January 26, 2024

By Audrey Smith

Ralph S. Baric, PhD, began studying coronaviruses decades before the COVID-19 pandemic hit. There is still much to learn about this family of viruses, and the Baric Lab remains among the world’s leaders in coronavirus research, exploring questions like “Where did COVID-19 originate?” and developing treatments for future coronaviruses. 

Baric, who is the William R. Kenan, Jr. Distinguished Professor of epidemiology at the UNC Gillings School of Global Public Health, was senior author on two recent coronavirus research papers. The first, published in the journal Nature Microbiology, investigated a pangolin SARS-CoV-2-like virus, including its biological capabilities, ability to elicit an immune response and ability to transmit between species. The second, published in the journal Science Translational Medicine, sought to identify broad therapeutics that can treat future outbreaks of MERS-CoV (the coronavirus that causes Middle East respiratory syndrome) and other similar coronaviruses.

 How did the COVID-19 virus move from animals to humans?

Our understanding of the way that animal coronaviruses spill into human populations is incomplete and only partially understood. Some researchers have always argued that the SARS-CoV-2 virus  – which causes COVID-19 – began in bats and then was transmitted to a key intermediate host species, where strains of the virus circulate and mutate, allowing it to be transmitted to humans. In this theory, the intermediate reservoir host species, in which the virus circulated freely and evolved, was critical to explaining how viruses spread into human populations. Yet, a reservoir species with a circulating virus has not been discovered.

Baric and team, however, believed that some zoonotic SARS-like viruses have the intrinsic properties necessary to replicate and transmit easily between multiple mammalian host species, eliminating the need for a “reservoir” species. 

In the paper recently published in Nature Microbiology, Baric and team examined whether the SARS-like coronavirus found in pangolins, small mammals that are often called scaly anteaters, carries these intrinsic properties. The pangolin coronavirus is closely related to SARS-CoV-2, but it has never infected people. 

Dr. Ralph Baric

Dr. Ralph Baric

“We want to understand how viruses move between species because this information helps to establish research priorities that are designed to protect global health,” Baric said. “For example, this information can identify hosts and environments that inadvertently promote virus jumping between species, providing us with the knowledge to identify and regulate high-risk environments, like open markets in dense population centers. The information helps to minimize the threat potential by informing the development and testing of diagnostics that can find early cases, and identifying broadly acting countermeasures that are effective. As a consequence, both the public health and medical communities will be positioned to rapidly implement intervention and treatment strategies in an emerging outbreak setting, saving lives.”

The team reconstructed the pangolin coronavirus using the genome length sequences for pangolin coronaviruses that had been reported in previous studies. The studies were performed under stringent containment conditions in the laboratory, and the pangolin virus was found to efficiently use the same receptor protein from more than 20 species of mammals, including pangolins, humans, mice and hamsters. They also found that the virus grew at similar numbers as SARS-CoV-2, it could naturally be transmitted between hamsters, and it was killed by the existing monoclonal antibodies, antiviral drugs and vaccines that target the original SARS-CoV-2 strain.

As the virus could transmit between non-reservoir hosts, the data argues that a reservoir species is unnecessary and that some SARS-like animal viruses have the intrinsic capabilities to infect and transmit naturally across multiple species without setting up a large reservoir. SARS-CoV-2 also readily transmitted between deer, mink and humans. This intrinsic capability to transmit across species potentially explains how SARS-CoV-2 emerged to cause the COVID-19 pandemic and why researchers have yet to identify this hypothetical reservoir host.

“Most United States citizens think that the COVID-19 pandemic is over and done, but we disagree,” said Baric. “Our data suggests that zoonotic coronavirus emergence events will accelerate throughout this century and that we need to remain aware and prepared with things like state-of-the-art diagnostic tests, global surveillance systems in place to catch these events early, and a supply of broadly effective antiviral drugs and vaccines to protect the public.

Do existing antivirals and vaccines work against other coronaviruses?

Over 1 million people died before the first countermeasure was available to treat COVID-19. To save lives during future coronavirus outbreaks, broad-based drugs and vaccines capable of providing an immediately available treatment are needed for global health preparedness.

In a paper recently published in Science Translational Medicine, Baric and team were the first to study the bat coronavirus BtCoV-422, which is similar to MERS-CoV. MERS-CoV is a coronavirus that emerged in 2012, causes Middle East respiratory syndrome, has a 35% mortality rate in humans and is still circulating at low levels in the Middle East and East Africa.

The team investigated whether antibodies that neutralize MERS-CoV and antivirals that inhibit SARS-CoV-2 would provide effective treatment strategies against this important group of MERS-like viruses.

The team analyzed the potential range of hosts that the MERS-like BtCoV-422 virus could infect by investigating its ability to use DPP4 entry receptors from multiple species, including humans, and its reliance on external proteases. The MERS-like virus was found to have broad host range potential, and BtCoV-422 replicated efficiently in multiple primary human cells, including airway epithelia, lung fibroblasts and lung endothelial cells. The data also indicated that BtCoV-422 has crossed multiple barriers that typically impede coronavirus emergence potential in humans, such as infectivity in human cells and the efficient use of human entry receptors. However, the virus has reduced growth potential in the human upper respiratory tract, which suggests that further mutations would be required for this virus to threaten human populations.

The researchers then tested current therapeutic countermeasures, including drugs, monoclonal antibodies (mAbs) and vaccine-elicited murine serum, and structurally characterized a group 2c CoV (also known as betacoronavirus) broadly cross-reactive epitope, all with the hope of informing future coronavirus global health preparedness strategies. Importantly, several SARS-CoV-2 drugs approved by the Food and Drug Administration (FDA) and one highly potent MERS-CoV human monoclonal antibody, JC57-11, potently neutralized BtCoV-422, providing ready countermeasures for future use. The virus’ replication was also potently inhibited by antivirals such as remdesivir and nirmatrelvir. This means that multiple therapeutics that have already been approved for use against SARS-CoV-2 by the FDA are ready for immediate testing against MERS-related viruses, providing several different and immediate treatment strategies for patients in an outbreak setting.

The team’s findings also support the hypothesis that these drugs should be evaluated in the context of early treatments for MERS-CoV infection. If approved, these drugs would be valuable tools to treat people experiencing new SARS- and MERS-like coronavirus infections.

“It’s vitally important that we have broad therapeutics immediately available to treat new emerging viruses,” said Baric. “We had done extensive studies that had shown that both remdesivir and molnupiravir were highly potent broad-spectrum coronavirus drugs, years prior to the emergence of COVID-19. In fact, that’s why these drugs were so quickly approved for human use. We know that there will be other zoonotic coronaviruses that infect and emerge to cause serious diseases in human populations and we need multiple broad-based drugs that can be accessed immediately if we’re going to protect the health of future populations. We also need effective policies that control ecologic settings for zoonotic virus emergence, like closing open markets and preventing the illegal trade of wildlife.”

Importantly, MERS-422 and the pangolin SARS-like coronavirus are being used to demonstrate the performance and breadth of broadly protective vaccines that protect against zoonotic, epidemic and pandemic SARS and MERS-related viruses that threaten human populations. The team’s ongoing studies have already contributed to the development of pan-coronavirus vaccine products that are moving toward human clinical research studies.

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

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