viruses, including the coronaviruses, have escaped the transcription-translation machine. And although they are not “alive” in the sense that they must hijack the genetic machinery of the cells they infect to make new copies of themselves, they are among the most fearsome creatures on the planet.

Most human coronaviruses are relatively innocuous, causing up to 30% of common colds. Since 2002, however, three animal coronaviruses have made the leap from bats and other small mammals, and caused severe, life-threatening respiratory illness in their new human hosts.

Unlike other RNA viruses like HIV that spread through the exchange of body fluids, coronaviruses catch rides on microscopic droplets when infected people cough, sneeze or even speak and thus can soar through crowds undetected and with diabolical rapidity.

These are the renegades of the virus world that so far have eluded capture. They emerge stealthily from the most remote corners of the globe. Experts fear there are more to come.

Mark Denison, MD, an internationally known expert on coronaviruses at Vanderbilt University Medical Center (VUMC), knew something like COVID-19 was coming. He just didn’t know when, or that it would arrive with such ferocity.

“We’ve been shocked by the dramatic impact, by its rapid worldwide spread, by its social, political, economic, health implications,” he said during the second episode of VUMC’s new podcast series, Vanderbilt Health DNA: Discoveries in Action. “This is unprecedented in human history.”

Does this mean that even if we stop SARS-CoV-2, we’ll be terrorized by one of its cousins in the not-too-distant future? Hopefully not.

The responsiveness of the human immune system “far exceeds the variability of an RNA … virus like SARS-CoV-2,” said James Crowe Jr., MD, whose group at VUMC is developing monoclonal antibodies as a potential treatment for COVID-19.

“So when people wonder, are these viruses going to drift away beyond the limits of the human capacity to recognize them, there’s no way that’s possible,” Crowe said in May during a webinar hosted by The Human Vaccines Project.

While it is true that the human immune system is complex enough to be able to recognize and respond to the next coronavirus that makes the leap from bats to humans, broad-spectrum antivirals, antibody treatments and a universal vaccine will be needed to protect the public from infection, serious illness and death.

That’s what Crowe, Denison and hundreds of their colleagues throughout the Medical Center are working tirelessly to discover: ways to stop the current pandemic — and prevent the next one.


Remdesivir Reboot
Mark Denison’s 30-year commitment to coronavirus research pays off

Mark Denison, MD. Photo by Donn Jones.

Mark Denison, MD, was already internationally known when the first coronavirus believed to cause severe acute respiratory syndrome (SARS) emerged from China in 2002. This time, humankind was lucky; a rapid and effective international response ended the outbreak in just four months and held the worldwide death toll to 916.

Once the first SARS-CoV virus burned out, the rest of the world forgot about coronaviruses. But not Denison, the Edward Claiborne Stahlman Professor of Pediatric Physiology and Cell Metabolism, professor of Pediatrics and of Pathology, Microbiology & Immunology, and director of the Division of Pediatric Infectious Diseases at the Monroe Carell Jr. Children’s Hospital at Vanderbilt.

He and his team kept on digging, thanks largely to continuing support from the National Institutes of Health (NIH) and the Elizabeth B. Lamb Center for Pediatric Research at VUMC.

In 2007 Denison’s team discovered coronaviruses have a “proofreading” enzyme that corrects errors while the virus is replicating, or copying its RNA.

Many of the most dangerous RNA viruses, including influenza, mutate constantly. That’s why the flu vaccine has to be updated every year. But because coronaviruses don’t change much over time, this may make it easier to develop effective and durable means to control them.

With Ralph Baric, PhD, his longtime colleague at the University of North Carolina at Chapel Hill, Denison also found that blocking the coronavirus proofreading enzyme accelerated the rate of uncorrected errors — mutations — and crippled its ability to cause disease in animals.

“In contrast to science fiction, where mutations are evil and endanger the world, our studies demonstrate that viruses have evolved to tightly control their mutation rates, and changing that rate is detrimental to virus survival and disease in nature,” Denison said at the time.

This suggested that drugs that block the proofreading enzyme potentially could be developed to treat coronavirus infections.

Then in 2012 a second dangerous coronavirus emerged.

Named for the illness it causes, the Middle East respiratory syndrome (MERS) coronavirus is thought to have jumped from bats to camels before striking humans. Since its first appearance in Saudi Arabia, it has infected more than 2,500 people in sporadic, localized outbreaks and caused more than 850 deaths.

Around this time Denison, Baric and their colleagues began to study remdesivir, an investigational drug developed by California-based Gilead Sciences to combat hepatitis C and respiratory syncytial virus, and later the Ebola virus. Remdesivir had been put on the shelf because it was less active in killing viruses than other drugs.

When the Vanderbilt and UNC researchers tested it against coronaviruses, they hit the jackpot. They were the first to perform detailed studies demonstrating remdesivir’s broad and highly potent activity against a wide range of coronaviruses, both in laboratory and animal tests.

Remdesivir was so effective in blocking viral replication that Denison called it “the Terminator.”

In January 2020, as the number of COVID-19 cases began to mount and despite the lack of confirmatory tests in humans, Gilead gave the drug to doctors to treat patients hospitalized with COVID-19 on a compassionate use basis.

Clinical trials in patients began in February. In April, a preliminary report from the multicenter Adaptive COVID-19 Treatment Trial, which included VUMC, suggested that patients who received the drug recovered more quickly. Today remdesivir is being distributed across the country on an emergency use basis for hospitalized COVID-19 patients.

Meanwhile Denison, Baric and their colleagues continued their investigations.

In their most recent paper, published in early July, they reported that remdesivir potently inhibited SARS-CoV-2 in human lung cell cultures and that it improved lung function in mice infected with the virus. These preclinical findings help explain the clinical effect the drug has had in treating COVID-19 patients.

“All of the results with remdesivir have been very encouraging, even more so than we would have hoped, but it is still investigational, so it was important to directly demonstrate its activity against SARS-CoV-2 in the lab and in an animal model of disease,” said Andrea Pruijssers, PhD, research assistant professor of Pediatrics at VUMC and lead antiviral scientist in the Denison lab.

The Denison and Baric labs have shown that remdesivir also is effective against a vast array of other coronaviruses, including other bat viruses that could emerge in the future in humans.

“We hope that will never happen, but just as we were working to characterize remdesivir over the past six years to be ready for a virus like SARS-CoV-2, we are working and investing now to prepare for any future coronavirus,” Denison said. “We want remdesivir and other drugs to be useful both now and in the future.”

Toward that end, Denison and his team are aiding development of another antiviral that also shows great promise against COVID-19. The drug, dubbed EIDD-1931, was developed at the Emory Institute for Drug Development in Atlanta.

In November 2019, the Denison lab reported that EIDD-1931 blocked replication of a broad spectrum of coronaviruses in laboratory tests and prevented these viruses from developing resistance against it.

Pruijssers provided the first evidence of the drug’s potent activity against SARS-CoV-2, and an animal study conducted at UNC-Chapel Hill also showed the drug was active against SARS-CoV and MERS-CoV. That paper, published in April, reported that EIDD-2801, a form of EIDD-1931 that can be taken orally, prevented severe lung injury in infected mice.

If clinical efficacy studies in humans, which were expected to begin later this year, are successful, EIDD-2801 could not only help stop the spread of SARS-CoV-2 but it also could control future outbreaks of other emerging coronaviruses.

“We are amazed at the ability of EIDD-1931 and -2801 to inhibit all tested coronaviruses and the potential for oral treatment of COVID-19,” Pruijssers said. “This work shows the importance of ongoing NIH support for collaborative research to develop antivirals for all pandemic viruses, not just coronaviruses.”

“We feel a profound responsibility to continue this work since we have the long-standing expertise and tools,” Denison added. “Our team is highly committed.”


Vaccines: the Holy Grail

 

The key to stopping the spread of SARS-CoV-2, of course, is a vaccine that can prevent people from being infected or getting sick if they are exposed to the virus.

Vaccines can be made in a variety of ways but typically involve injecting into muscle pieces of a virus that are not “live” or capable of causing an infection. The body’s immune system recognizes these genetic or protein components of the virus as foreign material and produces an immune response against it.

In September nearly 40 vaccine candidates for COVID-19 are in various stages of clinical testing in humans around the world, and nearly 100 other vaccine products are being tested in animals.

Ordinarily in the United States it takes years for vaccine candidates to proceed through three successive “phases” of clinical testing to ensure they are safe and effective before they are approved by the U.S. Food and Drug Administration (FDA). Only then can vaccine manufacturing, distribution and administration begin.

But this spring the U.S. government launched Operation Warp Speed, a partnership of several federal agencies with the goal of delivering — possibly as early as next year — 300 million doses of a safe and effective vaccine against SARS-CoV-2.

According to a U.S. Department of Health and Human Services (HHS) fact sheet, “Rather than eliminating steps from traditional development timelines, steps will proceed simultaneously, such as starting manufacturing of the vaccine at industrial scale well before the demonstration of vaccine efficacy and safety as happens normally.”

During the past few months, the National Institute of Allergy and Infectious Diseases (NIAID), part of the NIH, and the Biomedical Advanced Research and Development Authority (BARDA), under the HHS Office of the Assistant Secretary for Preparedness and Response (ASPR), have funded clinical testing of a handful of potential vaccines.

Among the leading contenders now in phase 3 clinical trials is a genetic vaccine candidate made by Moderna, Inc., a biotechnology firm in Cambridge, Massachusetts, in collaboration with the NIAID’s Vaccine Research Center.

Moderna’s product, mRNA-1273, includes genetic material (messenger RNA) that codes for the SARS-CoV-2 spike (S) protein, which protrudes in a crown-like array from the viral surface. The S protein binds to a receptor on human cells, a key step in infection. The goal of vaccination is to stimulate the body to generate antibodies against the S protein so that if the virus enters the body, it will be attacked and prevented from infecting cells.

Barney Graham, MD, PhD, a former Vanderbilt faculty member who is now deputy director of the Vaccine Research Center, led development of the S protein mRNA that is part of the Moderna product.

Progress has been extraordinarily rapid. In early February 2020, less than a month after Chinese scientists published the genetic sequence of the SARS-CoV-2 virus, Moderna announced that it had manufactured the first batch of mRNA-1273. In mid-March human testing began. The first 45 people were enrolled in a phase 1 trial to test safety and the ability of the vaccine to trigger an immune response. A phase 2 clinical trial in a larger group of 600 people began in May.

“We are pressing full speed ahead to provide an answer to this pandemic,” said Buddy Creech, MD, MPH, principal investigator of the NIH-funded Vanderbilt Vaccine and Treatment Evaluation Unit. Photo by Donn Jones.

In mid-July The New England Journal of Medicine published detailed findings from the phase 1 study, showing that mRNA-1273 stimulated robust immune responses against SARS-CoV-2 in the 45 participants and raised no safety concerns.

Researchers led by Mark Denison, MD, professor of Pediatrics and of Pathology, Microbiology & Immunology, co-authored the report and analyzed the ability of antibodies isolated from the blood of clinical trial participants to “neutralize” or block the SARS-CoV-2 virus from infecting cells in laboratory studies.

“Our results show that the vaccine induces a robust neutralizing antibody response in healthy volunteers, which looks similar to responses in people who had COVID-19,” said Jim Chappell, MD, PhD, research associate professor of Pediatrics and director of the vaccine and antibody studies in the Denison laboratory.

“This work, in conjunction with the results of other laboratory studies at the NIH and the acceptable safety outcomes among vaccine recipients, supports advancement of mRNA-1273 into a large phase 3 clinical trial,” he said.

VUMC is participating in the final phase 3 clinical trial, called the Coronavirus Efficacy and Safety (COVE) Study, which will evaluate the safety and effectiveness of the vaccine in 30,000 volunteers nationwide.

In late July the COVE study began recruiting volunteers ages 18 or older, including older people and racial and ethnic minorities who are at higher risk for COVID-19 as well as essential workers who are in close contact with potentially infected people. VUMC began recruiting volunteers in August.

The placebo-controlled and randomized phase 3 clinical trial will evaluate whether mRNA-1273 can trigger production of enough antibodies to reduce or prevent illness in people exposed to the virus.

Volunteers will receive either the vaccine or a placebo and will be followed for about two years.

Within a few months, however, scientists should know if the vaccine candidate is producing an immune response, said Buddy Creech, MD, MPH, principal investigator of the NIH-funded Vanderbilt Vaccine and Treatment Evaluation Unit (VTEU).

At that point, “we may be able to launch a public vaccine program based on whether the vaccine generates high enough levels of antibodies that can blunt, or even prevent altogether, COVID-19 symptoms,” said Creech, who also is associate professor of Pediatric Infectious Diseases and director of the Vanderbilt Vaccine Research Program.

VUMC’s participation in the phase 3 clinical trial is being conducted through the VTEU and Vanderbilt’s HIV Vaccine Clinical Research Site, part of the HIV Vaccine Trials Network (HVTN).

Spyros Kalams, MD, associate professor of Medicine and Pathology, Microbiology and Immunology, is the HVTN principal investigator and co-leader of the vaccine clinical trial with Creech.

VTEU and HVTN sites are part of the NIAID-supported COVID-19 Prevention Network (CoVPN), which is harnessing the resources and expertise of national research networks to rapidly evaluate COVID-19 prevention strategies.

“This massive effort to rapidly and safely test COVID-19 vaccines takes advantage of these existing networks, each with multiple clinical research sites and a great deal of vaccine and immunology expertise,” Kalams explained.

“We are pressing full speed ahead to provide an answer to this pandemic, while also taking the necessary steps to ensure that new vaccines and therapeutic drugs are both safe and effective,” Creech added.

The VUMC vaccine studies are supported by NIAID grants AI108197, AI048452(S2) and AI069439, by the Vanderbilt Institute for Clinical and Translational Research (VICTR), which is directed by Gordon Bernard, MD (NIH grant TR002243), and by the Dolly Parton COVID-19 Research Fund.

There are no guarantees, of course. Promising candidate vaccines for other infectious diseases have failed in the past.

“It’s not magic. It’s not science fiction. It’s not a one-hour TV show,” Denison cautioned during an interview with Vanderbilt University’s student newspaper, The Vanderbilt Hustler, in early March. “There’s a lot of careful things you have to do.”


Antibodies: Guardians at the Gate

 

One way or another, antibodies will be the key to stopping COVID-19. These Y-shaped proteins are produced by a type of white blood cell called a B cell in response to a foreign invader. In the case of a viral infection, antibodies are programmed to recognize and latch onto unique parts of the viral coat called antigens, thereby preventing the virus from infecting its target cell. For SARS-CoV-2, the S protein is what attracts antibody attention.

Some antibodies triggered by an infection are better than others in recognizing foreign antigens, however. That’s why researchers have developed methods for creating potent “monoclonal” antibodies. When injected into the body, the hope is that these tiny guided missiles will rapidly identify — and destroy — their targets with a laser-like focus.

James Crowe Jr., MD, director of the Vanderbilt Vaccine Center. Photo by John Russell.

One of the world’s leaders in the development of monoclonal antibodies is VUMC’s James Crowe Jr., MD, director of the Vanderbilt Vaccine Center (VVC), holder of the Ann Scott Carell Chair and professor of Pediatrics and of Pathology, Microbiology & Immunology.

During the past 25 years, Crowe and his colleagues have isolated human monoclonal antibodies for many pathogenic viruses, including Zika, HIV, dengue, influenza, Ebola, norovirus, respiratory syncytial virus (RSV) and rotavirus.

Their research has led to patents and licensures for several neutralizing antibodies and vaccines, some of which have progressed to clinical trials.

Crowe’s team collaborates with scientists who work in other universities, companies and governmental entities all over the world. Key funding sources include NIAID and the Defense Advanced Research Agency (DARPA) of the U.S. Department of Defense.

In 2018 DARPA signed a five-year cooperative agreement with VUMC worth up to $28 million to develop methods for preventing the global spread of viral diseases like Zika, a tropical, mosquito-transmitted illness that can cause severe birth defects in babies whose mothers are infected while pregnant.

The goal of DARPA’s Pandemic Protection Platform (P3) program is to develop protective antibody treatments that can be rushed to health care providers even in the most remote areas within weeks after the outbreak of a viral disease.

In January 2019, the researchers, led by Associate VVC Director Robert Carnahan, PhD, received their first audacious assignment — to develop in less than 90 days a protective antibody-based treatment that potentially would stop the spread of the Zika virus.

With colleagues from Washington University in St. Louis, they isolated neutralizing antibodies from the blood of people who had recovered from Zika infection. At the Ragon Institute of MGH, MIT and Harvard in Boston, the antibodies were tested for additional functions beyond neutralizing activity that may enhance their virus-fighting ability. The most promising lead candidates then were sent to Seattle, where the Infectious Disease Research Institute applied novel approaches to create RNA formulations of the antibodies carried by nanoparticles. Laboratory tests confirmed that the RNA-delivered antibodies neutralized the Zika virus. The team’s “Zika sprint” was completed on April 2, 12 days ahead of schedule.

This experience was crucial when, just nine months later, the first cases of COVID-19 began to trickle into the United States. With the help of researchers at the University of Toronto, Canada, the VUMC scientists obtained blood samples from a man and his wife from Wuhan, China, who’d been diagnosed with COVID-19 in Toronto in late January. They were two of the earliest confirmed cases of COVID-19 in North America.

With other academic and corporate partners, the researchers built a comprehensive “toolkit” for rapidly isolating clones of B cells that produced thousands of antibodies showing activity against SARS-CoV-2. The goal was to develop and manufacture the most promising lead antibodies in preparation for initiating clinical trials to test their efficacy in humans. Further laboratory analysis enabled the researchers to pluck out the rare antibodies that targeted the surface S protein that enables the SARS-CoV-2 virus to infect lung cells.

By July the researchers reported that they had isolated hundreds of monoclonal antibodies against the S protein.

Reporting in the journal Nature, VVC research fellow Seth Zost, PhD, Pavlo Gilchuk, PhD, senior staff scientist in the VVC, and their colleagues described how two of the antibodies bound to distinct sites on the virus’s S protein. When given alone or in combination, the antibodies protected infected mice from virus-induced weight loss and lung inflammation.

The researchers also showed that single administration of one of those antibodies, and a third one, protected rhesus macaques from being infected by SARS-CoV-2. These results suggest that these monoclonal antibodies, either alone or in combination, “are promising candidates for prevention or treatment of COVID-19,” they concluded.

DARPA, NIAID, the German science and technology company Merck KGaA, and the Dolly Parton COVID-19 Research Fund at Vanderbilt supported the research. Academic partners included Washington University in St. Louis, Beth Israel Deaconess Medical Center/Harvard Medical School in Boston, UNC-Chapel Hill, Emory University in Atlanta, the University of Washington in Seattle and Leipzig University in Germany. Corporate partners included California-based companies Berkeley Lights Inc., 10x Genomics and Twist Bioscience. Scientists from the global pharmaceutical company AstraZeneca participated in the research and co-authored the Nature paper.

AstraZeneca has licensed some of the antibodies for clinical evalua-tion and development. In late August, AstraZeneca launched a phase 1 clinical trial of two of the antibodies given in combination for treating and preventing COVID-19.

Prophylactic antibodies that make it through the gauntlet of clinical safety and efficacy testing probably will be given first to people at high risk for exposure to SARS-CoV-2 to prevent infection and then to those early in infection to reduce the chance they’ll get sick.

Injected under the skin or into a muscle, the antibodies probably will bolster immunity against the virus for three to six months, Crowe predicted. “This is a bridge to a time in one, two or more years,” he said, “when we have a vaccine.”

“The preclinical results recently published in Nature instill confi-dence in our selection of these monoclonal antibodies as a promising combination to potentially prevent and treat COVID-19,” said Mark Esser, PhD, vice president, Microbial Sciences, BioPharmaceuticals R&D at AstraZeneca. “We believe a combination approach may increase effi-cacy and could reduce the impact of any mutations of the SARS-CoV-2 virus as it continues to evolve.”

“We strongly believe the future of infectious disease treatment will increasingly involve rationally designed therapeutic antibody cocktails like those we have designed with our partners for SARS-CoV-2,” added Carnahan, associate professor of Pediatrics and Radiology and Radiolog-ical Sciences at Vanderbilt.


Pandemic 101: School of Medicine quickly designs new teaching strategies

 

COVID-19 — and the mandate for social distancing to curb its spread — meant rethinking how nearly 400 Vanderbilt University School of Medicine students would master the clinical and didactic skills they need to stay on a rigorous track to satisfy both VUSM academic standards and those set forth by the Liaison Committee on Medical Education (LCME).

Within a two-week timeframe in April, School of Medicine curriculum leaders designed and implemented a brand new course for the second-, third- and some fourth-year students who saw their clinical clerkships and clinical immersion experiences come to a sudden halt. The Pandemic Medicine Integrated Science Course, which covers all aspects of pandemic education, rolled out in the spring.

“Normally, it would take us months to design a new course, which would typically be offered to a maximum of 24 students after we’d had a chance to pilot it. We designed a course in two weeks, with no pilot period, and offered it to 200 students all at once,” said Bill Cutrer, MD, M.Ed., associate dean for Undergraduate Medical Education.

Calling upon his faculty colleagues, who also happen to be among the nation’s top vaccine and infectious disease experts, Cutrer and Kendra Parekh, MD, associate professor of Emergency Medicine and co-course director, with support from Donald Brady, MD, senior associate dean of Health Sciences Education, designed a course that gave the medical students a front-row seat to myriad aspects of a pandemic.

“From a logistical standpoint, and a greater ‘what’s going on in the world’ standpoint, it made sense to bring them all together and to think through pandemics — what can we learn from the current one, what can we learn from prior pandemics and how can we provide the students an experience that will allow them to learn, as well as make an impact on our patients,” Cutrer said.

The new course paired foundational science with clinical content. There were three main goals: 1) understanding pandemics, everything from epidemiology through emerging therapeutics; 2) leadership in turbulent times; and 3) evidence, information and data and how to make decisions, especially when there is a lack of data on which to base decisions.

Third-year VUSM student Catie Havemann, participating in the new Pandemic Medicine Integrated Science Course from home in the spring, helped coordinate volunteer activities that students could use to fulfill the clinical credit requirement of the course.

“How do you enable these future doctors to participate in and be part of something historic and something real while also keeping them safe, recognizing their role as students and preparing them for the future?” Brady said, sharing the thought process that went into designing the course. “With the COVID-19 pandemic, we are not dealing with a sprint; we’re not dealing with a marathon. We’re in an ultra marathon of interval training — a mix of sprint and jogging — where we haven’t defined the distance of the race. This provides us all a unique opportunity to help learners think about how they deal with uncertainty at all levels — the uncertainty of the science, with the clinical piece, and the mental task of dealing with uncertainty.”

The clinical content was addressed through the students’ assistance with telehealth visits and volunteer experiences. The didactic portion was a four-week course. Week one provided foundational content; weeks two and three were a combination of case-based learning, focusing on prior pandemics — the 1918 Spanish flu and the SARS virus.

Additionally, the students chose one of seven different tracks that allowed a nuanced lens through which to view the pandemic. Week four involved the students in a pandemic simulation exercise when they will share what they learned in their tracks and work in teams.

The seven tracks available to the students were: health inequities and vulnerable populations; population health; communication and information-sharing; ethics; global health; leadership; and emerging therapeutics.

Kathy Edwards, MD, Sarah H. Sell and Cornelius Vanderbilt Chair and professor of Pediatrics, conducted a live session that walked the students through what it would be like to create a phase 3 trial for a new vaccine. Edwards played a key role in the development of the H1N1 vaccine. Students watched a recorded lecture by Mark Denison, MD, director of the Division of Pediatric Infectious Diseases and Craig-Weaver Professor of Pediatrics, and James Crowe, MD, director of the Vanderbilt Vaccine Center and Ann Scott Carell Professor, on emerging therapeutics and vaccine development, and a recorded grand rounds led by Stephan Heckers, MD, William P. and Henry B. Test Professor and chair of Psychiatry & Behavioral Sciences, on mental health and the pandemic. These are just a few examples of resources that the students and faculty preceptors accessed.

“It has given so much creative freedom to our faculty and it has been so energizing and fun to watch them come up with these great ideas. To me, this has been a very visible picture of the Vanderbilt culture — that sense of collaboration, working together and solving problems and innovating, and for me this class is that in a nutshell,” Cutrer said. “To have experts from around our campus be willing to hit the pause button on actually trying to solve these problems for this pandemic to teach the next generation of physicians because they recognize how important it is, has been a real gift.”

The first-year medical students, who were still in the midst of their mostly classroom-based academic year that ended in late July, transitioned well to virtual learning.

Lectures, typically offered in person, were recorded and are available online. Case-based learning, usually conducted in small teams, and the physical diagnosis course were held via virtual meeting software. The anatomy lab was available for individual students to attend according to their own schedule. First-year clinical placements were suspended. COVID-19 affected them in other ways as well: in-person study groups halted; some returned home to live with family while studying virtually; many wanting to contribute to the medical efforts, yet not knowing the best route.

“I am absolutely confident the students will be where they need to be. The faculty very quickly jumped on board to get things moving forward. Everything they are going to get during this time will meet the needs to continue the pace they were already on to move to the second year and to graduation,” Brady said. “We have to realize our students are our future. They will be the next generation who will have to deal with future pandemics.”


VUSM students help patients, clinicians with telehealth

 

When in-person visits to Vanderbilt Eskind Diabetes Clinic needed to be quickly converted to telehealth appointments in response to COVID-19, a novel solution was hatched to bring both clinicians and patients up to speed on videoconferencing.

Vanderbilt University School of Medicine (VUSM) students completing their upper-level Immersion course at Eskind Diabetes Clinic didn’t blink when asked by Michael Fowler, MD, associate professor of Medicine, to instead become instant telehealth consultants.

“These third- and fourth-year students would ordinarily have spent about half the day taking care of patients with diabetes and half the day studying and doing research,” said Fowler, who co-directs the Immersion course with Al Powers, MD, director of the Division of Diabetes, Endocrinology and Metabolism and the Vanderbilt Diabetes Center. “But then COVID-19 happens and after just two of their four weeks, they’re pulled out of their clinical rotations.

“The students really, really wanted to help, and they were understandably frustrated that they couldn’t be in the clinical environment. So, what Al and I decided to do was to put students in charge of, one, educating providers about how to use the Zoom videoconferencing app and Epic for telehealth appointments to connect with patients; and two, calling patients ahead of their appointments to help them learn how to get logged in and communicate with their providers.”

Eskind Diabetes Clinic’s older patients and patients living in rural areas were anticipated to have challenges getting connected, and older, more at-risk faculty members who had been asked to work remotely often had less experience with conducting telehealth appointments, but as soon as the four medical students pivoted to troubleshoot and assist, things began working smoothly.

“They’ve just done a spectacular job,” Fowler said. “In a situation like this, it would have been easy for them to throw up their hands and say, ‘Well, our clinical experience is over,’ but they genuinely rose to the occasion. They made a real difference for our patients and our providers.”

Medical students Shaunak Amin, Thomas Day, Emily Long and Zijun Zhao connected with faculty members who needed assistance downloading the Zoom app onto their computers or devices and worked through any issues with them.

+
Fourth-year medical student Emily Long assisted Paul Epstein, MD, as they conducted telemedicine calls with endocrine/diabetes patients in the spring. Photo by Susan Urmy.

Then, they divided up lists of patients with upcoming appointments and called each one, taking as much time as needed to answer all of their questions and make sure they were prepared for their telehealth visit.

Janie Lipps-Hagan, ANP-BC, who works at Vanderbilt Eskind Diabetes Clinic, emailed Fowler and Amin to express gratitude for the help.

“Shaunak called all three of my patients before their visit and got them set up for their visit,” she wrote. “Each patient expressed their thanks for his help. I heard him talking with the patients in a kind and patient way as he worked them through technology issues with success for all three visits.”

“We’re just so grateful that we were in a position to help,” said fourth-year student Amin. “We were able to sit and spend time virtually with each patient and work out any issues they might have so providers on the front line could focus on taking care of the patient during the telehealth visit.”

Amin, who matched into the University of Washington-Seattle’s ENT program, said this wasn’t at all how he expected medical school to end, but he’s grateful to Fowler and Powers for turning the situation into something beneficial for everyone.

Emily Long, who matched into the Beth Israel Deaconess Medical Center/Harvard Plastic Surgery program, said she was also grateful for the opportunity to assist clinicians and patients with telehealth visits.

“Our medical school experience ended in a way that I don’t think any of us could have expected, but I also think we were reminded of why we all went to medical school, which was to help people,” Long said. “It’s been an interesting couple of weeks, but it was rewarding.”

Long called clinic patients to answer any questions they might have about telehealth.

And even though the medical students weren’t able to be there in person to observe the clinical appointments, if patients gave their consent, they could join in on telehealth visits.

“So even though I was in my living room on my couch, by joining the telemedicine visit, I could essentially be in the exam room and learn from the providers, which I think is such a unique experience.”

Long also worked for the past four years at the Shade Tree Clinic, the medical student-run free clinic for underserved individuals in Nashville, co-directed by Fowler.

She’s excited about the possibility of the clinic using telehealth more extensively in the future as many patients work during the clinic’s hours or have limited access to transportation.

“I honestly think this will change how we view health care and medical education,” she added. “What we can take away from this is that there are a lot of ways to learn medicine. I think this is something we’re going to look back on 10 years from now and say, ‘Why didn’t we do this all along?’”

Medical students Kaustav Shah, Austin Triana and Roman Gusdorf also stepped up to serve as student leaders to coordinate volunteer efforts to support telehealth efforts for all of Vanderbilt Health’s approximately 90 adult medicine clinics.

Gusdorf, a second-year medical student, was completing his Pediatrics clerkship when everything changed, but said he was grateful for the opportunity to contribute to the provision of medical care by coordinating telehealth volunteers.

“I was distressed to have my clerkship interrupted, and I was longing for a way to continue serving our patients in this difficult time,” he said. “Helping develop this telehealth program has been the perfect avenue to make a difference in the lives of my community, even while having clinical duties suspended.

“Witnessing the Vanderbilt students and faculty rally quickly around this cause has given me hope in a dark time. The gratitude I’ve received from the patients I’ve helped, the providers I’ve assisted and from fellow students who were also eager for a way to help in this awful situation, has given me the motivation to keep building upon this program.”

With assistance from Sara Horst, MD, MPH, associate professor of Medicine, and Michelle Griffith, MD, assistant professor of Medicine, student leaders put together a training manual for medical students to guide them as they made calls to patients with upcoming telehealth appointments.

They then developed a spreadsheet listing all the clinics and assigned medical students to support telehealth outreach for the clinics. The medical students were able to assist individual patients as they set up their My Health at Vanderbilt access and downloaded the Zoom videoconferencing app in preparation for their upcoming telehealth visits.

Approximately 75 medical students were trained and volunteered their time to call patients. During just the first two days of providing this assistance, medical student volunteers contributed more than 80 hours as they reached out to more than 500 patients with upcoming clinical appointments.


COVID-to-Home program ensures follow-up of patients

 

Bill Boyce, 73, was the first patient intubated on Vanderbilt University Medical Center’s dedicated COVID-19 unit where he spent 28 days. Photo by Susan Urmy.

On March 27, Nashville resident Bill Boyce, 73, earned the unwelcome distinction of becoming the first patient intubated on Vanderbilt University Medical Center’s dedicated COVID-19 unit.

He spent 28 days under the vigilant care of the inpatient COVID-19 team, ultimately recovering to be discharged to home on April 24. He credits a broad network of care at VUMC, a continuum of watchfulness that extended both before and after his hospitalization, for saving his life.

“Honestly, I didn’t know how sick I was until I woke up, and I discovered I had wires and tubes in places I didn’t know I had places,” Boyce said. “I was on a ventilator, but I have no memory of that. Vanderbilt took this seriously, and I’m still here, bad jokes and all.”

Boyce was in the first wave of COVID-19 patients at VUMC, when clinicians were learning daily about the virus and its progression.

In the pandemic’s early weeks, a plan was put in place at the Medical Center to ensure anyone who tested positive for the novel coronavirus at any site across the VUMC network would have some form of follow-up monitoring.

The VUMC COVID-to-Home program, which became a part of Boyce’s care after his positive test result, includes three levels of care: care coordination, telemedicine support and hospital-to-home support, ensuring close oversight of these individuals.

Once an individual’s positive test result is entered into an electronic patient registry, a team of care coordinators and clinicians call that individual for an initial check-in.

If a patient already has a primary care provider, the team contacts that provider and that physician’s office typically takes over their follow-up monitoring and care.

Since mid-March, more than 5,500 patients have been monitored by phone by the VUMC COVID-19 Care Coordination team for 14 days following their positive test to track symptoms and ensure they are progressing toward recovery.

In addition, the COVID-to-Home program, a joint program staffed by Vanderbilt Health OnCall and Vanderbilt Home Care Services (VHCS) clinicians, has served more than 178 patients with frequent in-home nursing visits, close involvement by nurse practitioners and regular phone calls to assess symptoms and vital signs.

When Boyce initially began having flu-like symptoms in mid-March, he got a COVID-19 test at the Vanderbilt Walk-In Clinic in Bellevue.

Boyce’s physician at Vanderbilt Primary Care North One Hundred Oaks, Tiffany Hines, MD, received notification that he had tested positive for the virus. Boyce had just completed radiation therapy for prostate cancer, and his age also put him at greater risk, so Hines was very concerned.

As soon as his positive result was received, Hines and her team, as well as the VUMC Care Coordination COVID-19 team led by Julie Scott, RN, began providing telehealth follow-up phone calls as he quarantined at home.

Despite Boyce’s continual insistence that he “was just fine,” his family, who was also checking on him through phone calls for their safety, and Hines weren’t convinced. His sister Nell Smith even hired a private ambulance crew to take him to the emergency room, but he turned them away.

“I was listening to that awful COVID cough and hearing his shortness of breath, and I knew he wasn’t fine,” said his sister Mary Etta Boyce, a retired emergency room nurse. “When he rolled out in the ambulance, he was on his way to death’s door.”

Due to Boyce’s worsening symptoms, on March 27 Hines requested an in-person visit by a VUMC provider. Mary Walden, MSN, FNP-BC, part of the COVID-to-Home program, made a telehealth phone call to Boyce that same day, and shortly after Melissa Duque, RN, with VHCS, visited him at home.

While he still insisted he was fine, his oxygen saturation level in the 70s told a different story. He was raced to the VUMC Emergency Department, and after evaluation he was moved to the COVID Unit to begin his nearly monthlong stay.

“Kristin Nguyen, RN, cared for him the night he was intubated and said they had to tell him to quit telling jokes so they could intubate him,” said Neil Stinson, RN, a member of the Communicable Disease Response Team who cared for Boyce. “He has a very dry sense of humor.

“I cared for him the following day. He was the first COVID patient I took care of who was intubated. Without any family presence, caring for someone who is intubated, awake and alone is very challenging. I could not stay in his room the whole time, but I felt that I needed to. He was very uncomfortable. Over the following days, he became sicker and sicker. We all worried that he might not recover,” Stinson said.

Boyce experienced life-threatening cardiac arrhythmias and pneumonia, and Hines followed his condition through his electronic medical record and calls to the COVID unit team. She couldn’t visit in person, and Hines knew the isolation was hard for him. As soon as she could call him to provide encouragement, she did.

One day when he was off the ventilator, Boyce pressed his call button. Paul Cloutier, RN, asked what he needed, and his response was “just five minutes of conversation.” Cloutier was happy to keep him company.

“Bill had a stormy ICU course,” Cloutier said. “Through extended intubation and high doses of vasopressors, I had thought several times he would never make it, but he did.”

As Boyce left the hospital, he told his care team his sister, Mary Etta, was dedicating the Gratitune, “Staying Alive,” to everyone who played a part in his recovery. Gratitunes (www.Gratitunes.com) is a consumer-generated music platform that celebrates and thanks members of the VUMC family, through the power of music, during the COVID-19 pandemic.

Boyce himself chose another song, and as he said his goodbyes he sang, “I’ve had the time of my life, and I owe it all to you.”

Casey Lary, RN, said she will never hear that song without shedding a tear and thinking of him.

“We watched as Bill’s journey went from intubation, to extubation, to sitting in a chair, eating food, moving to the step-down unit, to going home,” she said. “Bill became our floor mascot and a symbol of recovery.”

Tara Horr, MD, who oversees VHCS, is part of the daily huddle that decides what care is most appropriate for patients when they leave the hospital. Unfortunately, Boyce’s COVID-19 tests continued to come back positive well after he was healthy enough for discharge, meaning he could not transfer directly to a rehabilitation facility.

“Fortunately, he had stayed here for so long and had such great care by our physical and occupational therapists, it was felt he could safely return to his home,” Horr said.

Because of the complexity of his case, Boyce was monitored by phone calls once again at home by the COVID-to-Home program.

A complaint of leg pain during one call indicated a possible blood clot – a complication associated with COVID-19. An ultrasound confirmed the diagnosis, and it was successfully treated.

Boyce now says he’s feeling great and getting stronger each day.

“When I left, they gave me a send-off party,” he said. “I was crying and some of the nurses were crying. I’m here today because of Vanderbilt.”

“It’s a blessing he was at Vanderbilt,” agreed his sister, Mary Etta. “The Emergency Room staff, COVID-19 unit, the step-down unit — to a person, everyone I spoke with and interacted with — saved my brother’s life.”

One Response to “The Race to Rein in Renegade RNA”

  1. Stephen L Hines, MD

    This is an interesting and relevant article. I am enrolled in the Phase 3 Moderna vaccine trial in Dallas, TX, and was especially interested to read of Barney Graham’s significant input in the vaccine’s development. He was an IM Intern during my IM Residency years at Vanderbilt; I’m not surprised to see him make such important contributions to population health.

Leave a Reply