Juan Andres woke up three times during the night after putting his precious vials of vaccine on the back of a delivery lorry. In late February, Moderna, a biotech group based outside Boston, smashed the record for the fastest time between identifying a virus — in this case Covid-19 coronavirus — and creating a vaccine ready to test in humans: just 42 days.
In the lab, the team had been excited but in the early hours Mr Andres, a 30-year pharma veteran in charge of manufacturing, was nervously checking his phone to track the lorry carrying the potential vaccine to a discreet location. There the US National Institutes of Health would start the trial to test whether it works.
“The pride comes from this [being] a race,” he says. “Doing this as fast as possible is something that is a duty.” Once they were sure the vaccine had arrived safely, the team celebrated with ice cream. At least 100 Moderna staff worked on the project but Mr Andres says everyone is excited to be involved, even people’s families. “I can’t remember the last time my 15-year-old thought I did something cool,” he laughs.
Moderna is one of more than 20 companies and public sector organisations worldwide racing to develop a vaccine against Covid-19, which in little more than two months has exploded from a few people suffering from respiratory disease in the Chinese city of Wuhan to a near-pandemic with 95,000 cases and 3,300 deaths worldwide so far.
The Coalition for Epidemic Preparedness Innovations — a partnership of governments, industry and charities, created three years ago to fight emerging diseases that threaten global health — is already sponsoring four Covid-19 vaccine projects, including Moderna’s. It is also on the point of signing contracts for four more, says Richard Hatchett, CEPI chief executive. He estimates that developing Covid-19 vaccines at the speed required will cost about $2bn over the next 12-18 months.
Moderna is off to the fastest start, Dr Hatchett believes, but several others are close behind. “We received 48 applications from all over the world following our call for proposals in February,” he adds. “There is a real sense of urgency . . . because the threat we are facing is unprecedented in the last 100 years in terms of its speed and potential severity,” he says, referring to the 1918 Spanish flu pandemic.
The trigger for Moderna came when Stéphane Bancel, its chief executive — who had worked on the 2009 H1N1 swine flu pandemic which came from Mexico — called a contact at the National Institutes of Health. In the autumn, the two organisations had agreed to run a test at the company’s manufacturing plant to see how quickly they could respond to a pandemic. But before any dry run was possible, coronavirus — part of a family of viruses that cause respiratory diseases ranging from mild colds to fatal pneumonia — provided a real test.
Nestled on a hill outside Boston, Moderna’s Norwood factory is smaller than a standard pharmaceuticals plant. It was built to be quickly adaptable, as some of its potential products are personalised for each patient. Work at the Massachusetts facility and at other early entrants in the Covid-19 vaccine race began in earnest as soon as Chinese scientists published online the genome of coronavirus — all 30,000 biochemical “letters” of its genetic code — on January 10.
“With the genomic sequence, we were off to the races,” says Anthony Fauci, head of the US National Institute of Allergy and Infectious Diseases.
Ahead of an outbreak, it is impossible to predict what virus is coming next. “Instead of trying to develop a vaccine for a pathogen [virus], which is kind of tough . . . you have to try to develop platform technology to facilitate rapid development of vaccines,” Dr Fauci says.
One such platform is Moderna’s production of vaccines based on viral genetics. By February 7, the company’s scientists had manufactured dozens of doses of clinical grade vaccine, enough for the NIH’s early trial in healthy volunteers, scheduled for April. Researchers then had to wait to see if the batch was sterile, giving any bacteria two weeks to grow. Staff quickly completed other necessary tests in case they needed to start again. Fortunately everything went right, every step of the way.
Despite the rush, vaccine experts say that it will be at least a year to 18 months before one is available for widespread use — typically the process takes several years. After an initial safety trial, there must now be larger clinical studies to test efficacy. Meanwhile, the epidemic is likely to spread across the world, killing many more thousands or even millions of people.
The work of Moderna and its competitors may only be useful if coronavirus comes back again in another outbreak next year or becomes an endemic infection like seasonal flu. With commercial returns uncertain, industry’s response to epidemics carries elements of corporate social responsibility and excitement in meeting a scientific challenge — though sometimes there is a big pay-off, as Wellcome, later part of GlaxoSmithKline, found with its pioneering zidovudine Aids drugs in the 1980s.
Moderna may be the first to test in humans but many more are trying to create a vaccine, from big pharma companies such as Johnson & Johnson and Sanofi to academics including those at the University of Queensland. Genetic sequencing and new structural biology tools are transforming vaccine development, allowing scientists to create their own synthetic versions of viruses — rather than waiting for someone to FedEx a specimen.
This is opening the field to new players, says Paul Duprex, director of the Center for Vaccine Research at the University of Pittsburgh. “You have more people thinking about the problems in different ways, not limited by having to grow the virus in a particular lab,” he adds.
Shane Crotty, a professor at La Jolla Institute for Immunology in California, says one approach being pursued is to search for the best immune response in a patient with the disease — and try to copy it so the vaccine can elicit a more robust defence. “That’s been the biggest, most exciting advance in the past five years. Several of those have gone into human trials looking good. It’s a much more sophisticated way to make a vaccine,” he adds.
Mr Bancel signed the Cepi contract that helped fund Moderna’s vaccine in January on an iPhone at the World Economic Forum in Davos, where the coalition had been founded in 2017 to help quash epidemics quickly. He told Dr Hatchett that in this case “quickly” meant now — and the agreement was signed two days after their first conversation about the outbreak.
As a nine-year-old lossmaking company with several candidate vaccines and treatments in trials but none on sale, Moderna could not shoulder the costs of creating a new Covid-19 vaccine on its own. Even profitable big pharma groups have shied away from investing in vaccines for outbreaks without public funding, because the chances of cashing in are small. Several companies have lost money over vaccines developed for past outbreaks, such as Ebola and Sars, which were almost over before any products were ready.
Now Moderna is over the first hurdle, it must start preparing to scale up. The Norwood facility could produce a larger batch for the next trial but not create a vaccine for all those who might need it. Mr Bancel is in talks with governments about how they would manufacture millions or even billions of doses. Inevitably Moderna will have little option but to strike a deal with a larger manufacturer.
Production capacity will be key if and when licensed products emerge successfully from clinical trials, says Roger Connor, president of global vaccines at GSK. “Everybody will want it immediately. It may then take a period of time to create the supply organisation after that,” he warns.
GSK, the world’s largest vaccine maker, has announced a partnership with Clover Biopharmaceuticals of China, which runs one of the country’s largest in-house biopharmaceutical manufacturing operations. GSK has also made its “adjuvant” technology, which proved effective in the H1N1 flu pandemic, available free to any company that it judges can make use of it.
When added to a vaccine an adjuvant agent can trigger a stronger immune response. “The dose that you have to give of the vaccine can be smaller, which means you can get it to more people faster,” he says. GSK has had “lots” of approaches since announcing it would make the technology available, and is running a “structured assessment” process to determine who receives it.
Not all vaccines “will technically benefit from an adjuvant, so we do a technical scan, first of all, that their candidate vaccine will actually benefit, and our experts can tell. Then we want to understand how capable they are and what’s their probability of success to bring it through,” he adds.
For now any commercial gain from involvement in creating a successful vaccine is a secondary concern to the drive to find a treatment, Mr Connor says. “At the minute we’re completely focused on the science and focused on who to partner with . . . to bring together a vaccine fast.”
Negotiations over commercial terms can wait, he says: “We think the priority is to get the scientific collaboration together, get the product to them free, get it tested pre-clinically and let’s see if this thing can work.”
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In the US, where politicians and patients are railing against high drug prices, more than 40 members of Congress wrote to Donald Trump in February to demand that the president ensure that any government funding of a vaccine or treatment came with an important string attached: everyone will be able to access it.
“If we manage to find, at taxpayer expense, some treatment or cure through a vaccine, we need to be able to afford it everywhere,” says Jan Schakowsky, a Democratic congresswoman from Illinois, who led the initiative. “It should not be turned over to private pharma companies.”
“We are very concerned about access,” says Cepi’s Dr Hatchett. “With H1N1 flu in 2009, the wealthiest countries put contracts in place and monopolised vaccine supplies.”
Cepi has done a lot of scenario planning, including asking whether a Covid-19 vaccine will be needed when it is ready next year. “I don’t think it is plausible any longer that containment will be a success and the disease knocked out,” he says. “There is a business case that there will be a long-term commercial niche for these vaccines.”
Back at the Moderna headquarters, Mr Bancel says Covid-19 proved the company’s technology was faster than anyone imagined. And next time he thinks it could be even faster still.
Yet as the death toll rises, his colleague Stephen Hoge, the company’s president, worries that even quicker is not quick enough. Just when he thought Moderna would have time to breathe after the first batch of its potential vaccine was out the door, he watched the outbreak spreading to South Korea, Europe and beyond.
Like Mr Andres, he has had his own sleepless nights. “I’m going to bed thinking we made some progress”, he says, “and waking up every morning feeling further and further behind.”
Variety of options pursued to avoid risk of failure
Traditionally, vaccines contain a weakened live virus, a dead virus or proteins produced by the virus. The vaccine is often grown inside living cells such as bacteria or in eggs. Once purified and injected, it primes the body’s immune system, which then recognises and attacks the virus the next time it sees it.
Some Covid-19 vaccine candidates, such as the one produced by China’s Clover Biopharmaceuticals, are high-tech versions of these traditional approaches — making viral proteins in genetically engineered cells. A favourite is the “spike protein” on the outside of the virus, which coronavirus uses to grab and enter human cells.
The University of Queensland uses innovative “molecular clamp” technology to hold the proteins in a shape that antibodies are most likely to recognise. Sanofi plans to engineer a different, harmless virus to carry Covid-19 proteins into people.
Others, including Moderna, are developing “nucleic acid vaccines”, which contain the genetic recipe for viral proteins in the form of DNA or messenger RNA (mRNA). That leaves the human recipients to produce the proteins inside their body. No viral vaccine made from nucleic acids has yet been licensed for human use.
At Moderna’s Norwood factory, 40 scientists in the pre-clinical lab created mRNA coding for Covid-19 spike protein. The first batch was created in days in a large white room, where colour is a warning sign and mini robots move trays of tiny vials. The spike mRNA was then put into microscopic bubbles of fat called lipid nanoparticles — a delivery vehicle to carry genetic instructions into patients.
One concern was that Covid-19 has unusually large spike genes which are longer than those in most of Moderna’s previous vaccines. When the scientists had confirmed that both the tail and the cap of the mRNA had made it into the vaccine, the work moved downstairs for completion in a lab that makes personalised cancer vaccines.
“We want to hedge against the various risks by supporting a diversity of different approaches,” says Richard Hatchett, Cepi chief executive.
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