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

Paul Bastard, Eleftherios Michailidis, Hans-Heinrich Hoffmann, Marwa Chbihi, Tom Le Voyer, Jeremie Rosain, Quentin Philippot, Yoann Seeleuthner, Adrian Gervais, Marie Materna, Patricia Mouta Nunes de Oliveira, Maria de Lourdes S. Maia, Ana Paula Dinis Ano Bom, Tamiris Azamor, Deborah Araujo da Conceicao, Ekaterini Goudouris, Akira Homma, Gunther Slesak, Johannes Schaefer, Bali PulendranJoseph D. Miller, Ralph Huits, Rui Yang, Lindsey B. Rosen, Lucy Bizien, Lazaro Lorenzo, Maya Chrabieh, Lucia Erazo, Flore Rozenberg, Mohamed Maxime Jeljeli, Vivien Beziat, Steven M. Holland, Aurelie Cobat, Luigi D. Notarangelo, Helen C. Su, Rafi Ahmed, Anne Puel, Shen-Ying Zhang, Laurent Abel, Stephen J. Seligman, Qian Zhang, Margaret R. MacDonald, Emmanuelle Jouanguy, Charles M. Rice, Jean-Laurent Casanova

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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.

Original languageEnglish
Article numbere20202486
JournalJournal of Experimental Medicine
Issue number4
Number of pages16
Publication statusPublished - 2021


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


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