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Fusing antigens to chemokines to target antigen presenting cells (APC) is a promising method for enhancing immunogenicity of DNA vaccines. However, it is unclear how different chemokines compare in terms of immune potentiating effects. Here we compare Ccl3- and Xcl1-fusion vaccines containing hemagglutinin (HA) from influenza A delivered by intramuscular (i.m.) or intradermal (i.d.) DNA vaccination. Xcl1 fusion vaccines target cDC1s, and enhance proliferation of CD4 +  and CD8 +  T cells  in vitro . In contrast, Ccl3 target both cDC1 and cDC2, but only enhance CD4 +  T cell proliferation in combination with cDC2. When Ccl3- or Xcl1-HA fusion vaccines were administered by i.m. DNA immunization, both vaccines induced Th1-polarized immune responses with antibodies of the IgG2a/IgG2b subclass and IFNγ-secreting T cells. After i.d. DNA vaccination, however, only Xcl1-HA maintained a Th1 polarized response and induced even higher numbers of IFNγ-secreting T cells. Consequently, Xcl1-HA induced superior protection against influenza infection compared to Ccl3-HA after i.d. immunization. Interestingly, i.m. immunization with Ccl3-HA induced the strongest overall  in vivo  cytotoxicity, despite not inducing OT-I proliferation  in vitro . In summary, our results highlight important differences between Ccl3- and Xcl1- targeted DNA vaccines suggesting that chemokine fusion vaccines can be tailor-made for different diseases.

Dendritic cell targeted Ccl3- and Xcl1-fusion DNA vaccines differ in induced immune responses and optimal delivery site