Killed but Metabolically Active Salmonella typhimurium: Application of a New Technology to an Old Vector
Infectious Diseases Division, Massachusetts General Hospital, Harvard Medical School, Boston
Previous studies have shown that attenuated salmonellae utilized as vaccine vectors engender strong immune responses; however, balancing immunogenicity with reactogenicity remains problematic. Recent work in other bacteria has shown that photochemical treatment of DNA excision repair mutants (ΔuvrAB) renders organisms “killed but metabolically active” (KBMA). Here, we extend this concept to Salmonella typhimurium. A strain of attenuated S. typhimurium previously evaluated in human volunteers was further deleted for uvrAB genes and designated CKS362. Photochemical treatment of CKS362 resulted in significant inactivation. These KBMA organisms were metabolically active as shown by radioactive methionine incorporation and lactate dehydrogenase activity. In mice inoculated intraperitoneally, KBMA CKS362 was markedly less reactogenic and stimulated a humoral immune equivalent to its live counterpart. Because the parental strain has previously been found to elicit strong immune responses to Salmonella antigens, we propose CKS362 as a prototype strain to test the immunogenicity of KBMA organisms in humans.
Received 15 September 2006; accepted 18 November 2006; electronically published 5 March 2007.
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Online publication date: 1-Oct-2008.
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Potential conflicts of interest: none reported.
Financial support: National Institutes of Health (grant R01 AI67103 to E.L.H.).