CD40 signaling converts a minimally immunogenic antigen into a potent vaccine against the intracellular pathogen Listeria monocytogenes

Conventional vaccination strategies have failed for numerous pathogens, and the development of novel approaches to vaccine development Is a major publ ic health priority. Killed or subunit vaccines represent an attractive appr oach due to their safety, but they suffer from low immunogenicity and gener ally require adjuvants. In this study, the possibility of harnessing CD40 s ignaling for enhancing the immunogenicity of killed vaccines was investigat ed. Intravenous immunization of C57BL/6 mice with heat-killed Listeria mono cytogenes (HKL) induced minimal immunity, but HKL administered together wit h an agonistic anti-CD40 mAb induced high levels of both CD4(+) and CD8(+) T cells capable of producing IFN-gamma following in vitro HKL stimulation. HKL/anti-CD40 vaccination elicited robust protection against subsequent Lis teria challenge. Approximately 1000-fold fewer bacteria were detected in th e liver and spleen of vaccinated mice, and vaccinated mice were also able t o resist a normally lethal Listeria challenge. CD40-mediated adjuvant activ ity required endogenous IL-12 at the time of vaccination, and protection wa s mediated by both CD8(+) and CD4(+) T cells. Thus, CD40 signaling can deli ver potent adjuvant activity for vaccination against intracellular pathogen s and is particularly effective for pathogens requiring both CD4(+) and CD8 (+) T cells for effective control. The Journal of Immunology, 2001.