By Elizabeth Ralph 09/11/2020 04:00 AM EDT
In April, Sarah Gilbert, the British scientist leading Oxford’s Covid-19 vaccine effort, said she was 80 percent confident her team would be able to produce a successful vaccine by September.
It was a remarkable statement—conspicuously confident—especially given the timing: Oxford’s vaccine had yet to be tested in a single human, and the results from a preliminary trial involving monkeys hadn’t yet been published.
With pandemic death rates in the U.S. and Britain ratcheting upward, Gilbert’s forecast soothed panicky citizens who had been told that it typically takes years to develop a successful vaccine. The New York Times wrote that Oxford had leapt ahead of the competition and was “sprinting fastest” to the finish line. Within weeks, Oxford had partnered with British pharmaceutical giant AstraZeneca and the two were inking deals around the world to manufacture and distribute hundreds of millions of doses. The vaccine became one of the world’s best hopes: By late August, with Phase III trials to determine safety and efficacy ongoing, the world had ordered more of the Oxford candidate than any other, at least 2.94 billion doses.
Now, Gilbert’s and the world’s hopes are coming back down to earth, with the news that AstraZeneca paused Phase III trials after one participant in Britain showed symptoms consistent with transverse myelitis, a rare neurological disease caused by inflammation of the spinal cord. Obstacles like this one are not unexpected in vaccine development, say experts. The fact that AstraZeneca is pausing trials to investigate, they point out, is a good thing—a signal that that system is working as it should, that drug companies are taking safety seriously, that there are some scientific norms that politics hasn’t trampled.
But the interruption is also a reminder that no amount of hype—from the endless media headlines, from politicians on Twitter, from the vaccine scientists themselves—is going to save the world from the deadliest pathogen in a century. This week’s news is a cautionary note for those who think a magic bullet might be around the corner—or who think that it might be worth slashing safety protocols to get one.
In fact, the Oxford/AstraZeneca group’s self-assurance raised some eyebrows right from the start.
“I felt this way about a number of the companies,” says Paul Offit, director of the Vaccine Education Center at Children’s Hospital of Philadelphia and co-creator of a rotavirus vaccine. “They would do small Phase I trials, basically dose-ranging trials, and then talk about how they could make tens of millions of doses.”
“How about a little humility?” he thought.
Gilbert’s prediction reflected more “pride than reality,” says Michael Kinch, director of the Centers for Research Innovation in Biotechnology and Drug Discovery at Washington University in St. Louis. “The reality is that developing a vaccine … is generally quite challenging. Oftentimes, you don’t see the big problems coming.”
This week, that reality arrived for the Oxford vaccine. An independent committee must now determine whether the illness is directly linked to the vaccine or not—both possible outcomes. If the two are related, that will likely be the end of this vaccine. If not, the trial will likely resume after several weeks.
The hitch is also a reminder that a lot of Covid-19 science is uncharted territory. “We don’t have much experience with these types of vaccines,” says Tom Frieden, former director of the Centers for Disease Control. Adenovirus vectored vaccines, like Oxford’s, are relatively new, and mRNA vaccines—like those developed by Moderna and Pfizer—have never been used before in humans. The Trump administration is reportedly making plans to distribute the Moderna and Pfizer candidates, which are still in Phase III trials, in the U.S. by early November.
Kinch is worried that many countries are placing big bets on these newer vaccine technologies, while shunning old, established ones like inactivated virus vaccines, which China is pursuing. That’s one more reason to take safety with Covid-19 vaccines very, very seriously.
“Well designed and executed studies are so crucial,” he wrote in an email. “Autoimmune sensitives can be rare … and often take time (weeks or months) to develop.” Which means rushing a trial can be deadly. “A one in a thousand [reaction] sounds rare except when you scale those numbers up to 350 million Americans, or seven billion humans worldwide, the outcomes can be disastrous.”
Oxford was at the front of the pack from day one.
A few years ago, Gilbert, a top scientist at the university’s Jenner Institute, created a MERS vaccine by inserting genetic material of the MERS surface spike protein into a weakened chimpanzee adenovirus (a common cold virus). Once in the body, the adenovirus infects cells and unloads the gene, hopefully generating an immune response. The vaccine started trials in December in Saudi Arabia, where MERS is still a concern.
A month later, in January, when Gilbert heard about a mysterious, deadly pathogen raging through Wuhan, she was ready: Her team simply inserted genetic material from the spike protein of the SARS-CoV-2 virus inside the chimp adenovirus instead, theorizing that would confer immunity to the new virus.
“The MERS study was absolutely critical,” one of Gilbert’s vaccine colleagues told Bloomberg. “We could say, ‘OK, we can start tomorrow.’”
In the first test of the vaccine, scientists inoculated six monkeys before exposing them to a large dose of SARS-CoV-2. Adrian Hill, Gilbert’s colleague who leads the Jenner Institute, called the results “fantastic”— none of the vaccinated monkeys showed signs of sickness after being exposed. In April, around the time the monkey results came in, the Jenner team began planning to mass produce their vaccine. “The aim is to have at least a million doses by about September,” Hill said at the time, describing that number as a “fairly modest target.” The Trump administration’s Operation Warp Speed announced a billion-dollar investment in May.
The results of a combined Phase I/II trial in July reported no serious safety issues and showed that the vaccine produced neutralizing antibodies in those tested—an outcome that was deemed “encouraging” and “ promising.” “This is very positive news. A huge well done to our brilliant, world-leading scientists & researchers at @UniofOxford,” tweeted British Prime Minister Boris Johnson before adding “there are no guarantees.”
But the vaccine had its skeptics, too. Nasal swabs showed the monkeys from the first test still had the virus in their nose, meaning they might still be able to spread the virus to others, and their neutralizing antibody count was quite low. In a Forbes article, former Harvard Medical School professor and prominent cancer and HIV researcher William Haseltine argued the Jenner Institute didn’t have the data to support their claim that their vaccine protected the monkeys. “Time will tell if [proceeding to human trials] is the best approach,” he wrote. “I wouldn’t bet on it.” The Phase I/II trial, meanwhile, reported levels of neutralizing antibodies comparable to those seen in recovered Covid-19 patients, but lower than those generated by other
vaccine candidates. And the scientists administering the trial only tested 35 participants for antibodies out of 543 who had received the vaccine.
It was too early, scientists cautioned, to know whether this vaccine, or any other, was effective or safe. Incremental and early trial data might bump up stock prices, or even land a government contract, but it can’t predict the future.
The final determination would only come at the end of large Phase III trials, which AstraZeneca began in the U.S. in late August. (The company began smaller Phase II/III trial in Britain, Brazil and South African in July.) Today, there are nine other vaccines currently in the Phase III stage—with no definitive results yet. “Let’s be clear: No one knows anything” about the specifics of the vaccine timeline right now, says Zeke Emanuel, former Obama adviser and chair of the Department of Medical Ethics and Health Policy at the University of Pennsylvania. “We’re all bullshitting.”
That doesn’t mean that governments shouldn’t be dealing for doses or investing in vaccine projects—that is no doubt why the Covid-19 vaccine process is unfolding historically fast. But scientists have worried that all the vaccine hype could push politicians to cut off the normal scientific process too soon. While Anthony Fauci and other top U.S. government health officials insist the U.S. will not rush science, President Donald Trump continues to agitate scientists with his rosy vaccine predictions, now a keystone of his election campaign, that the U.S. will have a vaccine ready by Election Day; just last month the Financial Times reported the Trump administration was considering fast-tracking approval of the Oxford vaccine if results from a 10,000-person late-stage clinical trial looked promising, rather than waiting until the 30,000-person Phase III U.S. trial was complete. (AstraZenenca said it had not discussed this with the Trump administration.)
But the news of AstraZeneca’s pause seems to have relaxed scientists a bit, confirming that drug companies are proceeding with caution and not neglecting safety even as they’re under pressure from governments to produce. It even soothed some early skeptics of the Oxford team’s bravado.
“This is a hopeful sign that the organizations (both the private sector sponsors and the regulators) are taking their responsibilities seriously,” wrote Kinch in an email, adding that it would be premature to presume the vaccine is toxic. “The fact that the trial was halted, despite the considerable pressure to push on, is a good sign that the system is working as it normally does.”
At the same time, some see the incident as confirmation that Phase III vaccine trials must not be cut short before the full 30,000 people have been enrolled—even if a vaccine has already been shown to be effective.
Consider the Oxford trial, which was scheduled to give 20,000 people the vaccine and 10,000 a placebo. To determine effectiveness, that is whether inoculation protects against severe Covid-19, enough of the placebo patients need to get very sick to show that there is a statistically significant difference between the two groups. That only takes a total of about 150 Covid-19 cases—a threshold that can be reached fairly quickly, especially while a virus is still widespread. It could happen before all 30,000 people have been enrolled in the trial.
But stopping too soon might mean a failure to catch rare side effects. “What many of us are afraid of is that the FDA will find an efficacy signal before the enrollment of the 30,000 has completed,” says Frieden, “and then they will approve it for at least some groups” with an Emergency Use Authorization. “It’s much easier to document efficacy than it is to document safety,” he cautions.
So, what’s next for the Oxford vaccine? This is the second time that AstraZeneca has paused trials for safety reasons; in the first case, the participant was eventually diagnosed with multiple sclerosis, deemed to be unrelated to the vaccine. But this second incident might prompt reconsideration of that last case.
“This is routine,” says Michael Mina, professor of epidemiology at Harvard T. H. Chan School of Public Health, referring to pauses in vaccine trials. “But these also are the ‘routine’ items that can cause a vaccine to tank—which is why we focus so intently on safety at this stage . . . We just don’t have enough information to know what to make of this.”
“However, transverse myelitis is both rare and a complication that can arise from . . . vaccines,” he adds.
If the illness is found to be unrelated, AstraZeneca’s trials will continue. The company’s CEO said Thursday that its vaccine could still be ready by the end of the year. If vaccine did cause the illness, experts guess, AstraZeneca will cancel its trials and retire the vaccine. It is theoretically possible for a company to seek approval of, and for the FDA to approve, a vaccine that carries a very rare, severe side effect. But that’s extremely unlikely. “The reputational damage to a company could be fierce,” says Kinch.
“Even if it’s not a regulatory death sentence, it’s a public trust one,” adds Emanuel.
If this vaccine is shown to be toxic, that isn’t a reason to panic. There are over 200 in development, and most experts are confident that at least several are likely to work.
Whatever happens, scientists say, this is a reminder that vaccine developers can never predict how safe their vaccine is going to be. Emanuel mentioned Maurice Hilleman—a famed microbiologist who created over 40 vaccines in his career, saving countless lives: “He used to say he didn’t sleep comfortably about the safety of one of those vaccines until three million people had the vaccine.”
Offit says he didn’t discover a rare, serious side effect of his rotavirus vaccine until after the FDA had approved it. His Phase III trial had enrolled 72,000 infants in 11 countries and had taken four years to complete. The vaccine is still used—because it saves many more lives than it takes. But the experience taught him a lesson: “The road is often lined with tragedy. There’s often a human price.”