Implementing sequence-based antigenic distance calculation into immunological shape space model

BMC Bioinformatics. 2020 Jun 19;21(1):256. doi: 10.1186/s12859-020-03594-3.


Background: In 2009, a novel influenza vaccine was distributed worldwide to combat the H1N1 influenza "swine flu" pandemic. However, antibodies induced by the vaccine display differences in their specificity and cross-reactivity dependent on pre-existing immunity. Here, we present a computational model that can capture the effect of pre-existing immunity on influenza vaccine responses. The model predicts the region of the virus hemagglutinin (HA) protein targeted by antibodies after vaccination as well as the level of cross-reactivity induced by the vaccine. We tested our model by simulating a scenario similar to the 2009 pandemic vaccine and compared the results to antibody binding data obtained from human subjects vaccinated with the monovalent 2009 H1N1 influenza vaccine.

Results: We found that both specificity and cross-reactivity of the antibodies induced by the 2009 H1N1 influenza HA protein were affected by the viral strain the individual was originally exposed. Specifically, the level of antigenic relatedness between the original exposure HA antigen and the 2009 HA protein affected antigenic-site immunodominance. Moreover, antibody cross-reactivity was increased when the individual's pre-existing immunity was specific to an HA protein antigenically distinct from the 2009 pandemic strain. Comparison of simulation data with antibody binding data from human serum samples demonstrated qualitative and quantitative similarities between the model and real-life immune responses to the 2009 vaccine.

Conclusion: We provide a novel method to evaluate expected outcomes in antibody specificity and cross-reactivity after influenza vaccination in individuals with different influenza HA antigen exposure histories. The model produced similar outcomes as what has been previously reported in humans after receiving the 2009 influenza pandemic vaccine. Our results suggest that differences in cross-reactivity after influenza vaccination should be expected in individuals with different exposure histories.

Keywords: 2009 pandemic; Antigenic distance; Antigenic sites; Artificial immune systems; Computational immunology; Epitopes; Gillespie algorithm; H1N1; HA; Hemagglutinin; Humoral immune system; Influenza; Shape space; Simulations; Stalk; Stem; Vaccines; pH1N1.

MeSH terms

  • Amino Acid Sequence
  • Antibodies, Viral / blood
  • Antibodies, Viral / immunology*
  • Antigens, Viral / chemistry
  • Antigens, Viral / immunology
  • Computer Simulation
  • Cross Reactions
  • Hemagglutinin Glycoproteins, Influenza Virus / chemistry
  • Hemagglutinin Glycoproteins, Influenza Virus / immunology*
  • Humans
  • Influenza A Virus, H1N1 Subtype / immunology*
  • Influenza Vaccines / immunology*
  • Models, Immunological*


  • Antibodies, Viral
  • Antigens, Viral
  • H1N1 virus hemagglutinin
  • Hemagglutinin Glycoproteins, Influenza Virus
  • Influenza Vaccines