Dengue Virus mRNA Lipid Nanoparticle Vaccine

Abstract: Dengue virus (DENV) is a mosquito-transmitted flavivirus that causes ~390 millions infections annually. A febrile illness can progress to severe disease that leads to ~500,000 hospitalizations and ~12,500 deaths per year. DENV is currently endemic in more than 100 countries, and about 40% of the world’s population lives in dengue fever endemic areas. Several vaccine candidates are under development; the leading vaccine (Dengvaxia®, Sanofi), a four-component mixture of chimeric yellow fever virus containing the glycoprotein E sequences of the four Dengue serotypes (DENV-1-4), was recently licensed in Mexico, the Philippines, and Brazil. Although highly encouraging, this vaccine did not afford any protection to naïve individuals in phase III trials suggesting that alternative strategies and potential boosting agents should be explored as next-generation candidates. Subunit vaccines (immunogens) provide an attractive option due to ease of manufacturing, favorable safety profile, and avoidance of premature clearance of the vaccine due to pre-existing immunity to vaccine vector components of live attenuated vaccines. A critical concern for Dengue vaccine development is the potential for antibody-dependent enhancement (ADE) of infection, a phenomenon whereby non-neutralizing cross-reactive antibodies cause increased infection of heterotypic virus in vivo by virtue of interaction with Fc-receptors. Thus, the ideal immunogen would elicit bNAbs and not non-neutralizing antibody responses. Furthermore, ADE activity for Zika virus (ZIKV), another flavivirus, has recently been demonstrated in sera from DENV immune patients, suggesting that next-generation global flavivirus vaccine efforts should focus on candidates that elicit broadly neutralizing responses against DENV1-4 as well as ZIKV. The research outlined in this proposal brings forth two broadly innovative approaches to counter Dengue virus (DENV) disease that has remained refractory to traditional vaccine approaches; 1.) utilization of a next generational vaccine delivery platform, 2.) immune engineering to shape the desired immune response, and 3.) interrogate vaccine immunogenicity and efficacy in a immune competent animal model, which can recapitulate human flavivirus disease.