Did Pfizer Peak Too Soon?

The Delta variant’s arrival this summer delivered a blow to the nation’s entire coronavirus arsenal, but its impact on the champion of last year’s vaccine race—Pfizer—has been particularly humbling. Compared with Moderna’s competing shot, Pfizer’s vaccine seems to induce half the amount of virus-fighting antibodies, and is associated with nearly twice as many breakthrough infections, according to two recent studies. Pfizer’s shots remain highly protective against hospitalization, but the latest numbers from the U.S. Centers for Disease Control and Prevention suggest that their effectiveness has dropped from 87 percent to 80 percent during the Delta wave, while that of Moderna’s shots remains in the 90s.

Although Pfizer has now sold authorities around the world on the imminent need for third shots to combat waning immunity, the company doesn’t believe that its vaccine, worth more than $30 billion to its bottom line, is inferior in any way to competitors. Recipients of Moderna’s shots, after all, may also need a booster eventually. “All of the real-world evidence you have to take with caution,” Pfizer’s chief scientific officer, Mikael Dolsten, told me recently. “It’s very hard to compare two very effective interventions.” Other experts see the evidence of a difference, however slight, starting to grow. Shane Crotty, a researcher at the La Jolla Institute for Immunology, told me that after looking at some of the recent data, he went to double-check his own vaccination record and was pleased to find Moderna listed on it. Is it possible that Pfizer, in its all-out sprint to bring the first-ever human mRNA vaccine to market, ended up delivering the second-best product?

In reporting my forthcoming book on the COVID-19 vaccine race, I never got the sense that Pfizer had cut any unnecessary corners, but I knew that the story for all the companies had been one of compromise, of making the least-bad decisions in the shortest time possible. Pfizer’s first decision, in early 2020, was to sit things out. In January of that year, the company turned down a chance to help its German partner, BioNTech, develop an mRNA vaccine for the emerging coronavirus disease, figuring that the outbreak would burn out on its own, as many such outbreaks do. By the time the two companies joined forces in March, a rival product, developed by Moderna and the National Institutes of Health, had already been given to the first participants in a Phase 1 safety trial. Operation Warp Speed, a joint effort of the Department of Health and Human Services and the Department of Defense, began to come together the following month and promised pharmaceutical companies billions of dollars to fund the manufacture of vaccines before any had even proved effective in large-scale Phase 3 trials.

As a term of these investments, any company taking Warp Speed money would have to plan its Phase 3 clinical trials with the input of scientists from the NIH and other agencies. I quickly learned that these negotiations were often contentious and sometimes protracted. Moderna was forced to push back the start date of its Phase 3 trial by several weeks, from July 9 to July 27, because of protocol changes demanded by the Warp Speed team. Pfizer, by contrast, was playing catch-up and decided that it didn’t want to be hamstrung by government bureaucracy. Instead, it sank $2 billion into its own development efforts and refused Warp Speed handouts.

[Read: How mRNA technology could change the world]

Moving fast meant navigating significant uncertainties. Dosing was a particularly fraught issue, and the prospects for producing a successful mRNA drug or vaccine hinged on getting it right. A smaller dose would be easier to manufacture and less likely to produce side effects. At the same time, previous experimental mRNA vaccines had not been shown to induce the kind of long-lasting cellular immunity one could get from, say, an adenovirus vector vaccine, such as Johnson & Johnson’s. Back in 2019, Moderna published data from a Phase 1 trial of two mRNA-based bird-flu vaccines: The results had looked solid in the first month or two, but antibody levels dropped back toward baseline by month six. The two doses of those vaccines had been spaced just three weeks apart, which may have limited the body’s immune memory. John Mascola, the head of the Vaccine Research Center at the NIH, told me that durability was going to be a big unknown with all of the COVID-19 vaccines, and the Moderna team “wanted to be conservative” in selecting sufficiently large doses and spacing those doses at four weeks. They knew from early-stage trials that with just 25 micrograms, the immune response declines by one-fourth after a month. A 250-microgram dose seemed, conversely, clearly too high. In the end, they settled on 100 micrograms.

In the meantime, Pfizer and BioNTech were still scrambling to choose among four possible mRNA-vaccine candidates. At first, the internal favorite of the scientific team was one named BNT162b1, which consisted of just a fragment of the coronavirus spike protein, known as the receptor-binding domain. (Moderna was using the full spike for its vaccine.) As was the case for Moderna, the Pfizer-BioNTech team had to figure out the right dose. Across Phase 1 trials in Germany and the U.S., the companies had tested that candidate at doses of 10, 20, 30, and 100 micrograms, injected in volunteers at just three weeks apart, compared with Moderna’s four. The highest dose produced such severe side effects, including fever and chills, that it was dropped from the trial. That’s what vaccine makers call a “hot” reaction, and it’s something Dolsten’s team wanted to steer well clear of.

Then Pfizer and BioNTech tested their own version of the full-length spike vaccine, BNT162b2—this time going up to only 30 micrograms. Because the full-length spike’s gene sequence was about five times as long as the fragment’s, each microgram of vaccine contained one-fifth the number of copies. It was immediately obvious that the side effects were less intense as a result, but the antibody response might end up being smaller too. That would take several weeks to assess—and the clock was ticking.

Dolsten said that during a virtual meeting on July 24, 2020, he told the team that it was time to make a final decision on the candidate and the dose if they were to have any hope of rolling out a vaccine in the fall, when COVID cases were expected to rise. Days earlier, Pfizer had finalized a purchase agreement with Operation Warp Speed. If its vaccine received emergency authorization from the Food and Drug Administration, the U.S. government would pay the company about $20 for each of 100 million doses. And if Pfizer got to the finish line before its Warp Speed competitors delivered their promised doses, the government would be more likely to exercise a purchase option, locking in up to 500 million more doses.

Moderna had now published its antibody data, and the company’s trial with a 100-microgram dose was scheduled to start any day now. According to Dolsten, the dilemma for Pfizer’s scientists was that they still had more human data on their first candidate (the fragment) than on their second (the full-length spike). The two candidates looked comparable, but the team still didn’t know how much of an immune response the full-length spike would produce among the most vulnerable, elderly subjects. Those first data points wouldn’t reveal the durability of the response, simply whether it was on par with the one seen among people who had recovered from COVID. Waiting a few weeks for those data (and potentially adding a higher dose or changing the dose spacing), as one might do during a more relaxed vaccine-development process, was out of the question.

Although Dolsten told me that Pfizer wasn’t necessarily looking over its shoulder, such a delay would certainly have set its Phase 3 efficacy trial back on a timeline akin to AstraZeneca’s or Johnson & Johnson’s. By the end of the meeting, Dolsten and Pfizer’s CEO, Albert Bourla, had persuaded the vaccine team to follow Moderna’s lead and advance the full-length sequence, but at Pfizer’s lower dose of 30 micrograms. That would likely give Pfizer’s vaccine a safer profile in terms of side effects. It would also be cheaper and easier to manufacture, though Dolsten said the scientific team didn’t weigh that in its decision.

Two months into Pfizer’s efficacy trial, in early October, the team was still poring over the antibody data that had come in from the elderly subjects in the dosing study. Measuring the vaccine’s efficacy would involve comparing the number of symptomatic infections in the vaccinated group with those in the placebo group. Moderna and the other companies in Warp Speed gave their own vaccines two full weeks to protect a person following the second dose before any breakthrough infections would be counted against them. Under Pfizer’s more aggressively paced protocol, however, breakthroughs would be tallied at just seven days after the second dose. It now seemed likely that the antibody response in the elderly would not have reached its peak by that point, though no one knew for certain how high it needed to be to protect against infection. At Pfizer’s request, the FDA made a rare allowance, agreeing to let the company add a fall-back measure to its statistical analysis plan, scoring the vaccine at 14 days, like the other companies.

In the end, that last-minute change didn’t affect the final result, as the vaccine proved to have more than 90 percent efficacy at preventing symptomatic COVID infections just 11 days after the first dose. The FDA granted it emergency authorization on December 11, 2020. As the first COVID-19 vaccine on the market, Pfizer’s vaccines were deployed to hard-hit nursing homes and senior-living facilities, both in the U.S. and around the world. Pfizer soon became the “hot-person vaccine,” grabbing the largest market share in countries that could afford it.

[Read: Pfizer gang is pfinished]

What no one could have predicted at the time was just how fleeting Pfizer’s status at the top of the pack would prove. Phase 3 trials of Moderna’s mRNA vaccine produced very similar efficacy numbers; the only hint of a difference was that Moderna’s more potent shot produced more complaints of fever and headaches. Indeed, until the latest observational studies came out, most scientists figured that the two vaccines were equivalent in terms of real-world effectiveness. “It’s surprising that this enormous group of patients already needs a new dose of Pfizer,” says Deborah Steensels, a microbiologist at East Limburg Hospital, in Genk, Belgium, who led the recent study comparing antibody levels generated by the two vaccines. If seniors who received the Pfizer vaccine had gotten Moderna instead, she notes, “we might have had an impact on the duration of protection.”

Shane Crotty, the immunologist, said that Pfizer’s dosing might not have been the optimal choice for the durability of an individual’s immune response, but that doesn’t mean it was the wrong decision for public health. “The decision process was very much about what’s the fastest we could vaccinate people and be successful,” he said. There were clearly benefits to stretching out the limited mRNA supply during a pandemic. Three doses of Pfizer, at 30 micrograms each, still amount to less material than a single, 100-microgram dose of Moderna. That means more lives saved for every droplet of vaccine. Indeed, Moderna may have erred in the other direction: The company has now asked the FDA to consider a half dose for its own potential booster.

As for Pfizer’s Dolsten, he has no doubts about the path his company took last July. “Clearly, you can go with a hotter dose,” he said. “You may get a slightly higher immune response, it may be longer-lasting, but that’s not the right thing to do for a medicine or a vaccine.” He insisted that the company was never racing against Moderna; it was just racing against the virus. “If I could relive that moment,” he told me, “I am absolutely certain it was the right decision.”