In this last episode of our six-part series on vaccinations, supported by the National Institute for Health Care Management Foundation, we cover vaccine development – particularly in the context of the current global pandemic. We discuss the timeline of Covid-19 vaccine development and the mRNA vaccine approach.
She grew up in Hungary, daughter of a butcher. She decided she wanted to be a scientist, although she had never met one. She moved to the United States in her 20s, but for decades never found a permanent position, instead clinging to the fringes of academia.
Now Katalin Kariko, 66, known to colleagues as Kati, has emerged as one of the heroes of Covid-19 vaccine development. Her work, with her close collaborator, Dr. Drew Weissman of the University of Pennsylvania, laid the foundation for the stunningly successful vaccines made by Pfizer-BioNTech and Moderna.
For her entire career, Dr. Kariko has focused on messenger RNA, or mRNA — the genetic script that carries DNA instructions to each cell’s protein-making machinery. She was convinced mRNA could be used to instruct cells to make their own medicines, including vaccines.
But for many years her career at the University of Pennsylvania was fragile. She migrated from lab to lab, relying on one senior scientist after another to take her in. She never made more than $60,000 a year.
By all accounts intense and single-minded, Dr. Kariko lives for “the bench” — the spot in the lab where she works. She cares little for fame. “The bench is there, the science is good,” she shrugged in a recent interview. “Who cares?”
Dr. Anthony Fauci, director of the National Institutes of Allergy and infectious Diseases, knows Dr. Kariko’s work. “She was, in a positive sense, kind of obsessed with the concept of messenger RNA,” he said.
Dr. Kariko’s struggles to stay afloat in academia have a familiar ring to scientists. She needed grants to pursue ideas that seemed wild and fanciful. She did not get them, even as more mundane research was rewarded.
“When your idea is against the conventional wisdom that makes sense to the star chamber, it is very hard to break out,” said Dr. David Langer, a neurosurgeon who has worked with Dr. Kariko.
Dr. Kariko’s ideas about mRNA were definitely unorthodox. Increasingly, they also seem to have been prescient.
“It’s going to be transforming,” Dr. Fauci said of mRNA research. “It is already transforming for Covid-19, but also for other vaccines. H.I.V. — people in the field are already excited. Influenza, malaria.”
‘I Felt Like a God’
For Dr. Kariko, most every day was a day in the lab. “You are not going to work — you are going to have fun,” her husband, Bela Francia, manager of an apartment complex, used to tell her as she dashed back to the office on evenings and weekends. He once calculated that her endless workdays meant she was earning about a dollar an hour.
For many scientists, a new discovery is followed by a plan to make money, to form a company and get a patent. But not for Dr. Kariko. “That’s the furthest thing from Kate’s mind,” Dr. Langer said.
She grew up in the small Hungarian town of Kisujszallas. She earned a Ph.D. at the University of Szeged and worked as a postdoctoral fellow at its Biological Research Center.
In 1985, when the university’s research program ran out of money, Dr. Kariko, her husband, and 2-year-old daughter, Susan, moved to Philadelphia for a job as a postdoctoral student at Temple University. Because the Hungarian government only allowed them to take $100 out of the country, she and her husband sewed £900 (roughly $1,246 today) into Susan’s teddy bear. (Susan grew up to be a two-time Olympic gold medal winner in rowing.)
When Dr. Kariko started, it was early days in the mRNA field. Even the most basic tasks were difficult, if not impossible. How do you make RNA molecules in a lab? How do you get mRNA into cells of the body?
In 1989, she landed a job with Dr. Elliot Barnathan, then a cardiologist at the University of Pennsylvania. It was a low-level position, research assistant professor, and never meant to lead to a permanent tenured position. She was supposed to be supported by grant money, but none came in.
She and Dr. Barnathan planned to insert mRNA into cells, inducing them to make new proteins. In one of the first experiments, they hoped to use the strategy to instruct cells to make a protein called the urokinase receptor. If the experiment worked, they would detect the new protein with a radioactive molecule that would be drawn to the receptor.
“Most people laughed at us,” Dr. Barnathan said.
One fateful day, the two scientists hovered over a dot-matrix printer in a narrow room at the end of a long hall. A gamma counter, needed to track the radioactive molecule, was attached to a printer. It began to spew data.
Their detector had found new proteins produced by cells that were never supposed to make them — suggesting that mRNA could be used to direct any cell to make any protein, at will.
“I felt like a god,” Dr. Kariko recalled.
She and Dr. Barnathan were on fire with ideas. Maybe they could use mRNA to improve blood vessels for heart bypass surgery. Perhaps they could even use the procedure to extend the life span of human cells.
Dr. Barnathan, though, soon left the university, accepting a position at a biotech firm, and Dr. Kariko was left without a lab or financial support. She could stay at Penn only if she found another lab to take her on. “They expected I would quit,” she said.
Universities only support low-level Ph.D.s for a limited amount of time, Dr. Langer said: “If they don’t get a grant, they will let them go.” Dr. Kariko “was not a great grant writer,” and at that point “mRNA was more of an idea,” he said.
But Dr. Langer knew Dr. Kariko from his days as a medical resident, when he had worked in Dr. Barnathan’s lab. Dr. Langer urged the head of the neurosurgery department to give Dr. Kariko’s research a chance. “He saved me,” she said.
Dr. Langer thinks it was Dr. Kariko who saved him — from the kind of thinking that dooms so many scientists.
Working with her, he realized that one key to real scientific understanding is to design experiments that always tell you something, even if it is something you don’t want to hear. The crucial data often come from the control, he learned — the part of the experiment that involves a dummy substance for comparison.
“There’s a tendency when scientists are looking at data to try to validate their own idea,” Dr. Langer said. “The best scientists try to prove themselves wrong. Kate’s genius was a willingness to accept failure and keep trying, and her ability to answer questions people were not smart enough to ask.”
Dr. Langer hoped to use mRNA to treat patients who developed blood clots following brain surgery, often resulting in strokes. His idea was to get cells in blood vessels to make nitric oxide, a substance that dilates blood vessels, but has a half-life of milliseconds. Doctors can’t just inject patients with it.
He and Dr. Kariko tried their mRNA on isolated blood vessels used to study strokes. It failed. They trudged through snow in Buffalo, N.Y., to try it in a laboratory with rabbits prone to strokes. Failure again.
And then Dr. Langer left the university, and the department chairman said he was leaving as well. Dr. Kariko again was without a lab and without funds for research.
A meeting at a photocopying machine changed that. Dr. Weissman happened by, and she struck up a conversation. “I said, ‘I am an RNA scientist — I can make anything with mRNA,’” Dr. Kariko recalled.
Dr. Weissman told her he wanted to make a vaccine against H.I.V. “I said, ‘Yeah, yeah, I can do it,’” Dr. Kariko said.
Despite her bravado, her research on mRNA had stalled. She could make mRNA molecules that instructed cells in petri dishes to make the protein of her choice. But the mRNA did not work in living mice.
“Nobody knew why,” Dr. Weissman said. “All we knew was that the mice got sick. Their fur got ruffled, they hunched up, they stopped eating, they stopped running.”
It turned out that the immune system recognizes invading microbes by detecting their mRNA and responding with inflammation. The scientists’ mRNA injections looked to the immune system like an invasion of pathogens.
But with that answer came another puzzle. Every cell in every person’s body makes mRNA, and the immune system turns a blind eye. “Why is the mRNA I made different?” Dr. Kariko wondered.
A control in an experiment finally provided a clue. Dr. Kariko and Dr. Weissman noticed their mRNA caused an immune overreaction. But the control molecules, another form of RNA in the human body — so-called transfer RNA, or tRNA — did not.
A molecule called pseudouridine in tRNA allowed it to evade the immune response. As it turned out, naturally occurring human mRNA also contains the molecule.
Added to the mRNA made by Dr. Kariko and Dr. Weissman, the molecule did the same — and also made the mRNA much more powerful, directing the synthesis of 10 times as much protein in each cell.
The idea that adding pseudouridine to mRNA protected it from the body’s immune system was a basic scientific discovery with a wide range of thrilling applications. It meant that mRNA could be used to alter the functions of cells without prompting an immune system attack.
“We both started writing grants,” Dr. Weissman said. “We didn’t get most of them. People were not interested in mRNA. The people who reviewed the grants said mRNA will not be a good therapeutic, so don’t bother.’”
Leading scientific journals rejected their work. When the research finally was published, in Immunity, it got little attention.
Dr. Weissman and Dr. Kariko then showed they could induce an animal — a monkey — to make a protein they had selected. In this case, they injected monkeys with mRNA for erythropoietin, a protein that stimulates the body to make red blood cells. The animals’ red blood cell counts soared.
The scientists thought the same method could be used to prompt the body to make any protein drug, like insulin or other hormones or some of the new diabetes drugs. Crucially, mRNA also could be used to make vaccines unlike any seen before.
Instead of injecting a piece of a virus into the body, doctors could inject mRNA that would instruct cells to briefly make that part of the virus.
“We talked to pharmaceutical companies and venture capitalists. No one cared,” Dr. Weissman said. “We were screaming a lot, but no one would listen.”
Eventually, though, two biotech companies took notice of the work: Moderna, in the United States, and BioNTech, in Germany. Pfizer partnered with BioNTech, and the two now help fund Dr. Weissman’s lab.
‘Oh, It Works’
Soon clinical trials of an mRNA flu vaccine were underway, and there were efforts to build new vaccines against cytomegalovirus and the Zika virus, among others. Then came the coronavirus.
Researchers had known for 20 years that the crucial feature of any coronavirus is the spike protein sitting on its surface, which allows the virus to inject itself into human cells. It was a fat target for an mRNA vaccine.
Chinese scientists posted the genetic sequence of the virus ravaging Wuhan in January 2020, and researchers everywhere went to work. BioNTech designed its mRNA vaccine in hours; Moderna designed its in two days.
The idea for both vaccines was to introduce mRNA into the body that would briefly instruct human cells to produce the coronavirus’s spike protein. The immune system would see the protein, recognize it as alien, and learn to attack the coronavirus if it ever appeared in the body.
The vaccines, though, needed a lipid bubble to encase the mRNA and carry it to the cells that it would enter. The vehicle came quickly, based on 25 years of work by multiple scientists, including Pieter Cullis of the University of British Columbia.
Scientists also needed to isolate the virus’s spike protein from the bounty of genetic data provided by Chinese researchers. Dr. Barney Graham, of the National Institutes of Health, and Jason McClellan, of the University of Texas at Austin, solved that problem in short order.
Testing the quickly designed vaccines required a monumental effort by companies and the National Institutes of Health. But Dr. Kariko had no doubts.
On Nov. 8, the first results of the Pfizer-BioNTech study came in, showing that the mRNA vaccine offered powerful immunity to the new virus. Dr. Kariko turned to her husband. “Oh, it works,” she said. “I thought so.”
To celebrate, she ate an entire box of Goobers chocolate-covered peanuts. By herself.
Dr. Weissman celebrated with his family, ordering takeout dinner from an Italian restaurant, “with wine,” he said. Deep down, he was awed.
“My dream was always that we develop something in the lab that helps people,” Dr. Weissman said. “I’ve satisfied my life’s dream.”
Dr. Kariko and Dr. Weissman were vaccinated on Dec. 18 at the University of Pennsylvania. Their inoculations turned into a press event, and as the cameras flashed, she began to feel uncharacteristically overwhelmed.
A senior administrator told the doctors and nurses rolling up their sleeves for shots that the scientists whose research made the vaccine possible were present, and they all clapped. Dr. Kariko wept.
Things could have gone so differently, for the scientists and for the world, Dr. Langer said. “There are probably many people like her who failed,” he said.
A new report out later today concludes that basic scientific research plays an essential role in creating companies that later produce thousands of jobs and billions in economic value.
Why it matters: The report uses the pandemic — and especially the rapid development of new mRNA vaccines — to show how basic research funding from the government lays the necessary groundwork for economically valuable companies down the road.
By the numbers: The Science Coalition — a nonprofit group that represents 50 of the nation’s top private and public research universities — identified 53 companies that have spun off from federally funded university research.
- Those companies — which range from pharmaceutical startups to agriculture firms — have contributed more than $1.3 billion to U.S. GDP between 2015 and 2019, while supporting the creation of more than 100,000 jobs.
What they’re saying: “The COVID-19 pandemic has shown that the need for the federal government to continue investing in fundamental research is far from theoretical,” says John Latini, president of the Science Coalition. “Consistent, sustained, robust federal funding is how science evolves.”
Details: Latini praised the Biden administration’s first budget proposal to Congress, released last week, which includes what would be a $9 billion funding boost for the National Institutes of Health (NIH) — the country’s single biggest science research funding agency.
- The National Oceanic and Atmospheric Administration would see its budget rise to a record high of $6.9 billion, including $800 million reserved for climate research.
The catch: The Biden budget proposal is just that, and it will ultimately be up to Congress to decide how much to allocate to research agencies.
Context: Government research funding is vital because private money tends to go to applied research. But without basic research — the lifeblood of science — the U.S. risks missing out on potentially world-changing innovations in the future.
- The long-term value of that funding can be seen in the story of Katalin Kariko, an obscure biomedical researcher who labored for years on mRNA with little reward — until the pandemic, when her work helped provide the foundation for mRNA COVID-19 vaccines.
The bottom line: Because its ultimate payoff might lay years in the future, it’s easy to see basic research funding as a waste — until the day comes when we need it.
“No!” The doctor snapped. “Look at me!”
I had been staring her in the eyes, as she had ordered, but when a doctor on my other side began jabbing me with a needle, I started to turn my head. “Don’t look at it,” the first doctor said. I obeyed.
This was in early August in New Orleans, where I had signed up to be a participant in the clinical trial for the Pfizer-BioNTech COVID-19 vaccine. It was a blind study, which meant I was not supposed to know whether I had gotten the placebo or the real vaccine. I asked the doctor if I would really been able to tell by looking at the syringe. “Probably not,” she answered, “but we want to be careful. This is very important to get right.”
I became a vaccine guinea pig because, in addition to wanting to be useful, I had a deep interest in the wondrous new roles now being played by RNA, the genetic material that is at the heart of new types of vaccines, cancer treatments and gene-editing tools. I was writing a book on the Berkeley biochemist Jennifer Doudna. She was a pioneer in determining the structure of RNA, which helped her and her doctoral adviser figure out how it could be the origin of all life on this planet. Then she and a colleague invented an RNA-guided gene-editing tool, which won them the 2020 Nobel Prize in Chemistry.
The tool is based on a system that bacteria use to fight viruses. Bacteria develop clustered repeated sequences in their DNA, known as CRISPRs, that can remember dangerous viruses and then deploy RNA-guided scissors to destroy them. In other words, it’s an immune system that can adapt itself to fight each new wave of viruses—just what we humans need. Now, with the recently approved Pfizer-BioNTech vaccine and a similar one from Moderna being slowly rolled out across the U.S. and Europe, RNA has been deployed to make a whole new type of vaccine that will, when it reaches enough people, change the course of the pandemic.
Up until last year, vaccines had not changed very much, at least in concept, for more than two centuries. Most have been modeled on the discovery made in 1796 by the English doctor Edward Jenner, who noticed that many milkmaids were immune to smallpox. They had all been infected by a form of pox that afflicts cows but is relatively harmless to humans, and Jenner surmised that the cowpox had given them immunity to smallpox. So he took some pus from a cowpox blister, rubbed it into scratches he made in the arm of his gardener’s 8-year-old son and then (this was in the days before bioethics panels) exposed the kid to smallpox. He didn’t become ill.
Before then, inoculations were done by giving patients a small dose of the actual smallpox virus, hoping that they would get a mild case and then be immune. Jenner’s great advance was to use a related but relatively harmless virus. Ever since, vaccinations have been based on the idea of exposing a patient to a safe facsimile of a dangerous virus or other germ. This is intended to kick the person’s adaptive immune system into gear. When it works, the body produces antibodies that will, sometimes for many years, fend off any infection if the real germ attacks.
One approach is to inject a safely weakened version of the virus. These can be good teachers, because they look very much like the real thing. The body responds by making antibodies for fighting them, and the immunity can last a lifetime. Albert Sabin used this approach for the oral polio vaccine in the 1950s, and that’s the way we now fend off measles, mumps, rubella and chicken pox.
At the same time Sabin was trying to develop a vaccine based on a weakened polio virus, Jonas Salk succeeded with a safer approach: using a killed or inactivated virus. This type of vaccine can still teach a person’s immune system how to fight off the live virus but is less likely to cause serious side effects. Two Chinese companies, Sinopharm and Sinovac, have used this approach to develop vaccines for COVID-19 that are now in limited use in China, the UAE and Indonesia.
Another traditional approach is to inject a subunit of the virus, such as one of the proteins that are on the virus’s coat. The immune system will then remember these, allowing the body to mount a quick and robust response when it encounters the actual virus. The vaccine against the hepatitis B virus, for example, works this way. Using only a fragment of the virus means that they are safer to inject into a patient and easier to produce, but they are often not as good at producing long-term immunity. The Maryland-based biotech Novavax is in late-stage clinical trials for a COVID-19 vaccine using this approach, and it is the basis for one of the two vaccines already being rolled out in Russia.
The plague year of 2020 will be remembered as the time when these traditional vaccines were supplanted by something fundamentally new: genetic vaccines, which deliver a gene or piece of genetic code into human cells. The genetic instructions then cause the cells to produce, on their own, safe components of the target virus in order to stimulate the patient’s immune system.
For SARS-CoV-2—the virus that causes COVID-19—the target component is its spike protein, which studs the outer envelope of the virus and enables it to infiltrate human cells. One method for doing this is by inserting the desired gene, using a technique known as recombinant DNA, into a harmless virus that can deliver the gene into human cells. To make a COVID vaccine, a gene that contains instructions for building part of a coronavirus spike protein is edited into the DNA of a weakened virus like an adenovirus, which can cause the common cold. The idea is that the re-engineered adenovirus will worm its way into human cells, where the new gene will cause the cells to make lots of these spike proteins. As a result, the person’s immune system will be primed to respond rapidly if the real coronavirus strikes.
This approach led to one of the earliest COVID vaccine candidates, developed at the aptly named Jenner Institute of the University of Oxford. Scientists there engineered the spike-protein gene into an adenovirus that causes the common cold in chimpanzees, but is relatively harmless in humans.
The lead researcher at Oxford is Sarah Gilbert. She worked on developing a vaccine for Middle East respiratory syndrome (MERS) using the same chimp adenovirus. That epidemic waned before her vaccine could be deployed, but it gave her a head start when COVID-19 struck. She already knew that the chimp adenovirus had successfully delivered into humans the gene for the spike protein of MERS. As soon as the Chinese published the genetic sequence of the new coronavirus in January 2020, she began engineering its spike-protein gene into the chimp virus, waking each day at 4 a.m.
Her 21-year-old triplets, all of whom were studying biochemistry, volunteered to be early testers, getting the vaccine and seeing if they developed the desired antibodies. (They did.) Trials in monkeys conducted at a Montana primate center in March also produced promising results.
Bill Gates, whose foundation provided much of the funding, pushed Oxford to team up with a major company that could test, manufacture and distribute the vaccine. So Oxford forged a partnership with AstraZeneca, the British-Swedish pharmaceutical company. Unfortunately, the clinical trials turned out to be sloppy, with the wrong doses given to some participants, which led to delays. Britain authorized it for emergency use at the end of December, and the U.S. is likely to do so in the next two months.
Johnson & Johnson is testing a similar vaccine that uses a human adenovirus, rather than a chimpanzee one, as the delivery mechanism to carry a gene that codes for making part of the spike protein. It’s a method that has shown promise in the past, but it could have the disadvantage that humans who have already been exposed to that adenovirus may have some immunity to it. Results from its clinical trial are expected later this month.
In addition, two other vaccines based on genetically engineered adenoviruses are now in limited distribution: one made by CanSino Biologics and being used on the military in China and another named Sputnik V from the Russian ministry of health.
There is another way to get genetic material into a human cell and cause it to produce the components of a dangerous virus, such as the spike proteins, that can stimulate the immune system. Instead of engineering the gene for the component into an adenovirus, you can simply inject the genetic code for the component into humans as DNA or RNA.
Let’s start with DNA vaccines. Researchers at Inovio Pharmaceuticals and a handful of other companies in 2020 created a little circle of DNA that coded for parts of the coronavirus spike protein. The idea was that if it could get inside the nucleus of a cell, the DNA could very efficiently churn out instructions for the production of the spike-protein parts, which serve to train the immune system to react to the real thing.
The big challenge facing a DNA vaccine is delivery. How can you get the little ring of DNA not only into a human cell but into the nucleus of the cell? Injecting a lot of the DNA vaccine into a patient’s arm will cause some of the DNA to get into cells, but it’s not very efficient.
Some of the developers of DNA vaccines, including Inovio, tried to facilitate the delivery into human cells through a method called electroporation, which delivers electrical shock pulses to the patient at the site of the injection. That opens pores in the cell membranes and allows the DNA to get in. The electric pulse guns have lots of tiny needles and are unnerving to behold. It’s not hard to see why this technique is unpopular, especially with those on the receiving end. So far, no easy and reliable delivery mechanism has been developed for getting DNA vaccines into the nucleus of human cells.
That leads us to the molecule that has proven victorious in the COVID vaccine race and deserves the title of TIME magazine’s Molecule of the Year: RNA. Its sibling DNA is more famous. But like many famous siblings, DNA doesn’t do much work. It mainly stays bunkered down in the nucleus of our cells, protecting the information it encodes. RNA, on the other hand, actually goes out and gets things done. The genes encoded by our DNA are transcribed into snippets of RNA that venture out from the nucleus of our cells into the protein-manufacturing region. There, this messenger RNA (mRNA) oversees the assembly of the specified protein. In other words, instead of just sitting at home curating information, it makes real products.
Scientists including Sydney Brenner at Cambridge and James Watson at Harvard first identified and isolated mRNA molecules in 1961. But it was hard to harness them to do our bidding, because the body’s immune system often destroyed the mRNA that researchers engineered and attempted to introduce into the body. Then in 2005, a pair of researchers at the University of Pennsylvania, Katalin Kariko and Drew Weissman, showed how to tweak a synthetic mRNA molecule so it could get into human cells without being attacked by the body’s immune system.
When the COVID-19 pandemic hit a year ago, two innovative young pharmaceutical companies decided to try to harness this role played by messenger RNA: the German company BioNTech, which formed a partnership with the U.S. company Pfizer; and Moderna, based in Cambridge, Mass. Their mission was to engineer messenger RNA carrying the code letters to make part of the coronavirus spike protein—a string that begins CCUCGGCGGGCA … —and to deploy it in human cells.
BioNTech was founded in 2008 by the husband-and-wife team of Ugur Sahin and Ozlem Tureci, who met when they were training to be doctors in Germany in the early 1990s. Both were from Turkish immigrant families, and they shared a passion for medical research, so much so that they spent part of their wedding day working in the lab. They founded BioNTech with the goal of creating therapies that stimulate the immune system to fight cancerous cells. It also soon became a leader in devising medicines that use mRNA in vaccines against viruses.
In January 2020, Sahin read an article in the medical journal Lancet about a new coronavirus in China. After discussing it with his wife over breakfast, he sent an email to the other members of the BioNTech board saying that it was wrong to believe that this virus would come and go as easily as MERS and SARS. “This time it is different,” he told them.
BioNTech launched a crash project to devise a vaccine based on RNA sequences, which Sahin was able to write within days, that would cause human cells to make versions of the coronavirus’s spike protein. Once it looked promising, Sahin called Kathrin Jansen, the head of vaccine research and development at Pfizer. The two companies had been working together since 2018 to develop flu vaccines using mRNA technology, and he asked her whether Pfizer would want to enter a similar partnership for a COVID vaccine. “I was just about to call you and propose the same thing,” Jansen replied. The deal was signed in March.
By then, a similar mRNA vaccine was being developed by Moderna, a much smaller company with only 800 employees. Its chair and co-founder, Noubar Afeyan, a Beirut-born Armenian who immigrated to the U.S., had become fascinated by mRNA in 2010, when he heard a pitch from a group of Harvard and MIT researchers. Together they formed Moderna, which initially focused on using mRNA to try to develop personalized cancer treatments, but soon began experimenting with using the technique to make vaccines against viruses.
In January 2020, Afeyan took one of his daughters to a restaurant near his office in Cambridge to celebrate her birthday. In the middle of the meal, he got an urgent text message from the CEO of his company, Stéphane Bancel, in Switzerland. So he rushed outside in the freezing temperature, forgetting to grab his coat, to call him back.
Bancel said that he wanted to launch a project to use mRNA to attempt a vaccine against the new coronavirus. At that point, Moderna had more than 20 drugs in development but none had even reached the final stage of clinical trials. Nevertheless, Afeyan instantly authorized him to start work. “Don’t worry about the board,” he said. “Just get moving.” Lacking Pfizer’s resources, Moderna had to depend on funding from the U.S. government. Anthony Fauci, head of the National Institute of Allergy and Infectious Diseases, was supportive. “Go for it,” he declared. “Whatever it costs, don’t worry about it.”
It took Bancel and his Moderna team only two days to create the RNA sequences that would produce the spike protein, and 41 days later, it shipped the first box of vials to the National Institutes of Health to begin early trials. Afeyan keeps a picture of that box on his cell phone.
An mRNA vaccine has certain advantages over a DNA vaccine, which has to use a re-engineered virus or other delivery mechanism to make it through the membrane that protects the nucleus of a cell. The RNA does not need to get into the nucleus. It simply needs to be delivered into the more-accessible outer region of cells, the cytoplasm, which is where proteins are constructed.
The Pfizer-BioNTech and Moderna vaccines do so by encapsulating the mRNA in tiny oily capsules, known as lipid nanoparticles. Moderna had been working for 10 years to improve its nanoparticles. This gave it one advantage over Pfizer-BioNTech: its particles were more stable and did not have to be stored at extremely low temperatures.
By November, the results of the Pfizer-BioNTech and Moderna late-stage trials came back with resounding findings: both vaccines were more than 90% effective. A few weeks later, with COVID-19 once again surging throughout much of the world, they received emergency authorization from the U.S. Food and Drug Administration and became the vanguard of the biotech effort to beat back the pandemic.
The ability to code messenger RNA to do our bidding will transform medicine. As with the COVID vaccines, we can instruct mRNA to cause our cells to make antigens—molecules that stimulate our immune system—that could protect us against many viruses, bacteria, or other pathogens that cause infectious disease. In addition, mRNA could in the future be used, as BioNTech and Moderna are pioneering, to fight cancer. Harnessing a process called immunotherapy, the mRNA can be coded to produce molecules that will cause the body’s immune system to identify and kill cancer cells.
RNA can also be engineered, as Jennifer Doudna and others discovered, to target genes for editing. Using the CRISPR system adapted from bacteria, RNA can guide scissors-like enzymes to specific sequences of DNA in order to eliminate or edit a gene. This technique has already been used in trials to cure sickle cell anemia. Now it is also being used in the war against COVID. Doudna and others have created RNA-guided enzymes that can directly detect SARS-CoV-2 and eventually could be used to destroy it.
More controversially, CRISPR could be used to create “designer babies” with inheritable genetic changes. In 2018, a young Chinese doctor used CRISPR to engineer twin girls so they did not have the receptor for the virus that causes AIDS. There was an immediate outburst of awe and then shock. The doctor was denounced, and there were calls for an international moratorium on inheritable gene edits. But in the wake of the pandemic, RNA-guided genetic editing to make our species less receptive to viruses may someday begin to seem more acceptable.
Throughout human history, we have been subjected to wave after wave of viral and bacterial plagues. One of the earliest known was the Babylon flu epidemic around 1200 B.C. The plague of Athens in 429 B.C. killed close to 100,000 people, the Antonine plague in the 2nd century killed 5 million, the plague of Justinian in the 6th century killed 50 million, and the Black Death of the 14th century took almost 200 million lives, close to half of Europe’s population.
The COVID-19 pandemic that killed more than 1.8 million people in 2020 will not be the final plague. However, thanks to the new RNA technology, our defenses against most future plagues are likely to be immensely faster and more effective. As new viruses come along, or as the current coronavirus mutates, researchers can quickly recode a vaccine’s mRNA to target the new threats. “It was a bad day for viruses,” Moderna’s chair Afeyan says about the Sunday when he got the first word of his company’s clinical trial results. “There was a sudden shift in the evolutionary balance between what human technology can do and what viruses can do. We may never have a pandemic again.”
The invention of easily reprogrammable RNA vaccines was a lightning-fast triumph of human ingenuity, but it was based on decades of curiosity-driven research into one of the most fundamental aspects of life on planet earth: how genes are transcribed into RNA that tell cells what proteins to assemble. Likewise, CRISPR gene-editing technology came from understanding the way that bacteria use snippets of RNA to guide enzymes to destroy viruses. Great inventions come from understanding basic science. Nature is beautiful that way.
AstraZeneca on Monday became the third pharmaceutical company to announce remarkable results from late-stage trials of a coronavirus vaccine, saying that its candidate, developed by Oxford University, is up to 90 percent effective.
This is the third straight week to begin with buoyant scientific news that suggests, even as coronavirus cases surge to devastating levels in many countries, an end to the pandemic is in sight.
Pfizer and its German partner BioNTech and Moderna have each reported vaccines that are 95 percent effective in clinical trials. A direct comparison to the Oxford-AstraZeneca vaccine is complicated, due to the trial design, but the vaccine may be a more realistic option for much of the world, as it is likely to be cheaper and does not need to be stored at subzero temperatures.
Peter Piot, director of the London School of Hygiene & Tropical Medicine, who was instrumental in the battle against AIDS, said the positive results from three vaccine candidates cannot be overestimated.
“2020 will be remembered for the many lives lost from covid-19, lockdowns and the U.S. election. Science should now be added to this list,” said Piot, adding, “the only way to stop covid-19 in its tracks is having multiple effective and safe vaccines that can be deployed all around the world and in vast quantities.”
“I’m totally delighted,” said Hildegund C.J. Ertl, a vaccine expert at the Wistar Institute in Philadelphia. Adding to the results from Pfizer and Moderna, “what it tells me is this virus can be beaten quite easily: 90 to 95 percent efficacy is something we’d dream about for influenza virus, and we’d never get it.”
The Oxford-AstraZeneca team said in a video conference with journalists that its candidate offered 90 percent protection against the virus when a subject received a half-dose, followed with a full dose one month later. Efficacy was lower — 62 percent — when subjects received two full doses a month apart. The interim results, therefore, averaged to 70 percent efficacy.
Andrew Pollard, chief investigator of the Oxford trial, said the findings showed the vaccine would save many lives.
“Excitingly, we’ve found that one of our dosing regimens may be around 90 percent effective, and if this dosing regimen is used, more people could be vaccinated with planned vaccine supply,” he said.
Britain has preordered 100 million doses — which at a dose and a half per person would cover most of its population. The United States has ordered 300 million.
The results have yet to be peer-reviewed or published, and will be scrutinized by regulators. Many questions remain, including whether the vaccine can reduce transmission of the virus by people without symptoms, which would have repercussions for how soon people could stop wearing masks. It is also unclear how long the immunity from the vaccine lasts — a crucial question.
Sarah Gilbert, a lead Oxford researcher, cautioned that the dose-and-a-half regimen would have to be more closely studied to be fully understood. But she said the first half-dose might be priming a person’s immune system just enough, and that the second booster then encourages the body to produce a robust defense against sickness and infection.
AstraZeneca and Oxford have been conducting Phase 3 clinical trials worldwide, with the most recent data coming from an interim analysis based on 131 coronavirus infections in Britain and Brazil among 10,000 volunteers, with half getting the vaccine and half getting a placebo.
The company said it would present the results to Britain’s health-care products regulators immediately and would seek approval to fine-tune its clinical trials in the United States, to further assess the half-dose shot followed by a booster.
Because the vaccine is already in production, if approved, the first 4 million doses could be ready in December, and 40 million could be delivered in the first quarter of 2021, company executives said. By the spring, the company and its global partners in India, Brazil, Russia and the United States could be cranking out 100 million to 200 million doses a month.
British Health Secretary Matt Hancock said “should all that go well, the bulk of the rollout will be in the new year.”
In a statement to Parliament, Prime Minister Boris Johnson said that vaccines were “edging ever closer to liberating us from the virus, demonstrating emphatically that this is not a pandemic without end. We can take great heart from today’s news, which has the makings of a wonderful British scientific achievement.”
World markets have rallied on optimistic vaccine news, though shares in AstraZeneca were down Monday on the London stock exchange.
No participants who received the vaccine developed severe cases or required hospitalization, AstraZeneca said Monday. The drugmaker also said that no “serious safety events” were reported in connection with the vaccine, which was typically “well tolerated” by participants regardless of their dosing levels or ages.
The vaccine uses a harmless cold virus that typically infects chimpanzees to deliver to the body’s cells the genetic code of the spike protein that dots the outside of the coronavirus. That teaches the body’s immune system to recognize and block the real virus.
Although the reason the regimen with an initial half-dose worked better remains to be teased out, Ertl said that it could be related to the fact that the body’s immune system can develop a defense system to block the harmless virus that’s used to deliver the spike protein’s code. Giving a smaller initial dose may lessen those defenses, and make the vaccine more effective.
Several other vaccines in late-stage development use a similar technology, harnessing a harmless virus to deliver a payload that will teach the immune system how to fight off the real thing — including the Johnson & Johnson vaccine, the Russian vaccine being developed by the Gamaleya Research Institute and the vaccine made by CanSino Biologics in China.
While the results released by AstraZeneca indicate somewhat lower efficacy than Pfizer and Moderna, the vaccine can be stored and transported at normal refrigerated conditions for up to six months. That could make it significantly easier to roll out than Pfizer’s vaccine, which has to be stored at minus-70 degrees Celsius, or Moderna’s, which is stable in refrigerated conditions for only 30 days and must be frozen at minus-20 degrees Celsius after that.
The Oxford-AstraZeneca vaccine was first developed in a small laboratory running on a shoestring budget by Gilbert at Oxford and her team. The university kicked in 1 million pounds ($1.3 million) and then sought a manufacturing partner, before settling on AstraZeneca.
“We wanted to ensure there wouldn’t be any profiteering off the pandemic,” said Louise Richardson, the university’s vice chancellor, so that their vaccine would be widely distributed “and wouldn’t just be for the wealthy and the first world.”
The scientists said that although it appeared to be a race, or a competition, among the front-running vaccine developers, no one company could produce by itself the millions of doses needed to end the pandemic.
“We don’t have enough supply for the whole planet,” Pollard said, adding that the important message is that today there are at least three highly effective, safe vaccines, that also appear to work well among the elderly, and that they are produced using different technologies, ensuring the quickest route to manufacture the billions of doses that will be necessary.
Pollard said it is “unclear why” the different vaccines were producing different results, and he said he and the scientific community awaited full data sets from all the clinical trials to fully understand what is going on. He said different studies were also using different end points to describe efficacy.
“At this moment we can’t fully explain the differences,” Pollard said. “It’s critical to understand what everyone is measuring.”
IF YOUR TIME IS SHORT
• Scientists are expressing cautious optimism that a vaccine can be ready to go by the late spring of 2021, although it’s unclear how much longer it would take to distribute the vaccine widely.
• Two possible vaccines are in phase 3 clinical trials; once those trials are completed, they would be candidates for approval. Another eight vaccines have begun phase 2 trials. And more than 100 other vaccines that haven’t begun clinical trials are in the pipeline.
• The Food and Drug Administration recently produced guidelines for the minimum effectiveness of vaccines seeking the agency’s approval. Vaccine officials say these guidelines are important to ensure public confidence in vaccines.
More than four months into the coronavirus pandemic, how close is the U.S. and the world to a safe and effective vaccine? Scientists say they see steady progress and are expressing cautious optimism that a vaccine could be ready by spring of 2021.
As of early July, there were roughly 160 vaccine projects under way worldwide, according to the World Health Organization.
Generally, a vaccine trial has several phases. In an initial phase, the vaccine is given to 20 to 100 healthy volunteers. The focus in this phase is to make sure the vaccine is safe, and to note any side effects.
In the second phase, there are hundreds of volunteers. In addition to monitoring safety, researchers try to determine whether shots produce an immune-system response.
The third phase involves thousands of patients. This phase continues the goals of the first two, but adds a focus on how effective the vaccine is. This phase also collects data on more unusual negative side effects.
In ordinary circumstances, these phases take years to complete. But for coronavirus, the timeline is being shortened. This has spurred more public-private partnerships and significantly increased funding.
Here’s a rundown of the 13 vaccine candidates that are furthest along in the clinical phases:
Coronavirus vaccines that are the furthest along:
The three vaccine candidates that are furthest along are both in phase 3.
One is being developed by researchers at Oxford University in the U.K. It uses a weakened version of a virus that causes common colds in chimpanzees. Researchers then added proteins, known as antigens, from the novel coronavirus, in the hope that these could prime the human immune system to fight the virus once it encounters it.
Another candidate in a phase 3 trial is being developed in China. It uses a killed, and thus safe, version of the novel coronavirus to spur an immune reaction.
And on July 15, the biotech company Moderna, which is partnering with the National Institutes of Health, announced that it would be moving to phase 3 within two weeks.
Two others have made it as far as phase 2, while eight others are finishing their phase 1 trials while also beginning phase 2 trials.
These candidates are being developed by a mix of corporations and institutions in several countries. These efforts seek to leverage a range of different technologies.
One uses RNA material that provides the instructions for a body to produce the needed antigens itself. This is a relatively untested approach to vaccination, but if it works, it has aspects that could make it easier to manufacture. Another approach is similar, but uses DNA instead of RNA.
One U.S. biotech firm, Novavax, is receiving federal funding to produce a vaccine that uses a lab-made protein to inspire an immune response.
Beyond these, another 10 vaccine candidates are in phase 1 clinical trials, while another 140 haven’t reached the clinical phase yet.
Having so many potential vaccines this far along is impressive, experts say, given the short time scientists have known about the novel coronavirus.
“Overall, the pace of development and advancement to Phase 3 trials is impressive,” said Matthew B. Laurens, associate professor at the University of Maryland School of Medicine’s Center for Vaccine Development and Global Health. “The public-private partnerships have been highly successful and are achieving goals for rapid vaccine development.”
In addition, the fact that several types of vaccine approaches are being tested means we aren’t putting all of our eggs in one basket.
“We will need several candidates should any one of these experience difficulties in manufacturing or show a safety signal when implemented in larger numbers of people,” Laurens said.
Meanwhile, at a time of rising public skepticism of government and vaccines, the Food and Drug Administration recently released additional guidelines on vaccine effectiveness. The new guidance requires vaccines to prevent or decrease the severity of the disease at least 50% of the time if they are to win the agency’s approval.
The FDA guidelines “reaffirmed the very rigorous FDA process for approving any vaccine. That gives a great deal of reassurance that this was going to be handled by the book,” said William Schaffner, a professor of preventive medicine and infectious diseases at Vanderbilt University Medical Center. “The more we talk about doing things fast, the more the public thinks, ‘They’re probably cutting corners.’”
In early April, Kathleen M. Neuzil, director of the University of Maryland’s vaccine center, told PolitiFact that if all went well, there might be five or six vaccines in trials within six months. Now, three and a half months later, there are two to three times that number.
Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases, and other officials have remained consistent in their estimation of the timeline: 12 to 18 months from the start of the pandemic, or roughly the late spring of 2021.
Schaffner told PolitiFact that he continues to see the first quarter of 2021 as a reasonable target. “I think that’s where the needle is pointing,” he said.
It remains to be seen how fast vaccines can be manufactured and distributed once approved for general use. Officials are also grappling with which Americans will get access first. So it’s unclear how long a person would have to wait to get vaccinated.
Laurens said he is not overly concerned about the distribution, because that is something that officials have long experience with. “Well-established programs exist for vaccine distribution, including for seasonal vaccination of large numbers of individuals,” he said.
Another hopeful sign, Schaffner said, is that the coronavirus itself seems to be relatively stable. There had been concern that the novel coronavirus, like many other viruses, is mutating over time. If the virus changes enough, that could become a problem that bedevils vaccine researchers.
But so far, that hasn’t happened. Even if evidence emerges that mutations are making the virus more transmissible, or that a new variant is making people sicker, that shouldn’t affect the vaccine process. “The central core of the virus would remain the same,” Schaffner said.
During the past month, there has been relatively little news about how much progress is being made on particular vaccines. Schaffner is not worried by the relative quiet.
“In a vaccine trial, if there’s an adverse safety finding, the guillotine comes down and that trial is stopped,” he said. “So quiet is good, because we’d know if something bad happens.”
Heavy hearts soared Monday with news that Moderna’s Covid-19 vaccine candidate — the frontrunner in the American market — seemed to be generating an immune response in Phase 1 trial subjects. The company’s stock valuation also surged, hitting $29 billion, an astonishing feat for a company that currently sells zero products.
But was there good reason for so much enthusiasm? Several vaccine experts asked by STAT concluded that, based on the information made available by the Cambridge, Mass.-based company, there’s really no way to know how impressive — or not — the vaccine may be.
While Moderna blitzed the media, it revealed very little information — and most of what it did disclose were words, not data. That’s important: If you ask scientists to read a journal article, they will scour data tables, not corporate statements. With science, numbers speak much louder than words.
Even the figures the company did release don’t mean much on their own, because critical information — effectively the key to interpreting them — was withheld.
Experts suggest we ought to take the early readout with a big grain of salt. Here are a few reasons why.
The silence of the NIAID
The National Institute for Allergy and Infectious Diseases has partnered with Moderna on this vaccine. Scientists at NIAID made the vaccine’s construct, or prototype, and the agency is running the Phase 1 trial. This week’s Moderna readout came from the earliest of data from the NIAID-led Phase 1.
NIAID doesn’t hide its light under a bushel. The institute generally trumpets its findings, often offering director Anthony Fauci — who, fair enough, is pretty busy these days — or other senior personnel for interviews.
But NIAID did not put out a press release Monday and declined to provide comment on Moderna’s announcement.
The n = 8 thing
The company’s statement led with the fact that all 45 subjects (in this analysis) who received doses of 25 micrograms (two doses each), 100 micrograms (two doses each), or a 250 micrograms (one dose) developed binding antibodies.
Later, the statement indicated that eight volunteers — four each from the 25-microgram and 100-microgram arms — developed neutralizing antibodies. Of the two types, these are the ones you’d really want to see.
We don’t know results from the other 37 trial participants. This doesn’t mean that they didn’t develop neutralizing antibodies. Testing for neutralizing antibodies is more time-consuming than other antibody tests and must be done in a biosecurity level 3 laboratory. Moderna disclosed the findings from eight subjects because that’s all it had at that point. Still, it’s a reason for caution.
Separately, while the Phase 1 trial included healthy volunteers ages 18 to 55 years, the exact ages of these eight people are unknown. If, by chance, they mostly clustered around the younger end of the age spectrum, you might expect a better response to the vaccine than if they were mostly from the senior end of it. And given who is at highest risk from the SARS-CoV-2 coronavirus, protecting older adults is what Covid-19 vaccines need to do.
There’s no way to know how durable the response will be
The report of neutralizing antibodies in subjects who were vaccinated comes from blood drawn two weeks after they received their second dose of vaccine.
“That’s very early. We don’t know if those antibodies are durable,” said Anna Durbin, a vaccine researcher at Johns Hopkins University.
There’s no real way to contextualize the findings
Moderna stated that the antibody levels seen were on a par with — or greater than, in the case of the 100-microgram dose — those seen in people who have recovered from Covid-19 infection.
But studies have shown antibody levels among people who have recovered from the illness vary enormously; the range that may be influenced by the severity of a person’s disease. John “Jack” Rose, a vaccine researcher from Yale University, pointed STAT to a study from China that showed that, among 175 recovered Covid-19 patients studied, 10 had no detectable neutralizing antibodies. Recovered patients at the other end of the spectrum had really high antibody levels.
So though the company said the antibody levels induced by vaccine were as good as those generated by infection, there’s no real way to know what that comparison means.
STAT asked Moderna for information on the antibody levels it used as a comparator. The response: That will be disclosed in an eventual journal article from NIAID, which is part of the National Institutes of Health.
“The convalescent sera levels are not being detailed in our data readout, but would be expected in a downstream full data exposition with NIH and its academic collaborators,” Colleen Hussey, the company’s senior manager for corporate communications, said in an email.
Durbin was struck by the wording of the company’s statement, pointing to this sentence: “The levels of neutralizing antibodies at day 43 were at or above levels generally seen in convalescent sera.”
“I thought: Generally? What does that mean?” Durbin said. Her question, for the time being, can’t be answered.
Rose said the company should disclose the information. “When a company like Moderna with such incredibly vast resources says they have generated SARS-2 neutralizing antibodies in a human trial, I would really like to see numbers from whatever assay they are using,” he said.
Moderna’s approach to disclosure
The company has not yet brought a vaccine to market, but it has a variety of vaccines for infectious diseases in its pipeline. It doesn’t publish on its work in scientific journals. What is known has been disclosed through press releases. That’s not enough to generate confidence within the scientific community.
“My guess is that their numbers are marginal or they would say more,” Rose said about the company’s SARS-2 vaccine, echoing a suspicion that others have about some of the company’s other work.
“I do think it’s a bit of a concern that they haven’t published the results of any of their ongoing trials that they mention in their press release. They have not published any of that,” Durbin noted.
Still, she characterized herself as “cautiously optimistic” based on what the company has said so far.
“I would like to see the data to make my own interpretation of the data. But I think it is at least encouraging that we’ve seen immune responses with this RNA vaccine that we haven’t seen with previous RNA vaccines for other pathogens. Whether it’s going to be enough, we don’t know,” Durbin said.
Moderna has been more forthcoming with data on at least one of its other vaccine candidates. In a statement issued in January about a Phase 1 trial for its cytomegalovirus (CMV) vaccine, it quantified how far over baseline measures antibody levels rose in vaccines.
A vaccine manufacturer is reporting preliminary data suggesting its COVID-19 vaccine is safe, and appears to be eliciting in test subjects the kind of immune response capable of preventing disease.
Moderna, Inc., of Cambridge, Mass., developed the vaccine in collaboration with the National Institute of Allergy and Infectious Diseases. The results reported Monday come from an initial analysis of a Phase I study primarily designed to see if the vaccine is safe.
The company reports no serious side-effects; however, modest side-effects included redness at the injection site, headache, fever and flu-like symptoms, although none of these lasted more than a day.
The first 45 volunteers for the vaccine trial were divided into three groups, with each group getting a different dose of the vaccine. All groups got an initial shot, followed by a booster shot a month later.
In addition to safety, the company also looked at the vaccine’s ability to induce antibodies to the coronavirus — what’s known as its immunogenicity. It did, for all subjects at all dose levels. In addition, eight of the subjects were tested for the presence of neutralizing antibodies that prevent the virus from infecting cells in the laboratory. All eight did.
The Food and Drug Administration has given Moderna the green light to begin a Phase II study expected to enroll an additional 600 volunteers — half older than 55 — to provide additional immunogenicity data. The company hopes by July to begin a Phase III study, aimed at showing that the vaccine can actually prevent disease.
The Moderna vaccine is made using messenger RNA, or mRNA, a molecule containing the genetic instructions to make a protein on the coronavirus surface that is recognized by our immune systems. Although mRNA vaccines have been studied for several years, so far none has been licensed by the FDA.
The advantage of mRNA vaccines over more traditional vaccines is they can be made quickly. The company says it was just 63 days from the time Chinese scientists revealed the genetic sequence to the time a vaccine was injected into the first volunteer.
Moderna’s is one of about a dozen COVID-19 vaccine candidates that have begun studies in humans.
A vaccine would be the ultimate weapon against the coronavirus and the best route back to normal life. Officials like Dr. Anthony S. Fauci, the top infectious disease expert on the Trump administration’s coronavirus task force, estimate a vaccine could arrive in at least 12 to 18 months.
The grim truth behind this rosy forecast is that a vaccine probably won’t arrive any time soon. Clinical trials almost never succeed. We’ve never released a coronavirus vaccine for humans before. Our record for developing an entirely new vaccine is at least four years — more time than the public or the economy can tolerate social-distancing orders.
But if there was any time to fast-track a vaccine, it is now. So Times Opinion asked vaccine experts how we could condense the timeline and get a vaccine in the next few months instead of years.
Here’s how we might achieve the impossible.
Normally, researchers need years to secure funding, get approvals and study results piece by piece. But these are not normal times.
“If you want to make that 18-month timeframe, one way to do that is put as many horses in the race as you can,” said Dr. Peter Hotez, dean of the National School of Tropical Medicine at Baylor College of Medicine.
Despite the unprecedented push for a vaccine, researchers caution that less than 10 percent of drugs that enter clinical trials are ever approved by the Food and Drug Administration.
The rest fail in one way or another: They are not effective, don’t perform better than existing drugs or have too many side effects.
Fortunately, we already have a head start on the first phase of vaccine development: research. The outbreaks of SARS and MERS, which are also caused by coronaviruses, spurred lots of research. SARS and SARS-CoV-2, the virus that causes Covid-19, are roughly 80 percent identical, and both use so-called spike proteins to grab onto a specific receptor found on cells in human lungs. This helps explain how scientists developed a test for Covid-19 so quickly.
There’s a cost to moving so quickly, however. The potential Covid-19 vaccines now in the pipeline might be more likely to fail because of the swift march through the research phase, said Robert van Exan, a cell biologist who has worked in the vaccine industry for decades. He predicts we won’t see a vaccine approved until at least 2021 or 2022, and even then, “this is very optimistic and of relatively low probability.”
And yet, he said, this kind of fast-tracking is “worth the try — maybe we will get lucky.”
The next step in the process is pre-clinical and preparation work, where a pilot factory is readied to produce enough vaccine for trials. Researchers relying on groundwork from the SARS and MERS outbreaks could theoretically move through planning steps swiftly.
Sanofi, a French biopharmaceutical company, expects to begin clinical trials late this year for a Covid-19 vaccine that it repurposed from work on a SARS vaccine. If successful, the vaccine could be ready by late 2021.
As a rule, researchers don’t begin jabbing people with experimental vaccines until after rigorous safety checks.
They test the vaccine first on small batches of people — a few dozen during Phase 1, then a few hundred in Phase 2, then thousands in Phase 3. Months normally pass between phases so that researchers can review the findings and get approvals for subsequent phases.
But “if we do it the conventional way, there’s no way we’re going to be reaching that timeline of 18 months,” said Akiko Iwasaki, a professor of immunobiology at Yale University School of Medicine and an investigator at the Howard Hughes Medical Institute.
There are ways to slash time off this process by combining several phases and testing vaccines on more people without as much waiting.
Last week the National Academy of Sciences showed an overlapping timeline, describing it as moving at “pandemic speed.”
It’s here that talk of fast-tracking the timeline meets the messiness of real life: What if a promising vaccine actually makes it easier to catch the virus, or makes the disease worse after someone’s infected?
That’s been the case for a few H.I.V. drugs and vaccines for dengue fever, because of a process called vaccine-induced enhancement, in which the body reacts unexpectedly and makes the disease more dangerous.
Researchers can’t easily infect vaccinated participants with the coronavirus to see how the body behaves. They normally wait until some volunteers contract the virus naturally. That means dosing people in regions hit hardest by the virus, like New York, or vaccinating family members of an infected person to see if they get the virus next. If the pandemic subsides, this step could be slowed.
“That’s why vaccines take such a long time,” said Dr. Iwasaki. “But we’re making everything very short. Hopefully we can evaluate these risks as they occur, as soon as possible.”
This is where the vaccine timelines start to diverge depending on who you are, and where some people might get left behind.
If a vaccine proves successful in early trials, regulators could issue an emergency-use provision so that doctors, nurses and other essential workers could get vaccinated right away — even before the end of the year. Researchers at Oxford announced this week that their coronavirus vaccine could be ready for emergency use by September if trials prove successful.
So researchers might produce a viable vaccine in just 12 to 18 months, but that doesn’t mean you’re going to get it. Millions of people could be in line before you. And that’s only if the United States finds a vaccine first. If another country, like China, beats us to it, we could wait even longer while it doses its citizens first.
You might be glad of that, though, if it turned out that the fast-tracked vaccine caused unexpected problems. Only after hundreds or thousands are vaccinated would researchers be able to see if a fast-tracked vaccine led to problems like vaccine-induced enhancement.
“It’s true that any new technology comes with a learning curve,” said Dr. Paul Offit, the director of the Vaccine Education Center at the Children’s Hospital of Philadelphia. “And sometimes that learning curve has a human price.”
Once we have a working vaccine in hand, companies will need to start producing millions — perhaps billions — of doses, in addition to the millions of vaccine doses that are already made each year for mumps, measles and other illnesses. It’s an undertaking almost unimaginable in scope.
Companies normally build new facilities perfectly tailored to any given vaccine because each vaccine requires different equipment. Some flu vaccines are produced using chicken eggs, using large facilities where a version of the virus is incubated and harvested. Other vaccines require vats in which a virus is cultured in a broth of animal cells and later inactivated and purified.
Those factories follow strict guidelines governing biological facilities and usually take around five years to build, costing at least three times more than conventional pharmaceutical factories. Manufacturers may be able to speed this up by creating or repurposing existing facilities in the middle of clinical trials, long before the vaccine in question receives F.D.A. approval.
“They just can’t wait,” said Dr. Iwasaki. “If it turns out to be a terrible vaccine, they won’t distribute it. But at least they’ll have the capability” to do so if the vaccine is successful.
The Bill and Melinda Gates Foundation says it will build factories for seven different vaccines. “Even though we’ll end up picking at most two of them, we’re going to fund factories for all seven, just so that we don’t waste time,” Bill Gates said during an appearance on “The Daily Show.”
In the end, the United States will have the capacity to mass-produce only two or three vaccines, said Vijay Samant, the former head of vaccine manufacturing at Merck.
“The manufacturing task is insurmountable,” Mr. Samant said. “I get sleepless nights thinking about it.”
Consider just one seemingly simple step: putting the vaccine into vials. Manufacturers need to procure billions of vials, and billions of stoppers to seal them. Sophisticated machines are needed to fill them precisely, and each vial is inspected on a high-speed line. Then vials are stored, shipped and released to the public using a chain of temperature-controlled facilities and trucks. At each of these stages, producers are already stretched to meet existing demands, Mr. Samant said.
It’s a bottleneck similar to the one that caused a dearth of ventilators, masks and other personal protective equipment just as Covid-19 surged across America.
If you talk about vaccines long enough, a new type of vaccine, called Messenger RNA (or mRNA for short), inevitably comes up. There are hopes it could be manufactured at a record clip. Mr. Gates even included it on his Time magazine list of six innovations that could change the world. Is it the miracle we’re waiting for?
Rather than injecting subjects with disease-specific antigens to stimulate antibody production, mRNA vaccines give the body instructions to create those antigens itself. Because mRNA vaccines don’t need to be cultured in large quantities and then purified, they are much faster to produce. They could change the course of the fight against Covid-19.
“On the other hand,” said Dr. van Exan, “no one has ever made an RNA vaccine for humans.”
Researchers conducting dozens of trials hope to change that, including one by the pharmaceutical company Moderna. Backed by investor capital and spurred by federal funding of up to $483 million to tackle Covid-19, Moderna has already fast-tracked an mRNA vaccine. It’s entering Phase 1 trials this year and the company says it could have a vaccine ready for front-line workers later this year.
“Could it work? Yeah, it could work,” said Dr. Fred Ledley, a professor of natural biology and applied sciences at Bentley University. “But in terms of the probability of success, what our data says is that there’s a lower chance of approval and the trials take longer.”
The technology is decades old, yet mRNA is not very stable and can break down inside the body.
“At this point, I’m hoping for anything to work,” said Dr. Iwasaki. “If it does work, wonderful, that’s great. We just don’t know.”
The fixation on mRNA shows the allure of new and untested treatments during a medical crisis. Faced with the unsatisfying reality that our standard arsenal takes years to progress, the mRNA vaccine offers an enticing story mixed with hope and a hint of mystery. But it’s riskier than other established approaches.
Imagine that the fateful day arrives. Scientists have created a successful vaccine. They’ve manufactured huge quantities of it. People are dying. The economy is crumbling. It’s time to start injecting people.
But first, the federal government wants to take a peek.
That might seem like a bureaucratic nightmare, a rubber stamp that could cost lives. There’s even a common gripe among researchers: For every scientist employed by the F.D.A., there are three lawyers. And all they care about is liability.
Yet F.D.A. approvals are no mere formality. Approvals typically take a full year, during which time scientists and advisory committees review the studies to make sure that the vaccine is as safe and effective as drug makers say it is.
While some steps in the vaccine timeline can be fast-tracked or skipped entirely, approvals aren’t one of them. There are horror stories from the past where vaccines were not properly tested. In the 1950s, for example, a poorly produced batch of a polio vaccine was approved in a few hours. It contained a version of the virus that wasn’t quite dead, so patients who got it actually contracted polio. Several children died.
The same scenario playing out today could be devastating for Covid-19, with the anti-vaccination movement and online conspiracy theorists eager to disrupt the public health response. So while the F.D.A. might do this as fast as possible, expect months to pass before any vaccine gets a green light for mass public use.
At this point you might be asking: Why are all these research teams announcing such optimistic forecasts when so many experts are skeptical about even an 18-month timeline? Perhaps because it’s not just the public listening — it’s investors, too.
“These biotechs are putting out all these press announcements,” said Dr. Hotez. “You just need to recognize they’re writing this for their shareholders, not for the purposes of public health.”
What if It Takes Even Longer Than the Pessimists Predict?
Covid-19 lives in the shadow of the most vexing virus we’ve ever faced: H.I.V. After nearly 40 years of work, here is what we have to show for our vaccine efforts: a few Phase 3 clinical trials, one of which actually made the disease worse, and another with a success rate of just 30 percent.
Researchers say they don’t expect a successful H.I.V. vaccine until 2030 or later, putting the timeline at around 50 years.
That’s unlikely to be the case for Covid-19, because, as opposed to H.I.V., it doesn’t appear to mutate significantly and exists within a family of familiar respiratory viruses. Even still, any delay will be difficult to bear.
But the history of H.I.V. offers a glimmer of hope for how life could continue even without a vaccine. Researchers developed a litany of antiviral drugs that lowered the death rate and improved health outcomes for people living with AIDS. Today’s drugs can lower the viral load in an H.I.V.-positive person so the virus can’t be transmitted through sex.
Therapeutic drugs, rather than vaccines, might likewise change the fight against Covid-19. The World Health Organization began a global search for drugs to treat Covid-19 patients in March. If successful, those drugs could lower the number of hospital admissions and help people recover faster from home while narrowing the infection window so fewer people catch the virus.
Combine that with rigorous testing and contact tracing — where infected patients are identified and their recent contacts notified and quarantined — and the future starts looking a little brighter. So far, the United States is conducting fewer than half the number of tests required and we need to recruit more than 300,000 contact-tracers. But other countries have started reopening following exactly these steps.
If all those things come together, life might return to normal long before a vaccine is ready to shoot into your arm.
Humankind has never had a more urgent task than creating broad immunity for coronavirus.
One of the questions I get asked the most these days is when the world will be able to go back to the way things were in December before the coronavirus pandemic. My answer is always the same: when we have an almost perfect drug to treat COVID-19, or when almost every person on the planet has been vaccinated against coronavirus.
The former is unlikely to happen anytime soon. We’d need a miracle treatment that was at least 95 percent effective to stop the outbreak. Most of the drug candidates right now are nowhere near that powerful. They could save a lot of lives, but they aren’t enough to get us back to normal.
Which leaves us with a vaccine.
Humankind has never had a more urgent task than creating broad immunity for coronavirus. Realistically, if we’re going to return to normal, we need to develop a safe, effective vaccine. We need to make billions of doses, we need to get them out to every part of the world, and we need all of this happen as quickly as possible.
That sounds daunting, because it is. Our foundation is the biggest funder of vaccines in the world, and this effort dwarfs anything we’ve ever worked on before. It’s going to require a global cooperative effort like the world has never seen. But I know it’ll get done. There’s simply no alternative.
Here’s what you need to know about the race to create a COVID-19 vaccine.
The world is creating this vaccine on a historically fast timeline.
Dr. Anthony Fauci has said he thinks it’ll take around eighteen months to develop a coronavirus vaccine. I agree with him, though it could be as little as 9 months or as long as two years.
Although eighteen months might sound like a long time, this would be the fastest scientists have created a new vaccine. Development usually takes around five years. Once you pick a disease to target, you have to create the vaccine and test it on animals. Then you begin testing for safety and efficacy in humans.
Safety and efficacy are the two most important goals for every vaccine. Safety is exactly what it sounds like: is the vaccine safe to give to people? Some minor side effects (like a mild fever or injection site pain) can be acceptable, but you don’t want to inoculate people with something that makes them sick.
Efficacy measures how well the vaccine protects you from getting sick. Although you’d ideally want a vaccine to have 100 percent efficacy, many don’t. For example, this year’s flu vaccine is around 45 percent effective.
To test for safety and efficacy, every vaccine goes through three phases of trials:
- Phase one is the safety trial. A small group of healthy volunteers gets the vaccine candidate. You try out different dosages to create the strongest immune response at the lowest effective dose without serious side effects.
- Once you’ve settled on a formula, you move onto phase two, which tells you how well the vaccine works in the people who are intended to get it. This time, hundreds of people get the vaccine. This cohort should include people of different ages and health statuses.
- Then, in phase three, you give it to thousands of people. This is usually the longest phase, because it occurs in what’s called “natural disease conditions.” You introduce it to a large group of people who are likely already at the risk of infection by the target pathogen, and then wait and see if the vaccine reduces how many people get sick.
After the vaccine passes all three trial phases, you start building the factories to manufacture it, and it gets submitted to the WHO and various government agencies for approval.
This process works well for most vaccines, but the normal development timeline isn’t good enough right now. Every day we can cut from this process will make a huge difference to the world in terms of saving lives and reducing trillions of dollars in economic damage.
So, to speed up the process, vaccine developers are compressing the timeline. This graphic shows how:
In the traditional process, the steps are sequential to address key questions and unknowns. This can help mitigate financial risk, since creating a new vaccine is expensive. Many candidates fail, which is why companies wait to invest in the next step until they know the previous step was successful.
For COVID-19, financing development is not an issue. Governments and other organizations (including our foundation and an amazing alliance called the Coalition for Epidemic Preparedness Innovations) have made it clear they will support whatever it takes to find a vaccine. So, scientists are able to save time by doing several of the development steps at once. For example, the private sector, governments, and our foundation are going to start identifying facilities to manufacture different potential vaccines. If some of those facilities end up going unused, that’s okay. It’s a small price to pay for getting ahead on production.
Fortunately, compressing the trial timeline isn’t the only way to take a process that usually takes five years and get it done in 18 months. Another way we’re going to do that is by testing lots of different approaches at the same time.
There are dozens of candidates in the pipeline.
As of April 9, there are 115 different COVID-19 vaccine candidates in the development pipeline. I think that eight to ten of those look particularly promising. (Our foundation is going to keep an eye on all the others to see if we missed any that have some positive characteristics, though.)
The most promising candidates take a variety of approaches to protecting the body against COVID-19. To understand what exactly that means, it’s helpful to remember how the human immune system works.
When a disease pathogen gets into your system, your immune system responds by producing antibodies. These antibodies attach themselves to substances called antigens on the surface of the microbe, which sends a signal to your body to attack. Your immune system keeps a record of every microbe it has ever defeated, so that it can quickly recognize and destroy invaders before they make you ill.
Vaccines circumvent this whole process by teaching your body how to defeat a pathogen without ever getting sick. The two most common types—and the ones you’re probably most familiar with—are inactivated and live vaccines. Inactivated vaccines contain pathogens that have been killed. Live vaccines, on the other hand, are made of living pathogens that have been weakened (or “attenuated”). They’re highly effective but more prone to side effects than their inactivated counterparts.
Inactivated and live vaccines are what we consider “traditional” approaches. There are a number of COVID-19 vaccine candidates of both types, and for good reason: they’re well-established. We know how to test and manufacture them.
The downside is that they’re time-consuming to make. There’s a ton of material in each dose of a vaccine. Most of that material is biological, which means you have to grow it. That takes time, unfortunately.
That’s why I’m particularly excited by two new approaches that some of the candidates are taking: RNA and DNA vaccines. If one of these new approaches pans out, we’ll likely be able to get vaccines out to the whole world much faster. (For the sake of simplicity, I’m only going to explain RNA vaccines. DNA vaccines are similar, just with a different type of genetic material and method of administration.)
Our foundation—both through our own funding and through CEPI—has been supporting the development of an RNA vaccine platform for nearly a decade. We were planning to use it to make vaccines for diseases that affect the poor like malaria, but now it’s looking like one of the most promising options for COVID. The first candidate to start human trials was an RNA vaccine created by a company called Moderna.
Here’s how an RNA vaccine works: rather than injecting a pathogen’s antigen into your body, you instead give the body the genetic code needed to produce that antigen itself. When the antigens appear on the outside of your cells, your immune system attacks them—and learns how to defeat future intruders in the process. You essentially turn your body into its own vaccine manufacturing unit.
Because RNA vaccines let your body do most of the work, they don’t require much material. That makes them much faster to manufacture. There’s a catch, though: we don’t know for sure yet if RNA is a viable platform for vaccines. Since COVID would be the first RNA vaccine out of the gate, we have to prove both that the platform itself works and that it creates immunity. It’s a bit like building your computer system and your first piece of software at the same time.
Even if an RNA vaccine continues to show promise, we still must continue pursuing the other options. We don’t know yet what the COVID-19 vaccine will look like. Until we do, we have to go full steam ahead on as many approaches as possible.
It might not be a perfect vaccine yet—and that’s okay.
The smallpox vaccine is the only vaccine that’s wiped an entire disease off the face of the earth, but it’s also pretty brutal to receive. It left a scar on the arm of anyone who got it. One out of every three people had side effects bad enough to keep them home from school or work. A small—but not insignificant—number developed more serious reactions.
The smallpox vaccine was far from perfect, but it got the job done. The COVID-19 vaccine might be similar.
If we were designing the perfect vaccine, we’d want it to be completely safe and 100 percent effective. It should be a single dose that gives you lifelong protection, and it should be easy to store and transport. I hope the COVID-19 vaccine has all of those qualities, but given the timeline we’re on, it may not.
The two priorities, as I mentioned earlier, are safety and efficacy. Since we might not have time to do multi-year studies, we will have to conduct robust phase 1 safety trials and make sure we have good real-world evidence that the vaccine is completely safe to use.
We have a bit more wiggle room with efficacy. I suspect a vaccine that is at least 70 percent effective will be enough to stop the outbreak. A 60 percent effective vaccine is useable, but we might still see some localized outbreaks. Anything under 60 percent is unlikely to create enough herd immunity to stop the virus.
The big challenge will be making sure the vaccine works well in older people. The older you are, the less effective vaccines are. Your immune system—like the rest of your body—ages and is slower to recognize and attack invaders. That’s a big issue for a COVID-19 vaccine, since older people are the most vulnerable. We need to make sure they’re protected.
The shingles vaccine—which is also targeted to older people—combats this by amping up the strength of the vaccine. It’s possible we do something similar for COVID, although it might come with more side effects. Health authorities could also ask people over a certain age to get an additional dose.
Beyond safety and efficacy, there are a couple other factors to consider:
- How many doses will it be? A vaccine you only get once is easier and quicker to deliver. But we may need a multi-dose vaccine to get enough efficacy.
- How long does it last? Ideally, the vaccine will give you long-lasting protection. But we might end up with one that only stops you from getting sick for a couple months (like the seasonal flu vaccine, which protects you for about six months). If that happens, the short-term vaccine might be used while we work on a more durable one.
- How do you store it? Many common vaccines are kept at 4 degrees C. That’s around the temperature of your average refrigerator, so storage and transportation is easy. But RNA vaccines need to be stored at much colder temperature—as low as -80 degrees C—which will make reaching certain parts of the world more difficult.
My hope is that the vaccine we have 18 months from now is as close to “perfect” as possible. Even if it isn’t, we will continue working to improve it. After that happens, I suspect the COVID-19 vaccine will become part of the routine newborn immunization schedule.
Once we have a vaccine, though, we still have huge problems to solve. That’s because…
We need to manufacture and distribute at least 7 billion doses of the vaccine.
In order to stop the pandemic, we need to make the vaccine available to almost every person on the planet. We’ve never delivered something to every corner of the world before. And, as I mentioned earlier, vaccines are particularly difficult to make and store.
There’s a lot we can’t figure out about manufacturing and distributing the vaccine until we know what exactly we’re working with. For example, will we be able to use existing vaccine factories to make the COVID-19 vaccine?
What we can do now is build different kinds of vaccine factories to prepare. Each vaccine type requires a different kind of factory. We need to be ready with facilities that can make each type, so that we can start manufacturing the final vaccine (or vaccines) as soon as we can. This will cost billions of dollars. Governments need to quickly find a mechanism for making the funding for this available. Our foundation is currently working with CEPI, the WHO, and governments to figure out the financing.
Part of those discussions center on who will get the vaccine when. The reality is that not everyone will be able to get the vaccine at the same time. It’ll take months—or even years—to create 7 billion doses (or possibly 14 billion, if it’s a multi-dose vaccine), and we should start distributing them as soon as the first batch is ready to go.
Most people agree that health workers should get the vaccine first. But who gets it next? Older people? Teachers? Workers in essential jobs?
I think that low-income countries should be some of the first to receive it, because people will be at a much higher risk of dying in those places. COVID-19 will spread much quicker in poor countries because measures like physical distancing are harder to enact. More people have poor underlying health that makes them more vulnerable to complications, and weak health systems will make it harder for them to receive the care they need. Getting the vaccine out in low-income countries could save millions of lives. The good news is we already have an organization with expertise about how to do this in Gavi, the Vaccine Alliance.
With most vaccines, manufacturers sign a deal with the country where their factories are located, so that country gets first crack at the vaccines. It’s unclear if that’s what will happen here. I hope we find a way to get it out on an equitable basis to the whole world. The WHO and national health authorities will need to develop a distribution plan once we have a better understanding of what we’re working with.
Eventually, though, we’re going to scale this thing up so that the vaccine is available to everyone. And then, we’ll be able to get back to normal—and to hopefully make decisions that prevent us from being in this situation ever again.
It might be a bit hard to see right now, but there is a light at the end of the tunnel. We’re doing the right things to get a vaccine as quickly as possible. In the meantime, I urge you to continue following the guidelines set by your local authorities. Our ability to get through this outbreak will depend on everyone doing their part to keep each other safe.