TLR1/2 activation during heterologous prime-boost vaccination

• Published in: PLoS neglected tropical diseases Vol. 5; no. 6
• Main Authors: Jayakumar, Asha, Castilho, Tiago M, Park, Esther, Goldsmith-Pestana, Karen, Blackwell, Jenefer M, McMahon-Pratt, Diane
• Format: Journal Article
• Language: English
• Published: Public Library of Science 01-06-2011
• Subjects: Immune response; Leishmaniasis; Prevention; Risk factors; Vaccination; Australia
• ISSN: 1935-2727
• DOI: 10.1371/journal.pntd.0001204

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 IFNy 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.