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

J Exp Med. 2021 Apr 5;218(4):e20202486. doi: 10.1084/jem.20202486.


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.

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Antibodies, Neutralizing / immunology*
  • Autoantibodies / immunology*
  • Autoimmune Diseases* / genetics
  • Autoimmune Diseases* / immunology
  • COVID-19* / genetics
  • COVID-19* / immunology
  • Female
  • Genetic Diseases, Inborn* / genetics
  • Genetic Diseases, Inborn* / immunology
  • HEK293 Cells
  • Humans
  • Interferon-alpha* / genetics
  • Interferon-alpha* / immunology
  • Male
  • Middle Aged
  • Receptor, Interferon alpha-beta* / deficiency
  • Receptor, Interferon alpha-beta* / immunology
  • SARS-CoV-2* / genetics
  • SARS-CoV-2* / immunology
  • Vaccines, Attenuated / genetics
  • Vaccines, Attenuated / immunology
  • Yellow Fever Vaccine* / adverse effects
  • Yellow Fever Vaccine* / genetics
  • Yellow Fever Vaccine* / immunology
  • Yellow fever virus* / genetics
  • Yellow fever virus* / immunology


  • Antibodies, Neutralizing
  • Autoantibodies
  • IFNA2 protein, human
  • IFNAR1 protein, human
  • IFNAR2 protein, human
  • Interferon-alpha
  • Vaccines, Attenuated
  • Yellow Fever Vaccine
  • Receptor, Interferon alpha-beta