When the coronavirus pandemic struck, CureVac was supposed to be the first to bring a revolutionary vaccine technology to market. Instead, the German biotech was left in the dust.
Now executives, investors and industry watchers are struggling to understand what went wrong — and whether the company must change its approach to the messenger ribonucleic acid technology it was so critical to advancing.
CureVac’s troubles started not long after coronavirus began to spread. First, a brain haemorrhage forced founder Ingmar Hoerr — whose 2000 doctoral thesis has informed the development of all mRNA shots — to step aside in March 2020, just five days after he had moved from the supervisory board to be chief executive.
Then development setbacks led to delays, putting the company months behind its rivals. US-based Moderna and fellow German start-up BioNTech, following a tie-up with Pfizer, snatched the glory of delivering the first mRNA jabs in December 2020.
CureVac’s ambitions to catch up were finally dashed last month when its phase 3 trial results revealed an overall efficacy of 48 per cent, below the cut-off required for emergency regulatory approval. The company’s share price halved.
Based on the shot’s high protection against hospitalisation and death, CureVac still hopes to win a modified form of approval from the European Medicines Agency for the prevention of severe disease.
“It’s proven that mRNA really can make a difference here, especially if you compare it to other vaccine platforms, because it’s so fast and versatile,” said chief executive Franz Warner Haas in an interview at the CureVac headquarters. He and his fellow executives were reviewing “lessons learned”, Haas said.
Blame the variants
The company argues the main reason for the disappointing trial results was the arrival of new and more infectious variants — more than 15 strains — that its vaccine faced in 2021 due to the delayed phase 3 trial. In contrast, rivals Moderna and BioNTech dealt largely with the original coronavirus strain when testing their vaccines in 2020. Both recorded efficacy figures of over 90 per cent.
“Everyone of course first sees the 48 per cent versus the 91 per cent. But half a year and dozens of variants later, that is only part of the truth,” said investor and CureVac board member Friedrich von Bohlen und Halbach. “I won’t say I know the rest of the truth. All I’m saying is there’s much more that needs to be understood.”
Some experts suspect the real problem dates back to the company’s founding in 2000, when CureVac decided to work with unmodified mRNA.
All of the mRNA vaccines work by putting the genetic code of the virus’s spike protein in 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 recognise it.
Rein Verbeke, a researcher specialising in mRNA at Ghent University, said BioNTech and Moderna both modified one of the building blocks of mRNA called uridine. They did this for two reasons: to enable it to produce more of the protein and to ensure the immune system did not overreact, causing negative side effects.
CureVac chose not to tweak the uridine, possibly so it would not have to buy the patent for the modification, Verbeke said.
In response, CureVac said efficacy in an early rabies trial suggested the same unmodified approach could work for Sars-Cov-2. While it did not modify its mRNA, it said it did make other tweaks using a proprietary technique developed by its scientists.
Drew Weismann, who developed the patented mRNA modification alongside his former colleague Katalin Kariko, now at BioNTech, said unmodified mRNA had previously shown robust responses from T-cells — an important part of the immune system that is harder to measure than antibodies.
“I guess the hope was that the unmodified RNA might have better T-cellular 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.
The next-generation solution
CureVac has another chance to get back in the race. It is developing a second-generation vaccine in collaboration with GlaxoSmithKline, which appears to elicit 10 times more antibodies than its first.
Although they are still not modifying the mRNA, CureVac scientists have this time attached sequences at the head and tail of the mRNA strand that boost the amount of protein it produces, without increasing the dose and potentially running into problems with side effects.
Haas said such tweaking was all part of the development process. “Just remember how the first mobile phones looked. Now you have a computer in your pocket,” he said. “This is exactly what will happen with the mRNA technology. It’s not a done deal.”
However, continuing to use unmodified mRNA also means CureVac has to give a lower dose to avoid adverse effects. Each Moderna shot contains 100mcg of vaccine, BioNTech uses 30mcg, while CureVac uses just 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 might be used in a mouse experiment. “It worries me that it would be insufficient [for humans],” he said. CureVac said making comparisons between dosing in different mRNA vaccines was not useful.
CureVac may also have erred in going it alone at the start of the pandemic, while competitors struck early partnerships or secured vital public funding, said von Bohlen, the investor and board member. “We have learned that if you are late in financing, you are late in product development. But we cannot turn that clock back.”
CureVac’s partnership with GSK only began last July, after the British multinational bought a 9 per cent stake. BioNTech, in contrast, established a partnership with Pfizer in March 2020. The two companies were already working together on influenza vaccines, making the shift into a coronavirus collaboration comparatively easy.
Moderna has no partner but benefited from more than $1bn in US government funding to develop its vaccine. In comparison, Germany swooped in before CureVac’s initial public offering last August with a €252m investment, but in two tranches over two years.
Verbeke, at Ghent University, believes CureVac will learn from its disappointing results from round one. If the second-generation shot were to succeed, it could still become the more cost-effective and attractive option for developing countries, given it does not need to be frozen, he said.
Haas has also not ruled out the possibility of changing tack and developing a vaccine candidate using modified mRNA. “There is no constraint, no blinders,” he said. “You don’t exclude this one by principle.”
Other projects include a “vaccine printer”, developed in partnership with Elon Musk’s Tesla, that fits in the back of a truck and could produce and distribute CureVac treatments anywhere in the world.
And even if its Covid vaccine continues to struggle, CureVac’s original approach could work for other treatments. “It can be that there are 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 entire platform just yet.” T-cell responses, for example, are critical in oncology.
“It seems like at the moment we are number three,” acknowledged von Bohlen. “But the race is on. This is a race that has just begun, and we all have to accept the pace is going to stay high.”