Auto-antibodies to type I IFNs can underlie adverse reactions to yellow fever live attenuated vaccine

Abstract

Yellow fever virus (YFV) live attenuated vaccine can, in rare cases, cause life-threatening disease, typically in patients with no previous history of severe viral illness. Autosomal recessive (AR) complete IFNAR1 deficiency was reported in one 12-yr-old patient. Here, we studied seven other previously healthy patients aged 13 to 80 yr with unexplained life-threatening YFV vaccine–associated disease. One 13-yr-old patient had AR complete IFNAR2 deficiency. Three other patients vaccinated at the ages of 47, 57, and 64 yr had high titers of circulating auto-Abs against at least 14 of the 17 individual type I IFNs. These antibodies were recently shown to underlie at least 10% of cases of life-threatening COVID-19 pneumonia. The auto-Abs were neutralizing in vitro, blocking the protective effect of IFN-α2 against YFV vaccine strains. AR IFNAR1 or IFNAR2 deficiency and neutralizing auto-Abs against type I IFNs thus accounted for more than half the cases of life-threatening YFV vaccine-associated disease studied here. Previously healthy subjects could be tested for both predispositions before anti-YFV vaccination.

Experimental and natural evidence of SARS-CoV-2-infection-induced activation of type I interferon responses

“…Indeed, in our studies, exogenous type I IFN (IFNb1 and IFN-a2) treatment significantly reduced SARS-CoV-2 replication in human airway epithelial cells (Figures 4B, 4E and 4F), consistent with a recent study that compared the susceptibility of SARS-CoV and SARS-CoV-2 to type I IFNs (Lokugamage et al, 2020). Recent studies have identified the role of an impaired type I IFN response in COVID-19 disease severity (Bastard et al, 2020;Zhang et al, 2020), which support our conclusion that SARS-CoV-2 is capable of inducing a type I IFN response, and perhaps the inability of the host to mount this response contributes to disease severity. In addition, our data provide promising support for ongoing clinical trials that include type I IFN treatment.…”

“…Data from our study suggest that replication-competent SARS-CoV-2 induces type I IFN responses in human airway epithelial cells, and type I IFN (IFN-a2) level detected in patients with moderate COVID-19 is sufficient to reduce SARS-CoV-2 replication in these cells. Further mechanistic studies are warranted to identify host factors (Bastard et al, 2020;Zhang et al, 2020) that contribute to varying disease severity during the course of COVID-19, along with the regulation of inflammatory and anti-inflammatory cellular processes in SARS-CoV-2-infected cells.…”

SARS-CoV-2–related MIS-C: A key to the viral and genetic causes of Kawasaki disease?

“…Monogenic IEIs may underlie MIS-C in some children MIS-C affects previously healthy children and adolescents, with most other subjects from the same age group infected with SARS-CoV-2 presenting only very mild illness or remaining asymptomatic. We recently showed that single-gene inborn errors of type I IFN immunity or neutralizing autoantibodies against type I IFNs can underlie life-threatening COVID-19 pneumonia in at least 10% of patients (Bastard et al, 2020(Bastard et al, , 2021Zhang et al, 2020aZhang et al, , 2020bvan der Wijst et al, 2021 Preprint). We now suggest that some children may develop MIS-C because of a rare monogenic or digenic IEI that is clinically silent until infection with SARS-CoV-2, which triggers an inflammatory response.…”

Dolosigranulum pigrum Modulates Immunity against SARS-CoV-2 in Respiratory Epithelial Cells

“…It was shown that in addition to the cytopathic effect induced by the virus, the respiratory alterations caused by SARS-CoV-2 are mediated by an aggressive inflammatory response that significantly contributes to damage in the respiratory tissues. The impaired responses of type I and type III interferons (IFNs) and antiviral factors have been associated with more severe COVID-19 cases [ 3 , 4 , 5 ]. In addition, it was reported that the replication of SARS-CoV-2 induces extensive death in epithelial cells, and causes the release of pro-inflammatory cytokines/chemokines and the recruitment of inflammatory cells into the respiratory tract [ 6 ].…”