Variable efficacy of repeated annual influenza vaccination

Abstract

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.

Figure 1

Observed vaccine efficacy in repeat vaccinees relative to the efficacy in first-time vaccinees, and predicted vaccine efficacy based on the antigenic distance hypothesis.

Figure 2

An illustration of the antigenic distance hypothesis. Shape space diagrams are a way to illustrate the affinities between multiple B cells/antibodies and antigens, and also the antigenic distances between antigens (7). In these shape space diagrams, the affinity between a B cell or antibody (×) and an antigen (●) is represented by the distance between them. Similarly, the distance between antigens is a measure of how similar they are antigenically. (a) B cells with sufficient affinity to be stimulated by an antigen lie within a ball of stimulation centered on the antigen. Thus, a first vaccine (vaccine1) creates a population of memory B cells and antibodies within its ball of stimulation. (b) Cross-reactive antigens have intersecting balls of stimulation, and antibodies and B cells in the intersection of their balls—those with affinity for both antigens—are the cross-reactive antibodies and B cells. The antigen in a second vaccine (vaccine2) will be partially eliminated by preexisting cross-reactive antibodies (depending on the amount of antibody in the intersection), and thus the immune response to vaccine2 will be reduced (8, 9). (c) If a subsequent epidemic strain is close to vaccine1, it will be cleared by preexisting antibodies. (d) However, if there is no intersection between vaccine1 and the epidemic strain, there will be few preexisting cross-reactive antibodies to clear the epidemic strain quickly, despite two vaccinations. Note, in the absence of vaccine1, vaccine2 would have produced a memory population and antibodies that would have been protective against both the epidemic strains in c and d. For an antigen with multiple epitopes (such as influenza) there would be a ball of stimulation for each epitope.

Figure 3

An example of negative interference by v1 on v2 (a), a v2-only control for comparison (b), and positive interference by v1 on the epidemic challenge (c). The v1–v2 distance was 2 for the examples in a and c, and the v1–e distance was 4 for the example in a and 2 for the example in c. An enlarged region of a is included in the supplemental material (www.pnas.org).

Figure 4

Homologous vaccination over a range of v–e distances. (a) Comparison of giving the same vaccine in the prior influenza season, the current season, and both seasons. (b) Observed vaccine efficacy in repeat vaccinees relative to the efficacy in first-time vaccinees and predicted efficacy based on the antigenic distance hypothesis. Observed data are from the four outbreaks in the Hoskins and Keitel studies preceded by homologous vaccination [1972, 1984, 1985, and 1987 (B)]. The predicted vaccine efficacy is computed from panel a as 1 − attack rate. In computing the efficacy relative to first-time vaccinees we assumed that first-time vaccinees received the vaccine in the current season.

Figure 5

Predicted and observed vaccine efficacy in repeat vaccinees relative to the efficacy in first-time vaccinees for the outbreaks during the Hoskins and Keitel studies. Correlation 0.87 (P = 0.01); linear regression slope 1.03, intercept 0.07.