Tick-borne encephalitis virus (TBEV) is a human-pathogenic flavivirus that is endemic in large parts of Europe and Asia and causes severe neuroinvasive illness. A formalin-inactivated vaccine induces strong neutralizing antibody responses and confers protection from TBE disease. CD4+ T cell responses are essential for neutralizing antibody production, but data on the functionalities of TBEV-specific CD4+ T cells in response to vaccination or infection are lacking. This study provides a comprehensive analysis of the cytokine patterns of CD4+ T cell responses in 20 humans after TBE vaccination in comparison to those in 18 patients with TBEV infection. Specifically, Th1-specific cytokines (IFN-γ, IL-2, TNF-α), CD40 ligand and the Th1 lineage-specifying transcription factor Tbet were determined upon stimulation with peptides covering the TBEV structural proteins contained in the vaccine (C-capsid, prM/M-membrane and E-envelope). We show that TBEV-specific CD4+ T cell responses are polyfunctional, but the cytokine patterns after vaccination differed from those after infection. TBE vaccine responses were characterized by lower IFN-γ responses and high proportions of TNF-α+IL-2+ cells. In vaccine-induced responses-consistent with the reduced IFN-γ expression patterns-less than 50% of TBEV peptides were detected by IFN-γ+ cells as compared to 96% detected by IL-2+ cells, indicating that the single use of IFN-γ as a read-out strongly underestimates the magnitude and breadth of such responses. The results provide important insights into the functionalities of CD4+ T cells that coordinate vaccine responses and have direct implications for future studies that address epitope specificity and breadth of these responses.

• MeSH
• Cell Lineage immunology   MeSH
• CD4-Positive T-Lymphocytes drug effects   immunology   MeSH
• Cytokines biosynthesis   immunology   MeSH
• Adult MeSH
• Epitopes immunology   MeSH
• Encephalitis, Tick-Borne immunology   prevention & control   virology   MeSH
• Middle Aged MeSH
• Humans MeSH
• Antibodies, Viral blood   immunology   MeSH
• Aged MeSH
• T-Lymphocytes, Helper-Inducer drug effects   immunology   MeSH
• Vaccination * MeSH
• Viral Vaccines administration & dosage   immunology   MeSH
• Encephalitis Viruses, Tick-Borne immunology   pathogenicity   MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Cytokines MeSH
• Epitopes MeSH
• Antibodies, Viral MeSH
• Viral Vaccines MeSH