Abstract
Neutralizing antibodies (nAbs) are a critical component for protection against dengue virus (DENV) infection, but little is known about the immune mechanisms governing their induction and whether such mechanisms can be harnessed for vaccine development. In this study, we profiled 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. Monocyte/macrophage-driven inflammatory responses and interferon responses were characteristics of flavivirus infection and associated with induction of nAbs in humans immunized with the yellow fever vaccine YF-17D. The signatures were best reproduced by the combination of TLR agonists Pam3CSK4 and PolyI:C (PP). Immunization of both mice and macaques with a poorly immunogenic recombinant DENV-2 envelope domain III (EDIII) induced more consistent nAb and CD4+ T-cell responses with PP compared to alum plus monophosphoryl lipid A. Induction of nAbs by PP required interferon-mediated signals in macrophages in mice. However, EDIII + PP vaccination only provided partial protection against viral challenge. These results provide insights into mechanisms underlying nAb induction and a basis for further improving antigen/adjuvant combinations for dengue vaccine development.
Highlights
The dengue viruses (DENV) are single-stranded RNA viruses of the flavivirus family and are divided into four serotypes (DENV-1-4).[1]
Epidemiological studies have shown that high titers of pre-existing Neutralizing antibodies (nAbs) are associated with lower disease incidence.[8,9,10] nAbs are required for protection conferred by the most effective flavivirus vaccine developed to date, the yellow fever vaccine YF-17D.11
As observed in vaccinees,[12] YF-17D infection of peripheral blood mononuclear cells (PBMCs) induced upregulation of activation markers on various immune cells, including CD80 and CD86 on myeloid dendritic cells (DCs) and CD54 and CD69 on monocytes (Fig. 1a and Supplementary Fig. 2). These results suggest that the PBMC model system could be a useful alternative to in vivo experiments to study the signatures of early response to flaviviruses
Summary
The dengue viruses (DENV) are single-stranded RNA viruses of the flavivirus family and are divided into four serotypes (DENV-1-4).[1]. DENV-3 16562 and YF17D were the only two viruses that induced a significant associated with induction of high nAb responses to DENV in upregulation of the activation markers CD69 and CD25 on CD4, humans and mimic these mechanisms with targeted adjuvants to CD8 T cells and B cells. We reproduced these signatures using a selected combination of two TLR agonists Immunization of both mice and macaques with the recombinant EDIII in the presence of the adjuvant combination induced more consistent nAb and T-cell responses, as well as partial protection against virus challenge. DC maturation appeared as an important component of the cellular responses to infection that was shared by all viruses (Fig. 1c) This was consistent with the transcriptional activity of proinflammatory cytokines TNF and IFNs (IFN-α, IFN-γ, and IFN-λ)
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