Instructions Included

Vaccines from the U.S. company Moderna and its German rival BioNTech use RNA as a messenger inside cells. The message: Produce an immune reaction, stat

Robert Langreth and Naomi Kresge

Almost every antiviral vaccine ever sold works in a similar way: A dead or weakened virus, or a piece of one, is introduced into a healthy person. The weakened virus stimulates the immune system to generate antibodies, protecting the person when the real pathogen threatens to infect them.

Over the decades, this tried-and-true approach has vanquished polio, eradicated smallpox, and reined in chickenpox, measles, and mumps. But vaccine production has never been simple or fast. Many flu vaccines are still grown in chicken eggs. Newer approaches draw on genetic engineering to eliminate the need for whole viruses, but their viral proteins are still grown inside live cells.

The coronavirus vaccines from Moderna Inc., in Cambridge, Mass., and its German rival BioNTech SE propose to immunize people in a radically different way: by harnessing human cells to become miniature vaccine factories in their own right. Instead of virus proteins, the vaccines contain genetic instructions that prompt the body to produce them. Those instructions are carried via messenger RNA, or mRNA.

Moderna’s mRNA-1273 consists of a strand of mRNA that tells the body to produce the spike protein the coronavirus uses to latch onto human cells. The strand is like one side of a zipper; the “teeth” are a sequence of chemical letters that cells read to produce the 1,273 amino acids that make up the spike protein. If the vaccine works as intended, the body will start producing the proteins soon after injection, prompting the immune system to react and build up protective antibodies against them.

The great advantages of mRNA vaccines are speed and flexibility. No finicky live cells or hard-to-handle viruses are needed, and the basic chemistry is straightforward. Moderna’s vaccine reached Phase I human trials on March 16, only 63 days after the company began developing it. And at 6:43 a.m. on July 27, the first volunteer in Moderna’s 30,000-person, final-stage efficacy trial in the U.S. received an injection. Less than 12 hours later, BioNTech and its partner, Pfizer Inc., said they, too, were beginning a late-stage trial, a study that will be conducted in the U.S., Brazil, and several other countries. They took advantage of mRNA’s rapid-response capability to create four slightly different vaccines, which they compared in initial trials before selecting the best one for large-scale testing.

In Phase I trials, both the Moderna and BioNTech-Pfizer vaccines stimulated people’s immune systems to produce antibodies that neutralized the virus in lab experiments, a positive initial sign. “This is a relatively new platform, but it is looking quite good,” Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases, said after the results of Moderna’s Phase I trial, sponsored by NIAID, were published. “Neutralizing antibodies are the gold standard of protection.” Moderna, which has worked with NIAID for years, is receiving $955 million from the U.S. government to support its coronavirus trials.

How well mRNA vaccines will actually prevent Covid-19 remains unknown. No vaccine based on messenger RNA has ever been approved for any disease, or even entered final stage trials until now, so there’s little published human data to compare how mRNA stacks up against older technologies. And the vaccines have hardly been free of side effects: In Moderna’s Phase I trial, all 15 of the patients who received the median of three-dose sizes reported at least one side effect, though none were severe. Three of the 15 patients at the highest dose had temporary severe reactions. That dosage won’t be tested further.

Still, the accumulating data has some mRNA skeptics warming to the technology. “I don’t see the reason for focusing on mRNA vaccines. I don’t get that,” Peter Jay Hotez, dean of the National School of Tropical Medicine at Baylor College of Medicine in Houston, said in an interview in early June. “The old-fashioned vaccines may do a better job.” In late July he said his opinion had shifted based on encouraging monkey and human trial results. Moderna’s vaccine “is showing promise,” he said. “There is enough of a glimmer to warrant continuing its clinical development and progressing to larger clinical trials.”

The possibility of a Covid-19 shot has led investors to more than triple the value of Moderna’s shares this year, giving the company a market capitalization of about $28 billion, an astonishing number for a company with no products. BioNTech shares have more than doubled. A third company with an mRNA-based Covid-19 shot, CureVac AG, has said it’s considering an initial public offering. Both Stéphane Bancel, Moderna’s chief executive officer, and Ugur Sahin, his less flashy counterpart at BioNTech, have become multibillionaires.

The excitement around mRNA goes beyond the pandemic. Proponents hope it can become a wide-ranging platform that will lead to vaccines for other difficult-to-treat infections, as well as customized cancer shots and even heart disease treatments. “It’s a big moment for mRNA therapeutics in general, because now it’s a household word and everybody knows about it,” says Derrick Rossi, a stem cell biologist who was a co-founder of Moderna in 2010 but is no longer affiliated with the company. “For Moderna, it’s the first time on the global stage.”

Interest in using genetic material to turn the body’s cells into vaccine factories dates to a series of experiments in the early 1990s. In 1993 researchers at Merck & Co. injected lab mice with loops of DNA that contained instructions for influenza proteins. To the surprise of the scientists, the mice generated an immune response that protected against the flu. The concept, so elegant it seemed almost too simple to be true, produced a surge of excitement among vaccine experts.