Cytokine expression patterns associated with systemic adverse events following smallpox immunization

J Infect Dis. 2006 Aug 15;194(4):444-53. doi: 10.1086/505503. Epub 2006 Jul 13.


Vaccinia virus is reactogenic in a significant number of vaccinees, with the most common adverse events being fever, lymphadenopathy, and rash. Although the inoculation is given in the skin, these adverse events suggest a robust systemic inflammatory response. To elucidate the cytokine response signature of systemic adverse events, we used a protein microarray technique to precisely quantitate 108 serum cytokines and chemokines in vaccine recipients before and 1 week after primary immunization with Aventis Pasteur smallpox vaccine. We studied 74 individuals after vaccination, of whom 22 experienced a systemic adverse event and 52 did not. The soluble factors most associated with adverse events were selected on the basis of voting among a committee of machine-learning methods and statistical procedures, and the selected cytokines were used to build a final decision-tree model. On the basis of changes in protein expression, we identified 6 cytokines that accurately discriminate between individuals on the basis of adverse event status: granulocyte colony-stimulating factor, stem cell factor, monokine induced by interferon-gamma (CXCL9), intercellular adhesion molecule-1, eotaxin, and tissue inhibitor of metalloproteinases-2. This cytokine signature is characteristic of particular inflammatory response pathways and suggests that the secretion of cytokines by fibroblasts plays a central role in systemic adverse events.

Publication types

  • Evaluation Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Chemokine CCL11
  • Chemokines, CC / blood
  • Chemokines, CC / immunology
  • Cytokines / blood
  • Cytokines / immunology*
  • Decision Trees
  • Female
  • Granulocyte Colony-Stimulating Factor / blood
  • Granulocyte Colony-Stimulating Factor / immunology
  • Humans
  • Intercellular Adhesion Molecule-1 / blood
  • Intercellular Adhesion Molecule-1 / immunology
  • Male
  • Skin Diseases, Vesiculobullous / chemically induced
  • Skin Diseases, Vesiculobullous / pathology
  • Skin Diseases, Vesiculobullous / prevention & control
  • Smallpox / prevention & control*
  • Smallpox Vaccine / adverse effects*
  • Tissue Inhibitor of Metalloproteinase-2 / blood
  • Tissue Inhibitor of Metalloproteinase-2 / immunology
  • Vaccinia virus / immunology*


  • CCL11 protein, human
  • Chemokine CCL11
  • Chemokines, CC
  • Cytokines
  • Smallpox Vaccine
  • Intercellular Adhesion Molecule-1
  • Tissue Inhibitor of Metalloproteinase-2
  • Granulocyte Colony-Stimulating Factor