Derek J. Smith^1,2,3, Stephanie Forrest^2,4, David H. Ackley⁴, and Alan S. Perelson^2,5.

1: Erasmus University, 2: Santa Fe Institute, 3: Popular Power, 4: University of New Mexico, and 5: Los Alamos National Laboratory.

As the influenza virus evolves, the vaccine is updated to track the evolution and public health recommendations are that at-risk individuals are revaccinated annually. Vaccine efficacy in repeat vaccinees has been difficult to determine definitively. A meta-analysis of 19 repeat vaccination studies showed that on average repeat vaccinees were protected at least as well as first-time vaccinees; however, in a subset of 12 of the studies, there was statistically significant unexplained heterogeneity: In some years repeat vaccinees were better protected than first-time vaccinees, in other years they were not as well protected [Beyer, W.E.P. et al (1999) Arch Intern Med 159, 182-188]. We have proposed the 'antigenic distance hypothesis' as an explanation of this heterogeneity [Smith, D.J. et al. (1999) PNAS 96, 14001-14006]. 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. The hypothesis was tested by analyzing influenza outbreaks that occurred during the Hoskins [Hoskins, T.W. et al., (1979) Lancet i, 33-35] and Keitel [Keitel, W.A. et al. (1997) Vaccine 15, 1114-1122] repeated vaccination studies; 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 in 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). 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.