Dengue-Zika: Correlates of Cross-Protection in Non-Human Primates

Project Abstract: Little is known about the effect of a previous immunity to ZIKV on a subsequent DENV infection. During the recent ZIKV epidemic, part of the population naïve to DENV such as newborns, DENV-naïve children and adults, and travelers from non-flavivirus endemic areas could be exposed to a ZIKV infection before to DENV. Eventually, herd immunity will reduce ZIKV transmission allowing DENV to re-emerge and potentially infect the ZIKV-immune population. It has being well-described that ZIKV-immune serum can enhance DENV infection in vitro, however little evidence is available about this phenomenon occurring in vivo. Recently George et al., showed that a short-term immunity to ZIKV can enhance DENV infection in rhesus macaques inducing a pro-inflammatory cytokine profile and higher peak of DENV viremia. However, we have result showing that previous ZIKV immunity can modulate the immune response against DENV but does not result in enhancement (Perez-Guzman E, et al., submitted). We also showed that the T cells immune response plays a relevant role in the modulation of the immune response, but it is unclear if the role is protective or not. Currently there is not a known correlates of protection from previous DENV immunity against ZIKV or vice versa and this is a key information in order to design effective ZIKV vaccines to prevent the devastating effect associated with this virus like Guillain-Barré Syndrome and Congenital Zika Syndrome. In addition to our findings in Non-Human Primates (NHP), recent publications using small animals (immunodeficient mice), showing that CD8+ T cells are essential for the control of ZIKV viremia and pathogenesis including control of ZIKV viremia during pregnancy. Also the protective role of CD4+ T cells against neuroinvasive ZIKV disease have been documented by our collaborators. However, those experiments have been performed in immunodeficient animals lacking essential antiviral mechanisms that otherwise, will effectively contribute to the control of the viral replication. Because of that, it is highly necessary to characterize the cellular immune response in the control of a heterologous secondary DENV or ZIKV infection in the presence of previous DENV or ZIKV immunity in an immunological competent animal model that resemble the human immune system like the NHP. The overall hypothesis behind this work is that the cross-primed cellular immune response may be critical controlling the DENV and ZIKV infection and provides heterologous protection against each other.