New Class of Broad-Spectrum Antivirals Improves Influenza Virus Vaccine Development

Enveloped viruses can cause devastating zoonotic diseases and are the most likely to cause global pandemics. We identified a new class of small-molecule sulfur-containing antiviral compounds (XM series) that broadly inhibit enveloped viruses. The antivirals’ mechanism of action was explored via various multidisciplinary approaches, concluding that the XM antivirals alter membrane lipid chemical compositions, increase membrane order deep within the hydrophobic region of the bilayer, and increase membrane phase transition temperatures. Such effects cause inhibition of membrane fusion and viral entry, while leaving the viral glycoproteins and genomes largely unaffected. Consequently, we tested whether these features would lead to effective whole inactivated enveloped virus vaccines. As a proof-of-principle, we generated an inactivated influenza virus (IIV) vaccine using compound XM-01 (XM-01-IIV). We compared this new vaccine to traditional paraformaldehyde-inactivated, to control compound-inactivated, and to live virus vaccines, using a mouse model of disease. Excitingly, compared to a traditional IIV vaccine, XM-01-IIV vaccination improved neutralizing antibody responses against both hemagglutinin and neuraminidase, and decreased mouse morbidity and mortality following influenza virus challenge. Therefore, this study uncovers a novel class of broadly acting antivirals that enhances influenza virus vaccine development and offers great potential for broadly generating future highly-potent inactivated enveloped virus vaccines.