No shortcut to success

On January 11, 2020, researchers around the world got their first look at the genetic sequence of the novel coronavirus SARS-CoV-2. By March 16, the first volunteer was injected with an experimental vaccine. The FDA authorized another vaccine on December 11, and the first Americans were dosed three days later, touching off a gigantic rollout. The stunning speed of this success has no precedent in vaccine science. It’s the culmination of decades of investment and discovery, said Yale researchers.

“This is a watershed event in vaccinology and vaccine sciences,” said Saad Omer, MBBS, MPH, PhD, associate dean (global health research) and professor of medicine (infectious diseases). “They sped it up by finding efficiencies, by using and taking advantage of platform technology, et cetera. But they haven't cut corners in the scientific process.”

Normally, the pre-trial phase of vaccine development alone can last from three to nine years. Researchers discover and validate a target; study candidate vaccines in benchtop and animal research; develop a manufacturing process; and optimize an assay for testing the vaccine’s efficacy. So how was the pre-trial process accomplished so quickly this time?

For one thing, researchers had a target in sight from early on: the coronavirus’s spike protein or peplomer, with which it latches on to human cell surface receptors and begins the process of infection. From studies of other deadly coronaviruses, scientists know that an effective immune response includes antibodies capable of neutralizing the spike. That knowledge was invaluable when it came time to tackle SARS-CoV-2.

Another crucial piece of groundwork: a novel and powerful technology platform at the ready based on nucleic acid vaccine technology. Researchers have known for decades that directly injecting mice—or humans—with DNA or RNA that encodes a pathogen’s protein can induce an effective immune response. Though no human vaccine on this nucleic acid platform had yet been fully developed, the technology has been around since the 1990s and has seen heavy investment since the mid-2000s.

“There was definite interest in the area, and many people were trying this out experimentally, but it hadn't actually hit the mainstage,” said Richard Flavell, PhD, Sterling Professor of Immunobiology. “The pandemic accelerated this enormously; and luckily for the world, it looks to be working.”

“There has been an approach since 2005 or 2006 to invest in so-called platform technologies, such as mRNA technology, that would be useful irrespective of the pathogen that could lead to an outbreak,” Omer said. “Those things pay dividends.”

In the first approved coronavirus vaccine, synthetic messenger RNA stimulates human cells to create a simulacrum of the spike protein. That spike eventually gooses the immune system to tailor antibodies and immune cells that stand by in case the real thing happens along. “This approach is different from the initial trial-and-error approach,” Omer said. “Instead of looking at the pathogen, inactivating it, seeing [how] it works, tweaking the dose in an animal model, et cetera, now there's more focus on exploiting the genetic information of the pathogen using bioinformatics to identify targets and using a fine-tuned precision-based approach.”

In this field, precision means speed. When nucleic acids are the basis of a vaccine, all that laboratories need to design a vaccine is the virus’ genetic sequence. Once scientists received the genetic code for the viral spike protein, they designed an mRNA vaccine within two days.

Trials came next. Ordinarily, these can last up to a decade. In 2020, enrollment in trials went faster because it took place at a high number of sites, so what would have been done in series was instead done in parallel, saving time. Moreover, the virus’ spread was so unchecked that researchers didn’t need to wait long for enough study participants to become infected.

Moreover, manufacturing vaccines based on nucleic-acid technology is easier than for such traditional vaccines as the ones that require recombinant proteins. For the coronavirus vaccine, federal funds from Operation Warp Speed allowed companies to gamble on their own unapproved vaccines by pre-manufacturing large numbers of doses, according to Flavell.

“That's what they call at-risk manufacturing,” Flavell said. “Normally, a company would wait to see the results of clinical trials before manufacturing large numbers of doses of vaccine. In this case, that risk was assumed by the government, which enabled the entire process to be jump-started.”

The mRNA-based vaccines now being distributed around the world aren’t the last word. Dozens of others are in the pipeline, some of which will use other technologies and may prove to be easier to store or administer. But the first generation of SARS-CoV-2 vaccines carry the world’s hopes for holding the deadly pandemic at bay long enough to allow successive versions to emerge.

“It's a wonderful example of immunology in action,” Flavell said. “The investment in research in general by the United States, which goes back to the end of World War II, when they created the NIH system of funding science—all of what we're seeing now is a result of that investment. And it's specifically into immunology as well. If that hadn't happened, we'd be nowhere.”