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

• Published in: PLoS neglected tropical diseases Vol. 5; no. 6; p. e1204
• Main Authors: Jayakumar, Asha, Castilho, Tiago M, Park, Esther, Goldsmith-Pestana, Karen, Blackwell, Jenefer M, McMahon-Pratt, Diane
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 01-06-2011; Public Library of Science (PLoS)
• Subjects: Animal models; Animals; Biology; CD4-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - immunology; Deoxyribonucleic acid; Disease Models, Animal; DNA; Female; Genetic Vectors; Immune response; Immune system; Immunization, Secondary - methods; Immunology; Infections; Interferon-gamma - secretion; Interleukin-10 - secretion; Interleukin-13 - secretion; Leishmania; Leishmania - genetics; Leishmania - immunology; Leishmaniasis; Leishmaniasis - immunology; Leishmaniasis - prevention & control; Leishmaniasis Vaccines - administration & dosage; Leishmaniasis Vaccines - immunology; Mice; Mice, Inbred BALB C; Parasites; Peroxidases - genetics; Peroxidases - immunology; Prevention; Protected species; Protozoan Proteins - genetics; Protozoan Proteins - immunology; Risk factors; Rodent Diseases - immunology; Rodent Diseases - prevention & control; Toll-Like Receptor 1 - immunology; Toll-Like Receptor 2 - immunology; Tropical diseases; Vaccination; Vaccination - methods; Vaccines; Vaccines, DNA - administration & dosage; Vaccines, DNA - immunology; Vaccines, Synthetic - administration & dosage; Vaccines, Synthetic - immunology; Vaccinia virus; Vaccinia virus - genetics; Viannia; Viral Vaccines - administration & dosage; Viral Vaccines - immunology; Australia; Ankara Turkey; Turkey; Toll-Like Receptor 1; Toll-Like Receptor 2; Vaccination; Vaccines, DNA; Protozoan Proteins; CD8-Positive T-Lymphocytes; Immunization, Secondary; Female; CD4-Positive T-Lymphocytes; Rodent Diseases; Disease Models, Animal; Interferon-gamma; Interleukin-10; Interleukin-13; Leishmaniasis; Vaccinia virus; Animals; Peroxidases; Leishmania; Viral Vaccines; Vaccines, Synthetic; Leishmaniasis Vaccines; Mice; Mice, Inbred BALB C; Genetic Vectors
• ISSN: 1935-2735; 1935-2727; 1935-2735
• DOI: 10.1371/journal.pntd.0001204

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.
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.
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.
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.