Abstract
BackgroundFive 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.MethodsWe 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.ResultsIn 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.ConclusionsWe 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.
Highlights
Five observational studies from Canada found an association between seasonal influenza vaccine receipt and increased risk of pandemic influenza H1N1 2009 infection
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
Summary
Five observational studies from Canada found an association between seasonal influenza vaccine receipt and increased risk of pandemic influenza H1N1 2009 infection. Observational studies of seasonal influenza vaccination have been shown to be affected by confounding due to healthy-user effects and social determinants [3,4] Such unmeasured confounding is unlikely to be the whole explanation given the prevalence and strength of association needed to explain the observations [5]. Heath Kelly and colleagues demonstrated a potential biological mechanism to explain the findings [6] in an elegant analysis They postulated that a temporary cross-protective effect against pandemic influenza might have resulted from increased rates of seasonal influenza infection occurring in unvaccinated individuals in the months just prior to the start of the pandemic, when seasonal influenza was circulating in Canada. The idea of a temporary cross-protective effect is consistent with no similar risk being reported by the same Canadian partnership in the second pandemic wave in Canada [7]
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