Immune response after two-phase vaccination with mRNA COVID-19 vaccines might be stronger and longer-lasting than originally expected.

While both vaccines performed well in clinical trials and have received credit for disease reduction, they also were based on a technology never used before in FDA-approved vaccines. As a result, it was not clear how long immunity would last.

A new study published in the journal Nature raises the possibility that the immune response to mRNA vaccines is especially robust. Washington University School of Medicine–led researchers based that view on the discovery that patients who received the Pfizer-BioNTech vaccine continued to have lymph node germinal centers that generated immune cells directed against SARS-CoV-2, the virus that causes COVID-19. Germinal centers, which form as the result of natural infection or vaccination, enhance the ability of cells to fight infections.

The study team also determined that vaccination triggered high levels of neutralizing antibodies effective against three variants of the virus, including the Beta variant from South Africa that has shown some resistance to vaccination. In addition, vaccination was found to induce stronger antibody responses in recovered COVID-19 patients versus those who had never been infected.

Although this spring both Pfizer and Moderna reported that their products provided at least 6 months of protection, a finding  based on tracking infections in vaccinated individuals, no one had actually looked at how the immune system was reacting.

“Germinal centers are the key to a persistent, protective immune response,” said senior author Ali Ellebedy, PhD, an associate professor of pathology & immunology, of medicine, and of molecular microbiology. “Germinal centers are where our immune memories are formed. And the longer we have a germinal center, the stronger and more durable our immunity will be because there’s a fierce selection process happening there, and only the best immune cells survive. We found that germinal centers were still going strong 15 weeks after the vaccine’s first dose. We’re still monitoring the germinal centers, and they’re not declining; in some people, they’re still ongoing. This is truly remarkable.”

It is not completely understood why some vaccines, such as the one for smallpox, induce lifetime protection but others, such as that for pertussis, need regular boosters. The theory is that the quality of the germinal centers induced by different vaccines is the driver.

For the study, ultrasound-guided sampling of the minuscule germinal centers in lymph nodes in the armpit was performed. Radiologists extracted cells from 14 patients who had received the Pfizer vaccine 3 weeks before, as well as at Weeks 4, 5, and 7, with 10 of the participants providing additional samples 15 weeks after the first dose.

Researchers report that 3 weeks after the first dose, all 14 participants, none of whom had been infected with COVID-19, had germinal centers with B cells producing antibodies pinpointing a key SARS-CoV-2 protein. After the second shot, responses stayed robust. In fact, even 15 weeks after the first dose, eight of 10 patients still had detectable germinal centers containing B cells targeting the virus.

“This is evidence of a really robust immune response,” coauthor Rachel Presti, MD, PhD, emphasized. “Your immune system uses germinal centers to perfect the antibodies so they can bind well and last as long as possible. The antibodies in the blood are the end result of the process, but the germinal center is where it is happening.”

Another 41 patients receiving the Pfizer vaccine also provided blood samples, including eight who had recovered from novel coronavirus infection. The study team advises that, while those without prior exposure to the virus had slowly rising antibody levels after the first dose and a peak 1 week after the second, patients who previously had been infected already had antibodies in their blood before the first dose. As a result, their levels went up quickly after the first dose and peaked higher than the uninfected participants’ levels.

“We didn’t set out to compare the effectiveness of vaccination in people with and without a history of infection, but when we looked at the data we could see an effect,” said coauthor Jane A. O’Halloran, MD, PhD. “If you’ve already been infected and then you get vaccinated, you get a boost to your antibody levels. The vaccine clearly adds benefit, even in the context of prior infection, which is why we recommend that people who have had COVID-19 get the vaccine.”

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