Why Covid-19 vaccines are a freaking miracle – STAT

Two years into the Covid-19 pandemic, it’s easy to lament all that has come to pass. The devastating losses. The upending of what we regarded as normal ways of life. The sheer relentlessness of it all.

But let’s stop for a moment and consider something else that may have escaped you: You have witnessed — and you are a beneficiary of — a freaking miracle.

That miracle is the development, testing, manufacturing, and global distribution of Covid vaccines.

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If you’re reading this article, it’s a safe bet that you’ve been vaccinated. You may even have had three doses. Many of your family members, friends, colleagues, neighbors, even strangers you pass on the street are probably in the same boat. At this point if they aren’t vaccinated and boosted, it’s by choice.

Yes, the global rollout has been shamefully inequitable, with low-income countries having to wait far too long to be able to protect their citizens. Sub-Saharan African countries, in particular, still struggle to access and distribute vaccine.

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But at least 55% of the people inhabiting this planet have been fully vaccinated against Covid-19. In affluent parts of the world, anybody who believes in the protective powers of vaccines has had the opportunity to be vaccinated for months now. (The sole exception: children under the age of 5, for whom the vaccines are not yet authorized.) And it isn’t just wealthy countries. Colombia, Morocco, Sri Lanka, El Salvador, Mongolia, and Tonga have fully vaccinated about the same proportion of their populations — roughly 64% — as has the United States.

What has been accomplished in the 25 months since Chinese scientists first shared the genetic sequence of the newly discovered SARS-CoV-2 virus has defied the predictions of the most optimistic prognosticators.

“In one year, half the species vaccinated — wow!” said Eric Topol, the founder and director of the Scripps Research Translational Institute, referring to the period after which vaccines started to become available. He has been marveling on his well-followed Twitter feed about how lucky the world got with Covid vaccines; he calls them “an extraordinary human achievement.”

Topol was among the skeptics in early March of 2020 when Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases, told a Senate committee that it would take at least 12 to 18 months to develop a Covid vaccine. “I thought it was a fantasy. Total fantasy,” he told STAT in a recent interview.

Eight months after Fauci made that prediction, the United States started vaccinating with Pfizer and BioNTech’s messenger RNA vaccine, and a week later, with Moderna’s mRNA vaccine. At 18 months, the outside edge of Fauci’s estimate, the U.S. had already administered nearly 400 million doses of vaccine. Roughly 56% of the population was fully vaccinated by that point and administration of third doses had already begun.

True, the mRNA vaccines haven’t lived up to their initial billing, when they were shown to block roughly 95% of all infections. Over time, that level of protection against all infections declines. Still, they have fundamentally altered the threat SARS-2 poses. Most people who have received three doses are shielded from serious disease and death, even in the face of Omicron, which is so different from the vaccine strain some experts are puzzled at why protection against severe disease remains so strong.

Consider for a moment what might have happened without these vaccines.

According to modeling conducted by the Commonwealth Fund, 1.1 million additional Americans would have died from Covid — and that estimate was made based on data from before the massive Omicron wave that has swept across the country in past two months.

“We would have been broken,” said Topol. “Right now, we have a death toll of around 2,500 people a day. … Imagine what we would have with no vaccination.”

The miracle was based on a solid foundation

The scientists and public policy folk among you are probably bristling at the use of the “M” word. This isn’t a miracle, you’re likely grumbling, but the fruit of years of planning and research and major investments in science. The National Institutes of Health, the U.S. Biomedical Advanced Research and Development Authority, the Coalition for Epidemic Preparedness Innovations (CEPI), and other national and international funders have strived for years to get the world ready to respond to a pandemic.

It is true that we are reaping the benefits of all that, as well as of the $18 billion that Operation Warp Speed, the Trump administration’s program to kick-start the development of Covid vaccines and drugs, poured into the effort. That infusion of cash at a critical time helped companies embark on risky projects that could well — and in some cases did — fail.

“Trump has lots of warts,” said Michael Diamond, a viral immunologist at Washington University in St. Louis. “But he did support a rapid acceleration of the program and should get some credit for it. Without that rapid acceleration in investment, we wouldn’t have had this in time and a lot more people would have died.”

But even with all of that, there was no guarantee the world would be where it is today — and many reasons to believe it wouldn’t be. Up until Covid, after all, the fastest vaccine ever to be developed — the one for mumps — took four years.

At the beginning of this pandemic, Richard Hatchett, who heads CEPI and who has worked on pandemic response planning since 2005, dug as deeply as he could into what was recorded about how the legendary vaccinologist Maurice Hilleman managed to develop the mumps vaccine. He learned it took two years for Hilleman to even start conducting clinical trials.

If Covid vaccines had taken as long as the mumps vaccine to develop, the world would have had to face the Delta and Omicron waves with the vast majority of people on the planet armor-less against the virus that causes Covid.

Instead, it took just 66 days after the SARS-2 sequence was published for scientists at the NIH to begin enrolling people in a Phase 1 clinical trial of Moderna’s Covid vaccine. The first injection occurred on March 16, 2020.

“The previous fastest vaccine ever developed … would just be entering into the clinic now. And we’ve delivered 11 billion doses,” Hatchett noted. “That’s how much we’ve moved the needle.”

Some of it was luck. Scientists had been toiling for over a decade trying to figure out the right construct for coronavirus vaccines, work that was spurred by the 2003 SARS-1 epidemic and outbreaks from 2012 onward caused by a cousin virus, MERS, that jumps sporadically from camels to people on the Arabian Peninsula. It was clear coronaviruses, which originate in bats, were promiscuous enough that the world needed to be ready for more such incursions.

“For whatever reason, we had just the right information and had just the right partnerships and all the right things in place to do something for a coronavirus,” said Barney Graham, who with his team at the NIAID’s Vaccine Research Center designed the spike protein target that a number of vaccine manufacturers used to make their Covid vaccines.

The coronavirus vaccine research gave the world a head start when SARS-2 reared its head. “When the sequence was published, we knew how to modify it immediately because of what we’ve done a dozen times on other coronaviruses,” he said. Had the pandemic been triggered by a virus belonging to a less well-studied family, the world might still be waiting for vaccines.

“For some of the other virus families the design of the antigen is not as generalizable as we have found it for coronavirus,” said Graham, who retired from the Vaccine Research Center last August.

A lot of the pandemic preparedness funding went into developing different ways to make vaccines, methods that are less cumbersome or time-consuming, say, than the approach used to make influenza vaccines, which involves growing viruses in eggs. For Rick Bright, it came down to a simple mantra: “More, better, faster.”

Bright was the head of BARDA at the outset of the pandemic. At the time, the agency was providing funding to Cambridge, Mass.-based Moderna, whose messenger RNA approach was promising but had never been used in a licensed vaccine. In early 2020, Bright thought a Covid mRNA vaccine was a long shot, and that a more established platform — the viral-vectored vaccine being developed by Johnson & Johnson — was a more likely bet.

“I thought that would be our first vaccine. And the mRNA, if it worked, would be great, but I had my doubts because it had never scaled,” he said, referring to the fact that it’s one thing to design a vaccine and another entirely to learn, on the fly, how to produce it at commercial scale. “It was truly a Hail Mary pass with mRNA.” 

“I would have to say at the outset I would not have thought we’d be here by now, given the technology,” admitted Bright, who left the federal government early in the pandemic in a dispute with the Trump administration. He now heads the Pandemic Prevention Institute at the Rockefeller Foundation.

It could have been different. It would have been, if it had been flu

The scope of what has been achieved comes into clearer focus when it is compared to what happened in 2009, during the last pandemic, caused by an influenza virus called H1N1.

Multiple vaccine manufacturers produce somewhere in the order of 1.5 billion doses of flu vaccine every year. When the new virus emerged, there were plans in place for making vaccine that wouldn’t require the large-scale clinical trials Covid vaccines had to undergo. The new virus would replace old flu vaccine viruses, small studies would be conducted, and the world would start to vaccinate.

But, as is often the case with flu vaccine, there was a glitch. The viruses for the vaccine, produced in hen’s eggs, didn’t grow well initially. “Even if you yell at them, they don’t grow faster,” Tom Frieden, then-director of the Centers for Disease Control and Prevention, famously said in October of 2009, when cases in the U.S. were surging but vaccine doses were scarce. By the time vaccine was ready, the fall wave was already receding.

Countries with domestic production or pre-existing pandemic flu vaccine contracts pledged to donate 10% of their doses, from the point when they started to take delivery, to a pool from which the World Health Organization would redistribute it to countries without access to vaccine.

Hatchett, who worked in the Obama White House during the H1N1 pandemic and was overseeing the donations work, said by the time the vaccine redistribution effort wound down in the autumn of 2010, 78 million donated doses of vaccine had been distributed to 77 countries.

In the same time frame during this pandemic, the COVAX facility — an entity for vaccine sharing set up by the WHO, CEPI, and Gavi, the Vaccine Alliance — had sent 1 billion doses of vaccine to 144 countries. Not as much as it had planned, not as much as the world needed. And yet: Countries that needed help accessing Covid vaccine got 1 billion doses before the second anniversary of the WHO’s declaration of the pandemic.

Had the second pandemic of the 21st century been triggered by a virulent flu virus, scaling up of vaccine production likely wouldn’t have happened anywhere near as fast as it has with Covid vaccines. The fact that there were no coronavirus vaccines in production forced manufacturers to innovate, to move to new platforms. There wouldn’t have been the same innovation pressure with a new flu virus.

“We would have pressed hard on egg-based production. And it’s not extensible and it doesn’t scale,” Hatchett said.

Kathleen Neuzil, director of the Center for Vaccine Development at the University of Maryland Medical School and a co-lead of the clinical trials arm of Operation Warp Speed, worked for years on flu pandemic planning.

The best-case scenario, she thought, was that the world would be able to produce between 4 billion and 8 billion doses of flu vaccine in a year, with the stars having to align perfectly to get to 8 billion. The stars never align perfectly with flu vaccine production.

“People [believe] COVAX has been a terrible failure because it didn’t hit the 2 billion dose target. And it didn’t, and we’re disappointed,” Hatchett said. “But delivering a billion doses in 13 months relative to any historic example or any comparable experience with trying to move new medical products to create global equity — that’s clearly unprecedented.”

Amanda Glassman agrees. Last week she and colleagues from the Center for Global Development published a report on the Covid vaccine effort that compares it to previous global health endeavors, including the smallpox eradication campaign and the rollout of childhood vaccination programs worldwide. The report does not gloss over the Covid effort’s shortcomings for low-income countries. But it does shine a light on its successes in middle-income nations.

“Look at the curves on the delivery of doses and it’s so close in time to what was happening in high-income countries,” Glassman said in an interview. “There’s still an income gradient but that income gradient is over a period of weeks and months, not years and decades.”

“There’s been just an enormous amount of negative coverage on the global vaccine rollout effort. Much of the criticism is entirely merited but it lost the big-picture perspective,” she said. “This is actually the most important public health program or effort in history.”

This happened despite the fact that the giants stumbled

The enormity of these achievements becomes even more impressive when you consider this: Three of the four largest Western vaccine manufacturers — Merck, Sanofi, and GSK — have not contributed a vaccine to these efforts. (Sanofi is still trying.)

Before the pandemic, those three companies and Pfizer were the world’s largest vaccine producers, measured by sales; they controlled 90% of global vaccine value.

GSK, with vaccine sales in 2019 that were more than double those of its fellow giants, didn’t even attempt to produce a Covid vaccine. Instead, it offered to let others use its AS03 adjuvant, which boosts the potency of a vaccine dose. Merck tried two approaches and, after both failed, folded. Sanofi had an early setback and is still testing its vaccine, which uses GSK’s adjuvant. The company hopes to get its product authorized later this spring.

Anyone plotting out pandemic responses has to factor in the inevitability that some of the vaccine efforts will fail. No one planning pandemic responses would have anticipated the world could be where it is now with three of the four biggest vaccine manufacturers effectively standing on the sidelines. (All three have made batches of vaccines for competitors as a contribution to the effort.)

GSK, Sanofi, and Merck have since scrambled to buy into the messenger RNA business, the production platform Pfizer rode to such great success. “They aren’t reaping the rewards of those who set the level of their ambition higher and who took risks and who innovated in their process for vaccine development,” Hatchett said bluntly.

We mustn’t take this for granted

Despite the amazing progress that has been made in vaccinating the world against Covid, it’s hard to get people to crow about it. The failure to hit targets for distribution of vaccine to low-income countries and the inadequate levels of vaccine uptake in some countries — including the United States — have people focusing on what hasn’t been achieved, not what has.

“It’s really hard to celebrate when we’re still in such a mess,” said Graham, who is a proponent of developing vaccine production capacity in all regions of the world, so that places like Africa don’t have to wait for vaccine donations from wealthy countries next time.

There is also a fear that people will assume the next time will be easier or even more successful, that what happened with Covid will lead to complacency.

“I think the danger is that the world interprets what has been done as just something that we’re positioned to do, whatever the future threat is,” said Hatchett. “And the fact of the matter is … we’re not.”

He noted that all the Western vaccines that have succeeded were made using platforms that scientists had been working on for some time, things like AstraZeneca’s and J&J’s viral-vectored vaccines, Pfizer’s and Moderna’s mRNA vaccines, and Novavax’s protein vaccine. We cannot assume, Hatchett said, that just because these platforms work well for coronavirus vaccines, they will work as well for all future threats. Likewise, we should not suppose that scientists will succeed as quickly as Graham and colleagues did at devising a vaccine target for the cause of a future outbreak.

“If we want to be able to respond even as well as we did to Covid, then we have to make those investments in R&D going forward,” Hatchett said. “But people don’t understand that. That nuance is completely lost.”

We need to worry about next time. But we also need to recognize what happened this time. And that is a miracle.

Said Anna Durbin, director of the Center for Immunization Research at Johns Hopkins Bloomberg School of Public Health: “We’ve demonstrated that, given the resources, you can develop, evaluate, produce, and distribute a totally novel vaccine to hundreds of millions, if not billions of people, given a huge effort and extensive financial resources.”