Recombinant BCG Vaccines Reduce Pneumovirus-Caused Airway Pathology by Inducing Protective Humoral Immunity.

Jorge A Soto,Christian E Palavecino,Nicolás M S Gálvez,Susan M Bueno,Claudia A Rivera,Pablo F Céspedes,Alexis M Kalergis,Emma Rey-Jurado

doi:10.3389/fimmu.2018.02875

Abstract

The Human Respiratory Syncytial Virus (hRSV) and the Human Metapneumovirus (hMPV) are two pneumoviruses that are leading agents causing acute lower respiratory tract infections (ALRTIs) affecting young infants, the elderly, and immunocompromised patients worldwide. Since these pathogens were first discovered, many approaches for the licensing of safe and effective vaccines have been explored being unsuccessful to date. We have previously described that immunization with recombinant strains of Mycobacterium bovis Bacillus Calmette-Guérin (rBCG) expressing the hRSV nucleoprotein (rBCG-N) or the hMPV phosphoprotein (rBCG-P) induced immune protection against each respective virus. These vaccines efficiently promoted viral clearance without significant lung damage, mainly through the induction of a T helper 1 cellular immunity. Here we show that upon viral challenge, rBCG-immunized mice developed a protective humoral immunity, characterized by production of antibodies specific for most hRSV and hMPV proteins. Further, isotype switching from IgG1 to IgG2a was observed in mice immunized with rBCG vaccines and correlated with an increased viral clearance, as compared to unimmunized animals. Finally, sera obtained from animals immunized with rBCG vaccines and infected with their respective viruses exhibited virus neutralizing capacity and protected naïve mice from viral replication and pulmonary disease. These results support the notion that the use of rBCG strains could be considered as an effective vaccination approach against other respiratory viruses with similar biology as hRSV and hMPV.

Highlights

For almost a century, Mycobacterium bovis Bacillus Calmette-Guérin (BCG) has been widely used to prevent Tuberculosis and has been characterized as an effective T helper type 1 (Th1) inducer [1]
Mice from groups nt-human Metapneumovirus (hMPV), hMPV-transferred, and BCG-WT+hMPV transferred showed a significant loss of lung structure and an increase of inflammatory cell infiltration (Figure 6F). These data suggest that passive transfer of humoral immunity from recombinant BCG strains (rBCG)-vaccinated mice into naïve animals is able to significantly reduce virus-associated pathology symptoms, characterized by viral loads, neutrophil infiltration, and lung structure damage. Both human Respiratory Syncytial Virus (hRSV) and hMPV are respiratory viruses identified as the leading cause of most pathologies affecting the upper and lower respiratory tract of infants, children, elderly and immunocompromised people [10]
We sought to evaluate whether the previously found cellmediated immune response protection against hRSV and hMPV was accompanied by a virus-specific neutralizing antibodies production after viral infection

Summary

Introduction

Mycobacterium bovis Bacillus Calmette-Guérin (BCG) has been widely used to prevent Tuberculosis and has been characterized as an effective T helper type 1 (Th1) inducer [1]. To hRSV, human Metapneumovirus (hMPV) is the second cause of ALRTIs [9] and was first identified in 2001 [10]. Prospective surveillance studies have suggested that children affected by severe hMPV infections usually require longer recovery periods at intensive care units than do children infected with hRSV [11,12,13,14]. Both hRSV and hMPV are RNA single-stranded, negative sense enveloped viruses, belonging to the Pneumoviridae family, the Orthopneumovirus genus and the Metapneumovirus genus, respectively [15]. HRSV has been recently renamed as human Orthopneumovirus [15]

Methods

Results

Conclusion