Previous studies have found that neutralising antibodies (nAbs) are required to protect against dengue virus (DENV) infection. The authors were interested in the induction of this antibodies and whether this mechanism can be used to develop vaccines. They examined the early immune responses to flaviviruses in human peripheral blood mononuclear cells and screened a panel of toll-like receptor (TLR) agonists that stimulate the same immune signatures. Flavivirus infection was characterised by monocyte/macrophage-driven inflammatory and interferon responses and were associated with the induction of nAbs in humans immunised with the yellow fever vaccine YF-17D. These signatures were best reproduced by the combination of TLR agonists Pam3CSK4 and PolyI:C (PP). When mice and macaques were immunised with a weakly immunogenic recombinant DENV-2 envelope domain III (EDIII) they induced more consistent nAb and CD4+ T cell responses with PP compared with alum plus monophosphoryl lipid A. The induction of nAbs by PP was found to require interferon-mediated signals in the macrophages of mice. However, EDIII+PP vaccination only provided partial protection against subsequent viral challenge. Therefore this study goes some way to understanding the mechanisms behind nAb induction and forms a basis for further improving antigen/adjuvant combinations for dengue vaccine development.
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