Human T Cell Responses to Flavivirus Vaccines

Flaviviruses are major human pathogens that continue to pose a global health threat, and vaccination is an effective strategy to protect against disease from several flaviviruses. Flavivirus vaccines are believed to confer protection primarily through antibody responses; however, the role of T cells in vaccine immunity remains less explored despite demonstrated contribution in the response to natural infection. This review examines T cell responses induced by licensed or developing flavivirus vaccines, their contribution to protection, and key findings highlighting the importance of cellular immunity. We discuss the role of memory T cells, including CD4+ and CD8+ subsets, in flavivirus vaccine-induced immunity and compare the immunogenicity of live attenuated versus inactivated vaccines. We also discuss the significance of T cell immunity, cross-reactivity, and vaccine platform design in shaping durable and broad protection. Additionally, we broaden the discussion toward other human RNA viruses, including the influenza virus and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). A better understanding of the role of T cell immunity will be essential for optimizing the use of current flavivirus vaccines and developing next-generation approaches capable of providing long-lasting immunity against emerging and re-emerging flavivirus threats.