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“The race is on”: CureVac is looking for answers to the disappointment of vaccines

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When the coronavirus pandemic hit, CureVac was to be the first to bring a revolutionary vaccine technology to market. Instead, German biotechnology was left in the dust.

Now industry leaders, investors and observers are struggling to understand what went wrong – and whether the company should change its approach to messenger ribonucleic acid technology was so critical to advancing.

CureVac problems began shortly after the coronavirus began to spread. Earlier, a cerebral hemorrhage forced founder Ingmar Hoerr – whose 2000 doctoral dissertation informed the development of all mRNA strokes – to step down in March 2020, just five days after he died. he was removed from the supervisory board to be chief executive.

Then development contrasts brought delays, putting the company months behind its rivals. The US-based Moderna and its German partner BioNTech, following a link with Pfizer, have snatched the glory of providing the first mRNA jabs in December 2020.

CureVac’s ambitions to recover were finally shattered last month when its phase 3 test results revealed an overall effectiveness of 48 percent, below the cut-off required for emergency regulatory approval. The company’s stock price has halved.

Based on the high-impact protection against hospitalization and death, CureVac still hopes to win a modified form of approval from the European Medicines Agency for the prevention of serious illness.

“It’s shown that mRNA can really change here, especially if you compare it to other vaccine platforms, because it’s so fast and versatile,” Franz-Werner Haas, executive director, said in an interview at CureVac headquarters. He and his fellow executives have reviewed “lessons learned,” Haas said.

Guilt and variations

The company claims that the main reason for the disappointing results of the trial was the arrival of new and more infectious variants – more than 15 strains – that its vaccine will have in 2021 due to the delayed phase 3 trial. In contrast, rivals Modern and BioNTech have dealt extensively with the original strain of coronavirus when they tested their vaccines in 2020. Both have recorded efficacy figures of more than 90 percent.

“Everyone naturally sees 48 percent versus 91 percent first. But half a year and dozens of variants later, that’s just part of the truth,” said CureVac investor and board member Friedrich. von Bohlen und Halbach. “I’m not saying I know the rest of the truth.” All I’m saying is that there’s a lot more that needs to be understood. ”

Some experts suspect that the real problem dates back to the company’s founding in 2000, when CureVac decided to work with unmodified mRNAs.

All mRNA vaccines work by putting the genetic code of the virus’s spike protein into a fat bubble called a lipid nanoparticle. Once injected, the body’s cells translate the genetic code into the protein, teaching the immune system to recognize it.

Rein Verbeke, a researcher specializing in mRNA at the University of Ghent, said that BioNTech and Modern have both modified one of the blocks of mRNA called uridine. They do this for two reasons: to allow it to produce more protein and to ensure that the immune system does not overreact, causing negative side effects.

Franz-Werner Haas, CEO of CureVac © Thomas Kienzle / AFP via Getty

CureVac has chosen not to change the urine, perhaps because it will not have to buy the patent for the modification, Verbeke said.

In response, CureVac said that efficacy in an early rabies trial suggested that the same unmodified approach might work for Sars-Cov-2. While he did not modify his mRNA, he said he made other modifications using a proprietary technique developed by his scientists.

Drew Weismann, who developed the patented mRNA modification alongside his former colleague Katalin Kariko, now at BioNTech, said the unmodified mRNA had previously shown robust responses from T cells – an important part of the immune system. which is more difficult to measure than antibodies.

“I think the hope was that unmodified RNA could have better T cell responses and give better protection. But the phase 3 data doesn’t show that,” said Weismann, a professor of vaccine research at the University. of Pennsylvania.

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Graph the Efficacy bar against any disease severity, in participants aged 18 to 60 years (%) showing the effectiveness of the first-generation CureVac vaccine against various virus variants

A next generation solution

CureVac has another chance to return to the race. It is developing a second-generation vaccine in collaboration with GlaxoSmithKline, which appears to use 10 times more antibodies than its first.

Although the mRNAs have not yet been modified, CureVac scientists have added sequences this time to the head and tail of the mRNA strand that increase the amount of protein it produces, without increasing the dose and potentially encountering problems with side effects.

Haas said such changes were part of the development process. “It’s enough to remember what the first mobile phones looked like.” Now you have a computer in your pocket, ”he said.“ That’s exactly what will happen with mRNA technology. It’s not a done deal. ”

However, continuing to use unmodified mRNA also means that CureVac should give a lower dose to avoid adverse effects. Each Modern pill contains 100mcg of vaccine, BioNTech uses 30mcg, while CureVac uses only 12mcg.

Philip Santangelo, a professor at Georgia Tech who focuses on RNA viruses, said 12mcg was only slightly above the 5 or 10mcg dose that could be used in a mouse experiment. “I’m worried it’s going to be insufficient [for humans]”, He said. CureVac said making comparisons between dosages in different mRNA vaccines was not helpful.

A volunteer is given the CureVac coronavirus vaccine during its first trials © Luis Tejido / EPA-EFE

CureVac may also have gone wrong just at the start of the pandemic, while competitors have made initial partnerships or secured vital public funding, said von Bohlen, the investor and board member. “We have learned that if you are behind in funding, you are behind in product development. But we can’t turn that clock back. “

CureVac’s collaboration with GSK began only last July, after the British multinational bought a 9% stake. In contrast, BioNTech established a partnership with Pfizer in March 2020. The two companies are already working together on flu vaccines, making the transition to a coronavirus collaboration relatively easy.

Modern has no partners but has benefited from more than $ 1bn in U.S. government funding to develop its vaccine. In comparison, Germany fell short of CureVac’s initial public offering last August with an investment of 252 million euros, but in two tranches in two years.

A GSK production line that packs vaccines in Belgium © Kenzo Tribouillard / AFP via Getty

Verbeke, at the University of Ghent, believes CureVac will learn from its disappointing results from the first round. If the second-generation coup were to succeed, it could also become the most expensive and attractive option for developing countries, since it should not be frozen, he said.

Haas also did not rule out the possibility of cancer change and developing a vaccine candidate with modified mRNA. “There are no restrictions, no blinds,” he said. “Don’t rule this out in principle.”

Other projects include a “vaccine stamp,” developed in collaboration with Elon Musk’s Tesla, which sits at the bottom of a truck and could produce and distribute CureVac treatments anywhere in the world.

And even if their Covid vaccine continues to struggle, the original CureVac approach could work for other treatments. “There may be indications or disorders where unmodified might work or even do a better job,” said Ingrid Gafanhao, an analyst at the Kempen Life Sciences research group. “I don’t think we know enough to judge the whole platform just yet.” T cell responses, for example, are critical in oncology.

“It seems like at the moment we are number three,” von Bohlen acknowledged. “But Corsica is Corsican.” This is a race that has just begun, and we must all accept that the pace remains high. “


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