Evidence for long-term CD8+ memory and functionally diverse CD4+ helper responses following yellow fever vaccination: a systematic review

Yellow fever (YF) 17D-lineage vaccines are among the most effective vaccines ever developed, providing long-term protection traditionally attributed to neutralizing antibodies. However, growing evidence suggests that cellular immunity also contributes to durable vaccine-induced protection. This systematic review synthesized current evidence on the magnitude, kinetics, durability, and functional characteristics of antigen-specific T-cell responses following YF vaccination. A PRISMA 2020-compliant review, prospectively registered in PROSPERO, was conducted using searches of Ovid MEDLINE, Embase, Global Health, Scopus, Web of Science Collection, ClinicalTrials.gov and WHO ICTRP to identify human studies published between 2000 and 2025. Thirty-Six studies met the inclusion criteria and were synthesized narratively because of substantial methodological heterogeneity. The available evidence indicates that primary YF vaccination induces rapid expansion of activated CD8 + T cells that subsequently differentiate into long-lived memory populations detectable for years to decades after vaccination. CD4 + T-cell responses were broad and functionally diverse, targeting both structural and non-structural viral proteins and supporting adaptive immunity through helper functions. Circulating T follicular helper-cell responses emerged as important immunological correlates of neutralizing antibody development, while inter-individual variation in cellular immunity appeared to be influenced by factors such as early vaccine viral replication and baseline immune activation. Studies of booster vaccination generally demonstrated weaker cellular responses than those observed after primary vaccination. Overall, the evidence suggests that YF vaccination induces durable cellular immunity alongside established humoral responses, supporting a broader understanding of vaccine-induced protection. Nevertheless, definitive evidence linking specific T-cell responses to long-term clinical protection remains limited, and interpretation is constrained by methodological heterogeneity, predominantly observational study designs, and reliance on peripheral blood-based measurements. Further longitudinal and mechanistic studies are needed to define the cellular correlates of durable protection and clarify the contribution of T-cell immunity to long-term vaccine effectiveness. Systematic Review Registration https://www.crd.york.ac.uk/PROSPERO/view/CRD420261430765 , identifier CRD420261430765.