Mimicking immune signatures of flavivirus infection with targeted adjuvants improves dengue subunit vaccine immunogenicity

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.
Dengue vaccine: adjuvants for induction of neutralizing antibodies Neutralizing antibodies (nAb) are associated with protection from symptomatic dengue virus infection and current dengue vaccine development aims to elicit a strong nAb response. However, immune mechanisms underlying nAb development in response to dengue infection or vaccination are not completely understood. In this study, led by Jianzhu Chen from the Interdisciplinary Research Group in Infectious Diseases in Singapore, researchers identify a combination of two TLR agonists that elicits better nAb responses than currently used adjuvants. Comparison of transcriptomes of human PBMCs infected with flaviviruses identifies an immune signature that is associated with induction of nAbs and a similar immune signature can be elicited with a combination of two TLR agonists. Vaccination of mice or non-human primates using these two TLR agonists as adjuvant elicits a strong nAb response. However, this vaccination regimen could not confer protection in the animals, suggesting that further improvements of this vaccine candidate will be necessary.