Search

Pre-existing immunity to dengue virus (DENV) can either protect against or exacerbate, a phenomenon known as antibody dependent enhancement (ADE), a secondary DENV infection. DENV, as an escalating health problem worldwide, has increased the urgency to understand the precise parameters shaping the anti-DENV antibody (Ab) and T cell responses, thereby tipping the balance towards protection versus pathogenesis. Herein, we present the current state of knowledge of about the interplay between the Ab and T cell responses that dictate the outcome of DENV infection and discuss how this newfound knowledge is reshaping strategies for developing safe and effective DENV vaccines., (Copyright © 2020 Elsevier B.V. All rights reserved.)

The underlying mechanisms by which prior immunity to dengue virus (DENV) affords cross-protection against the related flavivirus Zika virus (ZIKV) are poorly understood. Here, we examine the ability of DENV/ZIKV-cross-reactive CD4 + T cells to protect against versus exacerbate ZIKV infection by using a histocompatibility leukocyte antigen (HLA)-DRB1 ∗ 0101 transgenic, interferon α/β receptor-deficient mouse model that supports robust DENV and ZIKV replication. By mapping the HLA-DRB1 ∗ 0101-restricted T cell response, we identify DENV/ZIKV-cross-reactive CD4 + T cell epitopes that stimulate interferon gamma (IFNγ) and/or tumor necrosis factor (TNF) production. Vaccination of naive HLA-DRB1 ∗ 0101 transgenic mice with these peptides induces a CD4 + T cell response sufficient to reduce tissue viral burden following ZIKV infection. Notably, this protective response requires IFNγ and/or TNF secretion but not anti-ZIKV immunoglobulin G (IgG) production. Thus, DENV/ZIKV-cross-reactive CD4 + T cells producing canonical Th1 cytokines can suppress ZIKV replication in an antibody-independent manner. These results may have important implications for increasing the efficacy and safety of DENV/ZIKV vaccines and for developing pan-flavivirus vaccines., Competing Interests: Declaration of Interests The La Jolla Institute for Immunology has a pending USA patent application, 16/537,447, covering methods and compositions utilizing the epitopes described in this manuscript for the treatment and prevention of flaviviruses, with S.S. listed as the inventor., (Published by Elsevier Inc.)