As more Covid-19 vaccines become available in the U.S., it is getting tougher to run large clinical trials to test a new vaccine’s ability to prevent disease because people are less willing to take a placebo—forcing drugmakers and researchers to look for workarounds as they vet the next generation of shots and test new uses for authorized ones.

One potential workaround would be to determine what level of immune response a vaccine has to trigger to protect people from the coronavirus, as measured in blood samples, and to use that information to create smaller, faster and less-expensive clinical trials.

Instead of requiring tens of thousands of volunteers and costing several hundred million dollars, such trials could involve only hundreds of people at a fraction of the cost. They could be used to speed the availability of new vaccines targeting emerging variants.

Moderna Inc., Pfizer and its partner BioNTech SE , and a federally funded network of researchers are conducting analyses to learn what immune response is necessary for protection with current vaccines, known as an immune correlate of protection. They say it could come in handy for new studies of already-authorized vaccines—such as testing the shots in children or whether reduced doses are effective—as well as for trials of the next generation of shots, including those targeting new coronavirus strains. Over time, such knowledge could also help determine how long protection from the vaccines lasts.

Another workaround is to run future large efficacy trials outside the U.S., in places where viral transmission is high and vaccine availability is more limited. Arcturus Therapeutics Holdings Inc. , whose Covid-19 vaccine is in mid-stage testing, may run a large Phase 3 trial of its experimental shot outside the U.S. because of the diminishing feasibility of running it in the U.S., Chief Executive Joseph Payne said in an interview. The company hasn’t disclosed which country or countries.