Stanford Research Shows Why Second Dose of COVID-19 Vaccine Shouldn’t Be Skipped

The second dose of a COVID-19 vaccine provides a powerful boost to a part of the immune system that provides broad antiviral protection, according to a study led by researchers at Stanford University School of Medicine.

The finding strongly supports the view that the second shot should not be skipped.

“Despite their excellent efficacy, little is known about exactly how RNA vaccines work,” says Bali Pulentran, PhD, professor of pathology and microbiology and immunology. “So we examined in great detail the immune response elicited by one of them.”

The study, published July 12 in Nature, was designed to find out exactly what effects the vaccine, marketed by Pfizer Inc., has on the numerous components of the immune response.

The researchers analyzed blood samples from individuals who had been vaccinated with the vaccine. They counted antibodies, measured levels of immune signaling proteins and characterized the expression of each gene in the genome by the type and status of 242,479 individual immune cells.

“The world’s attention has recently been drawn to COVID-19 vaccines, particularly the new RNA vaccines,” said Pulentran, the Violetta L. Horton Professor II.

He shares the study’s senior authorship with Kari Nadeau, MD, PhD, the Naddisy Foundation Professor of Pediatric Food, Allergy, Immunology, and Asthma and professor of pediatrics, and Purvesh Khatri, PhD, associate professor of biomedical informatics and biomedical data science. The study’s lead authors are Prabhu Arunachalam, PhD, a senior researcher in Pulentran’s lab; medical student Madeleine Scott, PhD, a former graduate student in Khatri’s lab; and Thomas Hagan, PhD, a former postdoctoral scientist in the Stanford lab at Pulendran and now an assistant professor at the Yerkes National Primate Research Center in Atlanta.

Unfamiliar territory

“This is the first time RNA vaccines have ever been given to humans, and we have no idea how they do what they do: provide 95% protection against COVID-19,” Pulendran said.

Traditionally, the main immunological basis for the approval of new vaccines has been their ability to induce neutralizing antibodies: individualized proteins, made by immune cells called B cells, that can attach to a virus and prevent it from infecting cells.

“Antibodies are easy to measure,” Pulentran said. “But the immune system is much more complicated than that. Antibodies alone don’t come close to fully reflecting the complexity and potential range of protection.”

Pulendran and his colleagues assessed the progress of all immune cell types affected by the vaccine: their numbers, their activation levels, the genes they express, and the proteins and metabolites they produce and secrete when inoculated.

A key component of the immune system examined by Pulendran and his colleagues was T cells: search-and-destroy immune cells that don’t attach to viral particles like antibodies do, but instead probe the body’s tissues for cells with telltale signs. of viral infections. When they find them, they tear those cells apart.

In addition, it is now understood that the innate immune system, an assortment of first-responder cells, is of immense importance. It’s the body’s sixth sense, Pulentran said, whose constituent cells are the first to become aware of the presence of a pathogen. While they aren’t good at distinguishing individual pathogens, they secrete “starting” signaling proteins that trigger the adaptive immune system’s response — the B and T cells that attack specific viral or bacterial species or strains. During the week or so it takes for the adaptive immune system to kick in, innate immune cells perform the mission-critical job of keeping incipient infections at bay by gobbling — or firing off harmful substances, albeit somewhat. randomly, on – whatever looks like a pathogen to them.

Another type of vaccine

The Pfizer vaccine, like the one from Moderna Inc., works very differently from the classic vaccines composed of live or dead pathogens, individual proteins or carbohydrates that train the immune system to target and eradicate a particular microbe. The Pfizer and Moderna vaccines instead contain genetic recipes for the production of the spike protein that SARS-CoV-2, the virus that causes COVID-19, uses to attach to cells it infects.

In December 2020, Stanford Medicine began vaccinating people with the Pfizer vaccine. This spurred Pulendran’s desire to compile a complete report on the immune response to it.

The team selected 56 healthy volunteers and took blood samples from them at multiple time points prior to and after the first and second admissions. The researchers found that the first injection increases SARS-CoV-2 specific antibody levels, as expected, but not nearly as much as the second injection. The second shot also does things that the first shot hardly does.

“The second shot has powerful beneficial effects that far exceed those of the first shot,” Pulentran said. “It stimulated a multiple-fold increase in antibody levels, a great T-cell response that was absent after the first injection alone, and a markedly enhanced innate immune response.”

Unexpectedly, Pulendran said, the vaccine — particularly the second dose — triggered the massive mobilization of a newly discovered group of first-responder cells that are normally sparse and quiescent.

First identified in a recent vaccine study led by Pulentran, these cells — a small subset of generally abundant cells called monocytes that express high levels of antiviral genes — barely give way in response to actual COVID-19 infection. But the Pfizer vaccine caused them.

This special group of monocytes, which is part of the congenital museum, made up only 0.01% of all circulating blood cells before vaccination. But after the second injection of the Pfizer vaccine, their numbers expanded 100-fold to represent a full 1% of all blood cells. In addition, their disposition became less inflammatory, but more intensely antiviral. They appear eminently capable of providing broad protection against a variety of viral infections, Pulentran said.

“The extraordinary increase in the frequency of these cells just one day after the booster immunization is surprising,” Pulentran said. “It is possible that these cells could mount a tenacious action against not only SARS-CoV-2, but other viruses as well.”

Reference: “Systems vaccinology of the BNT162b2 mRNA vaccine in humans” by Prabhu S. Arunachalam, Madeleine KD Scott, Thomas Hagan, Chunfeng Li, Yupeng Feng, Florian Wimmers, Lilit Grigoryan, Meera Trisal, Venkata Viswanadh Edara, Lilin Lai, Sarah Chang , Allan Feng, Shaurya Dhingra, Mihir Shah, Alexandra S. Lee, Sharon Chinthrajah, Sayantani B. Sindher, Vamsee Mallajosyula, Fei Gao, Natalia Sigal, Sangeeta Kowli, Sheena Gupta, Kathryn Pellegrini, Gregory Tharp, Sofia Hamilton Maysel-Aus Sydney , Hadj Aoued, Kevin Hrusovsky, Mark Roskey, Steven E. Bosinger, Holden T. Maecker, Scott D. Boyd, Mark M. Davis, Paul J. Utz, Mehul S. Suthar, Purvesh Khatri, Kari C. Nadeau and Bali Pulendran, July 12, 2021, Nature.
DOI: 10.1038/s41586-021-03791-x

Pulendran is a member of the Institute for Immunity Transplantation & Infection and Stanford Bio-X and a fellow of Stanford ChEM-H.

Other co-authors of Stanford studies include fundamental life science researcher Chunfeng Li, PhD; research scientists Natalia Sigal, PhD, Sangeeta Kowli, PhD, and Sheena Gupta, PhD; postdoctoral scholars Yupeng Feng, PhD, Florian Wimmers, PhD, Vamsee Mallajosyula, PhD, and Fei Gao, PhD; graduate student Lilit Grigoryan; life science research professionals Sofia Maysel-Auslender, Meera Trisal and Allan Feng; former life science research professional Shaurya Dhingra; student Sarah Chang; clinical research assistant Mihir Shah; clinical and laboratory research assistant Allie Lee; Sharon Chinthrajah, MD, associate professor of medicine; Sayantani Sindher, MD, clinical associate professor of medicine; Holden Maecker, PhD, professor of microbiology and immunology and director of Stanford’s Human Immune Monitoring Center; Scott Boyd, PhD, associate professor of pathology; Mark Davis, PhD, professor of microbiology and director of Stanford’s Institute for Immunity, Transplantation and Infection; and PJ Utz, MD, professor of medicine.

Researchers from Quanterix and Emory University of Billerica, Massachusetts also participated in the study.

The work was funded by the National Institutes of Health (grants U19AI090023, U19AI057266, U24AI120134, P51OD011132, S10OD026799, R01AI123197-04, U01AI150741-01S1, and AI057229), Open Philanthropy, the Sean Parker Cancer Institute, the Soffer Horton Endowment, the Violetta Stanford University, the Henry Gustav Floren Trust, the Parker Foundation, the Cooperative Centers on Human Immunology, and the Crown Foundation.

Stanford’s Institute for Immunity, Transplantation and Infection also supported the work.