For at least six months after COVID-19 vaccination, antibodies produced by immune cells become steadily more formidable and more precisely targeted to the virus that causes COVID-19, according to a study of the antibody response to the Pfizer-BioNTech vaccine by researchers at Washington University School of Medicine and St. Louis.
The idea that antibodies increase in quality as they decrease in quantity will come as no surprise to immunologists. The process was described in animals by Washington University immunologists Herman Eisen, MD, and Gregory Siskind, MD, in 1964. But this study, published Feb. 15 in Nature, is the first to track the maturation of the antibody response in detail in humans.
The results suggest that declining antibody levels in the months following vaccination primarily represent a shift to a sustainable immune response. Producing large amounts of antibodies burns a lot of energy. The immune system cannot maintain such a high level of activity indefinitely, so it gradually shifts to produce smaller amounts of more powerful antibodies.
Even quite low levels of antibodies would continue to provide some protection against disease, the researchers said – as long as the virus does not change.
“If the virus did not change, most people who received two doses of this vaccine would be in very good shape,” said the senior author. Ali Ellebedy, Ph.D., Associate Professor of Pathology & Immunology, Medicine and Molecular Microbiology. “The antibody response we saw is exactly what we would expect from a robust immune response. We never thought that six months after the second injection, many people would still actively improve the quality of their antibodies. To me, that’s remarkable. “The problem is that this virus keeps evolving and producing new varieties. So the antibodies get better at recognizing the original strain, but unfortunately the goal keeps changing.”
Immune cells that produce antibodies are from the B cell family. Following the B-cell response through all its stages – from initiation through maximal antibody production to the emergence of memory cells that can rapidly secrete new antibodies the next time the body encounters the same virus – requires repeated sampling from parts of the body that can be difficult to access. At various stages in the process, key members of the B-cell family are localized in the blood, lymph nodes, and bone marrow. Getting B cells from the lymph nodes is technically challenging and involves using ultrasound to locate minimal immune structures called germinal centers in the lymph nodes. Getting a sample of bone marrow involves inserting a needle into the pelvis.
The researchers collected blood from 42 participants and lymph node samples from 15 participants before each person received their first dose of the Pfizer-BioNTech COVID-19 vaccine and in weeks three, four, five, seven, 15 and 29 thereafter. The researchers also obtained bone marrow samples from 11 participants 29 and 40 weeks after the first vaccine dose.
Eight individuals provided all three kinds of samples, enabling the researchers to track the development of the antibody response over time in these individuals. None of the eight had been infected with the virus causing COVID-19, so their antibody reactions were due to vaccination alone. The research team was led by Ellebedy and co-first authors Wooseob Kim, PhD, a postdoc researcher, and Julian Q. Zhou, PhD, a staff researcher.
The researchers found that B cells targeting SARS-CoV-2 lasted in all participants’ germinal centers for several months. Even six months after vaccination, 10 out of 15 people still had B cells in their germinal centers. Germinal centers are like boot camps, where B cells are trained to make antibodies of ever better quality. The more time B cells spend in germinal centers, the more potent their antibodies become. Germinal centers were thought to last only a few weeks, so finding these boot camps, which still train B cells in a majority of people so long after vaccination, was a surprise, Ellebedy said, and an indication of a strong antibody response that continued to mature and improve.
Six months after vaccination, the antibodies were noticeably better than they had been in the beginning. In a set of experiments, the researchers found that only 20% of the early antibodies bound to a protein from the virus. Six months later, almost 80% of the antibodies from the same individuals bound to the viral protein.
“When you look at antibodies, the amount should not be your only concern,” Ellebedy said. “The antibodies after six months may be smaller in quantity, but they are much better in quality. And that refinement of the antibody response happens by itself. You get your shot, maybe your arm hurts for a day, and then you forget it. But “Six months later, your germ centers are still going strong, and your antibodies are getting better and better.”
The quality of the antibodies is of course measured against the original virus that was used to design the vaccine. If a new variant is different enough from the original, it may be able to escape antibodies that were once strong. Ellebedy and colleagues have begun studying the effects of variant-specific boosters on the antibody response to vaccination.
“Everything changes when a new variant comes along,” Ellebedy said. “You need to retrain your immune system. It’s like updating your anti-malware software to make sure it matches the latest computer viruses available. That does not mean that the old software was bad. It just means it no longer quite matches the viruses it’s going to encounter. “