J Immunol. 2025 Oct 30:vkaf286. doi: 10.1093/jimmun/vkaf286. Online ahead of print.

ABSTRACT

The efficacy of seasonal influenza vaccines varies across age groups, even in individuals with strong antibody responses. Since protection against influenza virus infection also involves cellular immunity, identifying immune markers beyond neutralizing antibodies is crucial for informing the design of next-generation vaccines. Participants were categorized by age, 28-60 and 65-85 yr, and were vaccinated with 1 of 4 influenza vaccines (Fluzone Standard-Dose [FSD], Flucelvax [FCEL], Fluzone High-Dose [FHD], or Fluad [FAD]) during the 2023-2024 influenza season. Blood samples were collected before and after vaccination and analyzed for hemagglutination inhibition (HAI) activity, antibody-secreting cells (ASCs), and HA-specific compartments: memory B cells (MBCs), circulating T follicular helper (cTfh) cells, and CD4+ T effector cells. Although all vaccines increased HAI titers, FHD, which contains 4 times more antigen content than the other vaccines, elicited superior cellular responses compared to FAD in older participants. FCEL, produced in mammalian cells, was more effective than the egg-produced FSD in younger adults. Notably, FHD triggered simultaneous ASC and cTfh1 activation in older adults, which were linked to HA-specific MBCs and long-term humoral responses. FCEL induced early and cytokine-secreting HA-specific CD4+ T cell responses in younger adults, correlating with early B cell proliferation and enhanced antibody production. These findings highlight the critical role of antigen dose and quality in inducing HA-specific cellular immunity and coordinating B and T cell activation. Synergistically engaging ASCs, cTfh, MBCs, and CD4+ T cells to enhance immunological memory and establish long-term vaccine-induced immunity should be considered in future influenza vaccine design.

PMID:41166714 | DOI:10.1093/jimmun/vkaf286