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Here’s Why the Second COVID-19 Vaccine Dose Is So Important

The second dose of the mRNA COVID-19 vaccines appears to be even more important than previously believed. Find out how a new study determined that the “booster” supercharges immunity against the novel coronavirus. The details might help persuade people to come back for their second shot.

STANFORD, CA – One of the most common questions pharmacists hear when administering COVID-19 vaccines is whether the second mRNA dose is really necessary.

A recent study from Stanford Medicine answered that question, emphasizing that the second dose induces a powerful boost to a component of the immune system that assures broad antiviral protection. The results were published in the journal Nature.

"Despite their outstanding efficacy, little is known about how exactly RNA vaccines work," explained Bali Pulendran, PhD, Stanford professor of pathology,microbiology and immunology. "So we probed the immune response induced by one of them in exquisite detail."

The study specifically explored what effects the Pfizer-BioNTech vaccine had on various areas of the immune system. To do that, researchers analyzed blood samples from 56 healthy volunteers who had been vaccinated, counting antibodies, calculating levels of immune-signaling proteins and assessing the expression of every gene in the genome of 242,479 separate immune cells' type and status.

"This is 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," said Pulendran.

They found that vaccination spurred robust production of neutralizing antibodies (nAbs) against the Wuhan strain and, although to a lesser extent, the B.1.351 strain. Researchers also identified significant increases in antigen-specific polyfunctional CD4 and CD8 T cells after the second dose. 

“Booster vaccination stimulated a strikingly enhanced innate immune response compared to primary vaccination, evidenced by a greater: (i) frequency of CD14⁺CD16⁺ inflammatory monocytes; (ii) concentration of plasma IFN-g; (iii) transcriptional signature of innate antiviral immunity,” the authors pointed out. “Consistent with these observations, single-cell transcriptomics analysis demonstrated a ~100-fold increase in the frequency of a myeloid cell cluster, enriched in interferon-response transcription factors (TFs) and reduced in AP-1 TFs, following secondary immunization. Finally, we identified distinct innate pathways associated with CD8 T cell and nAb responses, and show that a monocyte-related signature correlates with the nAb response against the B.1.351 variant strain.”

"The second shot has powerful beneficial effects that far exceed those of the first shot," Pulendran added. "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."

Especially significant, according to Pulendran, is that the second dose of the vaccine further sparked a group of first-responder monocyte cells that usually aren’t active. That group of monocytes made up only 0.01% of all circulating blood cells prior to vaccination but increased 100-fold after the second Pfizer shot to account for 1% of blood cells.

"The extraordinary increase in the frequency of these cells, just a day following booster immunization, is surprising," Pulendran 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."