Vaccine development against Schmallenberg virus: from classical inactivated to modified-live to scaffold particle vaccines.

Background: Subsequent to its first detection in 2011, the insect-transmitted bunyavirus Schmallenberg virus (SBV; genus Orthobunyavirus) caused a large-scale epizootic of fetal malformation in the European ruminant population. By now, SBV established an enzootic status in Central Europe with regular wave-like re-emergence, which has prompted intensive research efforts in order to elucidate the pathogenesis and to develop countermeasures. Since different orthobunyaviruses share a very similar structural organization, SBV has become an important model virus to study orthobunyaviruses in general and for the development of vaccines. In this review article, we summarize which vaccine formulations have been tested to prevent SBV infections in livestock animals. MAIN: In a first step, inactivated SBV candidate vaccines were developed, which efficiently protected against an experimental SBV infection. Due to the inability to differentiate infected from vaccinated animals (= DIVA capability), a series of further approaches ranging from modified live, live-vectored, subunit and DNA-mediated vaccine delivery to multimeric antigen-presentation on scaffold particles was developed and evaluated. In short, it was repeatedly demonstrated that the N-terminal half of the glycoprotein Gc, composed of the Gc head and the head-stalk, is highly immunogenic, with a superior immunogenicity of the complete head-stalk domain compared to the Gc head only. Furthermore, in all Gc protein-based vaccine candidates, immunized animals can be readily discriminated from animals infected with the field virus by the absence of antibodies against the viral N-protein.

Conclusions: Using SBV as a model virus, several vaccination-challenge studies in target species underscored the superior performance of antigenic domains compared to linear epitopes regarding their immunogenicity. In addition, it could be shown that holistic approaches combining immunization-challenge infection studies with structural analyses provide essential knowledge required for an improved vaccine design.