Het gele koortsvaccin aan het werk: mechanismen en platform voor vaccins tegen chronische hepatitis B en COVID-19

The live-attenuated yellow fever virus (YFV) vaccine YF17D has been administered hundreds of millions of times, since its development in the 1930s. It is considered an outstanding vaccine, because of its efficacy, a consequence of its ability to activate multiple arms of the immune system upon inoculation. Anti-YFV neutralizing antibodies (nAbs) have long been considered to be sufficient and required for protection. We have challenged this idea by showing that mice vaccinated with a YFV-Japanese encephalitis virus (JEV) chimera, which does not elicit anti-YFV nAbs, are protected against an otherwise lethal YFV challenge. This finding teaches us that nAbs are not required for protection, and that other responses such as NS1 antibodies, T cells, antibody-dependent cellular cytotoxicity (ADCC), or a combination thereof may be sufficient to protect mice against YFV challenge. Since the beginning of this century, several sites in the YF17D genome permissive for insertion of foreign antigens have been discovered. We have gratefully exploited this attribute of YF17D to serve as vaccine platform for the development of a therapeutic vaccine candidate against chronic hepatitis B, a liver disease caused by the hepatitis B virus (HBV), for which no cure exists to this date. The HBV core antigen (HBc) was inserted in two sites of the YF17D genome, and both candidates were compared side by side for the generation of anti-HBc responses. One of these candidates, when applied as booster after an HBc protein prime, elicited T cells that produce antiviral cytokines, and are able to destroy target cells in vivo. This YF17D-based vaccine may thus hold promise as part of a therapeutic regimen that aims to resolve HBV chronicity. Finally, in response to the COVID-19 pandemic, we set out to develop and test antivirals and a YF17D-based vaccine against SARS-CoV-2, an endeavor that requires setting up an adequate animal model. We have tested several mouse and hamster strains for their permissiveness for SARS-CoV-2, and determined that golden hamsters (Mesocricetus auratus) were a suitable model because of replication of SARS-CoV-2 to high titers in hamster lungs, and the appearance of COVID-19-like lung consolidations just four days after infection. Interestingly, we found more replication, yet an absence of disease in a STAT2 knock-out hamster line, suggesting that type I interferon signaling, while antiviral, also exacerbates lung disease.

Publication year:2021

Accessibility:Open