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Aging weakens how the immune system responds to vaccines, according to a new study from the Allen Institute published in Nature on Oct. 29. By analyzing more than 16 million immune cells from adults aged 22 to 65 after influenza vaccination, researchers found that aging reprograms memory T Cell function, limiting their ability to support antibody production and defend against infection.

Immune decline with age

As people grow older, their immune systems lose efficiency, making them more vulnerable to infectious diseases and less responsive to vaccination. While this decline has long been observed, its biological basis remains uncertain. The Allen Institute team sought to uncover how aging alters immune cell behavior and affects vaccine performance.

“The increasing TH2-bias in the memory T Cell function compartment with age may play a critical role in reduced antiviral immunity broadly in older adults,” said Claire Gustafson, an immunologist at the Allen Institute who led the study.

Study design and findings

The researchers examined immune responses in 96 adults over a two-year period. Participants were divided into two groups: younger adults aged 25 to 35, and older adults aged 55 to 65. Each received annual flu vaccines while their immune cell activity was tracked through RNA sequencing.

Using advanced single-cell sequencing methods, the team profiled 16 million peripheral blood mononuclear cells and categorized them into 71 immune cell types. They observed a key shift in the behavior of memory T Cell function among older individuals. These cells tended to adopt a T helper 2 (TH2) phenotype—an immune profile typically linked with activating general immune responses rather than the targeted adaptive responses required for effective antibody production.

This TH2 bias, the study found, led to reduced activation of memory B cells, which are responsible for producing antibodies that recognize and neutralize pathogens. As a result, vaccine-induced protection was weaker among older adults.

“A TH2-bias shift in memory T cells can change immune responses to viruses and lead to dysregulation of downstream interactions that are required for effective protection,” Gustafson said.

Implications for vaccines

The study highlights why vaccines, including those for influenza and COVID-19, are often less effective in older populations. Current vaccine formulations and schedules are largely designed based on immune responses in younger adults, creating challenges for protecting older individuals with reduced immune capacity.

According to Gustafson, understanding how T cell function changes with age could guide the design of more effective vaccines and treatments for older populations. “This may also be an important consideration for not just flu vaccines, but other vaccines that are given repeatedly over the course of a lifespan,” she said.

Medical experts note that such findings could help inform strategies such as age-specific vaccine doses, adjuvants that enhance immune responses, or treatments that target T cell reprogramming.

The Allen Institute team plans to expand their research through the Human Immune Health Atlas, a large-scale project aimed at mapping immune system changes over a lifetime. By characterizing the transitions from functional to weakened immune states, researchers hope to provide new insights into how aging shapes disease vulnerability and vaccine performance.

The study represents one of the most comprehensive efforts to date to track how the immune system evolves with age. It provides evidence that the gradual reprogramming of memory T cells—rather than a simple loss of immune cells—may be central to the decline in vaccine effectiveness seen in older adults.

As populations around the world continue to age, such research could be crucial for improving public health strategies and ensuring that vaccines remain effective across all stages of life.