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Infection and Immunity, July 2002, p. 3592-3601, Vol. 70, No. 7
0019-9567/02/$04.00+0     DOI: 10.1128/IAI.70.7.3592-3601.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Safety and Shedding of an Attenuated Strain of Listeria monocytogenes with a Deletion of actA/plcB in Adult Volunteers: a Dose Escalation Study of Oral Inoculation

Haroula Angelakopoulos,1 Katharina Loock,1 David M. Sisul,1 Eric R. Jensen,2 Jeff F. Miller,2 and Elizabeth L. Hohmann1*

Infectious Diseases Division, Massachusetts General Hospital, Boston, Massachussetts 02114,1 Department of Microbiology and Immunology, University of California at Los Angeles School of Medicine, Los Angeles, California 942702

Received 19 February 2002/ Returned for modification 28 March 2002/ Accepted 17 April 2002

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 (106 to 109 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.

* Corresponding author. Mailing address: Infectious Diseases Division, Gray/Jackson 504, Massachusetts General Hospital, 55 Fruit St., Boston, MA 02114. Phone: (617) 724-7532. Fax: (617) 724-3761. E-mail: ehohmann{at}partners.org.

Editor: D. L. Burns

Infection and Immunity, July 2002, p. 3592-3601, Vol. 70, No. 7
0019-9567/02/$04.00+0     DOI: 10.1128/IAI.70.7.3592-3601.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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