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Infection and Immunity, September 2009, p. 3958-3968, Vol. 77, No. 9
0019-9567/09/$08.00+0     doi:10.1128/IAI.01274-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Impact of Preexisting Vector-Specific Immunity on Vaccine Potency: Characterization of Listeria monocytogenes-Specific Humoral and Cellular Immunity in Humans and Modeling Studies Using Recombinant Vaccines in Mice {triangledown} ,{dagger}

Meredith L. Leong,1,2* Johannes Hampl,1 Weiqun Liu,1,§ Shruti Mathur,1 Keith S. Bahjat,1,{ddagger} William Luckett,1 Thomas W. Dubensky Jr.,1,¶ and Dirk G. Brockstedt1,2*

Anza Therapeutics, Concord, California,1 Aduro Biotech, Berkeley, California2

Received 17 October 2008/ Returned for modification 20 February 2009/ Accepted 3 June 2009

Recombinant live-attenuated Listeria monocytogenes is currently being developed as a vaccine platform for treatment or prevention of malignant and infectious diseases. The effectiveness of complex biologic vaccines, such as recombinant viral and bacterial vectors, can be limited by either preexisting or vaccine-induced vector-specific immunity. We characterized the level of L. monocytogenes-specific cellular and humoral immunity present in more than 70 healthy adult subjects as a first step to understanding its possible impact on the efficacy of L. monocytogenes-based vaccines being evaluated in early-phase clinical trials. Significant L. monocytogenes-specific humoral immunity was not measured in humans, consistent with a lack of antibodies in mice immunized with wild-type L. monocytogenes. Cellular immune responses specific for listeriolysin O, a secreted bacterial protein required for potency of L. monocytogenes-derived vaccines, were detected in approximately 60% of human donors tested. In mice, while wild-type L. monocytogenes did not induce significant humoral immunity, attenuated L. monocytogenes vaccine strains induced high-titer L. monocytogenes-specific antibodies when given at high doses used for immunization. Passive transfer of L. monocytogenes-specific antiserum to naïve mice had no impact on priming antigen-specific immunity in mice immunized with a recombinant L. monocytogenes vaccine. In mice with preexisting L. monocytogenes-specific immunity, priming of naïve T cells was not prevented, and antigen-specific responses could be boosted by additional vaccinations. For the first time, our findings establish the level of L. monocytogenes-specific cellular immunity in healthy adults, and, together with modeling studies performed with mice, they support the scientific rationale for repeated L. monocytogenes vaccine immunization regimens to elicit a desired therapeutic effect.

* Corresponding author. Mailing address: 626 Bancroft Way, 3C, Berkeley, CA 94710. Phone: (510) 848-4400. Fax: (510) 848-5614. E-mail for Dirk G. Brockstedt: dbrockstedt{at}adurobiotech.com. E-mail for Meredith L. Leong: mleong{at}adurobiotech.com

{triangledown} Published ahead of print on 15 June 2009.

{dagger} Supplemental material for this article may be found at http://iai.asm.org/.

Editor: V. J. DiRita

§ Current address: Cerus Corporation, Concord, CA.

{ddagger} Current address: Earle A. Chiles Research Institute, Robert W. Franz Cancer Center, Providence Portland Medical Center, Portland, OR.

Current address: Immune Design Corp., Seattle, WA.

Infection and Immunity, September 2009, p. 3958-3968, Vol. 77, No. 9
0019-9567/09/$08.00+0     doi:10.1128/IAI.01274-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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