Abstract
Background Leishmania (Viannia) parasites present particular challenges, as human and murine immune responses to infection are distinct from other Leishmania species, indicating a unique interaction with the host. Further, vaccination studies utilizing small animal models indicate that modalities and antigens that prevent infection by other Leishmania species are generally not protective.MethodologyUsing a newly developed mouse model of chronic L. (Viannia) panamensis infection and the heterologous DNA prime – modified vaccinia virus Ankara (MVA) boost vaccination modality, we examined whether the conserved vaccine candidate antigen tryparedoxin peroxidase (TRYP) could provide protection against infection/disease.ResultsHeterologous prime – boost (DNA/MVA) vaccination utilizing TRYP antigen can provide protection against disease caused by L. (V.) panamensis. However, protection is dependent on modulating the innate immune response using the TLR1/2 agonist Pam3CSK4 during DNA priming. Prime-boost vaccination using DNA alone fails to protect. Prior to infection protectively vaccinated mice exhibit augmented CD4 and CD8 IFNγ and memory responses as well as decreased IL-10 and IL-13 responses. IL-13 and IL-10 have been shown to be independently critical for disease in this model. CD8 T cells have an essential role in mediating host defense, as CD8 depletion reversed protection in the vaccinated mice; vaccinated mice depleted of CD4 T cells remained protected. Hence, vaccine-induced protection is dependent upon TLR1/2 activation instructing the generation of antigen specific CD8 cells and restricting IL-13 and IL-10 responses.ConclusionsGiven the general effectiveness of prime-boost vaccination, the recalcitrance of Leishmania (Viannia) to vaccine approaches effective against other species of Leishmania is again evident. However, prime-boost vaccination modality can with modulation induce protective responses, indicating that the delivery system is critical. Moreover, these results suggest that CD8 T cells should be targeted for the development of a vaccine against infection caused by Leishmania (Viannia) parasites. Further, TLR1/2 modulation may be useful in vaccines where CD8 T cell responses are critical.
Highlights
Vaccination against cutaneous leishmaniasis (CL) has involved leishmanization, which has been practiced throughout the Middle East and was employed in government sponsored vaccination programs both in Israel and Russia
We examined the ability of vaccination to protect against L. (Viannia) infection using the highly immunogenic heterologous prime-boost (DNAmodified vaccinia virus) modality and a single Leishmania antigen (TRYP)
We report for the first time that heterologous prime (DNA) -boost modality using the single antigen tryparedoxin peroxidase (TRYP) and including the TLR1/2 agonist N-palmitoyl-S-[2,3-bis(palmitoyloxy)-(2RS)-propyl]-[R]-cysteinyl-[S]-seryl-[S]-lysyl-[S]-lysyl-[S]lysyl-[S]-lysine (Pam3CSK4) as adjuvant during DNA priming is effective in achieving protection against L.(V.) panamensis
Summary
Vaccination against cutaneous leishmaniasis (CL) has involved leishmanization (inoculation of live Leishmania), which has been practiced throughout the Middle East and was employed in government sponsored vaccination programs both in Israel and Russia. An optimal vaccine against cutaneous leishmaniasis would consistently provide protection against the various disease-causing species. Studies indicate that distinct Leishmania species elicit different responses in their hosts, suggesting that a uniform approach might be challenging. (Viannia) subgenus can generate a hyperinflammatory response that fails to resolve [11,12,13,14, 15,16]. L. (V).panamensis elicits a mixed Th1/Th2 and non-resolving hyperinflammatory response to infection in humans [17,18]. Leishmania (Viannia) parasites present particular challenges, as human and murine immune responses to infection are distinct from other Leishmania species, indicating a unique interaction with the host. Vaccination studies utilizing small animal models indicate that modalities and antigens that prevent infection by other Leishmania species are generally not protective
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