No vaccine induced immune responses were associated with

No vaccine-induced immune responses were associated with the zoster events either in targeted immune or whole genome expression studies. This could be due to the absence of appropriate temporal sampling for the transcriptome analyses (no measurements were taken before 14days post-vaccination), or because the processes that led to VZV reactivation are not related to systemic inflammatory responses that would be measurable in peripheral blood transcriptomes. Both volunteers who developed zoster were found to constitutively express higher levels of EMR1 in their PBMCs. F4/80, the mature protein product of EMR1, has been identified on murine microglial nebivolol hcl (Zhou et al., 2013), and EMR1 has been shown to be expressed by human eosinophils (Legrand et al., 2014; Hamann et al., 2007), both of which could be relevant for control of VZV in latently infected individuals. The significance of high expression of EMR1 in the two zoster volunteers is unclear, but could represent high myeloid activation even at baseline, perhaps in some way influencing cross-talk between T cells and myeloid cells. Up-regulation of IFN-γ responses by AERAS-422 potentially could have led to higher suppression of type I IFN control of VZV reactivation. An in vitro guinea pig model for studies of VZV latency and reactivation has been developed to evaluate whether high doses of IFN-γ plus/minus activated myeloid cells (especially eosinophils) can increase VZV reactivation (Chen et al., 2011; Gan et al., 2014). In spite of the absence of robust associations between the transcriptomes and VZV reactivation, compelling and functionally relevant vaccine-induced transcriptome changes were observed that involved differential regulation of genes associated with T cell, myeloid cell, and inflammatory modules. Interestingly, up-regulation of the myeloid module-associated genes temporally matched the known peak of in vivo BCG replication. In this trial, an earlier and more robust activation of NK/cytotoxic responses was correlated with increased capacity of whole blood cell populations to inhibit mycobacterial growth post-vaccination (Fig. 7A). Control of mycobacterial growth is an important goal of the protective immune response against disseminated TB disease, and therefore these results suggest that early activation of NK/cytotoxic activity may serve as an important new target for TB vaccine improvement. In contrast, monocyte inflammatory responses were found to be negatively associated with mycobacterial growth inhibitory activity. This could be due to increased myeloid cell numbers providing a larger reservoir of target cells for infection, and/or direct interference of these cells with mycobacterial growth inhibitory mechanisms. Combined, these correlation analyses suggest that post-vaccination increases in mycobacterial growth inhibitory activity may be a manifestation of adaptive immune responses that can be prevented by too much myeloid inflammation. Additional work to confirm the importance of these early responses for optimal induction of protective long-term memory and effector functions against TB is warranted, as activators of the correct early innate immune responses could possess ideal adjuvant properties for subunit or other vaccines. The following are the supplementary data related to this article.
Contributors
Declaration of interests
Acknowledgments This work was supported by funding from Aeras, the FDA (to MB, 5U18FD004012) and the Bill and Melinda Gates Foundation (to DZ, OPP1066660). We thank Tom Evans and Ann Ginsberg of Aeras for critical comments on the manuscript, and Bridget Colvin for assistance with preparation of the manuscript.
The authors wish to point out that the units of CSF and plasma NFL in and should be corrected to ng/L. Corrected files are republished here.