SARS-CoV-2 has been met with a global mobilization of science rivaling the space race. Multiple vaccines around the world were granted emergency approval within a year. The same effort for Ebola took more than five years. From identification to the first clinical trials, the polio vaccine took 30 years. Science has a habit of advancing rapidly, especially in the face of a raging pandemic. Early on, a promising therapeutic antibody was discovered in record time at the Vanderbilt University Medical Center. In another corner of the globe, a cell line was developed at University of Queensland to produce a unique vaccine. Our technology and people — our two core strengths — helped make these potential treatments a reality.
The Vanderbilt University Medical Center (VUMC) in Nashville has been working since 2018 on a pipeline for developing antibody treatments that can be dispersed within 60 days of a viral outbreak. Our Beacon® optofluidic system had just been added to the pipeline when SARS-CoV-2 became a pandemic virus. It was the ultimate proving ground: when every day mattered, how fast would the Beacon system identify human antibodies capable of fighting a COVID-19 infection?
One of our Program Managers, Vincent Pai, spearheaded the project at BLI. To identify antibodies capable of countering the SARS-CoV-2 Spike protein, Pai saw opportunity in pairing a newly developed antigen blocking assay with an established antigen binding assay. “We had just developed the blocking assay, but it was worth bringing to the table.”
Pai flew to Nashville in early February to meet the VUMC team in person. Our Field Application Scientist, Jonathan Didier, joined him to prepare the Beacon system. Didier remembers, “It was a lot of hurry up and wait, because we weren’t the only ones in line for samples.” Convalescent samples are valuable as bearers of life-saving antibodies. But, it takes a month, post-infection, for your immune system to produce the memory cells researchers need. Convalescent samples were in high demand and getting one perfectly timed wasn’t guaranteed — the team was likely to get only one shot.
About a month later a sample was ready. Didier was helping the team in Nashville while Pai called in and watched the experiment live from his home in California. “The first couple of [binding] assays we ran were a success. Hundreds of pens were lit up. It was the first time we’d immediately seen a live cell from a human secrete against SARS-CoV-2.” It was time to run the blocking assay and find the most capable antibodies.
In the blocking assay, darkness rather than bright fluorescence indicates a promising antibody. When the sample didn’t go as dark as expected, there was momentary confusion. The binding-blocking behavior they were hunting for was present in what would end up being fewer than 10 cells in nearly 1,000. Pai remembers the moment like it was yesterday, “I freaked out, literally jumped out of my chair. And I’m yelling into my phone, ‘The assay works! We found cells, we found antibodies.’”
By early June, AstraZeneca announced that they’d signed an agreement with VUMC to advance a two-antibody cocktail into clinical development as a preventative treatment for COVID-19. Within 4 months, the cocktail proved promising enough to go into Phase III Clinical Trials. The antibodies in the cocktail, COV2-2196 and COV2-2130, were discovered in only 18 days on the Beacon system by our viral neutralization binding and blocking assays. You can explore the methods behind them, as well as the data, in our application note.
The University of Queensland (UQ) is an institution with world-leading expertise on viruses and, in particular, pandemics. Trent Munro, Keith Chappell, and Paul Young have led the UQ COVID-19 vaccine program equipped with something distinctive: their molecular clamp.
When SARS-CoV-2 infects a cell, the Spike protein extends and changes to reveal entirely different residues. The UQ molecular clamp protein is designed to stabilize Spike proteins to stay in their pre-infection conformation, allowing the native immune system to respond before infection. The approach has already been used successfully by the team against influenza and MERS.
To develop their unique vaccine candidate as quickly as possible, the UQ team needed a bespoke cell line development assay. Our Head of Business Development, Troy Lionberger, was close to the project. “Having been on the development team behind our original CLD workflow, I had a pretty good idea our development team could come up with a solid solution here and so introduced UQ to Philip Elms.”
Elms, one of our Application Engineers, had theorized to Lionberger that modifying our diffusion assay could make characterizing tricky proteins possible. Elms explains, “I actually had the hypothesis for a while. It was something I’d mentioned to Troy. If we ever ran into the need to find proteins, and we couldn’t use our standard flush assay, this could be the solution.” The modified assay uses fluorescent reagent to illuminate the most productive clones, but isn’t limited to antibodies or other large proteins. It’s a robust approach that can be applied to almost any protein and still be sensitive.
Helping the UQ team in the middle of border closures meant Elms’s assay would have to be tested on the other side of the planet, without him physically being there. Luckily, a bespoke solution could come in the form of a simple program script. Lionberger explains, “Philip had written a script that he emailed to UQ. He told them what to load into the Beacon system. In real time, he could analyze their data and troubleshoot with them.” Using Elms’s assay, in two weeks, the team got 10 times higher titer than with any other technology they’d ever tried before.
Four months later, the molecular clamp vaccine headed to human trials. By the end of the year, the vaccine, called UQ-CSL V451, entered Phase IIb/III trials and CSL Limited committed to manufacturing nearly 100 million doses if it proved successful. From the time UQ-CSL V451 went into Phase I to the CSL announcement, COVID-19 infections more than doubled from 12 million to nearly 27 million. Just under 1 million people had died.
Each of these stories highlights something special about the Berkeley Lights Platform — in the time it takes to quarantine for international travel, teams can discover and develop even when they can’t all be in the lab. In only a few months following cell processing, human clinical trials started (a process that once took years).
Covering our accomplishment with UQ in an interview with our SVP of Marketing, John Proctor, Samantha Black wrote, “Perhaps most impressive of all, these significant changes…were all made online. Due to COVID-19 travel restrictions, the scientists at Berkeley Lights and the University of Queensland worked together virtually to develop an entirely new assay and push the vaccine candidate toward a Phase I clinical trial.”
Hitting a virus smaller than a dust mote with the technological force of a planet has expedited progress. In his interview for this piece, Troy Lionberger remarked that the Berkeley Lights Platform and the methods it makes possible helped researchers get to their target faster than before. “Today, we’d be even faster. With the next virus, we’ll be faster than that.”
By the end of the year, the vaccine, called UQ-CSL V451, was pulled from Phase IIb/III Trials. It showed great efficacy early on in Phase I Trials, but yielded the side-effect of false-positive HIV tests in some individuals. The team at UQ has since said they’ll continue investigating the molecular clamp approach for other pathogens.
There’s still work to be done. If the Berkeley Lights Platform can help you, reach out to us and we’ll be in touch within 24 hours.
This story originally appeared in the Winter 2020/21 edition of BLI News. To read more, check out the latest edition.