Self-amplifying RNA as a tool to tackle emerging flavivirus outbreaks: lessons learned from the COVID-19 pandemic

Background

Outbreaks of multiple Flaviviruses have afflicted humankind for centuries due to their rapid spread predominantly by arthropod vectors. Global warming has caused epidemics to emerge in previously unaffected regions. The SARS-CoV-2 outbreak and subsequent race in vaccine development can provide strategies to the scientific community to avoid a flavivirus pandemic.

The COVID-19 battle led to the first-time authorization of messenger ribonucleic acid (mRNA) based vaccines that employ in vitro transcribed (IVT) synthetic mRNA molecules to instruct host cells to produce the viral antigen in a natural way. The mRNA platform has proven to carry several advantages over other vaccination strategies, including its flexibility due to relatively easy sequence engineering and its inability to integrate into the host`s genome. In recent years, mRNA vaccines have been generated against multiple flaviviruses, including tick-borne encephalitis virus (TBEV) and Dengue virus.

However, most of these vaccines target structural protein epitopes to induce neutralizing antibody responses, which is complicated by the potential induction of antibody-dependent enhancement (ADE). ADE is a phenomenon in which sub-neutralizing concentrations of anti-viral IgGs enhance infection of Fc gamma receptor positive cells, thereby increasing the risk of an exacerbated pathogenesis upon infection after vaccination.