HMN 2026: How Immune barrier may explain why mRNA shots struggle to block nasal infection

A consistent biological barrier that stops the immune system from making the antibodies most needed to protect the nose and throat from respiratory viruses has been identified. The discovery, led by researchers from the University of Surrey, in partnership with University College London, could guide the design of the next generation of vaccines built to protect at the point of infection.

The study, published in Cell Reports Medicine, followed 15 healthy adults who had 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 three weeks after the initial dose, with further samples at weeks 8, 10, and 12, and again at six months. The result is a granular timeline of the first-time human immune response, combining nearly 3.8 million antibody gene sequences with single-cell analysis of the B cells responsible for producing antibodies.

How the barrier was found

Central to the findings is a process called class switch recombination, by which B cells permanently change the type of antibody they produce. The team found that switching between these types can follow a stepwise path along the genome, with cells moving through antibody types in order over time rather than jumping freely between them.

Across all participants, the process consistently stopped at a gene called IGHG2, roughly halfway along the sequence. Beyond that point, switching to additional antibody types was rare and confined to a small number of specific B cell subtypes. Crucially, this barrier appeared regardless of whether the cells were specific for the vaccine or not, suggesting it is a fundamental feature of how the human immune system operates.

The consequence is that the mRNA vaccine generated a strong response in IgG₁ antibodies (which circulate in the blood and reduce disease severity) but produced very little IgA₂ (the antibody type that protects mucosal surfaces).

Since respiratory viruses, including SARS-CoV-2, enter the body through the nose, throat, and lungs, the limited IgA₂ response could help explain why some vaccinated individuals remain susceptible to infection and can continue to transmit the virus.

Why the timing matters

“We have known for some time that antibody class switching follows certain biological rules, but the consistency and precision of this barrier at IGHG2 in a first-time human response is new. The detail we have here changes how we think about what the immune system can and cannot do when encountering a vaccine for the first time. The next question is whether we can design vaccines that selectively push past that barrier to produce stronger protection where it is most needed,” says Professor Deborah Dunn-Walters.

The research also challenged a long-held assumption about how antibodies are refined. Class switching and somatic hypermutation (the process by which antibodies are progressively tuned to better fit their target) had long been thought to occur in parallel.

In this study, class switching happened rapidly in the weeks following vaccination, but meaningful antibody refinement was not detectable until six months after the first dose. The two processes were, in effect, separate.

“What struck us was that these B cells were switching their antibody types very efficiently in the early weeks after vaccination, but the fine-tuning of those antibodies was barely underway until much later. That separation tells us something important about the structure of the immune response and may have implications for how we think about the timing of booster doses in vaccine programs,” says Professor Franca Fraternali.

Unusual B cells after dose two

The research team also found that after the second vaccine dose, B cell subtypes known as “double negative” (DN) expanded substantially among the antigen-specific B cells tracked in the study. DN cells have been associated with chronic infections, autoimmune conditions, and aging.

“There are many more types of B cells than you would think from reading the textbooks and we are only just getting to grips with understanding the role they may play in the immune system. It may be that non-traditional B cells are favored by the mRNA platform, which triggers an interferon signal known to promote a type of immune activation that bypasses the germinal centers where antibodies are normally refined. These findings warrant further investigation,” says Professor Claudia Mauri.

The dataset produced by the study, combining bulk and single-cell gene sequencing with flow cytometry and serology across more than 20 timepoints per participant, is being made publicly available to support future research in vaccine design, B cell biology, and the regulation of antibody class switching.

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