title: 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.
abstract: 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.
authors.affiliation: Anza Therapeutics, Concord, California, USA. mleong@adurobiotech.com
authors.forename: Meredith L
authors.initials: ML
authors.lastname: Leong
authors.forename: Johannes
authors.initials: J
authors.lastname: Hampl
authors.forename: Weiqun
authors.initials: W
authors.lastname: Liu
authors.forename: Shruti
authors.initials: S
authors.lastname: Mathur
authors.forename: Keith S
authors.initials: KS
authors.lastname: Bahjat
authors.forename: William
authors.initials: W
authors.lastname: Luckett
authors.forename: Thomas W
authors.initials: TW
authors.lastname: Dubensky
authors.forename: Dirk G
authors.initials: DG
authors.lastname: Brockstedt
mesh_terms: D000328:Adult; D000818:Animals; D000907:Antibodies, Bacterial / Q000097:blood*; D001427:Bacterial Toxins / Q000276:immunology; D001428:Bacterial Vaccines / Q000276:immunology*; D002460:Cell Line; D005260:Female; D005822:Genetic Vectors; D006360:Heat-Shock Proteins / Q000276:immunology; D006460:Hemolysin Proteins / Q000276:immunology; D006801:Humans; D007376:Interleukin-2 / Q000096:biosynthesis; D008089:Listeria monocytogenes / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D013601:T-Lymphocytes / Q000276:immunology; D014613:Vaccines, Attenuated / Q000276:immunology; D014614:Vaccines, Synthetic / Q000276:immunology*
chemical_list: D000907:Antibodies, Bacterial; D001427:Bacterial Toxins; D001428:Bacterial Vaccines; D006360:Heat-Shock Proteins; D006460:Hemolysin Proteins; D007376:Interleukin-2; D014613:Vaccines, Attenuated; D014614:Vaccines, Synthetic; C038705:hlyA protein, Listeria monocytogenes