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The available evidence suggests that protective immunity to  Leishmania  is achieved by priming the CD4 +  Th1 response. Therefore, we utilised a reverse genetics strategy to generate influenza A viruses to deliver an immunogenic  Leishmania  peptide. The single, immunodominant  Leishmania -specific LACK 158–173  CD4 +  peptide was engineered into the neuraminidase stalk of H1N1 and H3N2 influenza A viruses. These recombinant viruses were used to vaccinate susceptible BALB/c mice to determine whether the resultant LACK 158–173 -specific CD4 +  T cell responses protected against live  L. major  infection. We show that vaccination with influenza-LACK 158–173  triggers LACK 158–173 -specific Th1-biased CD4 +  T cell responses within an appropriate cytokine milieu (IFN-γ, IL-12), essential for the magnitude and quality of the Th1 response. A single intraperitoneal exposure (non-replicative route of immunisation) to recombinant influenza delivers immunogenic peptides, leading to a marked reduction (2–4 log) in parasite burden, albeit without reduction in lesion size. This correlated with increased numbers of IFN-γ-producing CD4 +  T cells in vaccinated mice compared to controls. Importantly, the subsequent prime-boost approach with a serologically distinct strain of influenza (H1N1->H3N2) expressing LACK 158–173  led to a marked reduction in both lesion size and parasite burdens in vaccination trials. This protection correlated with high levels of IFN-γ producing cells in the spleen, which were maintained for 6 weeks post-challenge indicating the longevity of this protective effector response. Thus, these experiments show that  Leishmania -derived peptides delivered in the context of recombinant influenza viruses are immunogenic  in vivo,  and warrant investigation of similar vaccine strategies to generate parasite-specific immunity.

Induction of Protective CD4+ T Cell-Mediated Immunity by a Leishmania Peptide Delivered in Recombinant Influenza Viruses