It’s not exactly a wild concept. Every year, lab tests, rather than a large clinical trial, determine whether the updated flu vaccine induces enough antibodies to fire up the immune system. That said, researchers have generations of experience creating flu vaccines. Not so for Covid.

Leading the search for correlates is the Covid-19 Prevention Network, a federal group that studies vaccines and treatments. To pinpoint what the correlates may be, researchers are analyzing blood samples from the Moderna trial and other studies, comparing antibody levels in those who contracted the virus and those who didn’t. Further evidence can come from, for example, vaccine studies in animals. Plans call for pooling all this correlate data, potentially creating a benchmark that the next generation of vaccines could be compared against—via blood tests.

“If regulators accept an immune marker that’s an established correlate of protection, that’s going to be such a powerful thing, because it would be relatively easy to study vaccines,” says Peter Gilbert, a biostatistician with the Fred Hutchinson Cancer Research Center who is part of the Covid-19 Prevention Network.

But the various ways that vaccines strike at the virus complicate the bid for a universal standard. “The big question is, does the correlate translate across vaccine platforms?” Gilbert says. His team, instrumental to the correlate search, relies on biostatistical methods honed in researching other vaccines and HIV. When Covid-19 arrived, the team pivoted.

Hu says Covaxx is exploring the correlate concept in a bid to shorten the company’s Brazil trial, but the strategy hinges on a regulatory path that doesn’t exist yet. An FDA spokesperson wrote via email that establishing correlates is a “major focus of investigation by federal and nonfederal entities.” She added that the agency “will provide additional information as our discussions with the product manufacturers and our international counterparts progress.”

Drugmakers with already authorized vaccines are keen on correlates too. In an email, a Pfizer spokesperson wrote that these immune response markers could aid with testing its vaccine in children and those with compromised immune systems—or vetting boosters targeting variants.

Separately, the FDA recently announced that modified vaccines tuned to block new variants may be able to forgo lengthy clinical trials. Under that guidance, Novavax hopes a booster that was modified from its own current vaccine candidate could undergo a relatively small 400-person immune response study, a company spokesperson says.

The Covid-19 Prevention Network is searching for correlates of protection for Moderna’s vaccine, with analysis planned for vaccines from Novavax, Johnson & Johnson, and AstraZeneca. There’s an urgency behind the effort.

“Very soon, it will no longer be possible to conduct a big, placebo-controlled trial, at least in the US,” says Dan Barouch, a virologist at Beth Israel Medical Center in Boston. He contributed to a December study, published in Nature, that found certain antibodies in monkeys’ blood predicted protection against Covid-19. The findings raised wider confidence that blood tests could do the same in humans. “The data in our animal models is very encouraging,” Barouch says, but he cautions that variants pose yet another challenge in pinpointing correlates.