When the Omicron variant emerged in November, scientists at Moderna and Pfizer sacrificed their Thanksgiving holiday weekend to begin working on new shots tailored to the latest incarnation of the virus. Emboldened by the record-breaking speed of the designing, testing, and authorization of the original COVID-19 vaccines ― accomplished in under a year ― Pfizer chief executive Albert Bourla promised that updated shots would be available within 100 days.
“This vaccine will be ready in March,” Bourla emphatically told CNBC in January. “I don’t know if it will be needed. I don’t know if and how it will be used. But it will be ready.”
That self-imposed deadline passed with few updates and no explanations for the delay. By the time the US Food and Drug Administration convenes a meeting late this month to discuss plans for updating booster shots in the fall, more than 200 days will have elapsed since Moderna and Pfizer began working on their Omicron vaccines.
So what’s the holdup?
The pace — more like a brisk jog than a sprint — has frustrated some scientists who believe updated vaccines would help increase the strength and breadth of the immune system’s ability to fight Omicron. “The sense of urgency is lacking,” said Larissa Thackray, an infectious disease biologist at Washington University School of Medicine in St. Louis.
Pfizer and Moderna did not grant interviews, but vaccine scientists ticked off several reasons for the delay. To start, the virus keeps changing too quickly. There’s also conflicting data on the superiority of variant-specific boosters over what’s already available, casting doubt on their value. And with the majority of Americans yet to get even their first booster shot, the companies’ financial incentive for making new ones has diminished.
It took Pfizer and Moderna just over 300 days to go from the genetic sequence of SARS-CoV-2 to earning emergency authorization of their shots from the FDA — crushing Merck’s previous record of developing a mumps vaccine in four years. Some experts believe the 100-day turnaround time for updated vaccines could be possible under some circumstances. Apparently it was too ambitious in this case.
“People just got so accustomed to the fast pace of progress with the development of vaccines during the pandemic that their expectations are unrealistic,” said David Montefiori, a virologist at the Duke University School of Medicine whose lab is running tests on Cambridge-based Moderna’s updated vaccine.
Moderna chief executive Stéphane Bancel — never one to undersell the speed and flexibility of mRNA vaccine technology — has been unusually restrained when it comes to talking about the Omicron shots. Bancel has suggested that Moderna is focused on updating its vaccine for the fall. The company expects initial data from a clinical study of two updated booster shots later this month, which will help it decide which vaccine to offer.
In theory, designing the new vaccine is a simple matter of tweaking its mRNA sequence to match the genetic code of Omicron — something that Pfizer and Moderna scientists could have easily accomplished over the Thanksgiving weekend. But making enough of the vaccine to begin clinical trials takes at least several weeks. And so Pfizer didn’t announce the start of its Omicron vaccine clinical trial until Jan. 25.
That two-month turnaround — from announcing work on an updated booster to testing it in people — is still quick compared to traditional vaccine development. But the rapid evolution of the coronavirus has turned variant-specific vaccine development into a game of whack-a-mole, and drug companies are losing. Previous efforts to develop vaccines for the Beta and Delta variants moved too slowly for the vaccines to be useful. And since Omicron has evolved into several subvariants since November, the Omicron booster shot is at risk of becoming outdated before it’s authorized for use.
“Having the variant-specific vaccine only makes sense if that variant persists for a long enough period of time to vaccinate people against it,” said Dr. Lindsey Baden, an infectious disease doctor and clinical research director at Brigham and Women’s Hospital, who is involved in Moderna’s variant-specific booster shot trial.
Running clinical trials to test the safety and efficacy of the shots is the most time-consuming step of vaccine development ― regulators need to be sure that the updated shots are safe. Vaccines based on mRNA technology “are still too new to be fully confident in how they will behave,” Baden said. “We don’t just want to assume. So if you want data, you have to do the clinical study.”
But studies of the new boosters — each tested in several hundred people — will likely be too small to rigorously assess their ability to prevent infections and disease. Instead, the companies will take blood samples to see if the updated boosters spur bigger or better antibody responses than the existing boosters.
So far, studies testing Omicron boosters in mice and monkeys have yielded surprisingly mixed and mediocre results. “We expected the variant vaccine would be stupendously better, and that the original one wouldn’t work that well,” said Thackray, who led a study comparing the Omicron and original boosters in mice. Although the Omicron boosters triggered somewhat higher antibody levels against that variant, the original booster also worked fairly well.
Likewise, Sidi Chen, an associate professor of genetics at Yale University, found that an Omicron booster spurred higher neutralizing antibody levels against the Omicron variant, but he cautioned that “the effect isn’t dramatically different” from the original booster. In contrast, a National Institutes of Health study found that monkeys who got the Omicron booster actually developed fewer antibodies than animals who received the original booster.
In March, Moderna began testing a so-called bivalent booster that contains mRNA for both the original coronavirus and the Omicron strain — an effort to “hedge your bets” against the evolving virus, Thackray said. The FDA’s vaccine advisory committee will likely debate the relative merits of the original, Omicron, and bivalent boosters when it meets at the end of the month.
Dr. Eric Rubin, an immunologist at the Harvard T.H. Chan School of Public Health and a member of the committee, said he would like to see data that show an updated booster shot can broaden immunity to several SARS-CoV-2 variants. “Then we might feel much more comfortable that we can prevent things that we haven’t seen yet,” he said.
But if the updated vaccines are not markedly better, companies may lack the financial incentive to actually produce them. Moderna and Pfizer have already booked billions in vaccine sales through the remainder of the year, regardless of whether they provide the original vaccine or updated boosters. And given that less than half of vaccinated Americans and fewer than one-third of all people in the United States have yet to get their first booster shot, the lack of urgency to make second-generation boosters probably shouldn’t come as a surprise.
Throughout the pandemic, health officials have stressed that the goal of the vaccines is to prevent serious disease, hospitalization, and death. “I would argue that we’ve achieved that goal with the [existing] ancestral vaccine,” said Dr. Paul Offit, director of the Vaccine Education Center at Children’s Hospital of Philadelphia and a member of the FDA’s vaccine advisory committee.
Offit said he would like to better define what the precise goal of updated boosters would be. Although boosters every three to six months can raise antibody levels and prevent mild and moderation infections for a short time, he doesn’t see that as a “viable or necessary public healthy strategy” long term.
“We are going to have to get used to mild and moderate infection and have a reasonable goal for this vaccine, because we are driving people crazy,” Offit said. “There is already booster fatigue.”
Jonathan Saltzman of the Globe staff contributed to this report.