USA TODAY International Edition
‘ People are dying’: How Moderna vaccine crossed the finish line
About the series
As the pandemic worsened, pressure grew to speed a COVID- 19 vaccine from the lab to humans in record time. The team behind Moderna’s vaccine was the first to launch a Phase 1 trial in the United States. This is their story.
Monday: They created a vaccine in a day, relying on a decade of breakthroughs.
Today: They knew the vaccine was safe, but would it work?
By the end of March 2020, the coronavirus pandemic looked grim. The nation was in lockdown, nearly 200,000 cases had been confirmed in the United States, and the World Health Organization was estimating that without a vaccine at least 2 million Americans could die of the disease.
Country music legend Dolly Parton posted a hopeful video on Instagram for her 3.8 million followers.
“Hello, this is Dolly climbing the Stairway to Heaven because this virus is scaring the H- E- L- L out of us,” she sang.
Then, on April 1, she again took to the social media platform to announce that she had donated $ 1 million to her hometown school, Vanderbilt University, to help find a cure for COVID- 19. Months later she would learn that some of her money went to the Phase 1 vaccine trial of a Cambridge, Massachusetts- based biotechnology company, Moderna.
Moderna was one of several companies racing to stop COVID- 19 in record time. Its vaccine was the only one for which the government, through the Na
tional Institutes of Health, led the first clinical trial.
The company was named for the special technology behind the vaccine, which relied on messenger RNA, also known as the “software of life” because it carries out the instructions of our DNA. Another front- runner, Pfizer, based its vaccine on the same mRNA science.
One of the challenges of making a vaccine is money. Not all viruses become epidemics, reducing the public pressure – and funding – to stop them.
If a COVID- 19 vaccine was going to be available as soon as possible, the U. S. government was going to have to open the treasury to pay for research, buy doses in advance and get the manufacturing started well before the vaccines were even up for approval. Two weeks after Parton made her Instagram news, the Department of Health and Human Services pledged to spend $ 483 million on the Moderna vaccine. Later, it would add another $ 472 million to pay for the trial.
Other vaccines in development could save millions of lives each year worldwide with similar infusions of money. When asked why so much money was being poured into a COVID- 19 vaccine, Kizzmekia Corbett, one of the leaders of vaccine development at NIH, said: “I don't really have an answer other than people are dying. And also, frankly, people in the United States are dying, which changes a lot.”
Moderna’s Phase 3 trial begins
“It's a big day: It's the first Phase 3 of a COVID vaccine in the U. S.; it's the first Phase 3 of an mRNA vaccine ever; and it's the company's first Phase 3 as well,” Moderna CEO Stéphane Bancel told CNBC's Squawk Box on July 27. “So a big day came from a lot of work of a big team.”
Having fully taken the reins from scientist Barney Graham, deputy director of the NIH Vaccine Research Center, and his colleagues, Moderna now needed to recruit 30,000 people – a massive number set by the U. S. Food and Drug Administration – which Bancel estimated would take up to eight weeks. Infection rates would determine when they would have results; the worse the outbreak, the faster they would have data showing whether the vaccine worked.
Moderna owes its existence to a Harvard professor, Derrick Rossi. Both Moderna and BioNTech, which is working on the Pfizer vaccine, also were built upon the discoveries of two researchers at the University of Pennsylvania, Kaitlin Kariko and Drew Weissman.
The stories of the three academic scientists weave together. But while Kariko now works for BioNTech and Weissman is consulting for the company, Rossi has largely been written out of Moderna's history.
Most advances in science are incremental. Rossi's breakthrough built on a truly startling discovery.
On June 30, 2006, Shinya Yamanaka, a doctor and researcher at Japan's Kyoto University, gave a presentation at a Toronto conference that stunned a roomful of scientists, including Rossi. Yamanaka explained that he had been able to take mature cells from mice and convert them back to embryonic stem cells. It was akin to biological time travel.
His discovery had dramatic implications for future transplant patients, whose lives can depend on finding a perfect donor. His method might allow someone with end- stage liver disease to instead have a new liver grown from cells containing their own DNA.
Six years later, he would accept a Nobel Prize. Within a year of the Kyoto presentation, Rossi dove into Yamanaka's work to find a solution for its biggest drawback: the use of retroviruses.
By then Rossi was working at Harvard's Immune Disease Institute, where one of his postdoctoral fellows, Luigi Warren, had started to consider what would happen if instead of using a retrovirus to take a cell back in time, you used RNA.
DNA is the secret to life. It determines whether we're redheads or brunettes, tall or short. More important, DNA transmits the genetic signals that keep our bodies functioning.
DNA sends those signals by making RNA, which delivers DNA's messages to cells. Genetic scientists have a saying: DNA makes RNA makes proteins makes life.
In essence, Warren's theory was that RNA could instruct our bodies to produce the drugs needed to fight disease or to inoculate ourselves against viruses.
One day, Warren put RNA onto mouse cells in a petri dish to see if he could get them to produce protein. He opted for a protein that glows fluorescent green so it would be easy to tell if the process worked. After a while, Warren looked into the microscope. He rushed over to Rossi, urging him to come take a look.
Rossi couldn't believe what he saw: The cells were glowing green. Cells from mice had produced a protein that doesn't even exist in mice. RNA worked.
That day in 2009, Warren and Rossi thought they had found the solution – one that exposed additional problems. Making the conversion back to embryonic cells takes time; two weeks in mice, to be exact. RNA is notoriously unstable. To keep the proteins glowing, Warren was going to have to add more RNA each day. Every day, the cells grew dimmer, then stopped making the protein and died.
It dawned on Rossi that others had probably already tried this, which led him to the two scientists at the University of Pennsylvania, who had been working on RNA for more than a decade. When they gave RNA to mice, the mice refused to eat. Some died.
Weissman and Kariko had figured out RNA caused cells to become inflamed and reject the RNA as a foreign invader. They started toying with modifying RNA to disguise it, fooling the immune response. They'd been publishing about their successes for years.
Armed with their stealth method, Warren could keep his cells glowing for days. He also managed to convert the cells back to their embryonic state, an idea Rossi pitched to Flagship Ventures of Cambridge in 2010, starting the company today known as Moderna.
It would be years before Moderna began using the mRNA science to pursue vaccines. By then, Rossi was no longer with the company.
Trump: Vaccine is coming soon
On Aug. 6, trailing in the polls to rival Joe Biden, President Donald Trump suggested the COVID- 19 vaccine might be ready before Election Day. He had toured the NIH lab in March with Dr. Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases. Graham, Corbett and others were there as well. But Trump had previously demurred to the experts on the timing of a vaccine, focusing more on rapid tests and treatments. Outside the White House, a reporter asked if a vaccine would help him win.
“It wouldn't hurt,” Trump said. “But I'm doing it not for the election; I want to save a lot of lives.”
Critics jumped in, worried that the vaccine was being rushed for political gain. A poll taken by CNN days later showed Americans were nervous. Only 56% said they would get the vaccine when it was approved; 40% said they wouldn't. It didn't help that the program to accelerate development and production was called “Operation Warp Speed.”
Within a month of Trump's comments, one company – AstraZeneca – temporarily halted its trial because of a single case of spinal cord inflammation. Researchers would later determine the case was not vaccine- related, but it sent shockwaves through the public.
As time went on and COVID- 19 deaths mounted, Trump started taking shots at officials at the FDA and Centers for Disease Control and Prevention for what he said was playing politics by delaying the vaccine.
“So we're going to have a vaccine very soon, maybe even before a very special date. You know what date I'm talking about,” Trump said on Sept. 7.
Two days later, nine vaccine makers came together to respond, pledging in a joint statement to follow “high ethical standards and sound scientific principles” and to go through the normal channels of review by the FDA.
“We believe this pledge will help ensure public confidence in the rigorous scientific and regulatory process by which COVID- 19 vaccines are evaluated and may ultimately be approved,” the statement concluded.
Although Graham was not involved in the public statement, he knew that the vaccine makers had no choice. Science has to proceed through prescribed steps, even when lives are in the balance. The FDA could not green- light any vaccine until safety and efficacy data was available and reviewed.
Concern about lack of diversity
Not long after Moderna began recruiting volunteers for its final trial, the head of vaccine development for Operation Warp Speed noticed a problem: The company wasn't recruiting enough African Americans. Moncef Slaoui called Bancel and Moderna President Stephen Hoge. When Slaoui, a former Moderna board member, felt Bancel wasn't listening, he began shouting.
“There was a very big tension because we need to recruit very quickly and we need to recruit the right people,” Slaoui said.
To Slaoui, it was clear that having Black and Latino participants in the trial was key. The virus was disproportionately lethal for those communities; African Americans die of COVID- 19 at nearly three times the rate of white Americans. It also was important to show that the vaccine was safe for all.
Moderna relented. Its recruiter bought social media ads targeted to Black and Latino users. On Sept. 24, Slaoui joined a virtual town hall with the Rainbow/ PUSH Coalition, headed by civil rights icon Jesse Jackson.
“Frankly, developing a vaccine not used in the population or in a fraction of the population is the same as having no vaccine,” Slaoui said at the meeting.
Jackson blames the reluctance by Black and Latino people to participate on “racism in health care down through the years” in the United States.
“The history must inform us,” he said, “not paralyze us.”
The pause to recruit lasted two weeks and resulted in a 50% increase in Black people in the trial. It also caused Moderna to lose its front- runner status to another company, Pfizer.
Vaccine efficacy announced
Graham's boss called with astonishing news on the second Sunday in November. The government's data monitoring safety board – the only group allowed to know who in the trial received a vaccine or a saltwater placebo – had completed the first analysis of 94 volunteers who had gotten COVID- 19 in the Pfizer vaccine trial.
The data showed it was more than 90% effective.
As Graham hung up the phone, he took a deep breath and told his wife that the Pfizer vaccine – nearly identical to Moderna's – worked. Then he sat down and wept tears of relief. The type of vaccine he had been perfecting over a decade was far more successful than even he had imagined.
On Nov. 16, Moderna would make a nearly identical announcement: Its vaccine was 94% effective.
Jonas Salk became an overnight hero on April 12, 1955, when the news was delivered that the polio vaccine was 90% effective. With the COVID- 19 vaccine, Graham and his colleagues are not yet household names.
Graham is unconcerned about that, preferring the lab to the limelight. Corbett finds it more difficult to hide her emotions, at least on Twitter. Replying to her own tweet the day Haller was given the first vaccine in an NIH trial, Corbett wrote, “I.... I... This is... * tears*”:
The team was recognized on the first day of December with a scientific award that honors the research behind major breakthroughs. The 2020 Golden Goose Award went to Graham, Corbett, Jason McLellan and others for leading the effort to create a vaccine. McLellan, who worked with the team at NIH, was now at the University of Texas.
Corbett responded with more tweets, one aimed at McLellan: “Thanks Jason! We did it!!!”
In another video post, Corbett pauses at times to hold back tears, saying: “Part of the reason why I was given essentially the wings to fly with this project is because I had a mentor who allowed me to use his resources and sit in the back of his laboratory and to ask scientific questions that a lot of other people didn't really care about.”
Moderna seeks the green light
Then, it was showtime. Moderna's top scientific leaders went before a panel of 21 independent scientists on an FDA advisory panel to present their data. The Dec. 17 meeting was held remotely via webcast.
The panel's recommendation would weigh heavily in whether the FDA would grant an emergency use authorization.
Typically, the FDA spends months analyzing data to approve a vaccine. This time, that work was done in 21⁄
2 weeks, partly because the vaccine was so extraordinarily effective. In advance, the FDA had said it was willing to give the green light to a vaccine that was 50% effective. Moderna's data, like Pfizer's before it, was far more dramatic.
Of the 196 trial participants who had COVID- 19 with symptoms, only 11 had received the vaccine. All 30 cases of severe COVID- 19 happened among those who got the placebo.
Later in the afternoon, an FDA doctor walked the independent scientists through the side effects and adverse events. She found no safety concerns in the data. Six people in the vaccine group had died, but none of those deaths – ranging from a heart attack to suicide – was considered vaccine related.
At the end of the day, the biggest question was whether to make it clearer that the group was voting on emergency use authorization and not regular FDA approval. In the end, no change was made to the language: “Based on the totality of scientific evidence available, do the benefits of the Moderna COVID- 19 Vaccine outweigh the risks for use in individuals 18 years of age and older?”
The vote was 20 yes, with one abstention – an objection to the wording, not the vaccine.
Epilogue
More COVID- 19 vaccines are underway. Other than one developed by AstraZeneca in partnership with Oxford University, all relied on the breakthroughs coming from Graham and his colleagues. “As politically correct as I can say it,” Corbett said of the other major vaccine makers, “they're catching up because they are copying and pasting.”
The battle to stop pandemics is not over. Another one is coming, and it could be another coronavirus. Thousands of known strains exist in bats that could jump to humans at any time.
Graham already has set his sights on the next big battle in the war against viruses: a universal vaccine to protect us against any coronavirus.
Next time, Graham wants to stop it before it starts.