Auto-antibodies against type I interferons in patients with severe arboviral diseases

"Arthropod-borne viruses (arboviruses) pose a growing global health threat, as highlighted by recent epidemiological data indicating that these viruses already infect about four billion people annually. At least a third of human-tropic viral pathogens are arboviruses, amounting to a total of over 150. Although most arboviral infections are asymptomatic or paucisymptomatic, approximately one in every hundred infected individuals develop severe, and sometimes fatal diseases, with hemorrhagic fever, encephalitis, or multi-organ failure. In addition, live-attenuated viral vaccines, while very effective, can cause rare but severe adverse reactions, as reported for the Yellow Fever Virus vaccine (YFV 17D), the Dengue Virus vaccine (CYD-TDV), and more recently the Chikungunya Virus (CHIKV) vaccine. Although rare, adverse reactions to live-attenuated viral vaccines pose major questions in terms of public health, pertaining both to vaccine design and vaccine acceptance. Identification of individuals at-risk of severe viral disease or severe adverse reaction following live-attenuated vaccination is thus a major objective. In this context, we have already discovered that auto-antibodies neutralizing type I interferons (AAN-I-IFNs) underlie one third of severe adverse reactions to the YFV vaccine, 10% of cases of tick-borne virus encephalitis, 40% of cases of West Nile virus encephalitis, and most cases of rarer Usutu and Powassan virus encephalitis. Indeed, the odds ratios of viral disease in carriers of these auto-Abs are very high, often >100. Their pathogenicity was first discovered in 2020-2021, when they were found to account for 15% of cases of critical COVID-19 and 20% of COVID-19 deaths. Remarkably, AAN-I-IFNs are common in the general population, at all latitudes and longitudes tested, with a prevalence of about 0.5% under 65 years old and 4% above 70 years old. They thus emerge as the first identified strong, common, and global determinants of both respiratory viral diseases and arboviral encephalitis. We therefore now hypothesize that AAN-I-IFNs may underlie a significant proportion of rare cases of adverse reactions to other live-attenuated arboviral vaccine, such as the dengue vaccine (CYD-TDV), YFV 17D and the CHIKV vaccine; as well as a significant proportion of more common cases of life-threatening encephalitis triggered by the many human-tropic arboviruses, including CHIKV, ZIKV, YFV, and Japanese viral encephalitis (JEV) infections among others. We will test this hypothesis by measuring blood auto-Abs against type I IFNs by ELISA and neutralization assays in patients from international cohorts of Dengue, CHIKV, JEV, ZIKV and others with adverse reactions to live-attenuated vaccine (LAV). Our preliminary data are exciting. We have secured collaboration of a large network of French and international teams. We discovered that three of the five (60%) recent severe adverse reactions to the CHIKV vaccine reported in La Réunion are due to these auto- Abs. We have also found AAN-I-IFNs in mothers of children born with microcephaly following ZIKV infection. Overall, our project will pursue and expand our breakthrough discovery that human auto-Abs neutralizing type I IFNs are major, common, and global determinants of lifethreatening viral disease, including severe arboviral diseases and adverse reactions to liveattenuated vaccines. The biological and clinical implications of our project are considerable in terms of clinical care, both for diagnosis and treatment, as well as public health strategies and vaccine acceptance."