The molecules behind the success of two coronavirus vaccines are extremely fragile. Outside of the protective shell of a cell, they break apart, and the precious instructions they hold dissolve.
Called messenger RNA, the molecules are a facsimile of the body's genetic code and are used by cells to make the many proteins that enable life.
For the past decade, BioNTech and Moderna, two biotechnology companies an ocean apart, have been trying to work out how these microscopic messengers could be used to teach the body to make its own medicine.
Neither drugmaker had originally set out to make vaccines but, this year, each proved their technology is remarkably well-suited to the task. In record time, both companies designed and developed highly protective mRNA shots that could help end a pandemic that has killed one and half million people worldwide.
Their success defies expectations held at 2020's start, when the prospect of an effective vaccine for SARS-CoV-2 within the year looked remote. Vaccines are typically the product of a decade or more of research; the fastest developed to date took four years. And no medicine based on mRNA had ever been approved until the U.K. drugs regulator made BioNTech's vaccine the first earlier this month.
"This particular sprint took 10 months. But it took us a decade to be ready for it," said Stephen Hoge, Moderna's president.
Remarkably, not only did BioNTech's and Moderna's vaccines move through testing faster than any others previously, but both were shown to be about 95% effective in preventing COVID-19 — better than expected and as good as some of the best vaccines available for other infectious diseases.
"This will go down in history as one of science and medical research's greatest achievements," Eric Topol, a physician-scientist and director of the Scripps Research Translational Institute, wrote on Twitter in late November.
BioNTech and Moderna were helped in their endeavors by previous research on the related coronaviruses SARS and MERS, well-resourced partners and the grim acceleration of COVID-19 cases that propelled the companies' clinical trials forward.
While attempts to develop vaccines for first SARS and then MERS stalled once those outbreaks faded, the efforts laid a foundation for a quicker start once researchers identified SARS-CoV-2 and mapped its genome. In particular, scientists could be reasonably sure the spiky protein which protrudes from the surface of SARS-CoV-2 was the right target on which to train the immune system's fire.
BioNTech's and Moderna's vaccines also benefited from tricks of biochemistry learned from that research and incorporated in their design.
"That's a decade of basic biomedical research led by Anthony Fauci's folks," said Hoge, referring to the head of the National Institute of Allergy and Infectious Diseases.
Those advances gave both companies a leg up as they scrambled to fashion a template for their vaccines. And working with mRNA meant BioNTech and Moderna scientists could begin designing their candidate using the coronavirus' genetic sequence, rather than a virus sample.
Less than two days after Chinese researchers shared the sequence online, for example, Moderna finalized the mRNA sequence it planned to use for its candidate.
Both companies also leaned on larger partners to take their vaccine through clinical testing. Moderna, already a partner with NIAID, worked closely with the agency, which sponsored the first clinical trial of the biotech's shot. And the U.S. invested nearly $2.5 billion to help develop, manufacture and supply the vaccine, allowing Moderna to scale up production while trials were ongoing.
BioNTech, meanwhile, teamed up with Pfizer, tapping the large pharmaceutical company's deep pockets, international reach and powerful clinical trial infrastructure. (The U.S. agreed to pay nearly $2 billion to pre-order 100 million vaccines doses, but did not fund Pfizer and BioNTech's research and manufacturing.)
By late July, both groups had separately advanced their vaccines into large Phase 3 trials, which, together, enrolled about 75,000 volunteers in roughly three months.
Within days of each other in mid-November, first Pfizer and BioNTech, and then Moderna and NIAID reported their trials, respectively, showed vaccination to be similarly effective in preventing COVID-19.
Phase 3 trial results show BioNTech, Moderna vaccines to be highly protective against COVID-19
|Phase 3 trial participants
|COVID-19 cases, on vaccine
|COVID-19 cases, on placebo
"An extraordinary, unprecedented burst of biomedical research — huge amounts of brainpower, effort, money and resources — has come through for the world, " wrote Derek Lowe, a drug discovery researcher and industry commentator, when Pfizer and BioNTech reported their result.
Success was also due to the sacrifice of the trial volunteers, who accepted the chance they might receive a placebo. An infection surge in the U.S. beginning in October sped both trials along, sadly leading to the fast accumulation of COVID-19 cases among study participants who received a placebo.
By the time the trials reported results, between 100,000 and 150,000 new cases were being reported in the U.S. each day.
"They are the heroes," said Moderna's Hoge.
Many other vaccine developers are following closely on the heels of BioNTech and Moderna, and groups in China and Russia have already won early approvals. But, with their positive Phase 3 results, the two biotechs have delivered the strongest reason for hope the pandemic will soon come to an end.
Researchers and regulators still need to wade through the full data for each candidate, and the thorny problems of access and affordability must be solved for people globally to benefit.
Their achievements, though, could change how vaccines are developed for future outbreaks, or even for long-standing infectious disease threats.
"Have we proven to ourselves that the next time there is a pandemic we can get this done in 10 months? I think we have," said Hoge.
"Absent a pandemic, can we get it done in a year? No, but I think it will [only] take us a few."