Abstract
Lacking 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.
Highlights
In the past, vaccines were developed empirically requiring many animal studies with a long-term follow-up to assess vaccine efficacy
If blood transcriptional modules (BTMs) families are compared with those correlating with antibody levels measured at D3, we found that “myeloid cells/inflammation” and “DC/antigen presentation” BTM families were regulated in an opposite manner
The present study adapted BTM originally developed for human blood to sheep peripheral blood mononuclear cells (PBMCs) to understand vaccine-induced responses correlating with antibody and acute-phase responses
Summary
Vaccines were developed empirically requiring many animal studies with a long-term follow-up to assess vaccine efficacy. Systems immunology offers powerful approaches towards dissecting the early innate immune response relating to potent adaptive immune responses in human.[1,2,3] This enabled to identify genes expressed in peripheral blood leukocytes within the first days after vaccination, which correlated to CD8 T-cell or antibody responses.[2,3] a main problem with this relatively simple approach was the high heterogeneity of individual responders and the difficulty to understand immunological processes from individual gene information.
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