Vaccination is an effective and economical method of preventing disease. It is hoped that orally administered vaccines will have the widest application and induce immunity at mucosal surfaces. Live, orally administered attenuated bacterial vectors have been very effective in animal models. The purpose of this project is to gain important safety and immunogenicity data on Salmonella typhimurium vectors expressing a clinically relevant HIV-1 antigen by studying this prototype vaccine organism in human volunteers. The proposal describes an integrated laboratory and clinical project. The application proposes completion of an ongoing Phase I dose escalation study of a Salmonella typhimurium vector expressing HIV-1 Gag (CKS257), and describes follow-up studies designed to enhance immune responses to HIV-1 Gag in humans. These experiments include multi-dosing, transcutaneous boosting, and study of a """"""""mucosal prime/systemic boost"""""""" strategy, if possible. The phoP/phoQ/aroA-deleted bacterial vector and expression system were chosen based upon pre-clinical laboratory and animal studies which suggest that this strain will be safe and engender cellular immune responses to the vectored antigen. The phoP/phoQ and aroA genes are important for Salmonella persistence/virulence within mammals; deletion of these genes results in major attenuation. A rationally-engineeered HIV-1 Gag antigen is expressed from a balanced-lethal plasmid and secreted from the Salmonella vector via the Type III Secretion System(TTSS). In mice, antigens secreted via the TTSS results in superior immune responses and greater vaccine efficacy than vector associated antigens. Clinical safety and vaccine shedding is carefully evaluated and humoral, mucosal and cellular immune responses to the vector and HIV-Gag are measured. In addition, new constructs will be generated in the laboratory to clinically test a promising approach which enhances the immunogenicity of Salmonella-vectored antigens in animal models, but has never been tested in humans: driving antigens from PhoP-activated promoters. This will necessitate using a vector attenuation strategy different from the well-characterized PhoP/PhoQ null strains, and therefore require significant preclinical work. The laboratory has significant experience in translational investigation of live bacterial vectors. The major goal of the project is to provide practical safety and immunogenicity data in humans which will help efficiently direct development of live bacterial vectors.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
1R01AI067103-01
Application #
7006526
Study Section
Special Emphasis Panel (ZRG1-VACC (01))
Program Officer
Pensiero, Michael N
Project Start
2005-07-01
Project End
2010-06-30
Budget Start
2005-07-01
Budget End
2006-06-30
Support Year
1
Fiscal Year
2005
Total Cost
$489,596
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
Johnson, Paul V; Blair, Barbra M; Zeller, Skye et al. (2011) Attenuated Listeria monocytogenes vaccine vectors expressing influenza A nucleoprotein: preclinical evaluation and oral inoculation of volunteers. Microbiol Immunol 55:304-17
Charles, Richelle C; Harris, Jason B; Chase, Michael R et al. (2009) Comparative proteomic analysis of the PhoP regulon in Salmonella enterica serovar Typhi versus Typhimurium. PLoS One 4:e6994
Lankowski, Alexander J; Hohmann, Elizabeth L (2007) Killed but metabolically active Salmonella typhimurium: application of a new technology to an old vector. J Infect Dis 195:1203-11
Kotton, Camille N; Lankowski, Alexander J; Scott, Nathaniel et al. (2006) Safety and immunogenicity of attenuated Salmonella enterica serovar Typhimurium delivering an HIV-1 Gag antigen via the Salmonella Type III secretion system. Vaccine 24:6216-24