It takes two doses of the Pfizer-BioNTech COVID-19 vaccine to "wake up" cells that play a very important role in the body's immune response, with the second dose increasing their numbers 100-fold, according to new research.

The Stanford University study may help explain why getting the second dose of mRNA vaccines, such as the Pfizer or Moderna shots, is so crucial to building a strong immune system response against SARS-CoV-2.

As study co-author Bali Pulendran explained, the current pandemic marks "the first time RNA vaccines have ever been given to humans, and we have no clue as to how they do what they do: offer 95% protection against COVID-19." Pulendran is professor of pathology and of microbiology and immunology at Stanford.

It's never been clear how mRNA-based vaccines offer recipients such extraordinarily high levels of protection against the new coronavirus. In comparison, a seasonal influenza vaccine is judged to be quite effective if it reaches even 60% protection.

In their investigation, the Stanford team analyzed blood samples from 56 healthy volunteers at multiple points before and after they received their first and second shots of the Pfizer vaccine.

The results showed that the first shot increased SARS-CoV-2-specific antibody levels, but not nearly as much as the second shot.

"The second shot has powerful beneficial effects that far exceed those of the first shot," Pulendran said in a university news release. "It stimulated a manifold increase in antibody levels, a terrific T-cell response that was absent after the first shot alone, and a strikingly enhanced innate immune response."

The researchers also looked at immune system players besides the standard antibodies that are usually studied.

When they did this, intriguing new details emerged: The second shot appears to do things the first shot cannot, according to the study published July 12 in the journal Nature.

The Stanford team was surprised to find that a second dose of Pfizer vaccine triggered a significant mobilization of a small group of first-responder immune cells that are normally scarce and dormant.

These cells are a small subset of normally abundant cells called monocytes, which produce high levels of genes with virus-fighting power.

When the COVID-19 virus infects a person these monocytes are barely activated, if at all, the researchers found.

However, the study showed that monocytes do respond strongly to the vaccine -- but primarily only after the second dose.

According to Pulendran's group, the monocytes accounted for just 0.01% of all circulating blood cells before vaccination, but their numbers increased 100-fold after the second dose of Pfizer vaccine, when they comprised a full 1% of all blood cells.

Also, the cells became less inflammatory and more strongly antiviral, and appear capable of providing broad protection against a range of viral infections, according to Pulendran.

"The extraordinary increase in the frequency of these cells, just a day following booster immunization, is surprising," he said. "It's possible that these cells may be able to mount a holding action against not only SARS-CoV-2, but against other viruses as well."

Already, studies are showing that strong immune responses against SARS-CoV-2 may last at least eight months, and possibly for years, in people who've received two doses of mRNA vaccines.

Dr. Amesh Adalja is an infectious disease expert and senior scholar with the Center for Health Security at Johns Hopkins University in Baltimore. He wasn't involved in the new study, but said it again "demonstrates that the second dose of the mRNA vaccine regimens augments, significantly, the immunity in general provided by the first dose.

"This is the rationale for a two-dose regimen, and why people who are fully vaccinated are more protected than individuals who are partially vaccinated," Adalja said. "I suspect the findings would be very similar with the Moderna vaccine since they use similar technology."