Auto-Abs against type I IFNs: Strong, common, and global determinants of severe arboviral diseases

Human-tropic pathogenic arboviruses are spreading worldwide. There is immense interindividual clinical variability following infection with any arbovirus. Autoantibodies (auto-Abs) neutralizing antiviral type I IFNs (AAN-I-IFN) can underlie a small but growing number of severe arboviral diseases, whether transmitted by ticks (tick-borne encephalitis virus, TBEV; Powassan virus, POWV) or mosquitoes (West Nile virus, WNV; Usutu virus, USUV; Ross River virus, RRV) and whether due to flaviviruses (WNV, TBEV, POWV, and USUV) or alphaviruses (RRV). Evidence is documented in large cohort studies for WNV and TBEV. They can also account severe adverse reactions to the live-attenuated yellow fever virus vaccine. AAN-I-IFN are present before arboviral infection and are the cause of severe disease. Carriers of these auto-Abs are common worldwide (>100 million people), have a very high risk of severe disease (relative risk >100), and account for a sizeable proportion of cases (typically >10%). Other severe diseases due to different arboviruses may also be caused by these auto-Abs.