Vaccination with Heat-killed Leishmania Antigen or Recombinant Leishmanial Protein and CpG Oligodeoxynucleotides Induces Long-Term Memory CD4+and CD8+T Cell Responses and Protection Against Leishmania major Infection

CpG oligodeoxynucleotides (ODN) have potent effects on innate and adaptive cellular immune responses. In this report, the ability of CpG ODN to confer long-term immunity and protection when used as a vaccine adjuvant with a clinical grade of leishmanial antigen, autoclaved Leishmania major (ALM), or a recombinant leishmanial protein was studied. In two different mouse models of L. major infection, vaccination with ALM plus CpG ODN was able to control infection and markedly reduce lesion development in susceptible BALB/c and resistant C57BL/6 (B6) mice, respectively, up to 12 wk after immunization. Moreover, B6 mice immunized with ALM plus CpG ODNs were still protected against infectious challenge even 6 mo after vaccination. In terms of immune correlates of protection, ALM plus CpG ODN-vaccinated mice displayed L. major–specific T helper cell 1 and CD8+ responses. In addition, complete protection was markedly abrogated in mice depleted of CD8+ T cells at the time of vaccination. Similarly, mice vaccinated with a recombinant leishmanial protein plus CpG ODN also had long-term protection that was dependent on CD8+ T cells in vivo. Together, these data demonstrate that CpG ODN, when used as a vaccine adjuvant with either a recombinant protein or heat-killed leishmanial antigen, can induce long-term protection against an intracellular infection in a CD8-dependent manner.

[1]  Y. Belkaid,et al.  CD8+ T Cells Are Required for Primary Immunity in C57BL/6 Mice Following Low-Dose, Intradermal Challenge with Leishmania major , 2002, The Journal of Immunology.

[2]  R. Seder,et al.  CpG Oligodeoxynucleotides as Vaccine Adjuvants in Primates1 , 2002, The Journal of Immunology.

[3]  G. Weiner,et al.  Divergent Therapeutic and Immunologic Effects of Oligodeoxynucleotides with Distinct CpG Motifs1 , 2001, The Journal of Immunology.

[4]  R. Coler,et al.  Protection against Cutaneous Leishmaniasis Induced by Recombinant Antigens in Murine and Nonhuman Primate Models of the Human Disease , 2001, Infection and Immunity.

[5]  Y. Belkaid,et al.  The Potency and Durability of DNA- and Protein-Based Vaccines Against Leishmania major Evaluated Using Low-Dose, Intradermal Challenge , 2001, The Journal of Immunology.

[6]  E. Zijlstra,et al.  Immunogenicity and safety of autoclaved Leishmania major plus BCG vaccine in healthy Sudanese volunteers. , 2001, Vaccine.

[7]  S. Akira,et al.  A Toll-like receptor recognizes bacterial DNA , 2000, Nature.

[8]  R. Vabulas,et al.  Bacterial CpG‐DNA activates dendritic cells in vivo: T helper cell‐independent cytotoxic T cell responses to soluble proteins , 2000, European journal of immunology.

[9]  F. Modabber,et al.  Autoclaved Leishmania major vaccine for prevention of visceral leishmaniasis: a randomised, double-blind, BCG-controlled trial in Sudan , 2000, The Lancet.

[10]  K. Heeg,et al.  CpG-DNA-Mediated Transient Lymphadenopathy Is Associated with a State of Th1 Predisposition to Antigen-Driven Responses1 , 2000, The Journal of Immunology.

[11]  N. Glaichenhaus,et al.  The role of antigen and IL-12 in sustaining Th1 memory cells in vivo: IL-12 is required to maintain memory/effector Th1 cells sufficient to mediate protection to an infectious parasite challenge. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[12]  Y. Belkaid,et al.  A Natural Model of Leishmania major Infection Reveals a Prolonged “Silent” Phase of Parasite Amplification in the Skin Before the Onset of Lesion Formation and Immunity , 2000, The Journal of Immunology.

[13]  John T. Chang,et al.  Requirements for the Maintenance of Th1 Immunity In Vivo Following DNA Vaccination: A Potential Immunoregulatory Role for CD8+ T Cells , 2000, The Journal of Immunology.

[14]  E. Davila,et al.  Repeated Administration of Cytosine-Phosphorothiolated Guanine-Containing Oligonucleotides Together with Peptide/Protein Immunization Results in Enhanced CTL Responses with Anti-Tumor Activity1 , 2000, The Journal of Immunology.

[15]  E. Raz,et al.  Immunostimulatory DNA-based vaccines induce cytotoxic lymphocyte activity by a T-helper cell-independent mechanism , 2000, Nature Biotechnology.

[16]  G. Hartmann,et al.  CpG DNA: a potent signal for growth, activation, and maturation of human dendritic cells. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[17]  J. Blackwell,et al.  Immunostimulatory DNA as an Adjuvant in Vaccination against Leishmania major , 1999, Infection and Immunity.

[18]  A. Krieg,et al.  Immunostimulatory oligodeoxynucleotides promote protective immunity and provide systemic therapy for leishmaniasis via IL-12- and IFN-gamma-dependent mechanisms. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[19]  S. Gurunathan,et al.  Vaccine requirements for sustained cellular immunity to an intracellular parasitic infection , 1998, Nature Medicine.

[20]  S. Reed,et al.  Human and Murine Immune Responses to a NovelLeishmania major Recombinant Protein Encoded by Members of a Multicopy Gene Family , 1998, Infection and Immunity.

[21]  K. Heeg,et al.  CpG oligodeoxynucleotides trigger protective and curative Th1 responses in lethal murine leishmaniasis. , 1998, Journal of immunology.

[22]  C. Harding,et al.  CpG Oligodeoxynucleotides Act as Adjuvants that Switch on T Helper 1 (Th1) Immunity , 1997, The Journal of experimental medicine.

[23]  N. Glaichenhaus,et al.  Vaccination with DNA Encoding the Immunodominant LACK Parasite Antigen Confers Protective Immunity to Mice Infected with Leishmania major , 1997, The Journal of experimental medicine.

[24]  D. Richman,et al.  Immunostimulatory DNA sequences function as T helper-1-promoting adjuvants , 1997, Nature Medicine.

[25]  I. Xenarios,et al.  IL-4 Rapidly Produced by Vβ4 Vα8 CD4+ T Cells Instructs Th2 Development and Susceptibility to Leishmania major in BALB/c Mice , 1997 .

[26]  D. Klinman,et al.  Contribution of CpG motifs to the immunogenicity of DNA vaccines. , 1997, Journal of immunology.

[27]  S. Reed,et al.  Molecular cloning of a novel protein antigen of Leishmania major that elicits a potent immune response in experimental murine leishmaniasis. , 1996, Journal of immunology.

[28]  N. Glaichenhaus,et al.  Resistance to Leishmania major Induced by Tolerance to a Single Antigen , 1996, Science.

[29]  E. Raz,et al.  Immunostimulatory DNA Sequences Necessary for Effective Intradermal Gene Immunization , 1996, Science.

[30]  S. Beaucage,et al.  CpG motifs present in bacteria DNA rapidly induce lymphocytes to secrete interleukin 6, interleukin 12, and interferon gamma. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[31]  G. Trinchieri,et al.  IL-12 is required for natural killer cell activation and subsequent T helper 1 cell development in experimental leishmaniasis. , 1995, Journal of immunology.

[32]  G. Trinchieri,et al.  The adjuvant effect of interleukin-12 in a vaccine against Leishmania major. , 1994, Science.

[33]  R. Schaub,et al.  Resolution of cutaneous leishmaniasis: interleukin 12 initiates a protective T helper type 1 immune response , 1993, The Journal of experimental medicine.

[34]  R. Rerko,et al.  Recombinant interleukin 12 cures mice infected with Leishmania major , 1993, The Journal of experimental medicine.

[35]  R. Locksley,et al.  Cure of murine leishmaniasis with anti-interleukin 4 monoclonal antibody. Evidence for a T cell-dependent, interferon gamma-independent mechanism , 1990, The Journal of experimental medicine.