Listeria monocytogenes is an intracellular bacterial pathogen which causes bacteremia and has a tropism for the central nervous system and a propensity to cause maternofetal infection. L. monocytogenes has been shown to be an effective prophylactic and a therapeutic vaccine vector for viral and tumor antigens in animal models. L. monocytogenes mutants lacking the ActA protein, which is essential for intracellular movement, are attenuated but retain immunogenicity in mice. Given the pathogenic potential of L. monocytogenes, we created an attenuated mutant strain bearing double deletions in the actA and plcB virulence genes for an initial clinical safety study of a prototype L. monocytogenes vector in adults. Twenty healthy volunteers received single escalating oral doses (10 6 to 10 9 CFU, 4 volunteers per dose cohort) of this attenuated L. monocytogenes, designated LH1169. Volunteers were monitored in the hospital for 14 days with frequent clinical checks and daily blood and stool cultures, and they were monitored for six additional weeks as outpatients. There were no positive blood cultures and no fevers attributable to the investigational inoculation. Most volunteers shed vaccine bacteria for 4 days or less, without diarrhea. One volunteer had a late positive stool culture during outpatient follow-up. Three volunteers had abnormal liver function test results temporally associated with inoculation; one could be reasonably attributed to another cause. In the highest-dose cohort, humoral, mucosal, and cellular immune responses to the investigational organism were detected in individual volunteers. Attenuated L. monocytogenes can be studied in adult volunteers without serious long-term health sequelae.Listeria monocytogenes is a gram-positive bacterium which has long been studied in mice to elucidate mechanisms of cellular immune responses to intracellular pathogens (29, 35). Schafer and colleagues initially proposed that escape of L. monocytogenes from the phagocytic vacuole into the eukaryotic cytoplasm might make these organisms efficient vectors for delivery of antigens to the major histocompatibility complex class I-restricted antigen processing pathways (48). L. monocytogenes vectors have been used to deliver lymphocytic choriomeningitis virus (LCMV) nucleoprotein antigens to mice, with subsequent protection against fatal challenge with LCMV (21, 52, 53). Recombinant L. monocytogenes expressing cottontail rabbit papillomavirus E1 antigen has been successfully used as a therapeutic immunogen in animals bearing papillomavirus-induced cutaneous tumors (28). L. monocytogenes is being pursued as a vector for antigens derived from human papillomaviruses (23) and human immunodeficiency virus type 1 (HIV-1) (40,41). A murine study showed that oral inoculation of L. monocytogenes expressing HIV-1-gag induced mucosal and systemic immunity to this viral antigen (45). After careful review of available data on oral inoculation of wild-type L. monocytogenes in primates (17) and farm animals, (34,42,43) clinical data avail...

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