The extraordinary drive to develop Covid-19 vaccines was like a moonshot — and like that fabled acceleration of space exploration science, it delivered. Just a little over six months after the first Covid vaccines were authorized for use, nearly 3 billion vaccine doses have been administered around the globe.
The world got very lucky; so much went right in the quest for vaccines to end this pandemic. But there have been setbacks (see: Sanofi) and failures (see: Merck) along the way, and the progress toward supplying vaccine to less affluent parts of the world has been scandalously slow.
As life begins to return to normal — at least in countries with access to vaccines — STAT wanted to take stock of some of the things that worked in the fast-tracked development of vaccines and some of the things that didn’t. Interviews with a number of experts in immunology, drug development, and government research revealed a dozen lessons we should learn from the Covid vaccine project for next time. Sadly, there will be a next time.
Basic science investments can pay huge dividends
On Jan. 11, 2020, the genetic sequence of the new coronavirus, later named SARS-CoV-2, was published in Genbank, an international repository available to scientists around the world. Almost 11 months to the day later, the United Kingdom started immunizing people with the first vaccine authorized in the West, the one made by Pfizer and BioNTech. Clinical trials had shown it was 95% protective against Covid-19. Vaccines made by Moderna, AstraZeneca, and Johnson & Johnson quickly followed Pfizer into use.
This is a historic feat.
“Nobody expected to get a vaccine available within 2020 — I mean, it was just ridiculous to think that. So, to get multiple vaccines out there within a year, a full year, has been a pretty amazing accomplishment overall,” said John Moore, an immunologist at Weill Cornell Medical College.
But it wasn’t a miracle or a fluke, stressed John Mascola, who heads the National Institute of Allergy and Infectious Diseases Vaccine Research Center. The 2002-2003 SARS outbreak alerted scientists to the epidemic risk coronaviruses pose; that lesson was re-emphasized when a camel coronavirus, MERS, started causing sporadic outbreaks on the Arabian Peninsula in 2012. Scientists worked for years figuring out how to target coronaviruses with vaccines.
When China revealed a coronavirus was the cause of its fast-moving outbreak in Wuhan, scientists who design vaccines built on that early work, focusing on the main protein on the exterior of the virus, the spike protein, as a vaccine target. The rest is history.
The other part of this is the money governments — particularly the U.S. government — invested so the vaccines could be fast-tracked, said Anna Durbin, a vaccine researcher at the Johns Hopkins Bloomberg School of Public Health.
“Without the support from the federal government for the clinical trials and advanced purchase vaccines, we never would have been able to move to Phase 3 clinical trial so quickly and have the manufacturers commit to large-scale production,” Durbin said.
Redundancy is critical in a vaccine quest
Vaccine development is a fraught area of research. Historically, more projects fail than succeed. Knowing that, the leadership of Operation Warp Speed, the U.S. effort to fast-track vaccines, diagnostics, and drugs decided to spread the government assistance around.
Warp Speed funded different types of vaccines, and where possible, chose to support a couple of each type it funded or committed to purchase. “Several bets in each lane. … I think that was important,” said Bruce Gellin, chief of global public health strategy at the Rockefeller Foundation.
Warp Speed wasn’t interested in the old-school inactivated virus vaccines some Chinese developers were making; experience has shown those vaccines often don’t trigger a strong enough immune response. It chose two messenger RNA vaccines, two made using viral vectors, and two protein-based vaccines. Astonishingly, five of the six projects have led to vaccines that are already in use or will soon be, here or abroad.
“Having multiple shots on goal with different platforms, this was the best way to do this and, you know, let the chips fall,” said Larry Corey, co-leader of the National Institutes of Health’s Covid-19 Prevention Network and a virologist at the Fred Hutchinson Cancer Research Center.
mRNA was ready for prime time
Scientists had been working for years to harness the promise of messenger RNA as a vaccination platform. Like the preparatory work on designing vaccines to target coronaviruses, this paid off in spades.
It had long been recognized that vaccines based on messenger RNA would be faster to make. It wasn’t clear they would be as potent as other vaccine platforms. But potent they were. The Pfizer-BioNTech and Moderna vaccines were both shown to be more than 90% protective.
“Had it been five years ago, mRNA would not have been in the state of maturity, I don’t think, to have been rapidly used in the way it was here,” Mascola said.
This is one of the major scientific achievements of the pandemic. “Five or 10 years from now and when we look back and try to find a ‘positive side’ for the Covid pandemic, I think it will be that it gave the opportunity for RNA to show its full potential as a vaccine platform,” said Ali Ellebedy, an associate professor of pathology and immunology at Washington University School of Medicine in St. Louis who has been studying how the vaccines work.
Ellebedy calls these vaccines “remarkable in basically all aspects.”
mRNA vaccines aren’t the sole solution
CureVac is an important cautionary tale that mRNA is not a fail-proof vaccine platform. On Wednesday the German company revealed that the final results of its Phase 3 clinical trial were a disappointment. The vaccine was only 48% protective, which likely isn’t good enough to win regulatory approval. It’s not yet clear why it didn’t succeed, though crucial differences in its design versus those of the Pfizer and Moderna vaccines are thought to be responsible.
“So there’s still potential for failure. It’s not that every RNA works,” Corey said.
And despite the spectacular efficacy of the Pfizer-BioNTech and Moderna vaccines, some people are uncomfortable with the new technology, preferring techniques with longer track records, he noted.
“The world does need diversity,” Corey added. “The pathogens and the infectious agents are diverse, the diseases are diverse, and the solutions will always be diverse. There’s never going to be a single solution to every problem.”
When one vaccine crosses the finish line, challenges arise for other clinical trials
The questions started to emerge almost as soon as the Pfizer-BioNTech vaccine was granted an emergency use authorization in early December and began to become available. How do you keep people in blinded clinical trials — where they might have been given a placebo — to continue testing other vaccines once they have the option to quit and get the authorized product?
“All of a sudden there were questions that were … I don’t know if they were novel, but we hadn’t faced them in a while,” admitted Christine Grady, chief of the department of bioethics at the National Institutes of Health Clinical Center. “We probably should have anticipated it.’’
In the very early days, supply of the Pfizer vaccine was so scarce most people in clinical trials had no chance of getting doses. But the Moderna vaccine became available and supplies increased. So did the incentive for people to drop out of the trials that were still underway.
The Food and Drug Administration worried about the loss of long-term data and urged manufacturers to consider working a “crossover” into their trial designs to retain participants. Everyone who had received placebo would later receive vaccine; those who’d received vaccine would get placebo shots. Most of companies dismissed the idea as too complex and too expensive.
The sole exception among U.S. trialed vaccines was Novavax, which was several months behind the first vaccines. “They didn’t have a choice,” said Moore. “By the time they got their trial started, many people had access to the mRNA vaccines.”
Moore was enrolled in that study; within a month of its start he could have gotten vaccinated at work. He stayed in the trial, but Novavax had 5,000 dropouts, the company revealed earlier this month when it reported its vaccine was 90% protective.
Experience is important, but it’s not everything
When a research group from the University of Oxford teamed up with drug maker AstraZeneca to develop their Covid vaccine, the union raised some eyebrows. The Oxford researchers had a laudable goal; they wanted to make an inexpensive and easy to use vaccine that could be produced in multiple parts of the globe. The world’s vaccine, it was dubbed. But AstraZeneca was a minor player in vaccine production.
Conducting pivotal Phase 3 trials is complex stuff; these trials have to generate data that convince regulatory agencies of a vaccine’s safety and efficacy. Some unfortunate choices by the Oxford group left regulatory agencies in a quandary about how to use this vaccine. The Oxford team enrolled few people over age 65, the demographic that most needs Covid vaccines, and ran several studies that generated data that were hard to compare. The European Medicines Agency even noted in its ruling that the data generation might have benefited from more involvement of the manufacturer.
“AstraZeneca — that should be a Harvard Business School case study,” remarked one expert who didn’t want to be named.
But three of the world’s most experienced manufacturers have not managed to produce a Covid vaccine. Merck tried two approaches; both failed. Sanofi likewise entered two horses in the race, but a costly error with its most advanced vaccine forced it to redo its Phase 2 study. Unique among the major vaccine manufacturers, GSK didn’t even try to develop its own vaccine. It partnered with Sanofi — providing a boosting compound called an adjuvant — on one vaccine and is now working with CureVac on a second-generation mRNA vaccine.
Vaccines aren’t vaccinations
The Trump administration generously funded Operation Warp Speed, but seemed to ignore the challenges of the so-called last mile — what happens when vaccine doses arrive at the point of delivery. Initially that lack of planning and funding led to chaos.
“The big lesson is that as soon as you start coming up with a vaccine, you should start thinking about the vaccination end of it,” said Gellin, of the Rockefeller Foundation. “It’s worked out over time. But the ‘Hunger Games,’ to try to get a reservation to get a vaccine — that was not thought through.”
Claire Hannan agrees the early efforts were rocky.
“To me that was the hardest thing. To watch people not be able to find the vaccine. … To understand that, ‘OK, I need to wait my turn,’ but to not know when their turn was, and to have their turn be different in every state and to have that anxiety about their parents getting the vaccine or their loved ones getting the vaccine,” said Hannan, executive director of the Association of Immunization Managers.
“We’ve got to learn from that.”
Complex priority schedules are hard to execute
It was always apparent that demand for vaccine would far outstrip supply in the early days. A lot of effort went into trying to determine who should be first in line.
The National Academies of Sciences, Engineering, and Medicine appointed a panel of experts to come up with a plan for equitable allocation of vaccines. The Advisory Committee on Immunization Practices, which advises the Centers for Disease Control and Prevention on vaccine use, came up with its own plan. The documents weren’t identical, but both stressed the need to include essential workers near the front of the line.
But with the exception of health workers, who would be vaccinated at work, figuring out who qualifies as an essential worker is no small task. And asking vaccination clinics to check for people’s bona fides wasn’t going to happen; everyone knew it would function — if it functioned — on an honor system.
Many states ignored the plans.
“It’s very difficult to implement [an] essential workers [category],” Hannan said. “We don’t have a way of enforcing that. I think some states discovered ‘We know who’s 80. … We can do it a lot easier that way.’”
The first vaccine to be put into use was both a miracle and a nightmare. The Pfizer vaccine was 95% protective, a virtual home run. But it required ultra-cold storage, a capacity neither doctors’ offices nor pharmacies had.
To make matters worse, the company decided to set its minimum order at more than 1,000 doses, which benefited Pfizer but restricted where the vaccine could be used. The company shipped the vaccine in special freezer packs that could only be opened twice a day. There was nothing easy about putting this vaccine into the field, and Pfizer’s packaging made it harder.
“It very much limited the providers that could be used. And it placed an enormous amount of stress on the planners because it was an enormous challenge. And it took time away from all of the other little things because it was just such a huge undertaking,” Hannan said.
There’s power in numbers
With several new vaccines being rolled out at once, regulatory agencies have been keeping a keen eye out for any hints of adverse events. The authorized vaccines appeared safe in the clinical trials, but rare side effects will only show up when millions of people are vaccinated.
A number of regulatory agencies set up a “red phone” system — they call it that, but in truth, it’s a WhatsApp group — to share information about potential adverse events. If any member agency spots something that looks like a problem, it pings the other members. When needed, conference calls are rapidly convened.
The system has worked well, officials from the EMA and Health Canada revealed during an online conference last week hosted by MaRS, a Toronto-based innovation hub. The FDA, and regulatory agencies from Britain, Switzerland, South Korea, and Singapore, among others, are also members.
“The larger the group of people exposed, you have a better idea, you have more confidence in your findings,” Agnes Saint-Raymond, who heads the EMA’s division of international affairs, said during the panel.
Pregnant and lactating people were left in the lurch yet again
When new vaccines are being developed, manufacturers routinely test them in healthy adults first, later moving to more vulnerable demographic groups. Pregnant and lactating people and children are typically last on the list.
It’s born of a desire to protect, but it often ends up creating a conundrum. If pregnant people weren’t included in clinical trials, how would they know if it was safe to be vaccinated?
Johns Hopkins researcher Ruth Karron and colleagues argued from the earliest days of the pandemic that pregnant and lactating people should be included in the clinical trials. They were not. And though vaccine manufacturers promised to do the critical animal studies — known as developmental and reproductive toxicology, or DART, studies — needed before vaccines can be tested in pregnant people, they were slow to do them.
With the U.S. government helping to fund development of the vaccines, there was no excuse for not doing this work early, said Karron.
“When resources were limitless, nobody could claim, ‘Oh, we can’t do DART studies early because gee, the resources just don’t exist, and those are really expensive studies.’”
The lack of data left pregnant people and their doctors to decide on their own whether they wanted to be vaccinated. A recent study from the CDC showed that as of early May, only 16% of pregnant people in the U.S. had opted to be vaccinated.
“By all means, we should have learned this lesson,” Karron said.
Grady suggested it may require action from government to change this persistent problem, such as linking government assistance to a requirement to do early testing in pregnant people.
Vaccine inequity is well and truly entrenched
The United States has more vaccine than people willing to be vaccinated at this point. Nearly 78% of people over 65 are fully vaccinated; 54% of Americans over the age of 12 are fully vaccinated.
Canada, Britain, and a number of other rich countries have high and growing rates of vaccine coverage. Meanwhile, many less affluent countries haven’t yet vaccinated 1% of their populations.
There’s been a lot of talk about what to do, but it’s not translating into swift action. The lesson many countries are surely learning is that when it comes to pandemics, national interests trump global solidarity.
The director-general of the World Health Organization, Tedros Adhanom Ghebreyesus, regularly pleads with countries that have vaccine to share more of it, calling the situation a “catastrophic moral failure.”
Durbin, the Johns Hopkins researcher, said over the longer term, the answer has to be greater capacity to make vaccines — capacity that’s distributed across the globe, and not solely in rich countries.
“We need more vaccine manufacturing infrastructure (not only buildings but experience in producing vaccines and evaluating the safety and efficacy of vaccines) globally, particularly in [lower- and middle-income countries],” she wrote in an email.
“If they had the ability to produce them, they could meet the needs of their own countries. We need to continue to invest in the vaccine sciences and in vaccine manufacturing.”
This article has been updated to include the final results of CureVac’s Phase 3 vaccine trial.
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