Virus Mutation-Mapping Tool Could Yield Stronger COVID Boosters and Universal Vaccines

Irene Francino Urdaniz is working on her spike protein research at CU Boulder. Credit: Casey A. Cass/CU Boulder

Researchers at CU Boulder have developed a platform that can quickly identify common mutations on the SARS-CoV-2 virus, allowing it to escape antibodies and infect cells.

The research, recently published in Cell Reports, marks an important step towards the successful development of a universal vaccine for not only COVID-19, but potentially flu, HIV and other deadly global viruses.

“We have developed a predictive tool that can tell you in advance which antibodies will be effective against circulating virus strains,” said lead author Timothy Whitehead, an associate professor of chemical and biological engineering. “But the implications for this technology are more profound. If you can predict what the variants will be in a given season, you can get vaccinated to adjust the sequence that will occur and short-circuit this seasonal variation.”

The secret ingredient of the research team? Baker’s yeast.

They engineered a genetically modified version of this harmless material to express some of the SARS-CoV-2 viral spike proteins along the yeast’s surface, allowing them to map resulting mutations that form neutralizing antibodies and escape. The resulting roadmap could inform the development of more effective booster vaccines and tailored antibody treatments for patients with severe cases of COVID-19, Whitehead said.

An illustration of the coronavirus SARS-CoV-2, which causes the disease COVID-19. Note the dots that adorn the outer surface of the virus, giving the appearance of a corona around the virion. Credit: Centers for Disease Control and Prevention

The key to the crown

Spike proteins are sharp bumps that protrude from the surface of viruses in the coronavirus family. Under a microscope, they can look like a crown, where coronaviruses — corona is Latin for “crown” — get their name and how they bind to cells like a key in a lock. When antibodies recognize them, cling to them and prevent them from binding to cells, they prevent infection.

But when spike proteins mutate, antibodies do a double uptake.

“There are mutations on the spike protein that prevent an antibody from going in and recognizing it. Just like getting a new haircut, you look like a different person; this looks like a different virus than that antibody,” said Whitehead.

Irene Francino Urdaniz, a chemical and biological engineering graduate student, is working on this research in the Whitehead lab. Credit: CU Boulder

In the case of the more contagious Delta variant that emerged in 2021, mutations on the spike proteins have made it more contagious and reduced the efficacy of some antibody therapies.

What if there was a way to predict which mutations might arise next time—and therefore prepare for them? Earlier this year, Whitehead’s team set out to find a way.

What comes after Delta?

Some antibodies that can bind to different sites have been used in treatment cocktails given to COVID-19 patients. But the strains of the virus now circulating in the US are so different that some of these antibody therapies no longer seem effective, Whitehead said.

So first, the researchers had to identify mutations on the spike protein that could prevent these antibodies from working. Next, they wanted to predict which mutations are likely to occur — what could become the zeta, eta, or theta variant?

“When the pandemic started, we saw the opportunity to apply techniques mastered by our lab to contribute,” said Irene Francino Urdaniz, co-author of the paper, graduate student in chemical and biological engineering and a Balsells fellow. “When a new variant was discovered, I was usually able to guess which mutations were present based on my research. I am very excited that my work has contributed not only to this pandemic, but potentially to future vaccines as well.”

Irene Francino Urdaniz, a chemical and biological engineering graduate student, is working on this research in the Whitehead lab. Credit: CU Boulder

Francino-Urdaniz developed a genetically engineered strain of common baker’s yeast, which could display different parts of the viral spike protein on its surface. She then learned how to screen thousands of mutations in a single test tube to find the ones that evaded neutralizing antibodies.

As some home-bound bakers discovered in 2020 while experimenting with sourdough starters, yeast grows quite quickly. This means the researchers can see a wide variety of mutations develop at the same rate the yeast can grow — leaps and bounds faster than the rate at which mutations appear in real time. This could give scientists an invaluable head start.

A universal vaccine

The researchers have already found some of the same mutations that are now circulating around the world, and have also identified more mutations that could potentially evade our immune system. They will also provide all of their libraries of information, methods, and software as an openly available community resource to accelerate novel therapeutic strategies against SARS-CoV-2.

This means that the next COVID-19 vaccine or booster shot produced for the public could have the most potency. It also provides hope for those who are immunocompromised or at higher risk of contracting a bad case, as this research can be applied to proactively prepare antibody cocktails for specific mutations, giving them a better chance of survival and recovery.

But the promise doesn’t end there. Because of the adaptability of new mRNA vaccines that work with spike proteins, the applications of this research are not limited to one virus, Whitehead said.

“You can use it to map flu and potential HIV pathways; for other known viral diseases, as well as potentially emerging pandemic diseases,” he said.

Reference: “Single identification of SARS-CoV-2 S RBD escape mutants using yeast screening” by Irene M. Francino-Urdaniz, Paul J. Steiner, Monica B. Kirby, Fangzhu Zhao, Cyrus M. Haas, Shawn Barman, Emily R. Rhodes, Alison C. Leonard, Linghang Peng, Kayla G. Sprenger, Joseph G. Jardine, and Timothy A. Whitehead, Aug. 9, 2021, Cell Reports.
DOI: 10.116/j.celrep.2021.109627

Other authors of this publication include Paul Steiner, Monica Kirby, Cyrus Haas, Emily Rhodes, Alison Leonard, and Kayla Sprenger in Chemical and Biological Engineering at CU Boulder; Fangzhu Zhao, Shawn Barman and Linghang Peng of the Scripps Research Institute; and Joseph Jardine of the International AIDS Vaccine Initiative.