TLR1/2 activation during Heterologous prime-boost vaccination (DNA-MVA) enhances CD8+ T cell responses providing protection against Leishmania (Viannia)

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. methodology: using 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. results: heterologous 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. conclusions: given 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. © 2011 jayakumar et al.