As flu season approaches and public health officials roll out their annual push for vaccination, Allen Institute scientists are learning why vaccines can trigger a weaker response in older adults, around age 65, and what can be done to improve them. These insights open the door to designing more effective vaccines.  

In the largest study of its kind, published in Nature, scientists discovered that our T cells—key players in coordinating immune responses—undergo profound and specific changes as we age. These changes, far from being random or a byproduct of chronic disease and inflammation, are a fundamental feature of healthy aging and will happen to all of us as we get older.  

“We were surprised that inflammation is not driving healthy aging. We think inflammation is driven by something independent from just the age of a person,” said Claire Gustafson, Ph.D., assistant investigator at the Allen Institute and one of the lead authors of the study. “This is important because there’s been research showing similar findings that inflammation and aging don’t go hand in hand, and your immune system is just changing with age.”  

(Video of a 3-D “U-Map”. Each dot is a single cell of the blood, and each color is a different cell type. Video credit: Allen Institute)

The changes also point to why vaccines, including the annual flu shot and COVID-19 boosters, tend to be less effective in older adults.

The changes scientists discovered

T cells are a critical part of our immune system that help “train” white blood cells, called B cells, to produce antibodies in response to viruses and vaccines. But this study found that memory T cells in older adults undergo a dramatic shift toward what is known as a “Th2-like” state, which is a change in gene expression that fundamentally alters how these cells respond to threats. Researchers found this shift directly affects B cells’ ability to generate strong antibody responses. In other words, the flu shot might still deliver the right viral components, but if the memory T cells aren’t functioning properly, the body struggles to respond effectively.  

(Allen Institute automation engineer, Peter Wittig, with a research robot used to scale experiments. Video credit: Allen Institute)

How this could lead to better vaccines 

With this insight, doctors may be able to use a person’s immune profile to predict how well they’ll respond to a vaccine. Now that scientists can pinpoint how T cells become less effective with age, they can also start designing new vaccine formulas or immune-boosting treatments to address these issues.  

Since T cells in older adults function differently, scientists could reformulate vaccines to compensate specifically for age-related cellular changes rather than using a one-size-fits-all approach. Gene-editing tools like CRISPR could also be used to reprogram a person’s T cells before vaccination, essentially re-programming older immune cells to make them respond to vaccines like younger cells do—like CAR-T cell therapy that reprograms immune cells to fight cancer.  

Researchers say this work goes beyond just vaccines and reveals how our immune systems change in all of us as we get older and how our bodies fight age-related disease and viruses. It also opens the door to interventions like new therapies to restore key immune cells.  

How researchers made the discovery

Scientists tracked more than 96 healthy adults between the ages of 25 and 65 for over two years in collaboration with Benaroya Research Institute. The researchers then used cutting-edge techniques like single-cell RNA sequencing, proteomics, and spectral flow cytometry to profile the immune system of these individuals over time. The scientists then used this data on the immune system to create a detailed Human Immune Health Atlas, an online resource mapping 71 different immune cell types and how they change over time, and why those changes matter. Then, they applied this Atlas to study over 16 million individual immune cells from healthy adults ranging between 25 to 90+ years of age, offering an unprecedented tool for researchers worldwide to better understand—and support—the aging immune system. This online resource is the largest of its kind and freely available to researchers worldwide.  

“This research illustrates how working collaboratively can make a significant impact on our understanding of the immune system, both now and in the future,” said Jane Buckner, M.D., president of the Benaroya Research Institute. “It was made possible through the combined efforts of several Seattle-based research institutions, dedicated scientists, clinicians and research coordinators, as well as the individuals who generously volunteered their time, samples, and health information.”  

The significance of this work extends beyond aging research and provides a roadmap for understanding how immune dysfunction develops over time, offering concrete targets for intervention and potentially transforming how we approach immune health across the entire human lifespan.  

“There’s so much more information to be gained by looking at this dataset we’ve produced,” said Gustafson. “My hope is that it will be used for a long time to enable other researchers to look more deeply and find more insights into human immunity.”