Exploring the Field of Respiratory Virus Preventions. How to Deal with Future Pandemics

Abstract

Global pandemics pose an ever-looming threat to global health, as was recently exemplified during the SARS-CoV-2 pandemic. All major pandemics in modern history have been caused by respiratory RNA viruses, capable of rapid mutation and evolution. The rapid mutations affects our ability to fight the disease and require new and improved treatments. In this thesis, Tjärnhage worked on multiple aspects of protection from respiratory viral disease, including both new vaccine formats and new, broad spectrum antiviral drugs. Further, he examined the immunological consequences of repeated exposures to new variants of influenza. For development of broad-spectrum antiviral drugs, we selected candidate drugs for their ability to target host-mechanisms used for viral replication. More specifically, we explored the ability of previously established cancer drugs acting on protein transport from ER to inhibit viral replication. Importantly, protective effects were observed both in cell cultures and in mice. Work on next generation vaccines against influenza was done by making trimeric APC-targeted HA, and where the structure was designed to mimic that found on virions. A single vaccination could protect mice against a lethal viral challenge, both when vaccines were delivered in the form of DNA and proteins. However, vaccinating against influenza is more immunologically complicated than one might think, as we are repeatedly exposed to different viral variants circulating in the population. In particular, there is a risk of raising new responses against previous versions at the expense of responses against the new viral variant. Tjärnhage therefore studied the effect from sequential influenza infections in mice, and found that the order of infecting strains can have a large on the impact from secondary infections.