Variable efficacy of repeated annual influenza vaccination.

Conclusions have differed in studies that have compared vaccine efficacy in groups receiving influenza vaccine for the first time to efficacy in groups vaccinated more than once. For example, the Hoskins study [Hoskins, T. W., Davis, J. R., Smith, A. J., Miller, C. L. & Allchin, A. (1979) Lancet i, 33-35] concluded that repeat vaccination was not protective in the long term, whereas the Keitel study [Keitel, W. A., Cate, T. R., Couch, R. B., Huggins, L. L. & Hess, K. R. (1997) Vaccine 15, 1114-1122] concluded that repeat vaccination provided continual protection. We propose an explanation, the antigenic distance hypothesis, and test it by analyzing seven influenza outbreaks that occurred during the Hoskins and Keitel studies. The hypothesis is that variation in repeat vaccine efficacy is due to differences in antigenic distances among vaccine strains and between the vaccine strains and the epidemic strain in each outbreak. To test the hypothesis, antigenic distances were calculated from historical hemagglutination inhibition assay tables, and a computer model of the immune response was used to predict the vaccine efficacy of individuals given different vaccinations. The model accurately predicted the observed vaccine efficacies in repeat vaccinees relative to the efficacy in first-time vaccinees (correlation 0.87). Thus, the antigenic distance hypothesis offers a parsimonious explanation of the differences between and within the Hoskins and Keitel studies. These results have implications for the selection of influenza vaccine strains, and also for vaccination strategies for other antigenically variable pathogens that might require repeated vaccination.

Using lazy evaluation to simulate realistic-size repertoires in models of the immune system.

We describe a method of implementing efficient computer simulations of immune systems that have a large number of unique B- and/or T-cell clones. The method uses an implementation technique called lazy evaluation to create the illusion that all clones are being simulated, while only actually simulating a much smaller number of clones that can respond to the antigens in the simulation. The method is effective because only 0.001-0.01% of clones can typically be stimulated by an antigen, and because many simulations involve only a small number of distinct antigens. A lazy simulation of a realistic number of clones and 10 distinct antigens is 1000 times faster and 10,000 times smaller than a conventional simulation--making simulations of immune systems with realistic-size repertoires computationally tractable.