In quest for vaccine, US makes ‘big bet’ on company with unproven technology
One by one, vaccine developers at a White House roundtable convened by President Donald Trump in early March presented their product as a viable solution to the coronavirus that was spreading worldwide and killing Americans.
John Shiver, the director of R&D for Sanofi Pasteur vaccines, said he could have a product ready for the clinic in a year – maybe a vaccine for the public in “just a few years”.
Trump did not seem interested.
Next, Lenny Schleifer, founder and CEO of Regeneron – which aims to conduct clinical trials this summer – spoke of pumping 200,000 doses per month of its therapeutic vaccine from its factory, starting in August, “hopefully “.
This caught Trump’s attention. He leaned over the table and interrupted Schleifer in the middle of the field.
“So this process would be faster than John’s?” he said pointing to Shiver.
“It would,” said Schleifer, adding that the process could take “weeks to months”.
The only way to top it off was to start talking about the days, and that’s exactly what the next CEO did.
Stéphane Bancel of Moderna Inc. glanced across the table to the country’s leading infectious disease specialist, Dr. Anthony Fauci, and said he was “very proud to work with the US government and to have already sent, in just 42 days after the virus sequence, our vaccine to Dr. Fauci’s team at the NIH. “
Frenchman Bancel went on to say that he only needed “a few months” to start phase two of a three-part clinical trial of the type that characterizes the development of a vaccine. (The whole process often takes more than a decade.)
Trump seemed to ignore everything except the talk about time.
“So you’re talking over the next few months, do you think you might get a vaccine?” He asked.
“Right. Right,” said Bancel, raising a hand to recognize Fauci moving in his chair across the table. “With phase two,” said Bancel, just before Fauci intervened, for Trump’s benefit: “You won’t have a vaccine. You will have a vaccine to test.”
For some observers, it was a classic performance by Bancel – a rare public glimpse of his strange ability to say the right thing to the right people at the right time.
His supporters say, however, that he did what he always did: let Moderna’s achievements speak for themselves.
Either way, it turns out that Moderna had an advantage. Its scientists had previously collaborated with researchers from the National Institutes of Health on a vaccine against another coronavirus, Middle East respiratory syndrome (MERS). So when Chinese researchers released the genomic sequence for the new coronavirus – SARS-CoV-2, which causes the deadly disease known as Covid-19 – in mid-January, they got off to a quick start.
Created in 2010, Moderna has never put a product on the market, nor obtained one of its nine candidate vaccines to be approved by the FDA. He also never brought a product to the third and final phase of a clinical trial.
And yet, for the moment, it represents one of the best hopes in the country – and perhaps in the world – for a return to normalcy which vanished when the microscopic enemy put civilization in neutral.
Significant funds injected into the vaccine race
The effort was given new impetus on April 16 when the Federal Biomedical Advanced Research and Development Authority (BARDA) awarded Moderna up to $ 483 million to accelerate the development and manufacture of the vaccine. That is about half of what the federal agency distributed, Janssen Research & Development – part of Johnson & Johnson – receiving $ 456 million, and a third company, Sanofi, receiving up to $ 30 million.
In fact, although Moderna is not a household name, it is a company with a rich history.
CNN Investigates interviewed more than 20 experts and former employees for this story and found that while some scientists have expressed optimism that Moderna may withdraw it, others have expressed criticism of the hype that the company has generated over for years, as well as what has been described as a caustic work culture.
Others have expressed concerns about the science or disputed the wisdom of the federal government’s approved shortcuts in the current clinical trial, in particular the FDA’s approval to bypass normal animal trials that precede injecting untested vaccine into healthy humans.
Dr. Joseph Bolen, who was Chief Scientific Director of Moderna and President of Research and Development from 2013 to 2015, believes it was reasonable to give Moderna a shot, but was intrigued by the allocation BARDA’s massive – up to $ 483 million – calling it a “big bet”.
“I don’t know what they were thinking,” he said. “Why so much? … I just don’t know. When I read this, I was quite surprised.”
Dr. Tal Zaks, medical director of Moderna, admitted that the company had no product on the market, but said the government’s decision was wise.
“We are a young company with emerging technology and for this reason we have yet to contribute anything to obtain a full license,” he told CNN. “But if you look at the building blocks of what we have been able to demonstrate over time – from preclinical data to early clinical data – this is very promising technology.”
Moderna leads the pack
Moderna, Inc. – originally called Moderna Therapeutics – was founded on a big idea that was going to disrupt the pharmaceutical industry.
His vision is to exploit a new technology that synthesizes messenger RNA, or mRNA – essentially an instruction manual in each living cell to create proteins – to induce the human body to make its own medicine. The hope has been to find “transformative” treatments for heart disease, metabolic and genetic diseases, kidney failure, and even cancer.
BARDA said it plans to fund a variety of approaches.
“More than one vaccine is likely to be the solution,” said a BARDA spokesperson in an email. “It should be noted that Moderna was the first to enter the clinic with a vaccine.”
Over the years, Moderna has sold the revolutionary potential of its medicine to investors. Bancel was the chief narrator of the intoxicating history of the company.
Ambition, secrecy and money earned Moderna critics
But Moderna’s unbridled ambition, reputation for secrecy and concern for venture capital have earned her detractors.
“Agreements don’t validate science,” said the editor. “Biotechnology is littered with examples of deep-sea acquisitions or licenses canceled or later abandoned.”
“They were a little tight on their data,” said a former BARDA official who now works as a biotechnology expert at Biologics Consulting and has worked with Moderna. “And I interpret that to mean that the results so far have been disappointing.”
In a rare interview, Noubar Afeyan, one of Moderna’s four co-founders and current chairman of the board, told CNN that the company’s reputation for secrecy was poorly understood.
“They confuse secrecy and ambiguity,” he said of the critics, noting that the company hadn’t published at first because it had nothing to publish – it was in the experimental phase.
But Matthias John, a molecular biologist who was group leader and principal investigator at Moderna for almost four years ending in 2016, remembers being told not to publish even if he had good data.
“They were really afraid of disclosing the results,” he said, adding that the company was concerned that competitors would catch up with their innovations. “It was just a shame. … We had fantastic data at the time.”
Critics call for more skepticism
A former employee, who worked in the company for three years ending in 2019 – most recently as a manager – called the comparison “absurd”.
“I think Moderna has a strong culture of compliance,” said the former director, who spoke on condition of anonymity, saying that the biotech industry is a small world and that he did not feel at home. comfortable making a public statement. “They are very motivated. They have a strong vision, they work very hard.”
But a former business executive had a more mixed opinion on the matter. On the one hand, he said, science is on a “good foundation”.
“They really push the boundaries of understanding NRA,” said the former executive, who requested anonymity because he is still working in the field.
In his view, however, Moderna is a company that “believes in its own history, spins its own history and has managed to convince many investors – biotechnology investors and other non-biotechnology investors – that it is true”, a- he says. said. “I think (people) should approach it with a little more skepticism.”
Moderna’s turbulent start
In the early years, Moderna was a chaotic place. In the space of a decade, the size of its workforce has grown from four to over 700.
But there have been growing pains, some of which centered on Bancel, the only CEO the company has ever had.
Afeyan, a venture capitalist with a doctorate in biochemical engineering from MIT, had tried to recruit Bancel to lead other projects, but Bancel – former CEO of a French diagnostic company – had rejected him.
When Afeyan asked him to join Moderna, the idea was too big for Bancel to resist. The holder of a Master of Science in chemical engineering from the University of Minnesota and an MBA from Harvard Business School joined in 2011.
The former executive, who left in 2016, recalled that Bancel seemed to have two versions of himself: the calm public figure who gives speeches and appears on TED Talks, and the private version during company meetings.
“What you hear in corporate meetings is stuff like this,” What are you doing? This is complete bullshit … You just said six to nine months; I need five. “”
Dr. Suhaib Siddiqi, a chemist who served for a short time as a former director of chemistry at Moderna in 2011, said that Bancel was “hostile” and “arrogant” and punished the technicians for the failed experiments.
“Ninety percent of things in science fail – this is how inventions are made,” said Siddiqi. “When that failed (at Moderna), he simply blamed the technicians and fired them.”
Bancel disputes the characterization.
“The science is complicated and many things fail,” said Bancel, who declined an interview with CNN, in a statement. “I don’t remember that an employee has been laid off since we started the company, due to a scientific failure. If this had been the case, most scientists would have left the company and the company couldn’t have gotten to where it is. “
He added: “We are creating a new class of mRNA-transforming drugs to improve the lives of patients. When it is possible to help patients, every day counts. So there is an urgency to what we do because patients are waiting for. We are privileged to be part of a vast ecosystem of academics and industry researchers who are expanding understanding of mRNA. “
Some former employees have defended Bancel.
“As a person I love him,” said Matthias John, the molecular biologist who left in 2016. “He is a bit fanatic. But he is not in my opinion a cheater or a contender. is his personality – that he pushes hard and he expected everyone to do the same. “
The former director who left in 2019 said that Bancel had set up a management team with experience in biopharmaceutical development that “tempered the intensity”.
Rossi said he had hit his head with Bancel and that the company and its investors had a way to take credit for the ideas of its scientists, including his own – an allegation that Moderna’s leadership denies.
But Rossi, who later became an associate professor at Harvard Medical School and is now CEO of another biotechnology company called Convelo Therapeutics, said he believed in technology. He continues to have a financial stake in the business.
“I am very optimistic,” he said. “It continues to follow the exact concept on which it was founded.”
Rossi, who said he heard Moderna’s culture has softened, added that at one level, the fierce nature of the place made sense.
“I founded the company because I wanted to make an impact on human health,” he said. “The CEO’s job is to make money for investors.”
Afeyan, the chairman of the board of Moderna, fiercely defends Bancel. He told CNN that Bancel’s characteristics as a gifted fundraiser are out of place and even “derogatory”, saying it is a way for critics to smear him with low praise.
“He is a qualified team builder, he is a qualified product developer, he is a qualified strategist, he is a qualified partnership forger … he is all of that,” said Afeyan. “To fuel it all, he must have found the money and we have done it, in an unprecedented way in the biotechnology industry. Also by ten. That’s why he has detractors.”
The big businesses that shaped Moderna
Afeyan said it is true that Alexion’s experiments showed animal toxicity, but added that Moderna has since changed its formulations and, in human trials, “we have seen nothing like it.”
Moderna has gradually started to focus more on vaccines. Experts and former employees say progress in therapy has been much slower and more difficult to determine where it could be used as promised in humans. Messenger RNA activates the body’s instincts to get rid of the foreign invader, which works best for single-dose vaccines, but creates safety concerns for longer-term use in chronic diseases.
Jeff Ellsworth, who was the former senior director of preclinical pharmacology at Moderna and the head of rare genetic diseases until he left in 2013, remembers standing around a whiteboard in his office with two leaders from the company, discussing data used in animal studies for drugs meant to treat rare genetic diseases.
“We all looked at each other and said,” Oh. We should probably be a vaccine company, “because these things stimulate antibody responses,” he said.
Rossi said, “This is the perfect technology for the threat we face.”
“Most members of the biotechnology community did not value vaccines,” said Ellsworth. “It was very difficult to move these things forward. Because people said,” Oh, the vaccines, no one will pay for it – it doesn’t matter. “”
“In our lifetime?” Asked Cramer.
“This is happening now,” replied Bancel. “We compare each letter of DNA … from a cancer cell to a healthy cell, and we deduce what we need to do in our product, just for your cancer.”
“It’s almost science fiction, what you do,” replied Cramer. “I think it’s amazing.”
Moderna’s valuation has climbed to $ 7.5 billion, up from $ 5 billion already impressive a year and a half ago.
Then came the new coronaviruses and Covid-19, which have killed nearly 63,000 Americans since February and 233,000 people worldwide.
For the world, it was a disaster. For Moderna, it happened just in time.
As the economy collapsed, Moderna’s shares surged in February when news of its vaccine appeared. They jumped again – by more than 24%, to $ 26.49 – on March 16, the day the clinical trial of his vaccine hit the headlines. The share price continued to rise and soared on April 17 – with news of the federal government investing nearly half a billion dollars – beyond $ 45. Its valuation has reached $ 10 billion.
The vaccine pipeline is a funnel: “very little survives”
To try to put a vaccine on the market is to try to beat the odds.
Dr. Myron Levine, professor and expert in infectious diseases at the University of Maryland School of Medicine, has warned that most vaccines fail.
“I have been working in this field for a very long time – half a century,” he said. “A vaccine pipeline is funnel-shaped. A lot goes to one end; very little survives.”
However, Levine thinks that Moderna could make a breakthrough.
“There is a good chance this is the time for the RNA vaccine – they have been improved and modified,” he said. “I hope and pray that they will work.”
Moderna did not invent the mRNA approach, but it was the company that “cornered the market” for the idea, said the former executive who left in 2016.
“Henry Ford was not the first automaker, but he managed to evolve more efficiently,” he said.
The science of messenger RNA is complex, but the potential benefits often anticipated are easy to understand: safety and speed.
Conventional vaccines involve injecting a small piece of a weakened or dead virus into the body to stimulate an immune response in cells.
Le sosie coronavirus spike-protéine serait alors produit par les propres cellules du corps. Si tout se passe bien, le corps contre-attaque alors “l’envahisseur” – l’antigène synthétique créé par la propre cellule d’une personne – avec des anticorps.
La technologie “enseigne au corps humain à reconnaître le virus en lui apprenant à faire lui-même des extraits du virus”, a déclaré Zaks, médecin-chef de Moderna.
Le 11 janvier, des chercheurs chinois ont publié la séquence génétique de SARS-CoV-2, une chaîne de 30 000 caractères des lettres a, u, g et c.
En grande partie à cause de la coopération continue entre Moderna et NIH, le processus de conception de l’ARNm pour la livraison a été rapide comme l’éclair. En effet, cela n’a pris que 42 jours, comme Bancel l’a dit à Trump.
Les responsables des National Institutes of Health sont optimistes.
“Une grande partie de notre travail que nous avons effectué précédemment nous a essentiellement poussés vers ce que nous appelons une réponse rapide”, a déclaré le Dr Kizzmekia Corbett, scientifique principal pour la recherche sur les coronavirus aux National Institutes of Health, dans une récente interview avec CNN. Anderson Cooper et Dr Sanjay Gupta. “La partie vraiment intéressante à ce sujet est que nous avons une collaboration avec Moderna”, a-t-elle ajouté.
Un porte-parole de l’Institut national des allergies et des maladies infectieuses – une branche du NIH – a déclaré que la plate-forme de vaccins de Moderna est bien adaptée pour répondre aux épidémies émergentes telles que les nouveaux coronavirus.
Il “peut être produit plus rapidement qu’avec de nombreuses autres plates-formes vaccinales”, a déclaré Judith Lavelle. “Une fois que l’information génétique d’un virus émergent donné est disponible, les scientifiques peuvent rapidement sélectionner une séquence pour exprimer un immunogène dans la plate-forme d’ARNm existante.”
La science a ses sceptiques
Mais certains experts sont sceptiques quant à la science.
Pour commencer, pressée de commencer, la FDA a permis au vaccin à ARN de Moderna – appelé ARNm-1273 – de masquer essentiellement les tests sur les animaux qui précèdent généralement les essais cliniques chez l’homme. Étant donné la nature de cette urgence, elles se produisent en parallèle.
Siddiqi a déclaré que cela était alarmant.
“Je ne laisserais pas ça [vaccine] à injecter dans mon corps “, at-il dit.” Je demanderais: Où sont les données de toxicité du laboratoire? ”
Le professeur Nikolai Petrovsky de l’Université Flinders en Australie, qui collabore avec Oracle pour utiliser des modèles informatiques et la technologie de l’IA pour développer un vaccin Covid-19, s’inquiète des essais d’ARNm, insistant sur le fait que le gouvernement américain a pris un vaccin non prouvé et “mis (il ) directement chez l’homme. “
“C’est un double match”, a-t-il déclaré. “Une plate-forme non éprouvée pour une nouvelle maladie sans tests sur les animaux.”
Mais alors que ces experts estimaient que doser les humains avant que les essais sur les animaux puissent avoir lieu était discutable dans la pratique, Zaks of Moderna a déclaré qu’il serait “contraire à l’éthique d’attendre”, étant donné l’urgence de la pandémie.
La FDA, dans un communiqué à CNN, a déclaré qu’elle “n’était pas en mesure de commenter des produits spécifiques non approuvés”. Cependant, il a déclaré que lorsque l’agence évalue la nécessité d’une étude vaccinale, elle tient compte des données pertinentes. “Si l’évaluation par la FDA de ces données permet de lancer des études humaines sur un vaccin candidat contre le coronavirus sans avoir terminé au préalable des études toxicologiques supplémentaires, alors la FDA envisagerait d’autoriser de telles études humaines.”
Petrovsky a également noté que, alors que le NIH et Moderna travaillaient sur un vaccin MERS, ils n’avaient pas collaboré sur un vaccin contre le SRAS (syndrome respiratoire aigu sévère). Le MERS est “un virus très différent du SRAS et de Covid-19”, a-t-il déclaré. “Les liaisons MERS sont différents récepteurs, différents types de maladies. … Je serais beaucoup plus à l’aise avec les données sur le SRAS.”
Petrovsky a déclaré que, bien que les vaccins à ARN soient très rapides à fabriquer, les preuves qu’ils vont fonctionner sont rares.
“Dans le passé, nous avons vu qu’ils ont une faible immunogénicité, ce qui signifie qu’ils ne stimulent pas très bien le système immunitaire”, a-t-il déclaré.
Zaks a déclaré: “Nous avons démontré l’utilité de générer le bon type de réponse immunitaire à maintes reprises dans plusieurs essais de phase un.”
Le défi d’un phénomène dangereux
Un obstacle fréquent pour les développeurs de vaccins est un phénomène appelé amélioration de la maladie, dans lequel le vaccin favorise réellement l’infection et aggrave la maladie.
“La pire chose que vous puissiez faire est de vacciner quelqu’un pour prévenir l’infection et l’aggraver”, a déclaré Fauci lors d’un briefing à la Maison Blanche le mois dernier.
Ce phénomène souligne l’importance des essais sur les animaux, selon les experts.
Le Dr Peter Hotez, doyen de l’École nationale de médecine tropicale du Baylor College of Medicine, a travaillé à la mise au point d’un vaccin contre le SRAS. Certains des animaux qu’il a vaccinés se sont avérés plus malades que ceux qu’il n’a pas vaccinés, une fois qu’ils ont été exposés au virus.
“S’il y a une amélioration immunitaire chez les animaux de laboratoire vaccinés avec le vaccin Moderna, c’est un produit phare”, a-t-il déclaré à l’agence de presse.
A Moderna spokesperson said the company has not seen signs of enhanced disease in animal trials with the MERS vaccine that it was developing with NIH.
“Enhanced disease is a clinical finding that is very rarely seen,” she said in an email.
Potential setbacks fall into two broad categories: the vaccine isn’t strong enough to produce an immune response or the vaccine causes safety issues.
Anderson added that there is a “theoretical possibility” that the vaccine could trigger an “enhanced immune response” that actually worsens the illness.
Adjuvants stimulate the body’s immune system to react to the vaccine antigen — the molecules that trigger an immune response in the body. In other words, they boost the body’s immune response.
“Typically, what you see in any vaccine if they use adjuvants, they clearly identify that and say this is the purpose of using in the vaccine formulation as an adjuvant,” said Schrum, who is no longer with the company. “In that one [Moderna], I just don’t see that.”
Moderna confirmed that it is not using an adjuvant.
“We have not used adjuvants in our vaccine clinical trials,” the spokesperson wrote in an email, adding that the trials have shown that Moderna’s vaccines induce an immune response similar to that seen with natural infection.
The former BARDA official told CNN that Moderna generates a lot of “hype” for an organization that has never entered the third and final phase of a clinical trial for a drug or vaccine.
“I don’t think it’s misplaced to — I want to say question — but have some healthy skepticism about the current efficacy of their technology,” the expert said.
Ian Haydon of Seattle is one of the trial participants who volunteered to take a shot in the arm in April. He said that so far — after a couple of weeks — aside from a sore arm for a day or two after the injection, he has experienced no symptoms.
“I’m eating normally, I’m sleeping normally, I feel fine,” said Haydon, a 29-year-old science writer and a biotech consultant.
Far from assuming he’s immune, Haydon said he’s being more careful than ever.
“Now that I am a subject of study, now would kind of be the worst time for me to get sick with the coronavirus,” he said. “I’m keeping locked up at my house, only going out to get groceries, hand-washing, wearing a mask, just like everybody should be.”
Petrovsky said the United States is unique in how it has poured so much money into “one experimental technology.”
“The danger here is … if the US just backs one or two horses and they fall to the back of the pack, we’re not going to have an effective vaccine in the US anytime soon.”
But Zaks says Moderna has delivered on its promises to US officials about its coronavirus vaccine, saying, “When our CEO said that we would get this fast into the clinic, we did.”
That, he said, combined with the company’s potential, is why “the US government stepped in and picked our platform as one of the major investments that Tony Fauci and the team are making in. And I think if you stay in tuned, you should expect to see us be able to deliver on that.”
CNN’s Scott Bronstein and Drew Griffin contributed to this report.