Augmentation of SIV DNA vaccine-induced cellular immunity by targeting the 4-1BB costimulatory molecule

Vaccine. 2008 Jun 13;26(25):3121-34. doi: 10.1016/j.vaccine.2008.02.017. Epub 2008 Feb 22.


DNA vaccines are effective at inducing antigen-specific cellular immune responses. Approaches to improve these responses, however, are needed. We examined the effect of stimulating 4-1BB, an activation-inducible T-cell costimulatory receptor, by intravenously co-administering anti-human 4-1BB monoclonal antibody (mAb) in DNA-immunized cynomolgus macaques. Three groups of six cynomolgus macaques were immunized intramuscularly with a DNA vaccine encoding SIV Gag antigen (pSIVgag) at weeks 0, 4 and 8. At days 12, 15, and 19, six macaques received anti-4-1BB 4E9 mAb and six macaques received anti-4-1BB 10C7 mAb. Treatment with 10C7 mAb led to a significant augmentation of SIV Gag-specific IFN-gamma, granzyme B and perforin responses. Treatment with humanized 4E9 mAb also resulted in an enhancement of SIV Gag-specific cellular responses but the magnitude was lower compared to animals receiving 10C7 mAb. These responses persisted up to week 40 and were mostly mediated by CD8(+) T cells. Treatment with anti-4-1BB mAb was more effective in driving the CD8(+) T cells toward a more differentiated CCR7(-)/CD45RA(+) effector state. This study demonstrates that targeting the 4-1BB molecule in vivo results in an enhanced and long-lasting cellular immune response. 4-1BB stimulation may be a promising approach to enhance the effectiveness of DNA vaccines.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • 4-1BB Ligand / drug effects*
  • 4-1BB Ligand / immunology
  • Animals
  • Antibodies, Monoclonal
  • Humans
  • Immunity, Cellular / drug effects*
  • Immunity, Cellular / immunology
  • Lymphocyte Activation
  • Macaca fascicularis
  • SAIDS Vaccines / administration & dosage
  • SAIDS Vaccines / immunology*
  • Simian Acquired Immunodeficiency Syndrome / immunology*
  • Simian Acquired Immunodeficiency Syndrome / prevention & control
  • Simian Immunodeficiency Virus / immunology
  • Vaccines, DNA / administration & dosage*
  • Vaccines, DNA / immunology


  • 4-1BB Ligand
  • Antibodies, Monoclonal
  • SAIDS Vaccines
  • Vaccines, DNA