While several vaccine developers have issued statements looking into the future — setting possible timetables for study completion and vaccine manufacturing — the ethicists and doctors say one group in particular stands out as being the most aggressive in painting the rosiest picture: the University of Oxford in England.
Oxford has recently walked back some of its optimism, but for months, it set a tone that its vaccine was the most promising, without any solid evidence that this was based in fact.
First, in a field fraught with potential failure, two Oxford researchers stated that they’re “80% confident” that the vaccine will work, and that they might be able to complete large-scale clinical trials in just six weeks, a fraction of what some other vaccine companies estimate they can do.
Second, some experts have accused Oxford scientists of spinning results of their vaccine research in monkeys to make the vaccine look more powerful than it is, which Oxford denies.
Third, one leader in the Oxford team has gone so far as to denigrate other teams trying to get a Covid vaccine on the market, calling their technology “weird” and labeling it as merely “noise.” Such name-calling is highly unusual and aggressive among scientists.
Dr. William Schaffner, an infectious disease expert at Vanderbilt University Medical Center, said he “sat straight up” when he heard one of the Oxford scientists talk about how well their vaccine is progressing.
“Some of us in the scientific community here in the US have been a little surprised at the sprightly competitiveness of some of the comments from our colleagues at Oxford. We don’t usually see that in public pronouncements,” said Schaffner, a longtime adviser to the US Centers for Disease Control and Prevention. “We’ve been grumpy with our national political leaders about providing inaccurate information, and we should hold scientific leaders to those same standards.”
Dr. Paul Offit, a University of Pennsylvania pediatrician who developed a vaccine for rotavirus, agrees.
“At this point, the Oxford researchers have no idea whether they have something or not,” Offit said. “You just get so tired of this ‘science by press release.’ “
But one of the leaders of the Oxford research team says he and his colleagues are just being straightforward.
“We’re going to be first to finish,” said Dr. Adrian Hill, one of the lead Oxford researchers. “How can you criticize us for giving our honest opinion?”
On April 16, CNN’s Erin Burnett pressed Hill on his predictions.
“Do you have any concern that you’re being overly optimistic, that that just seems, for lack of a better word, too good to be true?” Burnett asked.
“We don’t think so,” Hill answered.
Weeks later, Hill would have to backtrack on his own optimism, warning against “over-promising” and ratcheting down his expectations of success.
Most vaccine efforts will fail
There are currently 10 vaccines in human clinical trials worldwide, according to the World Health Organization. Four of the teams are in the United States: Moderna, Pfizer, Inovio and Novavax.
Five Chinese companies have vaccines in human trials. Oxford is the only one in Europe. Worldwide, there are 114 more candidates in pre-clinical trial stages.
Vaccine development is a risky business. Sometimes even ones that get to large-scale clinical trials fail.
Even so, scientists from various experimental vaccine teams have made public statements about their interim results.
On May 18, Massachusetts-based Moderna put out a press release declaring that results in eight human study subjects showed that its vaccine “was generally safe and well tolerated.”
Moderna CEO Stéphane Bancel referred to the results as “positive interim Phase 1 data” and that “the Moderna team continues to focus on moving as fast as safely possible to start our pivotal Phase 3 study in July.”
Moderna’s stock soared, and the company was criticized for announcing results on just eight study subjects when the data hadn’t even been peer-reviewed or published in a scientific journal.
Moderna’s chief financial officer and chief medical officer were also criticized for selling shares in the company the day of and the day following the announcement of the data, with the two executives making a combined profit of $25 million. The transactions were completed through automated plans that lay out future stock trades at set prices or on set days. While legal, the sales raised eyebrows.
Moderna is collaborating on its vaccine development with the National Institute of Allergy and Infectious Diseases. Dr. Anthony Fauci, the director of NIAID, said while Moderna’s numbers were limited, “it was good news” and he was “cautiously optimistic” about the vaccine.
The Oxford scientists have voiced less caution, frequently appearing in the media and making public proclamations that theirs will likely be successful and first.
On April 11, lead researcher Sarah Gilbert told The Times of London that she was “80% confident” that the Oxford vaccine will work.
Her own colleague questioned that statement a few weeks later.
“So obviously, people who have dedicated their careers to this kind of a problem have a tendency to get excited about the prospects, because the prospects are pretty good. I certainly wouldn’t put the possibility at 80%. That’s a pretty big number,” Dr. John Bell, a professor of medicine at Oxford, said on NBC’s “Meet the Press” on May 3.
But Hill, the director of the Jenner Institute at Oxford, which specializes in vaccine development, dismissed Bell’s comments.
“It’s like asking me about a renal drug, asking John about a vaccine. It’s not what he does. It’s what Sarah does every day and has done for 25 years,” Hill said.
Bell did not respond to CNN’s multiple requests for comments.
On May 19, Hill told CNN he stood by Gilbert’s estimate.
“We did not exaggerate anything. We’re not backtracking at all from the 80%,” he said.
The wisdom of Spider-Man
Inovio and Moderna have said they expect their large-scale clinical trials, known as Phase 3 trials, to last around six months. Pfizer hasn’t given a timetable for its Phase 3 trial.
On May 19, Hill told CNN that his group is planning to start its Phase 3 trial sometime before July 1, and that they could finish by the end of the July, which means the trial would be between a month and six weeks long, although he thought August or September was more likely.
“I’ve not seen anyone wrap up a Phase 3 trial in a month to six weeks,” said Dr. Saad Omer, a Yale University infectious disease expert who’s done clinical trials on polio, pertussis and influenza vaccines. “We need to benchmark this against realistic expectations.”
Hill said he thought it was important to benchmark his trial progress because “it has huge public policy implications” for officials who are trying to make rules about when to open up communities.
But Omer said that’s exactly why it’s important to be realistic about how long the vaccine development process will take.
“I buy that this is a pandemic and we may need to show progress and show steps, and I’m OK with making forecasts if decision makers want that, but do it with a level of uncertainty, because that’s what’s warranted,” said Omer, director of the Yale Institute for Global Health.
He said the issue isn’t Oxford’s specific vaccine technology — he said they were “scientifically solid” — but rather that unexpected events can happen during a vaccine trial.
One big stumbling block for any vaccine trial is that Covid-19 infection rates in many areas of the world are flattening out or declining. The point of Phase 3 is to vaccinate people and then see if they naturally become infected, and with lower rates of circulating virus, the study subjects are less likely to be exposed to the virus in the first place.
“Just because things have gone right does not mean the next steps will go exactly on time, and won’t go sideways, even if eventually we’ll get there,” Omer said.
That’s why he encourages humility in making any projections about reaching the finish line.
“As Spider-Man says, with great power comes great responsibility, and being responsible is not projecting things with more precision than the field and the history of vaccine development suggests,” he added.
Oxford scientist insults other vaccine teams
Hill, the Oxford scientist, has several arguments about why he thinks his vaccine is more promising than the others currently in human clinical trials.
First, he cites his team’s many years of research on the technology used in their Covid vaccine.
The Oxford vaccine uses what’s called an adenovirus vector. Adenoviruses cause the common cold, but in this case, the adenoviruses are weakened and modified to deliver genetic material that codes for a protein from the novel coronavirus. The body then produces that protein and, ideally, develops an immune response to it.
Hill and his colleagues have been working on adenovirus vaccines for nearly 20 years, and it’s been used on thousands of study subjects in vaccines targeting more than 10 different diseases, according to the website for the Oxford vaccine.
Despite all this research, none of the Oxford vaccines has made it on the market, Hill said.
Still, Hill told CNN in the May 19 interview that his vaccine, plus one in China that also uses an adenovirus vector, are “the front runners” among the vaccines in clinical trials.
Hill then proceeded to disparage other teams’ vaccines — a highly unusual and aggressive move.
The four US vaccine candidates use a different technology — or vaccine “platform” — than Oxford.
Two of them, Moderna and Pfizer, use RNA vaccines, which inject a piece of genetic material from the novel coronavirus into human cells to stimulate immunity.
Hill described RNA vaccines as merely “noise from the new boys.”
A Harvard University blog describes it differently.
“Compared to previous vaccines, this method is more robust, more versatile, and yet, equally efficient,” according to the blog, which notes that the Bill & Melinda Gates Foundation invested $53 million in a German biotech company that specializes in RNA vaccines.
Hill was particularly disparaging of Moderna, which he said has “weird and wonderful technology.” When asked what he meant by “wonderful,” Hill said, “I was being sarcastic.”
“They’ve got an unproven technology,” he said.
CNN asked Moderna for its response, as well as Pfizer.
“Our only competitors in this race are the virus and the clock. We are rooting for multiple vaccines to succeed because we believe no manufacturer can make enough doses for the planet,” according to the Moderna statement.
In March, Pfizer CEO Dr. Albert Bourla put out a five-point plan for companies to “work as one team across the industry.”
“Our industry peers, the other pharmaceutical and biotechnology companies as well as health authorities, have come together like never before. We’re acutely aware that we are all on the same side, and COVID-19 and other diseases are the enemy,” Pfizer spokeswoman Amy Rose wrote in an email to CNN.
Hill also took a jab at Inovio, a US vaccine maker in clinical trials, saying “they can’t scale up to get into phase three,” clinical trials.
Inovio’s technology uses a brief electrical pulse to deliver plasmids, or small pieces of genetic information, into human cells. Inovio says those cells then produce the vaccine, which leads to an immune response.
Jeff Richardson, a spokesman for the company said that “our competition is the virus, not other companies. There needs to be three or four winners to vaccinate the world. Most likely, there will be a number of vaccines that make it, and that’s a good thing.”
As for the four Chinese companies in clinical trials with a potential Covid vaccine, Hill said “they have a problem.”
For a vaccine clinical trial to be successful, there needs to be sufficiently high levels of the virus circulating in the community. If there isn’t enough virus around, it will be impossible to tell if the vaccine protected the study subjects, or if they were just never exposed to the virus.
“There’s no Covid left in China. They can’t finish,” Hill said.
There is still a bit of Covid left in China, with a few dozen cases left, according to the latest briefings by the nation’s National Health Commission. While this is likely not enough for a full-scale clinical trial, the researchers could conduct trials in other countries where the vaccine is still circulating more widely.
Oxford not in ‘slam dunk’ territory
The Oxford scientists have sometimes tempered their positive statements with more cautious ones.
On April 19, the BBC’s Andrew Marr said he asked Gilbert “if it’s guaranteed that a workable vaccine can actually be produced.”
“Nobody can be absolutely sure it’s possible. That’s why we have to do trials. We have to find out. I think the prospects are very good, but it’s clearly not completely certain,” Gilbert answered.
But the US and British media have focused more on the positive statements, often writing glowing reports about the vaccine’s progress.
A few weeks ago, a headline in a US newspaper story proclaimed that the “Oxford group leaps ahead” even though it’s not clear there’s a single front runner among the vaccines.
A British newspaper declared that “[Oxford’s] confidence is built on past success” — despite the fact that Oxford has never had a vaccine on the market. Omer tweeted out a link to the article with words of caution.
“Should be careful when talking about #COVID19 vaccine progress. As a vaccine researcher, I am cautiously optimistic; but we must be mindful of projecting too much confidence. We are not in slam dunk territory,” he wrote.
Oxford’s monkeys, in particular, have received attention.
On May 13, Oxford scientists, together with researchers from the National Institutes of Health, posted a study on bioRxiv.org on nine monkeys who were intentionally exposed to the novel coronavirus. Six of them were vaccinated and three were not.
BioRxiv.org is a pre-print server, meaning the articles have not been reviewed by other scientists and have not been published in the medical literature.
After the monkeys were vaccinated and then exposed to the virus, they were euthanized and examined for lung damage. According to the Oxford study, none of the vaccinated animals had signs of pneumonia or other lung problems, but two out of three unvaccinated monkeys did develop some degree of viral pneumonia.
“It certainly worked in monkeys,” Oxford’s Hill told CNN’s Burnett May 15. “That was quite an impressive impact and that was our first try, if you like, with a standard dose, a single dose of vaccine.”
“We were very excited by seeing that in the first try,” he added.
But William Haseltine, a virologist and former professor at Harvard Medical School, said Hill was being “misleading.”
“In this interview Hill is like a magician who distracts the audience with one shiny object to detract you from the fact that his accomplice is picking your pocket,” Haseltine told CNN in an email.
In an article published by Forbes on May 16, Haseltine said the fact that the monkeys didn’t develop pneumonia is beside the point, considering that all of the vaccinated monkeys became infected with Covid-19.
Also, he said the monkeys had just as much viral RNA in their nasal secretions compared to the unvaccinated monkeys, an indication to him that the vaccine didn’t work and the monkeys could possibly spread the virus to others.
Thirdly, Haseltine pointed to neutralizing antibodies. A vaccine should elicit high levels of antibodies capable of disabling the virus and preventing it from infecting human cells. Haseltine said the level of these antibodies in the monkeys who received the Oxford vaccine was “extremely low.”
Haseltine told CNN that the monkey study on the Oxford vaccine was an “outright failure.”
The Oxford scientists quickly wrote a statement rebutting Haseltine’s article. They had been given the novel coronavirus directly into their noses — called an intranasal challenge — and so the presence of virus in the nasal swabs “may reflect use of a very high intranasal challenge dose greater than that transmitted in natural infections,” according to the statement.
They also wrote that there were neutralizing antibodies present in all the monkeys who were vaccinated, but not in the unvaccinated monkeys.
“The comment by Haseltine appears to misunderstand the impressive efficacy of the [Oxford] vaccine in the non-human primate model,” according to the statement.
Offit, the co-inventor of the rotavirus vaccine, said he thinks it’s not a deal breaker that the vaccinated monkeys got infected. People sometimes still get the flu when they get a flu vaccine, but they often get only mild symptoms. Children still can get rotavirus after getting his vaccine, but again, typically a milder version that’s less life-threatening.
He said the fact that the monkeys did not develop pneumonia after receiving the Oxford vaccine is “encouraging,” but he was not convinced that the Oxford vaccine would ultimately work, since vaccines that show signs of success in animals sometimes fail in humans.
“As vaccine researchers like to say, mice lie and monkeys exaggerate,” Offit said.
Offit and others say they sometimes cringe when they hear Oxford scientists talk about their vaccine.
Bioethicist Alta Charo said sometimes scientists can become “overly optimistic” about their work, especially as they race to put an end to the pandemic.
“It is very easy to get caught up in the potential of a new medical product when early development and testing seem to show promise. It is very easy to believe in your own work,” said Charo, a professor at the University of Wisconsin Law School.
Art Caplan, a bioethicist at NYU Langone Health and CNN medical analyst, said it’s especially important to be circumspect about vaccines, since so many people have lost trust in vaccines and are hesitant to vaccinate their children, or downright refuse to do so.
“The world is watching, and if you’re puffing something up that’s uncertain, that’s really troubling,” he said.
On Saturday, after months of rosy predictions, Hill deflated his predictions of success considerably and softened his competitive tone.
He told The Telegraph that the Oxford trial has about a 50% chance of getting “no result” since the spread of the novel coronavirus appears to be slowing in Britain, where the trial is taking place.
In that interview, Hill warned against “over-promising” and said that developing a vaccine is “not a race against the other guys. It’s a race against the virus disappearing, and against time.”
Offit said this was much more realistic.
“This tells you he’s starting to back away from his original statements, as he’s noticed the impracticality of his original statements,” he said.
Offit has some advice for Covid vaccine developers: Be quiet.
“Now researchers can’t wait to step out to the microphone — and there are so many microphones out there — to say, ‘I’ve got it! This looks really good!’ ” Offit said.
When he and his team were developing the RotaTeq vaccine, he said they didn’t speak to the media until they received final approval from the US Food and Drug Administration in 2006.
Today that vaccine saves hundreds of lives a day worldwide, Offit said, mostly children under the age of 2.
“When we discovered our rotavirus vaccine was safe in mice, we didn’t say anything. When we finished our Phase one clinical trials, we didn’t say anything. We just moved forward,” he said.