A Vesicular Stomatitis Virus Recombinant Expressing Granulocyte-Macrophage Colony-Stimulating Factor Induces Enhanced T-Cell Responses and Is Highly Attenuated for Replication in Animals

Abstract

Live attenuated vectors based on recombinant vesicular stomatitis viruses (rVSVs) expressing foreign antigens are highly effective vaccines in animal models. In this study, we report that an rVSV (VSV-GMCSF1) expressing high levels of murine granulocyte-macrophage colony-stimulating factor (GM-CSF) from the first position in the viral genome is highly attenuated in terms of viral dissemination and pathogenesis after intranasal delivery to mice. However, this highly attenuated virus generated antibody and T-cell responses equivalent to those induced by a control virus expressing enhanced green fluorescent protein (EGFP) from the first position (VSV-EGFP1). The better containment and clearance of VSV-GMCSF1 may be due to enhanced recruitment of macrophages to the site of infection but is not explained by a greater induction of interferons. The primary CD8 T-cell and neutralizing antibody responses to VSV-GMCSF1 were equivalent to those generated by VSV-EGFP1, while the CD8 T-cell memory and recall responses to the vector were enhanced in mice infected with VSV-GMCSF1. It is likely that the GM-CSF produced by immunization with this virus results in an enhanced recruitment of antigen-presenting cells, leading to better acute and long-term T-cell responses. This recruitment appears to cancel out any negative effect of viral attenuation on immunogenicity.