As the Biden administration prepares to recommend booster shots for the majority of Americans, some experts are saying the third dose could be the final one.

But what evidence leads them to believe that COVID-19 can be defeated by a three-dose series?

For starters, a longer duration between the second and third dose may provide stronger and longer-lasting immunity, experts said.

Peter Hotez, MD, PhD, of Baylor College of Medicine in Houston, said on CNN Monday night that a 3-week interval between the first and second doses of Pfizer’s mRNA vaccine, for instance, may not have been enough time to spur an extended immune response, with the initial shots acting only as a primary immunization.

An 8-month lag, on the other hand, could boost immunity significantly, Hotez said, with the potential to yield high levels of virus-neutralizing antibody and an immune response that is “really robust.”

“That may be it for a while, we may not need annual boosters,” Hotez said. “This could be the third and done.”

Since it’s typical for antibodies to wane over time, it’s common for vaccines to be administered in multiple doses over a longer time period. People get three shots over a 6-month period for hepatitis B, for instance, and a four-dose regimen is recommended for polio.

“In fact, it is unusual to give a one-dose, give-and-go vaccine,” John Moore, PhD, professor of microbiology and immunology at Weill Cornell Medicine in New York, told MedPage Today. “Most vaccines require at least two shots.”

In a multi-dose vaccine regimen, a longer interval between doses gives the immune system time to mature, Moore said. During this time period, a process called affinity maturation takes place, which causes antibodies to improve in quality while dwindling in number, he said.

Moore said studies have shown that people who were previously infected with COVID-19 experience affinity maturation, as they have higher quality antibodies months after initially getting sick.

However, a third dose may also promote this process, he added. When a vaccine delivers another round of antigen to the body, it activates memory B cells, and allows them to produce improved, higher-quality antibodies to fight COVID-19.

Monica Gandhi, MD, MPH, of the University of California San Francisco, said that a longer duration between COVID-19 injections will certainly improve the immune response. Gandhi — who does not believe a third dose for immunocompetent people should be given ahead of global vaccination distribution — added that boosters would likely not be recommended if not for the highly transmissible Delta variant.

Once caseloads are down, she added, people probably won’t need regular COVID-19 vaccinations in the future.

“I don’t think we are going to need boosters every year,” Gandhi told MedPage Today. Coronaviruses do not have a high propensity to mutate like influenza, so by the time antibodies wane — an expected outcome — higher levels of immunity in the general population will probably prevent people from needing additional jabs, she said.

But Moore said there’s still not enough data to know for sure whether an annual booster will be needed. Unknown factors such as new outbreaks or emerging variants will influence recommendations for additional immunizations.

“It’s crystal-ball gazing,” Moore said. “Who knows where we are going to be in a year’s time.”