According to a study led by researchers at Stanford University School of Medicine, the second dose of COVID-19 vaccine induced a powerful boost to a part of the immune system that provides broad antiviral protection. The findings strongly support the idea that a second dose of the vaccine should be given. Dr Bali Pulendran, Professor of Pathology, Microbiology and Immunology, said: “Despite the remarkable effectiveness of RNA vaccines, very little is known about how exactly RNA vaccines work. So we looked in detail at the immune response induced by one of these vaccines.”
The study, published July 12 in The journal Nature, aimed to find out what effect the vaccine, sold by Pfizer, had on many components of the immune response. The researchers analyzed blood samples from people who had been vaccinated. They calculated antibodies, measured levels of immune signaling proteins, and described the expression of each gene in the genome of 242,479 individual immune cell types and states. “The world’s attention has recently been focused on COVID-19 vaccines, particularly novel RNA vaccines,” Pulendran said.
He was co-senior author of the study with Kari Nadeau, PhD, Professor of Pediatrics, Food, Allergy, Immunology and Asthma, Professor of Pediatrics, and Purvesh Khatri, PhD, associate professor of Biomedical Informatics and Biomedical Data Science, Nardisi Foundation. The lead author of the study is Dr. Prabhu ** AM, a senior research scientist at Pulendran Laboratories; Dr. Madeleine Scott, a former graduate and medical student in Khatri’s lab; And Dr. Thomas Hagan, a former postdoctoral scholar in Pulendran’s Stanford lab and now an associate professor at Yerkes National Primate Research Center in Atlanta.
“This is the first time that RNA vaccines have been provided to humans, and we don’t know how they do it: 95 percent protection against COVID-19,” Pulendran said.
Traditionally, the main immunological basis for approving new vaccines has been their ability to induce neutralizing antibodies: personalized proteins created by immune cells called B cells that stick to the virus and prevent it from infecting cells. “Antibodies are easy to measure,” Pulendran said. But the immune system is more complicated than that. Antibodies alone do not fully reflect their complexity and potential range of protection.”
Pulendran and his colleagues assessed the functioning of all the immune cell types affected by the vaccine: their number, their level of activation, the genes they expressed, and the proteins and metabolites they made and secreted after vaccination.
A key component of the immune system that Pulendran and his colleagues studied was T cells: These searching and damaging immune cells don’t attach to virus particles like antibodies do, but instead detect cells in the body’s tissues for signs of viral infection. When they find them, they tear them apart.
In addition, the innate immune system, the various first-responder cells, is now understood to be of great importance. Pulendran says this is the body’s sixth sense, where the cells that make up it are the first to recognize the presence of pathogens. Although they are not good at distinguishing between different pathogens, they secrete “starting gun” signaling proteins that kick-start an adaptive immune system response — B and T cells that attack a particular virus or bacterial species or strain. During the week or so it takes for the adaptive immune system to kick in, innate immune cells perform the critical task of stopping the initial infection by devouring or firing toxic substances (albeit somewhat indiscriminately).
A different type of vaccine
Pfizer’s vaccine, like Moderna’s, works in a very different way than classic vaccines made up of live or dead pathogens, individual proteins or carbohydrates, which “train” the immune system to target a particular microbe and kill it. The Pfizer and Moderna vaccines instead contain a genetic formula for making sarS-CoV-2, the virus that causes COVID-19, to target the spike glycoprotein in the cells it infects.
In December 2020, the Stanford School of Medicine began vaccinating people with Pfizer’s vaccine. This stimulated Pulendran’s desire to collect a complete report card on the immune response to it.
The team chose 56 healthy volunteers and took blood samples from them at multiple points before and after the first and second doses. The researchers found that the first dose increased sarS-CoV-2-specific antibody levels, as expected, but not as much as the second dose.
“The second dose has a powerful beneficial effect that far exceeds the first dose,” Pulendran said. It stimulated a doubling of antibody levels, a horrendous T-cell response not seen after the first dose alone, and an astonishing enhancement of the innate immune response. Surprisingly, Pulendran says, the vaccine — especially the second dose — caused a massive “mobilization” of the newly discovered population of first response cells, which are usually sparse and stationary.
In a recent vaccine study led by Pulendran, it was first found that these cells (a small branch of normally abundant cells called monocytes) express high levels of antiviral genes — barely moving in response to actual COVID-19 infection. But Pfizer’s vaccine induced them.
This particular group of monocytes accounted for only 0.01% of all circulating blood cells before vaccination. But after the second dose of Pfizer’s vaccine, their numbers had expanded 100 times, to a full 1 percent of all blood cells. In addition, they are more resistant to disease. Pulendran says they appear to have a unique ability to provide broad protection against a variety of viral infections.
“It was surprising to see an unusual increase in the frequency of these cells just one day after boosting immunity,” Pulendran said. It’s possible that these cells could be able to fight not only SARS-CoV-2, but other viruses as well.”