Research

Big Tent, one team

How a multidisciplinary research partnership built to fight HIV, Ebola and other infectious diseases turned its people, expertise and experience to fight COVID-19.

Dr. Emily Ciccone in Uganda with MUST/UNC staff in front of the Kasese Health Centre: Emmanuel Baguma, field site coordinator; Michael Matte, researcher; Jethro Muliro, lab technician; Rabbison Muhindo, program manager, Miriam Businge, research assistant; Edgar Mulogo, MUST/UNC cofounder; Moses Ntaro, researcher; Erisania Muthegheki, nursing officer (kneeling); Lydia Kabugho, study coordinator; and Ciccone beside an image of the coronavirus.
Before the COVID-19 pandemic, Dr. Emily Ciccone, a fellow with Carolina's Division of Infectious Diseases, worked in Uganda studying respiratory illnesses in children with staff of the Kasese Health Centre (left to right) Emmanuel Baguma, field site coordinator; Michael Matte, researcher; Jethro Muliro, lab technician; Rabbison Muhindo, program manager, Miriam Businge, research assistant; Edgar Mulogo, Mbarara University of Science and Technology/UNC collaboration co-founder; Moses Ntaro, researcher; Erisania Muthegheki, nursing officer (kneeling); Lydia Kabugho, study coordinator; and Ciccone.

Carolina’s Pandemic Year: This week last March, the University shifted to remote instruction. The Well is marking the occasion with a week of special stories, including reflections from Chancellor Guskiewicz, predictions from Carolina’s faculty on lasting changes to post-pandemic life and, below, ways the University has addressed the crisis.

People dying in great numbers around the world. A race to discover prevention and treatments, sometimes leading to dead ends, but sometimes leading to life-saving medicines.

Sounds like 2020, right?

A similar crisis arose in 1983, one year shy of researchers identifying the human immunodeficiency virus (HIV) as the cause of AIDS. Infectious disease doctors at Carolina were in the early stages of treating patients with the disease and learning about it. One of those doctors was 30-year-old Myron Cohen.

Dr. Myron Cohen smiles while facing the camera.

Dr. Myron Cohen

Dr. Cohen, Yeargan Bates Professor of Medicine, Microbiology and Immunology, would go on to lead the Division of Infectious Diseases for 30 years and equip an interdisciplinary research infrastructure that in 2007 became the Institute for Global Health and Infectious Diseases. That moment formalized an already strong partnership forged in the crucible of infectious diseases with the division and Carolina’s schools, departments and centers.

In 1992, a young virologist, Dr. Joe Eron, joined the division and soon discovered a passion for clinical trials and clinical care that led to key discoveries in HIV research. In 2019, Eron took over as division chief. The Herman and Louise Smith Distinguished Professor of medicine has been influential in Carolina’s extension and enhancement of research, care and prevention around the world, particularly as much of the research switched to COVID-19 prevention and treatment.

Since those early days, discoveries, research and patient care around the world positioned the institute to ramp up quickly in the search for treatments for COVID-19.

Today, U.S. News and World Report ranks UNC-Chapel Hill 11th among infectious diseases programs globally. But that’s only one measure. More important measures  — in lives saved, medicines discovered, suffering eased, jobs created and local economies improved — demonstrate the global importance of the partnership among the University’s researchers, physicians and committed workers on all levels.

The institute covers four continents, with flagship programs in the African countries of Liberia, Malawi, South Africa and Zambia; China and Vietnam; Nicaragua; and the U.S. Its researchers have completed more than 500 clinical trials and studies in their fight against a wide array of infectious diseases, including COVID-19, which has killed more than 2.6 million people worldwide.

Early days: focusing on HIV/AIDS

Cohen came to Carolina in 1980 to study white blood cells and the bacteria gonorrhea. Infectious diseases was a smaller specialty at the time. When HIV/AIDS numbers rose rapidly, the division grew as the need for treatment and research increased.

“So many people with hemophilia were exposed to HIV,” Cohen said. “We hired lots of people in medicine and public health and other departments in the mid-’90s to do research on HIV and work in other countries, including countries in southern and eastern Africa in particular.”

Dr. Joseph Eron

Dr. Joseph Eron

After Eron was hired to run the HIV clinic, “his leadership skills quickly became obvious,” Cohen said. Eron took over HIV treatment research and built the program, along with the late Dr. Charlie van der Horst and Dr. David Wohl.

Eron and Cohen hired the best faculty and staff, many of whom have stayed at Carolina. Cohen said that longevity in the faculty has been critical to building a world-class clinical trials unit, starting at a time when few drugs existed to treat HIV.

Today, the ideas, resources and opportunities have converged into a highly collaborative culture supported by key tenets of intellectual generosity, shared leadership, a Big Tent philosophy and a common mission.

Intellectual generosity

Among those tenets, Eron holds high what he calls intellectual generosity.

“If someone does something, they get the credit for it,” Eron said. “Intellectual generosity helps keep our group together.”

It’s a concept that he understands through personal experience. “A memory that strikes me so much is that at the beginning of doing HIV research, we were fortunate enough to participate in the first trial of the HIV cocktail, the thing that made all the difference.”

Eron ran the trial at the behest of senior investigator van der Horst. Study results published in 1998 in the New England Journal of Medicine indicated that the “HIV cocktail” of drugs indinavir, zidovudine and lamivudine effectively treated HIV. It was ground-breaking news.

The study sponsor wanted to include van der Horst as the lead Carolina investigator because he directed the HIV clinical research team. Instead, van der Horst insisted that Eron receive credit for running the trial, contrary to the practice of including senior investigators as study authors, regardless of their role in a study.

“Charlie was so intellectually generous,” Eron said. “In my career, I’ve tried to be the same way. It’s not easy because the urge is to take credit for everything. But that’s how it should work.”

With that lesson in mind, Eron uses his Twitter feed to highlight his colleagues’ successes.

Dr. Ada Adimora.

Dr. Ada Adimora

In some ways, that type of generosity stems from what Dr. Ada Adimora describes as collegiality. “What’s really unique about the institute is the way the collaborative nature of the relationships we have enables all the diverse types of research by really brilliant people,” said Adimora, the Sarah Graham Kenan Distinguished professor of medicine.

Adimora, who researches sexual behavior and sexually transmitted infections, including HIV, remembers former division chief Dr. Fred Sparling encouraging her shortly after she joined the division to write a handbook for clinicians on sexually transmitted diseases. “It was based on a textbook co-authored by Dr. Sparling and Dr. King Holmes. He gave me that opportunity. I was able to hone my writing skills and begin networking with some of the senior researchers in the world,” Adimora said.

“That collegiality and encouragement are really critical factors in the success of the institute,” she said.

Shared leadership

Cohen and Eron bring their own styles to leading the division and institute.

The University’s associate vice chancellor for global health and medical affairs, Cohen is known for his work on transmission and prevention of HIV. He is the architect and principal investigator of the multinational HIV Prevention Trials Network 052 study confirming that antiretroviral treatment prevents the sexual transmission of HIV-1. Under his guidance, the division grew from 10 to more than 50 faculty physicians.

Angela Kashuba. Photo by Jenna Miller.

Angela Kashuba. (Photo by Jenna Miller.)

Angela Kashuba, dean of Carolina’s Eshelman School of Pharmacy, said that Cohen gets everyone aligned and moving in the same direction. “He is focused on building teams to work on big ideas.”

Eron, an expert in clinical trials and observational data, is known as a humble leader who wants everyone to understand the reasons for clinical trials and who provides constant feedback on the importance of each person’s role. In leading faculty, he steps back to let them do what they do best — generate ideas.

He is an internationally recognized researcher, teacher and clinician, who treats people living with HIV at UNC Medical Center’s Infectious Diseases Clinic. Eron also directs the UNC Center for AIDS Research Clinical Core and is principal investigator for the UNC Global HIV Prevention and Treatment Clinical Trials Unit (UNC Global HIV CTU).

“We want to look at each study and say, ‘This is what we’ve learned here. Here’s how you have made a difference. Our group worked together to change things here. Look, the survivors are better with this treatment. You contributed to this.’ I want them to take those messages and understand them,” Eron said.

That understanding helps when things may not go well.

Susan Pedersen, lead study coordinator for the UNC Global HIV CTU, said, “One of the things we’ve learned is that it’s almost impossible to not have a mistake now and then. With the right people in place, it will happen infrequently and it will be self-correcting, not a continuing trend. And people of the quality that we have are so invested that you don’t really have to retrain them. They have already learned from the mistake and have figured out immediately how not to make the same mistake again.

Susan Pedersen

Susan Pedersen

“It’s easy when you have people who always are trying to do things perfectly. The hardest part about managing staff is supporting them when a mistake happens because they’re their own hardest critics. A lot of our job is telling people ‘It’s OK. No one can get through years of clinical research and not make a mistake.’”

There have been failures along the way. “One of the early failures is when we didn’t have the respect for or understanding of what clinical coordinators did, the people who were on the ground, enrolling participants and collecting and entering the data,” Eron said.

Instead, doctors without research experience were enrolling patients and entering information into a study database. “That was a mistake because we didn’t really have respect for the type of training and effort required to accomplish that work.”

Now, Eron said, “We have well-trained nurse coordinators and research assistants who are critical to the work on infectious diseases. They enroll participants, get consent, follow up by phone. They screen medical records and find the optimal people for our studies. Our data staff are meticulous with data entry and rapidly address queries. We’ve learned to respect expertise and to maximize strength and minimize weaknesses.”

The Big Tent

Finding the right combination of people and expertise has been a hallmark of the infectious diseases work since early on.

Kashuba, a pharmacologist, began interviewing for a tenure-track faculty position at universities while finishing her postdoctoral appointment. “I absolutely was interested in infectious disease but had honed my skills in pharmacology and clinical pharmacology,” she recalls. “I met with the infectious diseases team at Carolina, and from that first meeting I knew that this was a place of interdisciplinary research and care.”

By the time Kashuba arrived, Cohen had learned how to work with people across campus toward a common goal. “Part of that was hiring the best people to do different things, epidemiologists, people who were willing to work globally, pharmacologists at the student level, the postdoc level, the faculty level and the like,” Cohen said. “It all began to open up and grow.”

Cohen began to talk about the “Big Tent,” a phrase that all Carolina infectious diseases personnel instantly recognize. The Big Tent brings in professionals with all sorts of expertise who move in synchronization.

“That philosophy has no silos,” Cohen said. “We’re all working together on problems, and we all work together very successfully.”

The Big Tent’s canopy stretched wider and wider, covering everyone — those handling regulatory affairs, running virology labs, treating patients, researching promising drugs — around the world. “Our chancellor then, James Moeser, wanted us to have a global health institute to embrace all the activities already going on. We were working in Malawi, China, South Africa. Our operations, organization and clinical trials unit kept growing and growing,” Cohen said.

Eron said that one need only look at the clinical trials group, whose work spans the globe, to see the Big Tent in action.

“We’ve tried to incorporate as much as we can into our clinical trials group,” Eron said. “We started as an HIV group but have grown and do whatever we can to expand the research to all kinds of clinical trials and gather people under the Big Tent.”

Pedersen said that in the early days, “we did not have a big-tent concept. We were operating under our own small group. We had enough to take on with the HIV epidemic back in 1997.”

As the years passed, not only did the team become really good at researching HIV, but they became experts on developing clinical trials.

“We became very good at things like quality assurance, data management and regulatory affairs,” Pedersen said. “The Big Tent first arose maybe 10 years ago when we realized that not only did we have expertise in HIV research, but we could also be a resource for others who wanted to implement research really well.” No more trying to reinvent the research wheel for those folks; instead, they moved under the Big Tent.

As soon as Eron thinks of one person who embodies the Big Tent, he thinks of another. Dr. William “Billy” Fischer and Victor Garcia with development of a possible oral drug molnupiravir (EIDD-2801/MK-4482) for COVID-19, Dr. David Margolis and his research on HIV/AIDS, and Wohl’s Ebola work.

Years of standing up research sites and laboratories have made them quick and agile. Eron mentions Amy James Loftis, who jumped from COVID-19 vaccine work to help set up the University’s successful Carolina Together Testing Program, which launched Jan. 11.

“When they asked for her, I said ‘Well, why don’t you just cut off my right arm?’ She was the laboratory liaison for all our sites in North Carolina, Africa and Vietnam and she was the laboratory technologist for our multinational COVID-19 study ACTIV-2, which now has 100 sites all over the world trying to figure out new COVID-19 treatments. Her expertise was needed to help protect our students and our university.”

Gaps in the Big Tent fill quickly. That’s what happened with Kashuba, who stepped into the tent in her first foray into interdisciplinary research. “When I arrived in ’97, I quickly became part of the HIV team. My learning curve was steep, but I used my pharmacology skills to fill gaps in HIV,” she said.

During one of Kashuba’s interviews for the UNC-Chapel Hill job, Cohen said that he needed a pharmacologist on the team because he had ideas about drugs for HIV prevention. She joined the pharmacy faculty and an interdisciplinary group of clinicians, pathologists, epidemiologists, statisticians, students and postdocs working on HIV prevention. Within two weeks, Cohen charged her with figuring out how the group would study drugs, including applications, concentrations and best test models.

Translational medicine was and is the goal: to take a discovery from the lab to where it could help someone. “That was the beauty of it,” Kashuba said. Her work brought the pharmacy school into the team’s research, which the school’s administration supported. “Without their support to work across schools and across disciplines, I probably would not have been successful.”

Tania Hossain

Tania Hossain

The Big Tent also covers the division’s regulatory group. Tania Hossain, director for regulatory affairs for the past 15 years, said that her group brings in people as needs arise. With research in 50 countries, Hossain said that “it’s fascinating and interesting to keep up with the work in the different places and figure out how to best support them. We are all under the UNC umbrella, even though we might be in completely different corners of the globe.”

Standardization was one of the reasons Hossain was hired to create a centralized regulatory department to touch everything that the division and institute do involving people participating in clinical trials. “At that time, everyone handled their own ethical issues and IRB [institutional review board] issues, and they thought it would be more efficient to have a central group. When I started working here, my group consisted of one employee who worked in Chapel Hill, and I worked in Malawi, and we had about 70 studies,” Hossain said.

The group has since expanded to 12 employees and worked on over 500 studies.

They support staff in their ethical and regulatory concerns, whether the clinical trial is in the U.S. or subject to the IRB, FDA-equivalent regulatory body or ministry of health in another country. Hossain stresses that her group protects people who volunteer to participate in clinical trials during enrollment through the use of their private data.

Pedersen’s Chapel Hill staff has also increased, exploding from 10 to 80 because of the large COVID-19 vaccine trials.

Move to COVID-19 research

During the pandemic, the expertise and past work enabled Carolina’s infectious diseases personnel to shift quickly to COVID-19 vaccine research. “This last year has been so relevant,” Pedersen said. “To know that every day you are edging close to the answer to a problem that needs to be solved in the here and now has been reinvigorating.”

“What happened with COVID was resources and opportunity,” Cohen said. “So much money becoming available allowed us to work on the problem and make discoveries very fast. When we started our HIV work, we were in a horse and buggy. When we started our COVID work, we were in a Tesla.”

Carolina’s many basic scientists influence how other scientists translate discoveries into treatments and prevention, Cohen said. That combination has yielded many discoveries and milestones in the past year. Among them:

  • Cohen helped design and oversee a national trial of bamlanivimab, a monoclonal antibody that significantly reduces the risk of contracting COVID-19 among residents and staff of long-term care facilities. Wohl served as principal investigator for the trial’s UNC-Chapel Hill site.
  • Angela Wahl, Lisa Gralinski and Garcia recently published study results on EIDD-2801, an oral antiviral shown to be effective in treating and preventing COVID-19.
  • Fischer leads the clinical study of EIDD-2801 and engaged Ralph Baric and Tim Sheahan to help study the drug’s impact on infectiousness in people with COVID-19.
  • Wohl is a vice chair of Accelerating COVID-19 Therapeutic Interventions and Vaccines, an international trial of outpatient COVID-19 therapeutics, and the trial’s UNC-Chapel Hill site director.
  • Dr. Luther Bartelt leads a clinical trial determining safety and efficacy of convalescent plasma as a COVID-19 treatment and is working with Margolis and several colleagues including Dr. Edward Browne.
  • Dr. Cindy Gay led two phase-three vaccine clinical trials at Carolina, for the Moderna and Novavax vaccines, and is co-principal investigator for the 30,000-participant Novavax study in the U.S. and Mexico.
  • Dr. Michael Herce and Wohl lead a two-year implementation science study on scaling up COVID testing through community health workers and peer educators.
  • Dr. Ross Boyce and Allison Aiello study the spread of COVID cases in NC with mild or no symptoms.
  • Cohen is one of four leaders of the national COVID Prevention Network, coordinating work of clinical trials networks.

Past lessons now aid the fight against COVID-19.

Susan Fiscus, who retired in 2015 after 25 years as director of the UNC Retrovirology Core Laboratory and setting up labs and standardized measurement processes around the world, responded to her former colleagues’ pleas to un-retire in fall 2020 to help build the University’s COVID-19 testing centers. When institute affiliates built UNC Health’s drive-in testing centers, they tapped their experiences setting up clinics in West Africa during the Ebola outbreak.

And such proven models work for more than COVID-19. The division and institute have been sharing for many years expertise with others planning clinical trials.

“We’ve gained a substantial understanding of the importance of each component of the clinical research process,” Eron said. “That’s made a huge difference and allowed us to quickly move into other research areas because we know what the parts are and we know who can do them. We’re not going to do cancer research or psychiatric research but, for infectious diseases, we have proven ideas and can maybe improve on them.

“What we’ve done on the ground since COVID began is like our HIV work, except accelerated tenfold. So many things with COVID came up previously with HIV, but HIV has never been this transmissible.”

Eron sees parallels with COVID-19, if not exact comparisons. “We learned how it was transmitted and how it replicates. The same steps that we used for HIV, we’re using for SARS-CoV-2. We essentially opened our Big Tent to make the research happen.”

The doctors were on the frontlines in the 1980s and are there today. They were treating COVID patients in the hospital and clinic early on and now.

“It’s been a really incredible experience,” Eron said. “We need to be on the floors with patients to help understand the clinical consequences of the virus and use that knowledge to guide our treatment and prevention research.”

As with the early days of HIV research, an urgency pervades the COVID-19 efforts, coming partly from a longtime commitment to underserved and disadvantaged populations who may be more susceptible to disease.

Some parallels between the societal dimensions of HIV and COVID-19 call to those who want to help. “The people who have gravitated to this work have been ones interested in those who are disadvantaged due to their place in society or lack of resources or are stigmatized,” Eron said.

He said that in spring 2020 many of the COVID-19 patients in the UNC Medical Center were workers from meatpacking plants and factories. For them, working on site was necessary, so they couldn’t isolate. “Seeing that was super motivating,” Eron said.

Shared mission

A mission of helping people all over the world drives everyone, Hossain said. “We work with world renowned experts who are passionate about the people they care for, their study and their study patients.”

The way Hossain describes the mission reveals her fierce connection to the scientists and loyalty to the people who are voluntarily enrolling in studies. “We keep in mind the big picture of why we come in every day by working with people who are dedicated to what they’re doing and by knowing that our mission is to protect study subjects and provide them the best information we can when they’re helping us on an important research project.”

Pedersen refers to staff in Vietnam to illustrate: “They are so excited to be involved in clinical research. And I think they definitely appreciate the opportunity that’s in front of them, which has been reinvigorating, to see this as an opportunity to be a part of something bigger than yourself. They embody that every day.”

With the shared mission, comes a shared responsibility to help each other. “This comes from Mike [Cohen],” Eron said. “It permeates everything. The question he asks is ‘How do we get to the Yes?’ It’s not, ‘We can’t do that’ or ‘no.’ It’s ‘Well, that’s really interesting. How can we get to yes? How can we help you? How can we embrace this new area?’”

An impatience pushes along the common drive to solve the world’s most pressing infectious disease problems. “The challenges are now, and that impatience drives us forward and the alignment as well drives us forward,” Kashuba said. “You’re not doing something in isolation. You’re part of the bigger effort, part of the bigger team.

“Not only are we addressing the ‘now’ in the world of infectious diseases, but what happens here is collaborative, multidisciplinary research at its finest.”

See all the stories from Carolina’s Pandemic Year.