AbstractLacking immunogenicity, inactivated vaccines require potent adjuvants. To understand their effects, we used a system immunology-based analysis of ovine blood transcriptional modules (BTMs) to dissect innate immune responses relating to either antibody or haptoglobin levels. Using inactivated foot-and-mouth disease virus as an antigen, we compared non-adjuvanted to liposomal-formulated vaccines complemented or not with TLR4 and TLR7 ligands. Early after vaccination, BTM relating to myeloid cells, innate immune responses, dendritic cells, and antigen presentation correlated positively, whereas BTM relating to T and natural killer cells, as well as cell cycle correlated negatively with antibody responses. Interestingly, BTM relating to myeloid cells, inflammation and antigen presentation also correlated with haptoglobin, but in a reversed manner, indicating that acute systemic inflammation is not beneficial for early antibody responses. Analysis of vaccine-dependent BTM modulation showed that liposomal formulations induced similar responses to those correlating to antibody levels, while addition of TLR ligands reduced myeloid cells, inflammation and antigen presentation BTM expression despite promoting antibody responses. Furthermore, this vaccine was more potent at downregulating T and natural killer cell BTM. When pre-vaccination BTM were analyzed, we found that high vaccine responders expressed higher levels of cell cycle and myeloid cell BTMs as compared with low responders. In conclusion, we have transferred human BTM to sheep and identified early vaccine-induced responses associated with antibody levels or unwanted inflammation. Such readouts are applicable to other veterinary species and very useful to identify efficient vaccine adjuvants, their mechanism of action, and factors related to low responders.