Periodontitis is a major cause of tooth loss in adults in the US and worldwide. There is a compelling need for new approaches to prevention and control. Use of a vaccine may be possible since the disease is caused by a small group of gram-negative bacteria among which Porphyromonas gingivalis predominates. Vaccine development is hampered by a gap in our fundamental knowledge about the role of immune responses in modulating periodontal tissue destruction. Studies in animal models are necessary to obtain the needed information. The Principal Investigator has shown that immunization of the nonhuman primate Macaca fascicularis, using a killed P. gingivalis vaccine, suppresses or blocks periodontal destruction as assessed by alveolar bone loss. The mechanisms may involve antibody-mediated reduction in levels of PGE2 and other inflammatory mediators, and immune neutralization of P. gingivalis virulence factors as well as opsonization. Immunization studies are likely to continue to close the gaps in our understanding of the pathogenesis. The Principal Investigator and others have demonstrated that a vaccine containing cysteine protease from P. gingivalis has high potential for inducing protection. The Principal Investigator in a pilot study has demonstrated that immunization of M. fascicularis with a vaccine containing porphypain-2 was more effective that the whole cell vaccine in reducing bone loss. PGE2 levels in crevicular fluid were significantly reduced. The Principal Investigator proposes to confirm and extend these observations by studying 10 animals immunized with gingipains and 10 control animals using their well-established protocol. The primary outcome measure will be radiographic assessment of alveolar bone status. Titers and functional biologic properties of serum, salivary, and GCF antibodies will be measured, and P. gingivalis and five other bacteria in the flora monitored by DNA probes. Effects of immunization on levels of PGE2, IL-1beta, and TNF-alpha in GCF will be determined and antibody mediated modulation of P. gingivalis virulence factors assessed. Gingival biopsies will be taken to evaluate the effect of immunization on the cellular infiltrate by immunocytochemistry and inflammatory mediator expression by in situ hybridization. Additional safety data will be obtained by necropsy of some of the animals at the end of the study. These observations will contribute in a major way to closing the gaps in our knowledge of the role of the host immune response in the pathogenesis of periodontitis.