Researchers have identified a consistent biological barrier that prevents the immune system from producing the antibodies most needed to protect the nose and throat from respiratory viruses. The findings, led by researchers at the University of Surrey in collaboration with University College London, could help design the next generation of vaccines that protect at the point of infection.
The study, published in Cell Reports Medicine, followed 15 healthy adults with no prior exposure to SARS-CoV-2 as they received two doses of the Moderna mRNA-1273 vaccine. Blood samples were taken every other day for the first 3 weeks after the first dose, with additional samples taken at 8, 10, and 12 weeks, and again 6 months later. The result is the first detailed timeline of the human immune response, combining approximately 3.8 million antibody gene sequences with single-cell analysis of the B cells responsible for producing antibodies.
At the heart of this discovery is a process called class switch recombination that permanently changes the type of antibodies B cells produce. The researchers found that switching between these types can follow a stepwise pathway along the genome, with cells moving sequentially between antibody types over time rather than jumping freely between them.
In all participants, the process consistently stopped at a gene called IGHG2, located roughly in the middle of the sequence. Beyond that, switching to additional antibody types was rare and limited to a few specific B cell subtypes. Importantly, this barrier emerges whether or not the cells are specific for the vaccine, suggesting that this is a fundamental feature of the operation of the human immune system.
As a result, the mRNA vaccine produced a strong response to IgG1 antibodies (which circulate in the blood and reduce the severity of the disease) but little to IgA2 (the antibody type that protects mucosal surfaces). Respiratory viruses, including SARS-CoV-2, enter the body through the nose, throat, and lungs, so the limited IgA2 response may help explain why some vaccinated people remain susceptible and continue to transmit the virus.
Although it has long been known that antibody class switching follows certain biological rules, the consistency and precision of this barrier had not been demonstrated in IGHG.2 The first human reaction is new. The details here change the way we think about what the immune system can and cannot do when it first encounters a vaccine. The next question is whether we can design vaccines that selectively overcome that barrier and provide strong protection where it’s needed most. ”
Deborah Dunn Walters, Professor and Lead Author and Professor, University of Surrey
The study also called into question long-held assumptions about how antibodies are purified. Class switching and somatic hypermutation, a process by which antibodies are gradually tailored to better match their targets, have long been thought to occur in parallel. In this study, class switching occurred rapidly several weeks after vaccination, but meaningful antibody purification could not be detected until 6 months after the first vaccination. The two processes were effectively separate.
Professor Franca Fraternari, co-author from University College London, said:
“What struck us was that these B cells were very efficient in switching antibody types in the early weeks after vaccination, but little fine-tuning of those antibodies occurred until much later. This separation tells us something important about the structure of the immune response and could influence the way we think about the timing of booster shots in vaccine programs.”
The researchers also found that a B cell subtype known as “double negative” (DN) increased significantly among the antigen-specific B cells tracked in the study after the second vaccine dose. DN cells are associated with chronic infections, autoimmune diseases, and aging.
Professor Claudia Mauri, co-author from University College London, said:
“There are many more types of B cells than you might imagine from reading textbooks, and we are just beginning to understand the role they play in the immune system. Perhaps non-traditional B cells are favored by the mRNA platform, which triggers interferon signals that are known to promote a type of immune activation that bypasses the germinal centers where antibodies are normally purified. These findings warrant further research.”
The dataset created in this study combines bulk and single-cell genetic sequencing over 20+ time points per participant with flow cytometry and serology and is publicly available to support future research in vaccine design, B-cell biology, and control of antibody class switching.
