It was the fastest vaccine development in history. But now pharmaceutical companies are preparing to do it all over again.
With the emergence of worrying variants that could make Sars-Cov-2, the virus that causes Covid-19, more transmissible, more deadly or more resistant to vaccines, the drugmakers that responded in record time are rushing to head off new threats.
Scientists are confident they can respond. The question is: how quickly?
Moderna — which along with rivals such as BioNTech/Pfizer and the Oxford university/AstraZeneca partnership developed their vaccines in under 12 months — announced on Monday that it would begin human trials of a new booster that is tailored to target the 501.v2 strain first identified in South Africa.
“We just want to be super cautious because this virus is tricky, as we all learned the hard way last year,” Stéphane Bancel, Moderna’s chief executive, told the Financial Times. “We cannot not move now . . . because it would take months to get the next one ready in case we need it.”
Moderna decided to start a new trial after it discovered that its vaccine elicited antibody levels that were six times lower for 501.v2 than for other strains already identified.
One reason for the rush is that the more widespread the virus becomes, the more likely it is to mutate.
Although data so far suggest the existing vaccines are generally effective against some of the most widespread variants, including B.1.1.7 that has been responsible for a sharp rise in cases in the UK and the 501.v2 variant, no vaccine producer has published data on the worrying P.1 variant that has been found in Brazil.
For pharma companies, saving time where possible from initial development, trials and manufacturing will be crucial if existing vaccines stop working against emerging strains.
“The vaccines used today are all based on the original Wuhan [viral DNA] sequence and it’s likely if there’s an impact on vaccines it would be across the board,” said Dan Barouch, a Harvard researcher who helped design Johnson & Johnson’s vaccine candidate.
It is not about the underlying technology of how the vaccine is made, he added. “It’s about when do you pull the trigger about whether you make a new vaccine.”
Preparing prototype vaccines and boosters
In preparation for the worst, scientists have been working on trial vaccines that could work against recent variants such as 501.v2 and P.1.
“As soon as these variants became apparent, we started working on vaccines that targeted [them]” said Mene Pangalos, executive vice-president of biopharmaceutical R&D at AstraZeneca.
He said it would be one to three months before prototypes would be ready and the aim was to have a candidate that would target “all of the main variants in circulation”. Then the company would begin clinical trials.
Nathalie Landry, executive vice-president of scientific and medical affairs of Canadian pharmaceutical company Medicago which is developing three vaccine candidates, said they were also working on prototypes. “I would expect that every single vaccine manufacturer is doing the same.”
Ms Landry said it takes about 20 days to insert and grow the new variant’s genetic sequence in a plant culture so it forms virus-like particles. This then tricks the immune system into thinking it is meeting a viral particle.
Teams producing other types of vaccines have said the process of making a new vaccine prototype would take only a handful of days.
She pointed to the annual flu vaccine, which is tweaked every year depending on the most virulent strains in circulation. Because there are often several different strains, vaccine manufacturers produce four separate vaccines to put in the one shot.
Preparing prototypes vaccines and boosters now will enable companies to move quickly to small scale trials when new strains of the virus emerge.
With Sars-Cov-2, Ms Landry explained that if the World Health Organization or regulators determined that a previous strain was no longer circulating, “we would pivot manufacturing completely” but “if the recommendation is that we will need to add another strain, we would have to split our production in two”.
Existing technology can be used
Mr Bancel has said that Moderna went from seeing the sequence of the virus to shipping the first doses of its trial vaccine in 42 days, but that “we could probably be faster on a new version, if needed”.
He told the FT that switching manufacturing would be “very easy” because almost everything in the drug formulation would remain the same. The only thing that is different is the genetic sequence, made out of “plasmid”, a small circular piece of DNA. Moderna has plans to produce new plasmids for the 501.v2 variant and stockpile that ingredient in case it is needed.
Germany’s BioNTech which, like Moderna, has produced a new type of vaccine based on messenger RNA, has said it could use existing technology to rapidly produce a new vaccine against mutations of the virus.
“The beauty of the mRNA technology is we can directly start to engineer a vaccine that completely mimics this new mutation and we could manufacture a new vaccine within six weeks,” Ugur Sahin, BioNTech’s chief executive, said last month.
Mr Pangalos of AstraZeneca also conceded that mRNA vaccines “probably have a 4-6 week advantage”.
Umesh Shaligram, director of research and development at the Serum Institute of India, the world’s largest vaccine manufacturer, said that “remaking the vaccine is not going to take a lot of time”.
Partnering with five international pharmaceutical groups, including AstraZeneca and Novavax, the Serum Institute has committed to produce 1bn vaccine doses in 2021.
Dr Shaligram said the company has the technology to replace the crucial ingredient of the vaccine without changing any of the other components. Nonetheless, he conceded it could take six months to build up manufacturing capacity.
‘Bridging studies’ could be key
Discussions with regulators have resulted in loose commitments that compressed studies will be accepted as evidence of the safety and efficacy of new vaccine formulations. But there is still debate about exactly what such trials would involve.
The UK’s Medicines and Healthcare products Regulatory Agency has said that it would likely require “bridging studies” — to bring together existing data on quality, safety and effectiveness and information on the modified product. It said it would look to conduct these in the “shortest time possible”.
Moderna’s Mr Bancel pointed out that seasonal bridging studies for the flu vaccine — thought of as the best regulatory model for Covid-19 — usually involve a couple of thousand participants, rather than the tens of thousands required in preliminary studies.
Mr Pangalos said that if studies only needed to demonstrate a robust immune response they would likely only require up to 1,000 patients. For AstraZeneca, these trials might take up to three months, he added. “We’d get the data by the end of the year in time for next winter season, that would be the aim.”
For the Covid-19 vaccines that have already been authorised, the US Food and Drug Administration required an average of two months follow-up data to monitor safety, which extended how long it took to bring them to market.
But Andrey Zarur, chief executive of GreenLight Biosciences, which is developing an mRNA Covid-19 vaccine, said the FDA had informed the company that it would not need to redo safety trials if all of the vaccine ingredients were the same and only the viral sequence was changed.
“We have assurances from the FDA that if we proceed with one strain of DNA, and then we change it, then we would not need to start with early stage clinical trials at all,” he said.
The FDA said it had already “given thought to developing a potential pathway” for changes to Covid-19 vaccines and treatments.
Search for a holy grail vaccine
Several large laboratories are looking at how the virus mutates in the face of threats, to try to anticipate likely variants.
Others are busy researching a holy grail vaccine that would work against all coronaviruses, not just Sars-Cov-2.
Vir Biotechnology, a San Francisco-based infectious disease company, is working with GlaxoSmithKline on a universal vaccine.
“I think we have a good chance of finding [one] but it will take years not months,” said George Scangos, chief executive of Vir Biotechnology.
Barney Graham, deputy director of the Vaccine Research Center at the US National Institutes of Health, said a universal vaccine was the ultimate goal, and one he has been working on since 2017. But there was little time for this type of research during a pandemic.
Jesse Goodman, former chief scientist at the FDA and professor at Georgetown University, believes governments and regulators should be pushing hard for such a vaccine and that studies of promising candidates should start immediately.
“I don’t think it’s a matter of if someday we’ll get a different coronavirus strain that has significant potential to escape vaccine immunity, but more like when,” he said. “You don’t want to wait till that actually happens to sort out what you can do.”
Additional reporting by Stephanie Findlay