Usutu Too? Insights into vaccine development strategies for an emerging orthoflavivirus

Abstract

Despite major advances in infectious disease control, the world remains vulnerable to emerging mosquito-borne viruses, which are spreading ever more widely due to globalisation and climate change. This thesis focuses on Usutu virus (USUV), an emerging orthoflavivirus (the virus family containing dengue, Zika and yellow fever) which has become established across much of Europe in recent decades. USUV causes lethal disease in birds and, more rarely, neurological disease in humans.

The thesis gives an introduction to orthoflavivirus biology, and reviews vaccine design, including innovative approaches and associated challenges. The creation of two infectious USUV cDNA clones is described. An immunocompromised mouse model is optimised, revealing that low viral doses can cause rapid lethal disease, and used to compare different lineages of USUV circulating in the Netherlands. Attenuated USUV mutants were designed based upon mutations known from related orthoflaviviruses – but for many of these mutations the attenuation phenotype was not conserved. Chimeric vaccines using the yellow fever 17D backbone were still lethal in mice, highlighting the challenges around design strategies and research models.

The thesis concludes by discussing broader preparedness, the need for improved non-animal models, and the potential of pan-orthoflavivirus vaccines, alongside social, political, and biosecurity barriers to vaccine development.