A human dendritic cell-based in vitro model to assess Mycobacterium tuberculosis SO2 vaccine immunogenicity.

Marilena Etna

doi:10.14573/altex.1311041

Abstract

Among the tuberculosis (TB) vaccine candidates, SO2 is the prototype of the first live-attenuated vaccine that recently entered into clinical trials. To investigate the capacity of SO2 to stimulate an appropriate immune response in vitro within a human immunological context, a comparative analysis of the effects promoted by SO2, the current Bacille Calmette-Guerin (BCG) vaccine and Mycobacterium tuberculosis (Mtb) was conducted in human primary dendritic cells (DC), which are critical modulators of vaccine-induced immunity. In particular, we found that SO2 promotes the expression of maturation markers similarly to BCG but at a lower extent than Mtb. Moreover, SO2-infected DC released higher levels of interleukin (IL)-23 than BCG-infected cells, which account for the expansion of interferon (IFN)-γ-producing T cells in an IL-12-independent manner. In the autologous mixed leukocyte reaction setting, the expansion of IL-17-producing T cells was also observed in response to SO2 infection. Interestingly, apoptosis and autophagic flux, events required for the antigen presentation within MHC class II complex, were not affected in DC infected with SO2, conversely to what observed upon Mtb stimulation. Collectively, our results indicate that SO2 represents a promising TB vaccine candidate, which displays an attenuated phenotype and promotes in DC a stronger capacity to stimulate the Th response than BCG vaccine. Interestingly, the data obtained by using the human DC-based experimental setting mirrored the results derived from studies in animal models, suggesting that this system could be used for an efficient and rapid down-selection of new TB vaccine candidates, contributing to achieve the "3Rs" objective.

Highlights

Tuberculosis (TB) remains an urgent global health problem with about 9 million new cases and 1.4 million deaths each year (WHO, 2012)
We observed that Bacille CalmetteGuerin (BCG) was less efficient in inducing dendritic cells (DC) maturation and, in turn, in promoting a T helper (Th) 1-oriented T cell response compared to Mycobacterium tuberculosis (Mtb) (Giacomini et al, 2006). By using this DC-based setting, we found that Mtb H37Rv inhibits the fusion of autophagosome to lysosome, whereas no inhibition was observed in DC infected with either live or heat-inactivated Mtb H37Ra or BCG (Romagnoli et al, 2012; Martin et al, 2006; Cardona et al, 2009; Williams et al, 2005)
In line with the results obtained in animal models (Aguilar et al, 2007), we found that SO2 displays interesting features as a vaccine candidate since it possesses a stronger capacity to expand the Th1 and Th17 response than the BCG Danish vaccine

Summary

Introduction

Tuberculosis (TB) remains an urgent global health problem with about 9 million new cases and 1.4 million deaths each year (WHO, 2012). An estimated one third of the world population is latently infected with Mycobacterium tuberculosis (Mtb) and at risk of developing TB. The dual pandemic of TB and HIV/ AIDS and the increasing emergence of (multi) drug-resistant strains severely aggravate the issue and hamper current control strategies (WHO, 2012). To achieve effective and sustainable control of TB, there is a compelling need for vaccines that can reduce the development of disease both in adolescents and adults following exposure to new infection, and in the 2 billion individuals who have already been exposed to Mtb. The current TB vaccine, the live-attenuated Bacille CalmetteGuerin (BCG) derived from Mycobacterium bovis, is effective in preventing severe disseminated forms of TB, including meningitis and miliary TB, in infants. BCG is unsafe in HIV positive infants and is not recommended for use in this population (WHO, 2012)

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