Recent research comparing four influenza vaccines has shown that not all flu jabs stimulate the immune system in the same way, and that their performance varies according to age. Although the vaccines produced similar levels of antibodies—the standard measure of vaccine response—scientists found significant differences in how each one activated cellular immunity, a deeper layer of defence that helps build long-lasting protection. These findings could reshape how annual flu vaccines are recommended, especially for older adults.
The study followed one of the most severe recent flu seasons, during which roughly 47 million people in the United States became ill, and an estimated 27,000 died. In light of these high numbers, researchers publishing in The Journal of Immunology set out to expand the way flu vaccine effectiveness is evaluated. While antibodies are essential for reducing illness severity, they do not guarantee complete immunity. Many people still experience breakthrough infections, even when vaccinated. This limitation has encouraged scientists to explore how vaccines interact with the immune system beyond antibody production, particularly through cells that coordinate memory and long-term defence.
To gain a fuller picture, the team measured how four different vaccines—Fluzone High-Dose, Fluzone Standard-Dose, Flucelvax, and Fluad—activated B cells and T cells, the key immune cells that help build durable protection. Blood samples were collected before vaccination, and then at 7, 28, and 90 days afterwards. This allowed researchers to observe how quickly responses formed and how well they were maintained.
Among adults aged 65 to 85, the Fluzone High-Dose vaccine generated the strongest cellular response. It quickly activated circulating T follicular helper cells and antibody-secreting cells, both of which help the body form immune memory. Because immune responses weaken with age, this heightened activation indicates why older adults often benefit from high-dose vaccines: they provide the additional stimulus required for robust protection.
The results differed for younger adults aged 28 to 60. Flucelvax, a mammalian cell-based vaccine, outperformed the standard egg-based Fluzone dose in this group. Flucelvax elicited a stronger response from multifunctional cytokine-secreting CD4⁺ T cells and a more durable memory B cell response. This suggests that younger adults may derive greater benefit from cell-based vaccines, which appear to stimulate a broader, more coordinated immune response.
According to Dr Ted M. Ross, senior author and Global Director of Vaccine Development at the Cleveland Clinic, these age-specific findings illustrate why vaccine evaluation must move beyond antibody measurements alone. Understanding cellular immunity, he argues, can guide more tailored recommendations and accelerate the development of next-generation or universal flu vaccines. Such future vaccines aim to provide broader and longer-lasting protection without the need for yearly reformulation.
The research team now plans to expand the study to a larger population and hopes to identify biomarkers that predict strong, lasting immunity. If successful, these insights could reshape how influenza vaccines are designed and recommended, ensuring more consistent protection across age groups and ultimately reducing seasonal illness and deaths.
More information: Vanessa Silva-Moraes et al, Comparative analysis of cellular immune responses to four seasonal inactivated influenza vaccines in younger and older adults, The Journal of Immunology. DOI: 10.1093/jimmun/vkaf286
Journal information: The Journal of Immunology Provided by American Association of Immunologists Inc
