How Flu Vaccines Shape Immune Responses in Different Age Groups

A study published in The Journal of Immunology assessed four types of influenza vaccines—Fluzone High-Dose, Fluzone Standard-Dose, Flucelvax, and Fluad—during the severe 2024-2025 flu season, which led to at least 47 million illnesses, 610,000 hospitalizations, and 27,000 deaths. The research set out to determine whether not only antibody levels, but also cellular immune responses varied depending on age and vaccine type, aiming to inform future vaccine recommendations for different age groups.

Traditionally, antibody levels have served as the primary benchmark for a successful immune response to flu vaccination. While elevated antibody levels help reduce the chance of severe influenza, they do not guarantee full protection, and breakthrough infections can still occur. The current research expanded the focus to include cellular immunity, using blood samples collected before and at several intervals after vaccination to evaluate both B- and T-cell responses.

Older adults, aged 65 to 85, who received the Fluzone High-Dose vaccine experienced the strongest and most coordinated activation of B- and T-cell responses. Notably, this vaccine triggered an early activation of circulating T follicular helper cells and antibody-secreting cells, which help build robust immune memory. Younger adults, aged 28 to 60, responded best to Flucelvax, a cell-based vaccine. This vaccine was superior to Fluzone Standard-Dose in activating multifunctional cytokine-secreting CD4⁺ T cells and stimulating memory B cells, both critical for orchestrating complex and lasting immune protection.

All four vaccines enabled recipients to develop immunity against the four main flu strains circulating that season: H1N1, H3N2, B Yamagata, and B Victoria. However, distinctions among the vaccines in terms of cellular immunity may offer guidance on tailoring recommendations according to age group, as emphasized by senior author Ted M. Ross, Global Director of Vaccine Development at the Cleveland Clinic. “Our findings provide a more comprehensive understanding of how different influenza vaccines stimulate the cellular component of the immune system across various age groups which can help guide vaccine recommendations.”

Dr. Ross also suggested these insights could lead to better vaccine designs: “Ultimately, this research could guide the development of next-generation or universal influenza vaccines that offer broader and longer-lasting protection as our results emphasize the importance of including cellular immune markers in vaccine evaluation and design.” 

Looking forward, Dr. Ross and his team plan to extend their research to larger patient cohorts to further explore how vaccine types and formulations impact durable immune protection and identify biomarkers that might allow for improved flu vaccine development.