COVID-19 vaccine responses show four patterns, with 'rapid-decliners' at higher infection risk

Two health care workers get COVID-19 vaccinations on the same day. Both show strong antibody responses initially, but six months later one stays healthy while the other contracts the virus. A new study published in Science Translational Medicine could help explain this difference.

Researchers tracked individuals' antibody levels after vaccinations and identified four distinct patterns of immune response after the first booster vaccination. Notably, people in the group that started with the highest antibody levels but experienced a faster decline were infected earlier. People with lower blood levels of IgA(S) antibodies, which protect the nose and throat, were also at higher risk. The findings suggest that monitoring how antibody levels change over time could assist in identifying individuals at greater risk of infection.

The research team measured antibody levels in 2,526 people over 18 months to see how vaccine responses changed between the first vaccination and later booster shots. They developed a mathematical classification system for COVID-19 vaccine responses using long-term tracking and AI-based computer analysis, becoming the first to systematically identify and characterize the "rapid-decliner" group.

The researchers found that immune responses fell into four clear patterns: Some people maintained high antibody levels over time (durable responders), others started with strong levels but lost them quickly (rapid-decliners), a third group produced few antibodies that also declined rapidly (vulnerable responders), and the rest fell in between (intermediate responders).

A breakthrough or subsequent infection refers to infections that occur after vaccination because the virus overcomes the immune protection that vaccines provide. The researchers found that people whose antibodies declined faster, either because they started low or dropped quickly (vulnerable responders and rapid-decliners), were slightly more likely to get breakthrough infections earlier.

After booster vaccinations, 29% of participants fell into the durable responder category, 28% were vulnerable responders, and 19% were rapid-decliners. The remaining participants showed intermediate patterns. The differences in breakthrough infection rates between groups were modest—5.2% for durable responders and 6% for vulnerable and rapid-decliners.

Part 1

The study also revealed that participants who experienced breakthrough infections had lower levels of IgA(S) antibodies in their blood several weeks after vaccination. These antibodies protect the nose and throat and are our first line of defense against respiratory viruses.

Importantly, the researchers found a strong correlation between blood IgA(S) levels and nasal IgA(S) levels, suggesting that blood tests can reliably indicate the strength of immune protection in airways. As a result, measuring blood IgA(S) levels after vaccination may help identify individuals at higher risk for breakthrough infection, especially among vulnerable groups.
The researchers emphasize the importance of identifying the underlying biological mechanisms responsible for the rapid decline in antibody levels in order to develop more effective vaccination strategies.
Previous research points to factors such as age, genetic variation, vaccine-specific characteristics, and environmental influences, including sleep habits, stress levels, and medications being taken at the same time.
Identifying the rapid-decliner pattern is especially important—it helps explain why some people may need boosters sooner than others.

This could potentially contribute to better, more personalized vaccination strategies.

 Longitudinal antibody titers measured after COVID-19 mRNA vaccination can identify individuals at risk for subsequent infection, Science Translational Medicine (2025). DOI: 10.1126/scitranslmed.adv4214

Part 2

Scientists discover proteins that initiate cellular immunity in bone marrow

Researchers have shown how a critical pathway is fundamental to the immune system.

Establishing cellular immunity depends on the thymus, a lymph gland located in front of the heart. This gland produces and exports T cells, a workhorse white blood cell, out to the rest of the body, using the building blocks of stem cells from the bone marrow. But it has remained a riddle how T cell fate is initiated.

The new paper shows that two protein "transcription factors" called Tcf1 and Lef1 are critical modulators that direct bone marrow stem cells to the T cell path in the thymus.

By carefully removing these proteins via in vivo and ex vivo models, the team of scientists revealed a foundational event in the immune system, which represents essentially the very origin of a functional cellular immune competence.

This discovery illustrates a whole new understanding of T cell formation, and could lead to a wide range of novel approaches in treating immune deficiencies, autoimmune diseases, and optimizing immunotherapies in the ongoing fight against cancer.

"These findings reveal that Tcf1 and Lef1 act much earlier than previously recognized, extending beyond their roles in promoting T-cell lineage specification and commitment at later stages in the thymus," the authors write, adding that the "downstream" Notch signaling pathway is corrupted without these two assisting proteins.

 Xin Zhao et al, Single-cell multiomics identifies Tcf1 and Lef1 as key initiators of early thymic progenitor fate, Science Immunology (2025). DOI: 10.1126/sciimmunol.adq8970