The potential effect of temporary immunity as a result of bias associated with healthy users and social determinants on observations of influenza vaccine effectiveness; could unmeasured confounding explain observed links between seasonal influenza vaccine and pandemic H1N1 infection?

Background: Five observational studies from Canada found an association between seasonal influenza vaccine receipt and increased risk of pandemic influenza H1N1 2009 infection. This association remains unexplained. Although uncontrolled confounding has been suggested as a possible explanation, the nature of such confounding has not been identified. Observational studies of influenza vaccination can be affected by confounding due to healthy users and the influence of social determinants on health. The purpose of this study was to investigate the influence that these two potential confounders may have in combination with temporary immunity, using stratified tables. The hypothesis is that respiratory virus infections may activate a temporary immunity that provides short-term non-specific protection against influenza and that the relationship with being a healthy user or having a social determinant may result in confounding. Methods: We simulated the effect of confounding on vaccine effectiveness assuming that this could result from both social determinants and healthy user effects as they both influence the risk of seasonal influenza and non-influenza respiratory virus infections as well as the likelihood of being vaccinated. We then examined what impact this may have had on measurement of seasonal influenza vaccine effectiveness against pandemic influenza. Results: In this simulation, failure to adjust for healthy users and social determinants would result in an erroneously increased risk of pandemic influenza infection associated with seasonal influenza vaccination. The effect sizes were not however large. Conclusions: We found that unmeasured healthy user effects and social determinants could result in an apparent association between seasonal influenza vaccine and pandemic influenza infection by virtue of being related to temporary immunity. Adjustment for social determinants of health and the healthy user effects are required in order to improve the quality of observational studies of influenza vaccine effectiveness.