Abstract
Live-attenuated Listeria monocytogenes has shown encouraging potential as an immunotherapy platform in preclinical and clinical settings. However, additional safety measures will enable application across malignant and infectious diseases. Here, we describe a new vaccine platform, termed Lm-RIID (L. monocytogenes recombinase-induced intracellular death), that induces the deletion of genes required for bacterial viability yet maintains potent T cell responses to encoded antigens. Lm-RIID grows normally in broth but commits suicide inside host cells by inducing Cre recombinase and deleting essential genes flanked by loxP sites, resulting in a self-limiting infection even in immunocompromised mice. Lm-RIID vaccination of mice induces potent CD8+ T cells and protects against virulent challenges, similar to live L. monocytogenes vaccines. When combined with α-PD-1, Lm-RIID is as effective as live-attenuated L. monocytogenes in a therapeutic tumor model. This impressive efficacy, together with the increased clearance rate, makes Lm-RIID ideal for prophylactic immunization against diseases that require T cells for protection.
Highlights
Live-attenuated Listeria monocytogenes has shown encouraging potential as an immunotherapy platform in preclinical and clinical settings
To construct a vaccine with short-term viability that is still capable of robust antigen expression, we developed a suicidal L. monocytogenes strain that deletes essential genes upon reaching the intracellular milieu
The Cre recombinase gene was inserted at the actA locus under the control of the actA promoter, which is not expressed in broth but induced when L. monocytogenes reaches the host cytosol [25]
Summary
Live-attenuated Listeria monocytogenes has shown encouraging potential as an immunotherapy platform in preclinical and clinical settings. L. monocytogenes has been attenuated by the deletion of genes required for synthesis of the cell wall component D-alanine [21] These strains require D-Ala for growth in vitro and to generate functional immune responses in mice yet do not replicate inside host cells. All three of these attenuation strategies are less potent than live L. monocytogenes [3, 6, 20,21,22], which is consistent with lysis in host cells being detrimental to immunogenicity [23]
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