February 9, 2021

The number of new COVID-19 cases continues to rise in many parts of the world, with the highest incidence in the United States. There are many signs of hope, however, including a new study published in Nature that found the orally administered drug EIDD-2801 to be extremely effective at preventing SARS-CoV-2 infection and treating cases of COVID-19.

Scientists at the UNC Gillings School of Global Public Health and the UNC School of Medicine tested EIDD-2801 in a new in vivo model containing human lung tissue. Phase 2 and 3 clinical trials are currently evaluating the safety of the drug in humans and its effect on viral shedding in COVID-19 patients.

Although several highly effective vaccines have been authorized for emergency use, SARS-CoV-2 variants have emerged that appear to have increased transmissibility; this has added more challenges to an already complicated vaccine rollout. Therefore, alternative treatments and preventive approaches that can be widely and rapidly implemented are urgently needed to curb the risk for COVID-19 related hospitalization and death.

This study centers on a line of immune-deficient mice implanted with human lung tissue (LoM) that includes all the primary human cells infected when individuals fall ill with COVID-19. UNC scientists created this unique mouse model because human coronaviruses do not naturally replicate in mice.

Because LoM do allow for replication of SARS-CoV-2, they experienced infection that mirrors several features of early diffuse lung damage seen in COVID-19 patients. In addition, acute SARS-CoV-2 infection induced a robust and sustained Type I interferon and inflammatory cytokine/chemokine response in the mice.

To evaluate the therapeutic efficacy of EIDD-2801 for COVID-19, the researchers administered EIDD-2801 to LoM starting 24 hours or 48 hours post SARS-CoV-2 exposure and every 12 hours thereafter.

Dr. J. Victor Garcia-Martinez

Dr. J. Victor Garcia-Martinez

“We found that EIDD-2801 had a remarkable effect on virus replication after only two days of treatment — a dramatic, more than 25,000-fold reduction in the number of infectious particles in human lung tissue when treatment was initiated 24 hours post-exposure,” said senior author J. Victor Garcia-Martinez, PhD, professor of medicine and director of the International Center for the Advancement of Translational Science. “Virus titers were significantly reduced by 96% when treatment was started 48 hours post-exposure.”

Next, the researchers tested the ability of EIDD-2801 to prevent SARS-CoV-2 infection by administering the drug 12 hours prior to SARS-CoV-2 exposure and every 12 hours thereafter.

Dr. Angela Wahl

Dr. Angela Wahl

“Remarkably, we found that EIDD-2801 pre-exposure prophylaxis significantly inhibited SARS-CoV-2 replication — reducing virus titers in the human lung tissues of LoM by over 100,000 fold in two independent experiments,” said first author Angela Wahl, PhD, assistant professor of medicine and assistant director of the International Center for the Advancement of Translational Science.

Bats are the presumed source of SARS-CoV-2 and the highly pathogenic human coronaviruses SARS-CoV and MERS-CoV, all of which emerged into the human population within the past two decades.

Dr. Lisa Gralinksi

Dr. Lisa Gralinksi

“We show that LoM allow for the in vivo study of all recently emerged human coronaviruses in a single platform,” said co-first author Lisa Gralinski, PhD, assistant professor of epidemiology at the Gillings School. “Our model allows researchers to directly compare infection between human coronaviruses and the effectiveness of potential preventative and therapeutic approaches.”

“We also show efficient replication of endogenous bat coronaviruses in LoM human lung tissue without the need for prior adaptation of the viruses,” Gralinski added. “This confirms that bats harbor viruses that are capable of directly infecting humans without the need for further adaptation.”

Dr. Ralph Baric

Dr. Ralph Baric

“Previously, we demonstrated that EIDD-2801 is also efficacious against SARS-CoV and MERS-CoV infection in vivo and in primary human airway epithelial cultures,” said Ralph Baric, PhD, the William Kenan Distinguished Professor of Epidemiology at the Gillings School and the School of Medicine.  “Overall, these results indicate that EIDD-2801 may not only be efficacious in treating and preventing COVID-19, but could also prove highly effective against future coronavirus outbreaks.”

Other study authors are Claire Johnson, Wenbo Yao, Martina Kovarova, Kenneth Dinnon III, Hongwei Liu, Victoria Madden, Halina Krzystek, Chandrav De, Kristen White, Kendra Gully, Alexandra Schäfer, Tanzila Zaman, Sarah Leist, Paul Grant, Frederic Askin, Edward Browne, Corbin Jones and Raymond Pickles, all from UNC-Chapel Hill; and Gregory Bluemling, Alexander Kolykhaloy, Michael Natchus and George Painter, all from Emory University.

This work was supported through grants from the National Institutes of Health and the North Carolina Coronavirus Relief Fund.

Contact the UNC Gillings School of Global Public Health communications team at sphcomm@unc.edu.

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