The long-term goal of this project is to develop a mRNA replicon-based vaccine that provides long-lived protection against the four serotypes of dengue (DENV1-4) and Zika (ZIKV) viruses. To date, flavivirus vaccine development has focused almost exclusively on the induction of neutralizing antibodies (nAbs), as they have been assumed to be the key mechanism for protection against natural infection. However, DENV and perhaps ZIKV are unusual in that weak Ab responses to vaccination or prior infection can induce antibody-dependent enhancement (ADE) of infection and pathogenesis during subsequent reinfections. In fact, ADE with severe sequalae has been documented in children given the only currently licensed DENV vaccine. Thus, the primary objective of this application is to develop an effective vaccine against DENV and ZIKV that cannot mediate ADE. We hypothesize that this vaccine will need to elicit both strong nAb responses and strong T cell effector responses that will counterbalance the presence of any ADE-mediating Abs, based on our work investigating the interplay between Ab and T cell responses to DENV and ZIKV. In particular, we have shown that CD8 T cells mediate cross-protection against heterotypic DENV and ZIKV infections, and that DENV vaccine-elicited CD8 T cells can prevent ADE. In addition, our preliminary data show that a mRNA replicon-based vaccine expressing ZIKV nonstructural protein 3 elicits only T cell but not Ab responses and confers protection against ZIKV challenge in mice. Thus, we hypothesize that our pan-flavivirus mRNA replicon-based vaccine expressing both Ab- and T cell-targeting proteins of DENV1-4 and ZIKV will produce humoral and cellular immune responses that provide robust, long-term protection against all five viruses. We will test this hypothesis by achieving the following Specific Aims: 1: To evaluate immunogenicity and protective efficacy of a pan-flavivirus vaccine against DENV1-4 and ZIKV designed to elicit CD8 T cell and Ab responses in wild-type mice. 2: To assess durability and immune mechanisms underlying the pan-flavivirus vaccine-induced protective immunity and ADE in mice. 3: To assess the immune response and protection induced by the pan- flavivirus vaccine in nonhuman primates.
DENV and ZIKV are significant causes of morbidity and mortality worldwide, as half of the world?s population is at risk of DENV and ZIKV infection in tropical and subtropical regions. DENV and ZIKV vaccines are a global public health priority. To avoid the risk of immune-mediated enhancement of disease, DENV and ZIKV vaccines should ideally induce long-lasting, protective immunity to all four DENV serotypes and ZIKV. This project evaluates a novel pan-flavivirus vaccine designed to induce both nAb responses and T cell responses and to provide long-lived protection against infection with DENV1- 4 and ZIKV.
