The antibody response induced FMDV vaccines in sheep correlates with early transcriptomic responses in blood

Foot and mouth disease (FMD) is a highly contagious viral disease with high economic impact, representing a major threat for cloven-hooved mammals worldwide. Vaccines based on adjuvanted inactivated virus (iFMDV) induce effective protective immunity implicating antibody (Ab) responses. To reduce the biosafety constraints of the manufacturing process, a non-replicative human adenovirus type 5 vector encoding FMDV antigens (Ad5-FMDV) has been developed. Here we compared the immunogenicity of iFMDV and Ad5-FMDV with and without the ISA206VG emulsion-type adjuvant in sheep. Contrasted Ab responses were obtained: iFMDV induced the highest Ab levels, Ad5-FMDV the lowest ones, and ISA206VG increased the Ad5-FMDV-induced Ab responses to protective levels. Each vaccine generated heterogeneous Ab responses, with high and low responders, the latter being considered as obstacles to vaccine effectiveness. A transcriptomic study on total blood responses at 24 h post-vaccination revealed several blood gene module activities correlating with long-term Ab responses. Downmodulation of T cell modules' activities correlated with high responses to iFMDV and to Ad5-FMDV+ISA206VG vaccines as also found in other systems vaccinology studies in humans and sheep. The impact of cell cycle activity depended on the vaccine types, as it positively correlated with higher responses to iFMDV but negatively to non-adjuvanted Ad5-FMDV. Finally an elevated B cell activity at 24 h correlated with high Ab responses to the Ad5-FMDV+ISA206VG vaccine. This study provides insights into the early mechanisms driving the Ab response induced by different vaccine regimens including Ad5 vectors and points to T cell modules as early biomarker candidates of different vaccine-type efficacy across species. Foot and mouth disease virus: correlates of protection Foot and mouth disease virus (FMDV) is a serious pathogen of cloven hoofed mammals and is of high economic and veterinary importance. Inactivated vaccine (iFMDV) is effective but difficult to produce because of high biosafety level requirements; non-replicating adenovirus vectors carrying key FMDV antigens (Ad5-FMDV) might therefore represent an attractive alternative. Isabelle Schwartz-Cornil and colleagues use sheep to systematically compare vaccination with adjuvanted iFMDV, adjuvanted Ad5-FMDV, or non-adjuvanted Ad5-FMDV. All vaccines produce neutralizing antibody responses which are stable to at least one year, however the iFMDV group elicits the strongest response, followed by the adjuvanted Ad5-FMDV. Ad5-FMDV alone produces weak antibody titers. Blood transcriptomic analysis performed in the first 24 h following vaccination identifies a reduced T cell gene expression module as a correlate of high neutralizing antibody titers. Blood gene expression might therefore offer insights into the mechanistic underpinnings of humoral immunity as well as provide useful biomarker correlates of protection.