Structure-Based Design: A Path Toward a Universal Coronavirus Vaccine

By Mark Miller

On January 3, 2020, the cause of several pneumonia-like cases in Wuhan City, China, was confirmed to be a novel Betacoronavirus. Three days later, Jason McLellan, PhD, a professor of molecular biosciences at the University of Texas, Barney Graham, PhD, an immunologist and virologist with the National Institutes of Health (NIH), and their colleagues agreed to determine the structure of the virus and help develop a vaccine. According to the article “Jason McLellan: the scientist stopping coronavirus in its tracks” written by Rebecca Pool, PhD and published in Wiley Analytical Science, the virus genome was sequenced and the researchers knew their next steps in just four days.

McLellan and his colleagues were in a position to respond so rapidly as the result of years of work developing structure-based vaccines to fight diseases like COVID-19. Here is a look at how they got there and what may be coming next.

Locking the Protein

Around 2008, McLellan began working on the structures of HIV proteins. He then teamed up with Graham at the NIH Vaccine Research Center to apply a structure-based approach to the respiratory syncytial virus (RSV). By 2013, they had used X-ray crystallography to understand the structure of RSV's fusion protein and how it changed states to infect cells. They were able to lock the protein in its prefusion state to prevent transmission and develop an initial vaccine.

“We were all so excited,” McLellan said. “We had used structural information to create a vaccine antigen that was superior to anything else ever created.” It was this breakthrough, according to Pool’s article, that laid the foundation for the work that would be done on the SARS-CoV-2 virus.

"We had used structural information to create a vaccine antigen that was superior to anything else ever created."

2P Mutation

McLellan departed NIH to run a lab at Dartmouth College. There, he and his team encountered the Middle East Respiratory Syndrome (MERS), a Betacoronavirus similar to SARS.

“The RSV and MERS fusion proteins are ancestrally related and have a similar fold in one part so we thought, 'let's give this a try,' ” McLellan recalled. “I guess at the time of MERS we had been anticipating another coronavirus outbreak and so started work on this quickly. Like RSV, we knew we wanted to stabilize that spike protein, make vaccine antigens, and isolate the antibodies.”

But there was a problem. The MERS spike proteins would not crystallize, which excluded X-ray crystallography studies. The team turned instead to cryo-electron microscopy with the help of specialist Andrew Ward from Scripps Research Institute.

Applying the new technique along with knowledge about the human coronavirus HKU1, McLellan and team became the first to resolve a human coronavirus spike protein with HKU1. From there, they stabilized the MERS spike protein by using proline to replace two of the protein’s residues, an amino acid substitution known as a 2P mutation.

The Road Ahead

2P mutation proved a critical advancement when McLellan, now at the University of Texas, and the other researchers took on SARS-CoV-2.

“The SARS-CoV-2 was a Betacoronavirus and was very similar to the first SARS coronavirus, which was great in terms of rapidly developing a vaccine,” said McLellan. In a little over a month the team reported the results researchers needed to develop a vaccine based on the 2P mutation.

They had also discovered that proline could be added to the protein spikes of other coronaviruses, offering the potential for a universal vaccine — a single vaccine that could protect against many SARS-CoV-2 variants and emerging coronaviruses.

Since their initial work, four more proline molecules have been added to the structure to bring about a more stable spike protein known as a HexaPro. It’s in use in over 100 laboratories worldwide doing COVID-19 research, including vaccine development.

McLellan and his team continue to study coronaviruses and pursue a universal vaccine. In particular, they are investigating the virus’s S2 subunit, a strong target for vaccine development that’s shared across a range of coronaviruses.

Mark Miller is a Thermo Fisher Scientific staff writer.