The COVID-19 pandemic posed significant challenges to governments, researchers, and pharmaceutical companies across the globe, compelling them to expedite their efforts in developing treatments and vaccines. Each delay in delivering these solutions resulted in additional casualties linked to the pandemic. A pivotal aspect of vaccine creation was the urgent need to comprehend the viral spike protein of SARS-CoV-2, which is essential for the virus”s entry into human cells and has long been considered a viable target for coronavirus vaccines.
Jason McLellan, a professor of molecular biosciences and the Welch Chair in Chemistry at The University of Texas at Austin, had previously worked on elucidating the structure of a coronavirus spike protein back in 2016, well before the pandemic emerged. Thanks to their background in studying these proteins, McLellan”s team swiftly responded to the crisis, publishing the structure of the SARS-CoV-2 spike protein in February 2020 and creating stabilized versions for vaccine development by June 2020.
“During that stabilization we did back in 2016, we were… sort of anticipating the pandemic,” McLellan noted. He recalled the SARS outbreak in China in 2002 and the MERS outbreak in Saudi Arabia in 2012, which led his team to believe that another spillover event was inevitable. “We”ve had two big spillovers 10 years apart. There”s going to be another one. We should really start working on coronaviruses and figuring them out,” he explained.
Despite successfully resolving some configurations of the coronavirus spike protein, the inherent instability of other conformations posed challenges that required innovative protein engineering. “Some of these proteins we work on, like the coronavirus spike protein, are shape shifters. They exist in pre- and post-fusion states,” McLellan elaborated. “Generally, the pre-fusion state is the better vaccine immunogen. It contains all the neutralizing epitopes, but it”s also metastable. So we had to engineer the protein so it stayed in pre-fusion as you inject it into somebody”s arm and as it goes to germinal centers for antibody elicitation.”
To achieve this stability, McLellan”s team substituted two specific amino acid residues with proline, a nonpolar amino acid that limits the conformational flexibility of alpha helices and hinders the transition from pre-fusion to post-fusion states. “We identified where to place stabilizing proline substitutions in the coronavirus spike proteins. When the genome sequence of SARS-CoV-2 was released, we knew exactly where to make these substitutions, and they are incorporated in all the COVID-19 vaccines authorized in the US,” McLellan stated.
This swift response from the scientific community has earned McLellan a MacArthur Fellowship, a prestigious grant amounting to $800,000 that is awarded annually to approximately 20 remarkable individuals across various fields. Past recipients include notable figures such as playwright Lin-Manuel Miranda and science-fiction author Octavia Butler.
“Each year, about 20 to 30 people receive these fellowships. They are interesting because they encompass not just science but also a wide array of creative disciplines, including the arts and humanities,” McLellan remarked. “I believe this recognition is beneficial for the field and for our collaborative network.” The financial freedom provided by the fellowship enables McLellan to explore higher-risk studies and generate preliminary data necessary for obtaining additional funding.
Building on the experiences gained during the pandemic, McLellan”s team is intensifying their research into vaccine design through structural biology. “We are continuing to push and innovate in structure-based vaccine design,” he stated. “Structural biology raises essential questions about the shapes of viral proteins or protein complexes, their receptor interactions, and the conformational changes that facilitate entry into cells.”
Utilizing insights from studying the wild-type protein, McLellan employs protein engineering to create modified, stable complexes, and soluble versions of the protein, ultimately producing effective monoclonal antibodies. These antibodies guide vaccine design, aiming to develop vaccine antigens that prompt the body to generate robust protective antibodies against specific viruses.
“Our focus has shifted towards pandemic preparedness and prototype pathogens, striving to understand general principles applicable to viral families,” McLellan explained. “Even if the virus we are studying is not the exact one that spills over, we can still apply our knowledge to develop vaccines quickly.” Looking ahead, McLellan”s research intends to delve into the structural biology of bacteria and fungi, leveraging fundamental research to prepare for future pandemics.
“Currently, we are engaging in substantial pandemic preparedness work, focusing on pathogens that are not widely recognized, such as BSL 3 and BSL 4 agents, which could potentially trigger a pandemic,” McLellan mentioned. “We aim to have all the necessary research—structures and stabilization—completed in advance, so we can respond rapidly if any of these pathogens begin to spread significantly.”
McLellan credits his achievements in structural biology and vaccine development to his scientific approach, which encourages continuous innovation and experimentation. “One key to success I advise my students is to “work hard, be smart, and get lucky.” The more hours you spend in the lab and the more projects you juggle, the more likely one of them will lead to significant discoveries,” he concluded. “It”s also essential to be familiar with the literature so that when you encounter something noteworthy, you can recognize its significance. Science also involves creativity; you need time to think, experiment, and truly analyze your data.”
