FRANKFURT (FINANCIAL TIMES) - The call came on a Sunday evening, as Ugur Sahin and Ozlem Tureci were catching up with paperwork at their modest home near the German city of Mainz. It confirmed that their - at times controversial - lives' work had produced a breakthrough that could offer humanity a route out of the Covid-19 pandemic.
A vaccine candidate developed by BioNTech, the company they co-founded 12 years ago, was more than 90 per cent effective in preventing the disease - a far higher level than that of the widely used jabs for flu, shingles or rabies. It proved for the first time that the deadly virus could be vanquished by science.
But even as they basked in the good news - the two teetotallers celebrated on Sunday by brewing some black tea - neither Dr Sahin nor his research partner and wife, Dr Tureci, can explain precisely why their precious product - code-named BNT162b2 - works.
That is very much by design.
The shot, which is being tested in trials held by US pharma group Pfizer involving more than 43,000 people across six countries, is "an almost perfect vaccine, in some respects", Dr Sahin tells the Financial Times. It works by marshalling a number of pathogen-fighting tools simultaneously, in the hope that one, or several, will defeat Sars-CoV-2. But so far, they do not know which ones are actually succeeding.
"We have yet to understand - and this will come in the next six to 12 months - what drives the protection rate," explains Dr Sahin, who is also BioNTech's chief executive.
Unlike the vaccines that have almost eradicated diseases such as measles and polio, the novel platform on which BioNTech's vaccine is based, known as messenger RNA, or mRNA, does not use a weakened or inactivated virus to trigger an immune response. Instead, it injects genetic instructions into the body - a method that has never before been used in a licensed pharmaceutical and has faced scepticism from the scientific community for decades.
But the coronavirus crisis gave Dr Sahin and Dr Tureci an opportunity to prove that one of the technology's key characteristics - the ability to rapidly deploy the immune system's disparate forces against a precise target - could herald the revolution that they have been forecasting for 25 years.
"It was a fortunate coincidence that we were in a position to fight this disease," says Dr Tureci, who is also BioNTech's chief medical officer.
"We had a lot of experience with RNA in the context of manufacturing it for individualised cancer vaccines," she says, a process which BioNTech only recently managed to make stable enough for high-quality production. "If the pandemic were to have happened three years ago, it would have been much more difficult."
'Immune system whisperers'
For BioNTech, the timing of Sars-CoV-2's arrival is just one of several serendipitous events that led to the company's unlikely success.
Dr Sahin and Dr Tureci, both born in the 1960s to Turkish parents who made their way to Germany after the West German government signed an immigration agreement with Ankara in order to boost its dilapidated post-war labour force, grew up within 240km of each other, and pursued remarkably similar paths that would eventually converge.
Dr Sahin's father worked at a Ford car factory in Cologne. From the age of 11, he remembers being struck by the "incredibly beautiful and complex" immune system.
"We didn't have Google," the 55-year-old recalls. "Every time we went into town, I went to the bookstore." He adds: "I also had a good relationship with the local librarian, who ordered new (science and maths) books for me and set them aside for when I came in."
Dr Tureci's father, a surgeon who had a keen interest in technology and science, played a more direct role in her medical education.
From a young age, she would follow him as he did his rounds through the wards of his hospital in Lower Saxony, and even into the operating theatre. "I watched my first appendectomy at the age of six," she says.
At separate universities, they took almost identical routes, combining a medical degree with a doctorate programme: Dr Tureci's in molecular biology, Dr Sahin's in immunotherapy. They met in the early 1990s: She was on rotation at a ward dealing with blood cancers at a hospital in Saarland, where he was a junior resident and her supervisor. Early dates were spent discussing pre-clinical innovations - the reserved Dr Sahin was already able to quote results from scientific papers by rote - and a shared goal to create cancer therapies. Even on their wedding day, the duo made time for lab work.
"We found that our academic fields were complementary," Dr Tureci says, before adding, with a wry smile: "So we married them, and each other."
After she abandoned her physician training to dedicate herself to research, the couple, whose preoccupation Dr Tureci now humorously describes as "immune system whisperers", set about trying to find a unique tool to find and fight antigens on carcinogenic tumours.
Methods such as viral vectors, or recombinant proteins, "came with limitations", says Dr Sahin, until, in the mid-1990s, the couple heard about the niche platform known as mRNA.
As well as being a "non-infectious platform", meaning there is no risk of contracting the disease for which one is being inoculated, mRNA vaccines provided "a way to let the patient produce his or her own drug", by simply sending instructions that can be read by cellular machinery, says immuno-oncology pioneer Christoph Huber, who helped found both BioNTech and Ganymed, Dr Sahin and Dr Tureci's first company set up in 2002.
Proving the science
Nonetheless, the wider scientific world was largely dismissive of the technology, especially after early experiments with mRNA therapies showed that the body treated them as an intruder, and prevented it from reaching the intended cells.
"It was a small community, and even within the small community, we were ignoring each other," says Dr Sahin of the handful of researchers who were devoted to mRNA, and who are now hotly tipped for a Nobel Prize.
Capital markets, and large pharmaceutical companies, were also unconvinced, leading them to focus instead on antibody therapies at Ganymed, which was sold for roughly US$1.4 billion (S$1.9 billion) in 2016.
But at the same time, Dr Sahin brought a small team of scientists and collaborators with him to the University of Mainz which, along with Tubingen, 160km to its south, was home to a cluster of cutting-edge mRNA expertise.
That group remains at the core of BioNTech, and their experience with the agile manufacturing processes needed to make mRNA vaccines on an individual patient basis would prove invaluable at the start of the year.
In January, Dr Sahin, whose addiction to scientific journals is gently mocked by friends and colleagues, read an article in the Lancet about a new coronavirus that had emerged in China's Hubei province.
He quickly convinced both Dr Tureci and the rest of BioNTech's board that the evidence pointed to a pathogen that had the potential to spread much faster than even the authors of the report realised.
Just two weeks after the genetic sequence of Sars-CoV-2 was made public on Jan 12, BioNTech began its Covid-19 vaccine programme.
By the time the World Health Organisation declared a global pandemic in early March, the company had 20 mRNA candidates in development. Days later, it had signed deals with Pfizer and China's Fosun to help the company - which had roughly 1,300 employees - with clinical trials and mass production.
Speaking to the FT in March, Dr Sahin said that with the "goodwill" of regulators, an approved product could be available by the end of the year, although he warned this would be "pushing the limits of what is possible".
Behind the couple's quiet confidence that a vaccine could be delivered within a year was a discovery made during the Sars outbreak in 2003, which revealed the existence of "spike" proteins on viruses that bind to a receptor commonly found in lung cells, in which an mRNA vaccine can activate a response that brings antibodies to the fight.
If successful, those antibodies will bind to the spike protein - which is particularly strong in Sars-CoV-2 - to prevent it from docking, while simultaneously calling on cells to phagocytise, or consume, the virus.
As the company stepped up its Project Lightspeed, and tested its vaccines on mice, rats and monkeys, pre-clinical data was strong enough to convince Germany's medical regulator, the Paul-Ehrlich-Institut, to allow clinical trials in April. BioNTech whittled down its candidates to four. Public interest was immediately strong - more than 1,000 volunteers contacted the trial coordinators in a single day.
Respiratory viruses, however, are notoriously difficult to tackle, as the pathogen can reach the lungs via the nose or mouth very quickly. If a person is exposed to a high load of the virus, and the antibodies aren't fast enough, the coronavirus enters the cells' interior and proliferates there, creating millions of copies.
To fight this, BioNTech engineered its mRNA vaccine to activate a second line of defence, known as T-cells.
The vaccine produces two kinds of T-cell. The first is known as CD8, and is equipped with scanning molecules that can look into and kill infected cells if it encounters any virus, while also reducing the reproduction of the pathogen.
The second is CD4 cells, known as orchestrators, which make sure antibodies are directed against the right part of the virus and bind very strongly. They also help CD8 work, calling on many other parts of the immune system.
"You can switch on, via a snowball effect, an entire cascade of immune mechanisms which you can leverage," says Dr Tureci.
But much about how this would work when tested on humans was unknown until last week.
After eliminating three of the vaccine candidates - one of them led to 75 per cent of patients getting a fever - BioNTech and Pfizer launched a large-scale, final phase trial in late July, which was expanded beyond the United States and Germany to Brazil, Argentina, South Africa and Turkey, as the coronavirus subsided in some parts of the world over the summer.
Roughly half of trial participants were given a placebo, and approximately 21,000 were given two shots, three weeks apart, while Dr Sahin and Dr Tureci waited for the requisite 62 volunteers to contract Covid-19, in order for independent observers to be able to calculate the overall rate of effectiveness.
That threshold was passed soon after the US presidential election on Nov 3, and news of the external committees finding that the vaccine was 90 per cent effective came days later.
Dr Sahin, who was expecting about 80 per cent effectiveness and had busied himself in work while waiting for the results, heard the news from Pfizer chief executive Albert Bourla.
"Albert called me and said 'do you want to know the data?' - and I said 'no'!" he says. "It was a fantastic relief. There was a lot of indication that there was immunity, but no definitive proof."
But the global reaction was greater - and more politically charged - than anyone at BioNTech expected.
'Focus on the facts'
Dr Sahin and Dr Tureci, who do not own a television set and shun social media, have been hailed as an immigrant success story, and their company, which has become more valuable than Deutsche Bank, as an example of the power of private capital.
Snippets of such coverage were e-mailed to the couple by friends and colleagues, much to the exasperation of Dr Sahin, who has made a point of keeping his distance from the politics of the pandemic response, letting Pfizer's Mr Bourla deal with the attempts to influence the process by the Trump administration.
"Of course there are people with migrant backgrounds who are encouraged by our story," says Dr Sahin, who is frustrated by how their background is now being used in the debate on the contributions of immigrants and their children. "You can use us as an argument for migration, and if something is not optimal, you can use it against migration," he adds. "We should just focus on the facts."
The final success of BioNTech's candidate, which must still pass safety checks by American and European Union regulators, was due to a technology called nucleoside-modified mRNA and which was pioneered by an immigrant to the US - Hungarian scientist Katalin Kariko.
An early believer in mRNA vaccine design, she was overlooked by sceptical superiors at the University of Pennsylvania who saw no promise in her research, and when recruited by Dr Sahin to join the Mainz-based company in 2013, she was ridiculed by some in her own department. One former colleague "laughed at me", she recalls. "He said: 'The company doesn't even have a website!'"
Dr Kariko, however, is not relishing her newfound fame. "I can handle the rejection," she says, "but the limelight is terrifying."
While still operating with fewer than 2,000 employees, BioNTech - which received €375 million (S$598 million) from the German government in September - is also on its way to becoming a household name.
Most of the 1.35 billion doses of the Covid-19 vaccine that it plans to manufacture with Pfizer by the end of next year are already earmarked for the US, EU, Britain and Japan. Several other countries, including Brazil and Switzerland, are scrambling to secure any remaining supply.
But public health officials have urged caution, pointing out that it remains to be seen how different age groups or risk categories will react to the vaccine, or indeed if those immunised will still be capable of passing on the disease.
"The maths tells us that if we have such strong disease prevention, this would lead to a certain percentage of infection prevention," Dr Sahin says, though he predicts this would be "likely lower" than 90 per cent.
Dr Tureci also warns against complacency in the months until the vaccine can be rolled out globally - a challenge that will be initially complicated by the need to keep BNT162b2 at roughly minus 75 deg C during transportation.
Echoing the words with which US President-elect Joe Biden greeted the vaccine news, "we have to continue to wear our masks and do the social distancing", the 53-year-old says.
But the couple believe their success - which top US infectious disease specialist Anthony Fauci told reporters "validates the mRNA platform" - could prove even more consequential than stemming a pandemic that has killed 1.3 million people.
Despite being made a multibillionaire by last week's news, Dr Sahin plans to continue working on mRNA vaccines targeting prostate, ovarian, pancreatic and other cancers.
He hopes that as with the discovery of gene-editing tool Crispr, "there will be an extreme push for the technology".
On the back of a wealth of new mRNA safety data and increased investment, the duo could be just a few years away from realising the dream they had back in 1991 - of developing individualised cancer therapies.
Their efforts, centred in a city that for centuries was most famous as the birthplace of the printing revolution, will now be met with "less scepticism", Dr Tureci says, betraying the smallest hint of triumphalism.
"We still believe it could revolutionise the entire industry."