The tuberculosis vaccine candidate Bacillus Calmette-Guérin ΔureC::hly coexpressing human interleukin-7 or -18 enhances antigen-specific T cell responses in mice.
Bacillus Calmette-Guérin (BCG), the only approved tuberculosis vaccine, provides only limited protection. Previously, we generated a recombinant derivative (BCG ΔureC::hly), which secretes the pore-forming toxin listeriolysin O (LLO) of Listeria monocytogenes. This vaccine shows superior protection against tuberculosis in preclinical models and is safe in humans. Here we describe two new vaccine strains which express human interleukin-7 (hIL)-7 or hIL-18 in the genetic background of BCG ΔureC::hly to modulate specific T cell immunity. Both strains exhibited an uncompromised in vitro growth pattern, while inducing a proinflammatory cytokine profile in human dendritic cells (DCs). Human DCs harbouring either strain efficiently promoted secretion of IL-2 by autologous T cells in a coculture system, suggesting superior immunogenicity. BALB/c mice vaccinated with BCG ΔureC::hly, BCG ΔureC::hly_hIL7 or BCG ΔureC::hly_hIL18 developed a more robust Th1 response than after vaccination with parental BCG. Both strains provided significantly better protection than BCG in a murine Mycobacterium tuberculosis challenge model but efficacy remained comparable to that afforded by BCG ΔureC::hly. We conclude that expression of hIL-7 or hIL-18 enhanced specific T cell responses but failed to improve protection over BCG ΔureC::hly in mice.
Max Planck Institute for Infection Biology, Department of Immunology, Berlin, Germany.
Martin
M
Rao
Alexis
A
Vogelzang
Peggy
P
Kaiser
Stefanie
S
Schuerer
Stefan H E
SH
Kaufmann
Martin
M
Gengenbacher
D000818:Animals; D000942:Antigens, Bacterial / Q000276:immunology; D001500:BCG Vaccine / Q000235:genetics / Q000276:immunology*; D023201:CD40 Ligand / Q000378:metabolism; D002478:Cells, Cultured; D005260:Female; D015870:Gene Expression; D006801:Humans; D020382:Interleukin-18 / Q000096:biosynthesis* / Q000235:genetics; D015851:Interleukin-7 / Q000096:biosynthesis* / Q000235:genetics; D008168:Lung / Q000276:immunology / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D009169:Mycobacterium tuberculosis / Q000276:immunology*; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000235:genetics; D013154:Spleen / Q000276:immunology / Q000473:pathology; D018417:Th1 Cells / Q000276:immunology* / Q000378:metabolism; D014376:Tuberculosis / Q000517:prevention & control*; D014611:Vaccination
D000942:Antigens, Bacterial; D001500:BCG Vaccine; C000589760:IL18 protein, human; C508605:IL7 protein, human; D020382:Interleukin-18; D015851:Interleukin-7; D011994:Recombinant Proteins; D023201:CD40 Ligand