Listeria monocytogenes are Gram-positive intracellular bacteria which stimulate cellular immune responses, those necessary for elimination of viruses. Engineered L. monocytogenes are effective vaccine vectors for delivery of both viral and tumor antigens in animals. Both therapeutic and prophylactic approaches are successful in animals. Listeria spp. Are present in foods, enter the body through the intestine and may disseminate to cause serious infection with a tropism for the central nervous system and placenta. Safety is therefore a major consideration in use of L. monocytogenes as a vector in humans. We have initiated (to our knowledge) the first safety study of a live attenuated L. monocytogenes vector organism in human volunteers. A highly attenuated derivative of L. monocytogenes 10403S deleted for the virulence elements actA and plcB is being studied. There have been no serious adverse events to date in 18 volunteers who received single oral escalating doses of this attenuated strain (10E5 to 10E9 colony forming units). This proposal sets forth a plan for ongoing evaluation of Listeria bacteria as vaccine vectors in humans. Attenuated L. monocytogenes will be engineered to express defined influenza A and HIV Gag epitopes as secreted fusion proteins of listeriolysin. Strains constructed will be evaluated bacteriologically, in mice and in tissue culture systems. Promising strains will be carried on for evaluation in small inpatient clinical studies designed to evaluate safety, shedding and human immunogenicity. Contemporary immunological studies using tetramer, FACS and ELISPOT technologies will be used to determine whether discrete human cellular immune responses to vectored viral antigens can be detected in humans after these investigational immunizations. These studies will provide important data on the feasibility and utility of using Listeria monocytogenes vectors in humans.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI051206-03
Application #
6763110
Study Section
Special Emphasis Panel (ZRG1-VACC (01))
Program Officer
Pensiero, Michael N
Project Start
2002-06-15
Project End
2007-05-31
Budget Start
2004-06-01
Budget End
2005-05-31
Support Year
3
Fiscal Year
2004
Total Cost
$393,810
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199