One million € funding for the development of norovirus therapeutics

Human noroviruses are the dominant etiological agent of outbreaks of acute gastroenteritis and a major cause of sporadic infections. Noroviruses are highly infectious and less than 100 viral particles are sufficient for an infection. Despite the discovery of norovirus more than 40 years ago, there are still no approved vaccines, antivirals, or treatments. Human noroviruses are genetically and antigenically distinct.

Similar to the influenza virus, the norovirus genome is constantly evolving and novel strains emerge every other year that can lead to new epidemics and even pandemics. Human noroviruses cannot be grown robustly in cell culture, which has hampered the development of vaccines and antivirals. The first clinical studies of a norovirus vaccine were only recently, however the results were met with uncertainties, i.e., lower than expected coverage, little cross protection from other strains, and lack of long term-immunity. Nevertheless, the symptoms of gastroenteritis appeared to be slightly reduced in those immunized.

Grant Hansman's group aims at developing antivirals against human norovirus that can reduce infections, treat symptoms, or both. For this purpose, Hansman and colleagues have produced a library of "Nanobodies" that are directed against norovirus particles in order to identify ones that might inhibit norovirus infections.

Nanobodies are antibody fragments, which are composed of a monomeric, variable domain of an antibody. Hansman and colleagues identified one Nanobody (termed Nano-85) that is able to bind to antigenically distinct noroviruses with nanomolar affinities. They also found that Nano-85 binds to a highly conserved region on the virus particle and the binding interaction causes the particles to disassemble. The researchers believe that this region likely plays a central role in the stability of the particles.

The purpose of this proposal is to provide evidence that the binding of Nano-85 to this unique target region inhibits norovirus infections, since the structural integrity of particles is likely needed for replication and infection. As part of this project Hansman and colleagues will further develop Nano-85 and other Nanobodies to bind to murine norovirus with higher affinities. Overall, they will use a multidisciplinary approach to validate the interactions using bioinformatics, X-ray crystallography, molecular biology techniques, and cell culture.

The underlying concept is that Nanobodies directed against the highly conserved region(s) of the viral particles will disrupt infection, thereby reducing virus replication. Hansman will determine these effects, for the first time, in the murine norovirus cell culture system with the ultimate aim of developing antivirals for preclinical trials.