Bonds Old and New to the Rescue

In December 2019, Bill Gruber, MD, senior vice president of vaccine clinical research and development at Pfizer, sat looking at the news that a new SARS coronavirus had been identified as a major cause of disease in China. It was quickly recognized that this had pandemic potential, and by March the world was in lockdown.

Pfizer, which already had a relationship with BioNTech to develop an mRNA vaccine against influenza, believed this platform could also offer broad response to the virus and rapid vaccine production. An additional partnership to focus on a COVID vaccine was established, with BioNTech providing the mRNA technology and Pfizer offering the infrastructure that BioNTech lacked to move a product from concept to large-scale manufacturing.

Gruber’s team, challenged with figuring out how to do this, had to think backward. They had to forget everything they knew about the typical way to develop products and started with the idea that they had to have a vaccine licensed and delivered by the end of the year. In order to do that, they realized they had to remove all the white space that typically exists between the various phases of development. “We needed to have a seamless trial,” he says. “There was no true Phase I, II, III. We called it that, but it was basically all part of the same trial.”

Gruber credits the regulatory authorities, particularly in the US, for helping to expedite the process. Pfizer was able to get FDA approval to move from Phase I clinical development to Phase II/III in just two days, which could sometimes take months to achieve. Even though Moderna had a three-month head start and initiated its Phase III trial the morning of July 27, 2020, Pfizer began its Phase III trial the same afternoon. By virtue of condensing much of the work—not cutting corners—Pfizer was able to make up the difference.

“This was the No. 1 health priority, and when you’ve got focused attention, you can do remarkable things,” says Gruber.

The seeds of a solution

Life works in funny ways. In this case, the serendipitous meeting of two friends in the 1970s set the stage for worldwide impact. Gruber’s roommate of four years at Rice University was Barney Graham. Though they started out in different majors, both went on to pursue medical careers. They kept in touch after graduation, but neither had a clue that they would intersect throughout the rest of their lives.

Source: guteksk7/stock.adobe.com

Gruber first connected with Graham professionally in 1986 at Vanderbilt University, where Graham was researching respiratory syncytial virus (RSV), an area in which Gruber had also been involved. In 1999, Gruber left academia to join Wyeth, which ultimately became part of Pfizer. Graham went on to work at the NIH to head the viral vaccine laboratory and continue his RSV work. Then fate took another twist.

With time on his hands during the government shutdown in 2013, Graham and his wife took a trip to see the foliage in the Northeast where Gruber happened to live. Gruber had just returned from a scientific meeting that Graham planned on attending, too, but couldn’t because of the shutdown. During that visit, Gruber asked Graham about the pre-fusion structure research he had recently published in Science. Graham responded by pulling out what he planned to present at the meeting, had he been able to go, which was the fundamental basis for the RSV vaccine. That research was used in Graham and Jason McClellan’s work in SARS and MERS, which eventually was adapted to create BNT162b2, the first COVID vaccine to receive emergency use authorization in the US, on Dec. 11, 2020. While Gruber continued his path at Pfizer, Graham moved on to work at NIH, which partnered with Moderna, a COVID vaccine competitor.

On the right track

The first encouraging vaccine news for Pfizer was receiving the initial tolerability information, which was within the realm of reactions considered acceptable for vaccines, particularly in a pandemic setting.

The next reinforcement was getting the immune response or neutralizing antibody, in particular, and then showing that it was at or greater than the level of convalescent antibody in people recovering from infection. Getting a cell-mediated immune response like what they thought was needed to ensure both efficacy and safety was another confidence boost.

“People get torqued around this notion of antibody…but we really don’t know for certain that what you see in terms of what you get after you immunize is really the basis of the protection,” says Gruber. “It’s a good marker, but it may not well tell the whole story. We think that it’s the CMI (cell-mediated immunity), it’s the establishment of memory, so that when you encounter virus in the future you quickly generate it.”

The greatest moment not just in the development of the COVID vaccine but of Gruber’s entire career—and he’s had some remarkable milestones helping to develop Prevnar and Prevnar 13—was at the data monitoring committee (DMC) meeting on Nov. 8, 2020. As he recounts:

“The information was presented to the DMC in a closed virtual session. [As] people logged on, I was trying to read their body language. I looked at them and it was just kind of a flat affect. Finally, after everybody gathered, they broke out in smiles because we had 95%-plus efficacy. They were pretty much beside themselves. I was told later that there was a bit of delay when they were actually done with the meeting and when they met with us, because they had to regain their composure—they were in tears. Sometimes I still get choked up about this.”

This was the first moment Gruber heard the news, and he and his team were exuberant. “We went directly from there to the meeting with [Pfizer CEO] Albert [Bourla] and his leadership team,” he says. “That was the second-best moment of my life. They were all sitting there in suspense, distanced around a table wearing masks. Once we announced the results, the masks stayed on, but there was some embracing.”

Breaking the mold

Before COVID vaccines, the fastest developed vaccine in history was Merck’s mumps vaccine in the 1960s, which took about four years. “That helps put this in perspective,” says Gruber. “To have done something in nine months that typically takes nine years or more is unprecedented. It was blood, toil, tears, and sweat. We were working pretty much 24/7.”

What aided the around-the-clock effort was a strategy Gruber helped devise that pulled in leadership team members spanning the UK and US. While one team was working, the other could sleep and vice versa. It underscored for Gruber the importance of using a global team not just in the area where they are located.

Another advantage for Pfizer was that Gruber’s team was composed of vaccine veterans with decades of development experience. “We had the expertise that had been groomed for decades just for a moment like this,” he says. “I think that’s what lent itself not only to the speed but the quality that we were able to reach.”

As Gruber reflects on this watershed moment, he realizes the potential for the future. Pfizer intends to move forward with its influenza vaccine and is looking at other vaccine targets that would lend themselves to mRNA.

“This should open up possibilities for a host of other things,” he says. “Moderna is moving forward in other fields, and BioNTech is very interested in the oncology space. You could argue, had it not been for COVID-19, this type of momentous breakthrough might have been a much longer time in coming. I feel very fortunate to be at this time in history. It’s been a horrific year from a public health sense, but as far as advancing a potential tool, it’s been an extraordinary opportunity.”

Elaine Quilici is Pharm Exec’s Senior Editor. She can be reached at equilici@mjhlifesciences.com.