Researchers at Utah State University’s Institute for Antiviral Research are at work testing antiviral compounds and licensed drugs for their effectiveness against the novel coronavirus (SARS-CoV-2), the cause of the Covid-19 pandemic. The institute specializes in developing animal models for testing antiviral agents and vaccines and is doing the coronavirus work supported by a $2.5 million research grant from the National Institutes of Health (NIH).
Bart Tarbet, a research associate professor in USU’s Department of Animal, Dairy and Veterinary Sciences (ADVS), is lead investigator on the project, in collaboration with Brett Hurst, ADVS assistant research professor. The scientists will investigate how the virus affects organs and tissues causing disease—a critical step in developing treatments and vaccines—and how the virus responds to various treatments. Institute for Antiviral Research faculty and technicians have been working with the novel coronavirus in test tubes and cell culture plates since late February, and last week finalized the funding for animal model development to investigate possible treatments.
Because of the urgent need to better understand the virus and treat infection, the research team will experiment with different disease models simultaneously, Tarbet said.
“We understand the urgency. … I proposed studies with the virus in the lab, in a mouse model, and in (golden Syrian) hamsters that are genetically engineered to be susceptible to viruses that infect humans,” Tarbet said.
The hamsters are the result of genetic engineering done by USU ADVS Professor Zhongde Wang, whose lab first developed the model because viruses frequently attach to receptors in humans that are not present in animals, which severely limits the ways that potential drugs to prevent or treat diseases can be effectively tested. Hamsters from Wang’s lab have a human gene inserted in their DNA for the receptor to which this coronavirus binds.
“Of all the antiviral compounds that we evaluate in vitro, less than five percent will show good activity without toxicity in cell culture,” Tarbet said. “Then the compounds that appear to have an effect in vitro are evaluated in animal models. We consider many factors like the dose and route of administration. We also investigate the therapeutic window, how long before virus challenge it should be administered and how long after virus challenge it can still be effective as a treatment? So in cell culture and by computer modeling we make predictions, but it’s really in the animals that we find the truth, because animals are far more complex than cell cultures.”
Just as test tubes are not rodents, rodents are not humans, so at each step in the process of gaining approval to treat patients, more compounds are proven ineffective. The researchers recognize there is no perfect model for a disease, but they work to identify the ways in which an infection causes clinical signs in animals that are similar to those in infected humans. That may mean respiratory signs, virus in the blood, or effects on organs that can help identify targets for treatment.
In January, the World Health Organization published a short list of “candidate therapeutic agents” for evaluation against Covid-19 and the USU team has been working with some of those compounds. The NIH added several other potential drugs to the list, including chloroquine and azithromycin that have been mentioned in recent press briefings with the U.S. Coronavirus Task Force. Tarbet pointed out that azithromycin is an antibacterial drug — not an antiviral—suggested to protect against co-infections in patients, but the institute’s previous studies found no benefit from the antibiotic in mice that were infected with influenza virus.
“We also have a database of antiviral compounds from in vitro testing against the 2003 SARS and MERS viruses, so we will be evaluating everything that makes sense to test against this coronavirus,” Tarbet said. “We also work with medicinal chemists from around the world developing potential therapeutic agents. Recently, we have had many research sponsors requesting in vitro testing of new antiviral compounds. We have no shortage of potential drugs to evaluate.”
All work with the virus will be done by faculty researchers and lab technicians who are trained to work safely in the institute’s level 3+ biosafety containment laboratory. (Note: biosafety levels are ranked 1-4, with 4 being the most stringently regulated. There are few level-4 labs in the world other than those run by federal-level health and safety organizations. A graphic explaining the differences of laboratory biosafety levels 1 through 4 is available at the Centers for Disease Control and Prevention’s website, cdc.gov/cpr/infographics/biosafety.htm).
Hurst said, as a virologist, he has been concerned that many social media messages in the early days of Covid-19 tried to minimize its probable impacts with comparisons to rates of illness and death caused by seasonal influenza. Many more people typically get influenza, but the percentage of people who become extremely ill or die is much higher with Covid-19 infections.
He also pointed out that numbers are skewed because people have not been widely tested for the new virus.
“While the number (of deaths) may go down, it is still likely to be higher than influenza and thus it represents a greater threat at this time and something that we definitely need to be vigilant about,” Hurst said.
He added that although scientists and physicians don’t like to speak out about diseases that are not completely understood, he thinks it is important to talk about the dangers of coronavirus and its spread.
Tarbet, who worked in vaccine development for many years, said in addition to worries about the novel coronavirus, he is concerned about preparations for the 2020 seasonal influenza. Typically this is the time of year, public health leaders and virologists worldwide are making their best predictions for what strain of influenza virus they must prepare to fight the next winter and begin developing and producing sufficient amounts of flu vaccine. This year, they are largely focused on the current crisis.
“What is surprising about this virus is how rapidly it has evolved and spread around the world,” Tarbet said. “I’ve worked with infectious diseases for 25 years, and this is probably the fourth or fifth time that I’ve been involved with an emerging disease, developing vaccines, developing models to test treatments, but none of them have spread this rapidly….It’s almost daily that we’re seeing big changes and almost daily that new discoveries are made, but there are still many things we don’t know the answers to, so we’re working as quickly as we can.”