Reply to Skowronski and Chambers

To the Editor—We thank Skowronski and Chambers for their interest in our work. We agree on several points—that more detailed analyses are required to examine the mechanisms underlying why repeated vaccines may interfere with or reinforce protection, and that pooled analyses may hide clinically important effects. Indeed, Simpson's paradox (or the Simpson-Yule effect; memorably summarized as "good for men, good for women, bad for people" [1]) may result in a reversal of apparent effect in some situations. In vaccine effectiveness studies, this could occur when pooling data from a high-activity season with low vaccine effectiveness and a low-activity season with high vaccine effectiveness. Within the limitations of the data, we presented stratified results by year and by strain separately to exclude the possibility of this effect.

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