How can you avoid a strong immune response when preparing a vaccine?

There’s another factor that makes developing a vaccine against coronavirus a particularly tricky endeavor, says Peter Hotez, a vaccine researcher and dean of the National School of Tropical Medicine at Baylor College of Medicine. That’s something called “immune enhancement.” In the 1960s, scientists at the National Institutes of Health were working on a vaccine against respiratory syncytial virus, or RSV, a common, very contagious virus responsible for most of the colds that infants and toddlers get. During clinical trials, some children who received the vaccine later went on to get terribly sick when they caught RSV in the wild. The vaccine produced an exaggerated immune response, causing extensive damage in their bodies. Two kids died.

Decades later, when SARS hit, researchers including Hotez began working on a vaccine. But in early tests with lab animals, they saw something that raised a red flag. The animals’ immune cells were attacking their lungs, causing damage like what had been described in the RSV trials. “That alerted everyone in the coronavirus research community that there was potential for immune enhancement,” says Hotez. His group, which includes collaborators from the New York Blood Center, adapted its strategy. Instead of producing the entire spike protein, they built just a tiny piece of it—the piece that actually latches onto human cells, called the receptor binding domain. With this approach, Hotez says, when they tested in animals they saw immune protection but without the undesirable enhancement.

The prototype vaccine they developed wasn’t able to attract any investment after the SARS outbreak dissipated. But now, the group is currently submitting proposals to fund human testing of the vaccine, which has been sitting in a freezer in Texas since the mid-2000s. Because the virus that causes Covid-19 uses the same receptor as SARS to attack human lung cells, they believe it might offer some protection. But it will be important to come up with a clinical trial design that includes additional, longer-term monitoring of patients to watch out for potential immune enhancement. Hotez says any vaccines designed to fend off Covid-19 will likely have to do the same. “That’s going to really complicate things and slow them down,” he says. “I don’t think anyone’s going to have something ready in 12 to 18 months.”