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Distance calculation of residues neighbouring to lysozyme antigenic sites. Site-neighbouring residues whose evolutionary substitution can modify the characteristics and binding energy of the sites.

ABSTRACT: By using the antigenic structure of lysozyme determined in this laboratory and the X-ray co-ordinates we have calculated the closest-atom distances between each of the residues in the three antigenic sites and all the other amino acids of the lysozyme molecule. These calculations enabled us to identify the nearest neighbours to each of the site residues. Thus the immediate environment of each site residue is described. For the three antigenic sites there is a total of 71 neighbouring residues. The effects of evolutionary amino acid substitutions in site-neighbouring residues on the binding capacity of protein binding sites in general and on protein antigenic sites in particular are discussed. These, together with the direct replacements in site residues, will acount for the major effects. However, the limitations of this treatment are stressed. The smaller effects on antigenic sites of replacements at once-removed and even at more distant locations, which, when they become cumulative, could be considerable, are brought to attention, together with any influences of conformational readjustments that can take place as a result of evolutionary amino acid replacements.

SUBMITTER: Atassi MZ

PROVIDER: S-EPMC1162504 | biostudies-other | 1980 Apr

REPOSITORIES: biostudies-other

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Project description:The ease at which influenza virus sequence data can be used to estimate antigenic relationships between strains and the existence of databases containing sequence data for hundreds of thousands influenza strains make sequence-based antigenic distance estimates an attractive approach to researchers. Antigenic mismatch between circulating strains and vaccine strains results in significantly decreased vaccine effectiveness. Furthermore, antigenic relatedness between the vaccine strain and the strains an individual was originally primed with can affect the cross-reactivity of the antibody response. Thus, understanding the antigenic relationships between influenza viruses that have circulated is important to both vaccinologists and immunologists.Here we develop a method of mapping antigenic relationships between influenza virus stains using a sequence-based antigenic distance approach (SBM). We used a modified version of the p-all-epitope sequence-based antigenic distance calculation, which determines the antigenic relatedness between strains using influenza hemagglutinin (HA) genetic coding sequence data and provide experimental validation of the p-all-epitope calculation. We calculated the antigenic distance between 4838 H1N1 viruses isolated from infected humans between 1918 and 2016. We demonstrate, for the first time, that sequence-based antigenic distances of H1N1 Influenza viruses can be accurately represented in 2-dimenstional antigenic cartography using classic multidimensional scaling. Additionally, the model correctly predicted decreases in cross-reactive antibody levels with 87% accuracy and was highly reproducible with even when small numbers of sequences were used.This work provides a highly accurate and precise bioinformatics tool that can be used to assess immune risk as well as design optimized vaccination strategies. SBM accurately estimated the antigenic relationship between strains using HA sequence data. Antigenic maps of H1N1 virus strains reveal that strains cluster antigenically similar to what has been reported for H3N2 viruses. Furthermore, we demonstrated that genetic variation differs across antigenic sites and discuss the implications.

Project description:BackgroundIn 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.ResultsWe 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.ConclusionWe 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.

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Distance calculation of residues neighbouring to lysozyme antigenic sites. Site-neighbouring residues whose evolutionary substitution can modify the characteristics and binding energy of the sites.

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