Abstract
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.
Highlights
An estimated 30% of the world’s population is latently infected with Mycobacterium tuberculosis, the aetiological agent of tuberculosis (TB) [1]
A robust CD4+ T helper 1 (Th1) response represented by interferon gamma (IFN-c) and tumour necrosis factor-alpha (TNF-a) expression should be induced by the prime vaccine to eventually form a pool of memory T cells which control TB disease [8,9]
The stronger transcription of human interleukin-7 (hIL)-18 was associated with reduced amounts of hly mRNA which encode listeriolysin O (LLO), the integral component of Bacillus Calmette–Guerin (BCG) DureC::hly
Summary
An estimated 30% of the world’s population is latently infected with Mycobacterium tuberculosis, the aetiological agent of tuberculosis (TB) [1]. Of an estimated 8.7 million new TB cases worldwide in 2011, 1.4 million people died of whom 95% were from low- to middle-income countries [1]. Vaccines remain the most cost-effective means to counteract the global challenges related to infectious diseases including TB [5]. Bacillus Calmette–Guerin (BCG) is the only licensed vaccine for TB, and protects children but leaves adults unprotected from the most prevalent form of the disease, pulmonary TB [6]. This calls for better vaccines against TB. A robust CD4+ T helper 1 (Th1) response represented by interferon gamma (IFN-c) and tumour necrosis factor-alpha (TNF-a) expression should be induced by the prime vaccine to eventually form a pool of memory T cells which control TB disease [8,9]
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