In the race for the coronavirus vaccine, the insults launched and the wisdom of Spider-Man

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While several vaccine developers have released statements about the future – setting possible timetables for completing studies and making the vaccines – ethicists and doctors say one group stands out as the most aggressive to paint the most rosy picture: the University of Oxford In England.

Oxford recently backed off a bit from its optimism, but for months it set the tone that its vaccine was the most promising, with no solid evidence that it was actually based.

First, in an area fraught with potential failure, two Oxford researchers said they were “80% convinced” that the vaccine would work and that they might be able to carry out large-scale clinical trials in just six weeks, a fraction of what other vaccine manufacturers think they can do.

Second, some experts have accused Oxford scientists of turning the results of their research into vaccines in monkeys to make the vaccine more potent than it is, which Oxford denies.

Third, a leader of the Oxford team went so far as to disparage other teams trying to put a Covid vaccine on the market, calling their technology “weird” and calling it “noise”. These insults are very unusual and aggressive among scientists.

Dr William Schaffner, an infectious disease expert at Vanderbilt University Medical Center, said he “sat up straight” when he heard one of the scientists from Oxford talk about the progress of their vaccine.

“Some of us in the scientific community here in the United States were a little surprised at the lively competitiveness of some of the comments from our colleagues at Oxford. We don’t usually see this in public statements, ”said longtime adviser Schaffner. at the Centers for Disease Control and Prevention in the United States. “We have been cranky with our national political leaders about providing inaccurate information, and we must hold scientific leaders to the same standards. “

Dr. Paul Offit, a pediatrician from the University of Pennsylvania who developed a rotavirus vaccine, agrees.

“At this point, the Oxford researchers have no idea whether they have something or not,” said Offit. “You are so fed up with this” science by press release “. ”

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But one of the leaders of the Oxford research team said that he and his colleagues were just frank.

“We will be the first to finish,” said Dr. Adrian Hill, one of Oxford’s principal researchers. “How can you criticize us for giving our honest opinion?” “

On April 16, CNN’s Erin Burnett pressed Hill on her predictions.

“Are you afraid that you are too optimistic, that it seems, for lack of a better word, too good to be true? Asked Burnett.

“We don’t think so,” replied Hill.

A few weeks later, Hill is expected to reconsider his optimism, warning against “excessive promises” and lowering his expectations of success.

Most immunization efforts will fail

There are currently 10 vaccines in human clinical trials worldwide, according to the World Health Organization. Four of the teams are located in the United States: Moderna, Pfizer, Inovio and Novavax.

Five Chinese companies have vaccines in human trials. Oxford is the only one in Europe. Globally, there are 114 other candidates in the pre-clinical testing phase.

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Nevertheless, scientists from various experimental vaccine teams have made public statements about their interim results.

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Moderna, based in Massachusetts, released a press release on May 18 stating that the results of eight human studies have shown that its vaccine “is generally safe and well tolerated”.

Moderna CEO Stéphane Bancel described the results as “positive interim data from phase 1” and “the Moderna team continues to focus on moving as quickly and safely as possible to begin our pivotal study phase 3 in July ”.

Moderna’s shares soared, and the company was criticized for announcing results on only eight study subjects when the data had not even been peer reviewed or published in a scientific journal.

Moderna’s chief financial officer and medical director were also criticized for selling the company’s shares the day and the day after the data were released, with the two executives making a combined profit of $ 25 million. The transactions were carried out using automated plans which define future stock market transactions at fixed prices or on fixed days. Although legal, sales have raised eyebrows.

Moderna is collaborating on the development of its vaccine with the National Institute of Allergies and Infectious Diseases. Dr. Anthony Fauci, director of NIAID, said that although the number of Moderna was limited, “it was good news” and he was “cautiously optimistic” about the vaccine.

Oxford scientists have expressed less caution, appearing frequently in the media and publicly announcing that theirs is likely to be successful and the first.

Lead researcher Sarah Gilbert told the London Times on April 11 that she was “80% confident” that the Oxford vaccine would work.

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His own colleague challenged this statement a few weeks later.

“So obviously people who have dedicated their careers to this kind of problem tend to be excited about the prospects because the prospects are pretty good. I certainly wouldn’t put the option at 80%. That’s a pretty big number, “said May 3, Oxford professor of medicine Dr. John Bell on NBC’s” Meet the Press “.

But Hill, the director of the Jenner Institute at Oxford, which specializes in vaccine development, rejected Bell’s comments.

“It’s like asking me about a kidney drug, asking John for a vaccine. This is not what it does. That’s what Sarah has been doing every day and has been doing for 25 years, “said Hill.

Bell did not respond to CNN’s multiple requests for comment.

Hill told CNN on May 19 that he respected Gilbert’s estimates.

“We have not exaggerated anything. We are not backing down from the 80% at all, ”he said.

The wisdom of Spider-Man

Inovio and Moderna said they expect their large-scale clinical trials, called phase 3 trials, to last approximately six months. Pfizer did not give a schedule for its phase 3 trial.

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Hill told CNN on May 19 that his group plans to start its phase 3 trial sometime before July 1 and may end by the end of July, which means the trial will last between a month and six weeks, although he thought August or September was more likely.

“I haven’t seen anyone finish a phase 3 trial in a month to six weeks,” said Dr. Saad Omer, an infectious disease specialist at Yale University, who has conducted clinical trials of the vaccine against polio, whooping cough and the flu. “We have to compare this to realistic expectations. “

Hill said he thought it was important to compare the progress of his trial, as “it has huge public policy implications” for officials trying to set rules on when communities open .

But Omer said that is exactly why it is important to be realistic about the length of the process of developing a vaccine.

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“I buy this is a pandemic and we may have to show progress and show milestones, and I agree to forecast if the decision makers want, but do it with a level of uncertainty because that is what is warranted, “said Omer. , director of the Yale Institute for Global Health.

He said the problem is not Oxford’s specific vaccine technology – he said they were “scientifically sound” – but rather that unexpected events may occur during a vaccine trial.

A big stumbling block for any vaccine trial is that rates of Covid-19 infection in many parts of the world are flattening or decreasing. The goal of Phase 3 is to vaccinate people and then see if they are naturally infected, and with lower circulating virus levels, study subjects are less likely to be exposed to the virus first. location.

“Just because things have gone well does not mean that the next steps will go exactly on time and will not go sideways, even if we will get there eventually,” said Omer.

That’s why he encourages humility to make projections to reach the finish line.

“As Spider-Man says, great power comes with great responsibility, and being responsible does not project things more precisely than the field and the history of vaccine development suggest,” a- he added.

Oxford scientist insults other vaccine teams

Hill, the Oxford scientist, has several arguments as to 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 into the technology used in their Covid vaccine.

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The Oxford vaccine uses what is called an adenovirus vector. Adenoviruses cause colds, but in this case, the adenoviruses are weakened and modified to provide genetic material that codes for a protein in the new coronavirus. The body then produces this protein and, ideally, develops an immune response to it.

Hill and his colleagues have been working on adenovirus vaccines for almost 20 years, and they have been used on thousands of study subjects in vaccines targeting more than 10 different diseases, according to the Oxford Vaccine website.

Despite all of this research, none of the Oxford vaccines have been on the market, said Hill.

However, Hill told CNN in the May 19 interview that his vaccine, plus one in China that also uses an adenovirus vector, is “the first” among vaccines in clinical trials.

Hill then disparaged other teams’ vaccines – a very unusual and aggressive move.

The four US vaccine candidates use different Oxford technology – or “vaccine platform”.

Two of them, Moderna and Pfizer, use RNA vaccines, which inject a piece of genetic material from the new coronavirus into human cells to boost immunity.

Hill described the RNA vaccines as simply “the noise of new boys.”

A Harvard University blog describes it differently.

“Compared to previous vaccines, this method is more robust, more versatile and yet just as effective,” according to the blog, which notes that the Bill & Melinda Gates Foundation has invested $ 53 million in a German biotechnology company specializing in RNA vaccines.

Hill particularly belittled Moderna, who he said possessed “strange and wonderful technology.” When asked what he meant by “wonderful,” Hill replied, “I was sarcastic.”

“They have 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 want multiple vaccines to be successful because we believe that no single manufacturer can make enough doses for the planet, “said the Moderna press release.

In March, Pfizer CEO Dr. Albert Bourla presented a five-point plan for companies to “work as a team in the industry”.

“Our industry peers, other pharmaceutical and biotechnology companies, and health officials have come together like never before. We are fully 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 hit at Inovio, an American vaccine maker in clinical trials, saying “they can’t scale to enter phase three,” the clinical trials.

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Inovio’s technology uses a short electrical pulse to deliver plasmids, or small genetic information, into human cells. Inovio says that these cells then produce the vaccine, which triggers an immune response.

Jeff Richardson, a spokesperson for the company, said, “Our competition is the virus, not other companies. There must be three or four winners to vaccinate the world. Most likely, there will be a number of vaccines that will, and that is 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 succeed, there must be sufficiently high levels of virus circulating in the community. If there are not enough viruses around, it will be impossible to say whether the vaccine protected the study subjects or whether they were simply never exposed to the virus.

“There is no longer a Covid in China. They can’t finish, ”said Hill.

There is still a bit of Covid in China, with a few dozen cases, according to the latest briefings from the country’s National Health Commission. While this is probably not enough for a large clinical trial, the researchers could conduct trials in other countries where the vaccine is circulating even more widely.

Oxford is not in slam dunk territory

Oxford scientists have sometimes tempered their positive statements with more cautious ones.

BBC Andrew Marr said on April 19 that he asked Gilbert “if there is a guarantee that a workable vaccine can actually be produced.”

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“No one can be absolutely sure that this is possible. That’s why we have to try it out. We have to find out. I think the outlook is very good, but it is clearly not completely certain, “said Gilbert.

But the U.S. and UK media have focused more on positive statements, often writing glowing reports on the progress of the vaccine.

A few weeks ago, a headline in an American newspaper article proclaimed that the “Oxford group is leaping forward” even though it is not clear that there is only one favorite among vaccines.

A British newspaper said that ” [Oxford’s] confidence is built on past successes “- although Oxford has never had a vaccine on the market. Omer tweeted a link to the article with words of caution.

“You have to be careful when talking about the progress of the # COVID19 vaccine. As a vaccine researcher, I am cautiously optimistic; but we must be careful to project too much confidence. We are not in slam dunk territory, ”he wrote.

The Oxford monkeys, in particular, caught the eye.

On May 13, scientists from Oxford, in collaboration with researchers from the National Institutes of Health, published a study on bioRxiv.org on nine monkeys who were intentionally exposed to the new coronavirus. Six of them were vaccinated and three were not.

BioRxiv.org is a pre-print server, which means that articles have not been reviewed by other scientists and have not been published in the medical literature.

After the monkeys were vaccinated and exposed to the virus, they were euthanized and examined for lung damage. According to the Oxford study, none of the vaccinated animals showed signs of pneumonia or other lung problems, but two out of three unvaccinated monkeys developed some degree of viral pneumonia.

“It certainly worked in monkeys,” Oxford’s Hill told Burnett on May 15. “It was a pretty impressive impact and it was our first try, if you will, with a standard dose, a single dose of vaccine. “

“We were very excited to see it on the first try,” he added.

But William Haseltine, virologist and former professor at Harvard Medical School, said Hill was “misleading.”

“In this interview, Hill is like a magician who distracts the audience with a shiny object to distract you from having his accomplice take your pocket,” Haseltine told CNN in an email.

In an article published by Forbes on May 16, Haseltine said that the fact that the monkeys did not develop pneumonia was irrelevant, since all the vaccinated monkeys were infected with Covid-19.

In addition, he said the monkeys had just as much viral RNA in their nasal secretions as the unvaccinated monkeys, an indication to him that the vaccine did not work and that the monkeys could potentially spread the virus to others.

Third, Haseltine highlighted neutralizing antibodies. A vaccine must cause high levels of antibodies capable of deactivating the virus and preventing it from infecting human cells. Haseltine said the level of these antibodies in monkeys who received the Oxford vaccine was “extremely low”.

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Haseltine told CNN that the Oxford vaccine monkey study was “an outright failure.”

Oxford scientists quickly wrote a statement refuting Haseltine’s article. They had received the new coronavirus directly in their nose – called an intranasal challenge – and therefore the presence of virus in the nasal swabs “may reflect the use of a very high intranasal challenge dose higher than that transmitted in natural infections” , according to the declaration.

They also wrote that there were neutralizing antibodies present in all vaccinated monkeys, but not in unvaccinated monkeys.

“Haseltine’s comment seems to misunderstand the impressive effectiveness of [Oxford] vaccine in the non-human primate model, “the statement said.

Offit, the co-inventor of the rotavirus vaccine, said he did not think the vaccinated monkeys were infected. Sometimes people still get the flu when they get a flu shot, but they often have only mild symptoms. Children can still get rotavirus after getting their vaccine, but again, usually a milder, less life-threatening version.

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 because the vaccines that show signs of success in animals sometimes fail in humans.

“As vaccine researchers like to say, mice lie and monkeys exaggerate,” said Offit.

Offit and others say they sometimes cringe when they hear Oxford scientists talk about their vaccine.

Bioethicist Alta Charo said scientists can sometimes become “too optimistic” about their work, especially as they race to end the pandemic.

“It is very easy to get caught up in the potential of a new medical product when early development and testing looks promising. It’s very easy to believe in your own work, “said Charo, professor at the University of Wisconsin Law. School.

Art Caplan, bioethicist at NYU Langone Health and medical analyst at CNN, said it was especially important to be cautious about vaccines because so many people have lost confidence in vaccines and are reluctant to vaccinate their children, or flatly refuse to do so.

“The world is watching and if you inflate something uncertain, it’s really disturbing,” he said.

On Saturday, after months of optimistic forecasts, Hill considerably deflated his success forecasts and softened his competitive tone.

He told the Telegraph that the Oxford trial is about 50% likely to get “no results” because the spread of the new coronavirus appears to be slowing in Britain, where the trial is taking place.

In this interview, Hill cautioned against “excessive promises” and said that developing a vaccine is “not a race against other guys. It is a race against the disappearance of the virus and against time. “

Offit said it was much more realistic.

“This tells you that he is starting to back off from his original statements because he has noticed the impracticality of his original statements,” he said.

Offered a few tips for Covid vaccine developers: shut up.

“Now the researchers can’t wait to go out to the microphone – and there are so many microphones out there – to say,” I’ve got it! It looks really good! “Offit said.

When he and his team were developing the RotaTeq vaccine, he said that they did not speak to the media before receiving final approval from the United States Food and Drug Administration in 2006.

Today, this vaccine saves hundreds of lives a day around the world, said Offit, mostly children under the age of 2.

“When we found out that our rotavirus vaccine was safe for mice, we said nothing. When we finished our phase one clinical trials, we said nothing. We have just moved forward, ”he said.

CNN’s Wes Bruer, Arman Azad and Devon Sayers contributed to this report.



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