How UT researchers are working to thwart COVID-19’s resistance to treatments

Coronavirus

AUSTIN (KXAN) — By now, you’re likely familiar with depictions of a coronavirus, a sphere dotted with a halo or “corona” of protrusions.

Those protrusions, known as “spike proteins” are something the University of Texas at Austin bioscience researchers have been studying years prior to the current pandemic. Now, insight from these researchers into how the spikes work is helping to drive vaccines, treatments like antibody therapies and our understanding of COVID-19’s resistance to treatments.

Eyes on the spike (proteins)

Jason McLellan, Associate Professor in Molecular Biosciences at UT Austin, explained that back in 2013 in light of the Middle East respiratory system coronavirus, UT scientists began studying coronaviruses.

“We sort of assumed at that point, that there would be future coronavirus outbreaks and emergencies and we really need to come up with a method to generate good vaccine candidates,” said McLellan.

This illustration, created at the Centers for Disease Control and Prevention (CDC), reveals ultrastructural morphology exhibited by coronaviruses. Note the spikes that adorn the outer surface of the virus, which impart the look of a corona surrounding the virion, when viewed electron microscopically. A novel coronavirus, named Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2), was identified as the cause of an outbreak of respiratory illness first detected in Wuhan, China in 2019. The illness caused by this virus has been named coronavirus disease 2019 (COVID-19).

In 2017, McLellan’s lab published substitutions to stabilize the spikes in coronaviruses which he says have now been shared widely. During the present pandemic, McLellan explained, “many of the COVID-19 vaccine candidates encode for our version of the spike that contains the stabilizing mutations we engineered.”

McLellan added that some companies working on COVID-19 vaccines, such as Moderna, have been working directly with his lab’s collaborator, Dr. Barney Graham of the Vaccine Research Center at the National Institutes of Health. Other vaccine makers were simply aware of his lab’s research and patents, incorporating those into their vaccine efforts, McLellan said.

Moderna announced Monday that its COVID-19 vaccine was 94.5% effective and UT says McLellan’s lab contributed to the development of this vaccine in particular.

The spikes that his lab focuses on are now being targeted by companies making COVID-19 vaccines, antiviral treatments and antibody therapies. McLellan said their body of research allowed them to offer help during this international crisis.

“You know the research takes years, so you can’t wait for a pandemic to occur to then embark on years of study,” he explained.

McLellan’s lab has also worked with several companies to develop monoclonal antibody therapies. That work includes collaboration with Eli Lilly on their antibody bamlanivimab (LY-CoV555) which just received emergency use authorization from the U.S. Food and Drug Administration and is slated to be distributed in Texas as early as this week.

“We know the Spike is the weak point that we want to target,” he said, referring to the spike as an Achilles heel of sorts for coronaviruses because its critical in order for the virus to enter cells.

He said that while some of the early vaccines that look like they will be viable soon have shown to be very effective (the Pfizer vaccine candidate showed 90% efficacy) it is also important for research to continue into COVID-19 antivirals and antibodies to help treat those who have already been infected with the virus. Plus, McLellan notes, there are still many unknowns about how long the vaccines will last.

His lab is also aware of the challenges that come with trying to develop antibodies to work with these spike proteins. McLellan explained that if a spike develops a mutation, the antibody may no longer be able to bind at the one spot where it was supposed to, which could prevent the drug from working. One way to “hedge against” that risk, he noted, is to add in antibodies that bind in different places on the spike as a sort of insurance policy in case one of the connections gets lost due to a mutation.

Mutations in COVID-19

In a virtual COVID-19 conference hosted by UT Austin last week, professors specializing in different aspects of Molecular Biosciences distilled their latest understandings about how this coronavirus works and how knowledge of spike proteins might be used to address it. The speakers continually returned to the topic of drug resistance and dealing with potential mutations in COVID-19.

Ilya Finkelstein, an Associate professor of Molecular Biosciences at UT, explained during a discussion at the conference that he is on a team of UT faculty who have been working with clinicians in Houston to look at the blood plasma of 5,000 patients to understand how COVID-19 is mutating.

So far, Finkelstein said they have found that a single mutation has made the virus more “virulent” but it hasn’t increased the effects patients are seeing. The team also found that the severity of COVID-19 with different mutations has not increased. Finally, the team found no evidence that the virus has evaded the first round of vaccines and antibody therapies.

Finkelstein said the good news is that COVID-19 appears to be mutating relatively slowly. The bad news, he added, is that “because the infection has spread so globally the virus has lots of shots at goal to mutate itself.”

He also noted his team looked at potential mutations for COVID-19 for the place on the spike protein that antiviral medication remdesivir targets, and so far they haven’t found any.

“It’s invariably going to happen, right?” Finkelstein said of mutations that would block the effectiveness of remdesivir.

His fellow molecular bioscientists on the zoom call echoed a chorus of “yes” in response.

Cocktails

Greg Ippolito, Research Assistant Professor of Oncology and Molecular Biosciences at UT, shared his thoughts at the COVID-19 conference about how these mutations could impact antibody treatments for COVID-19. Ippolito said of the approximately 80 monoclonal antibodies being developed to treat COVID-19, the majority are separate companies developing them.

“There’s a few, a handful of them that are developing more than one — a cocktail — as we call it,” Ippolito said. “The rest, it’s just a single antibody, a monotherapy.”

He noted that it will likely be difficult for companies to reach deals to pool their individual antibodies into a cocktail, which he considers to be slightly concerning as cocktails help to increase the decrease the odds that a mutation will dull the effectiveness of a treatment.

“I would think the winners in this field on the antibodies side are those who are making cocktails,” Ippolito said.

Antibody cocktails have made headlines after President Donald Trump was treated for COVID-19 with the Regeneron antibody cocktail and former New Jersey Governor Chris Christie was treated with an Eli Lilly antibody cocktail.

“The cocktails definitely seem to be more protective because it’s harder for the vaccine to escape,” noted Jennifer Maynard, UT Professor in Chemical Engineering, who was hosting the panel discussion.

She asked Jon Huibregtse, UT Professor of Molecular Biosciences, if COVID-19 can become resistant to antibody therapies, can it also become resistant to anti-viral therapies?

“Yes, for sure,” Huibregtse responded. “I think it’s almost guaranteed that we would see that.

“So it comes back to the word that Greg [Ippolito] used there: cocktail, ” Huibregtse continued.  

“We’ve all gotten pretty good at making cocktails in 2020,” Huibregtse laughed. “We have to apply that to anti-virals as well.”

UT Austin Professor Jon M Huibregtse shows a PowerPoint slide at a virtual conference on COVID-19 explaining the use of vaccines, antiviral treatments and antibody therapies during the trajectory of a person’s COVID-19 infection.

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