Date Published: April 6, 2010
Publisher: Public Library of Science
Author(s): Cécile Viboud, Lone Simonsen
Partial Text: As the novel pandemic influenza A (H1N1) (pH1N1) virus spread around the world in late spring 2009 with a well-matched pandemic vaccine not immediately available, the question of partial protection afforded by seasonal influenza vaccine arose. Coverage of the seasonal influenza vaccine had reached 30%–40% in the general population in 2008–09 in the US and Canada, following recent expansion of vaccine recommendations.
The spring 2009 pandemic wave was the perfect opportunity to address the association between seasonal trivalent inactivated influenza vaccine (TIV) and risk of pandemic illness. In this issue of PLoS Medicine, Danuta Skowronski and colleagues report the unexpected results of a series of Canadian epidemiological studies suggesting a counterproductive effect of the vaccine . The findings are based on Canada’s unique near-real-time sentinel system for monitoring influenza vaccine effectiveness. Patients with influenza-like illness who presented to a network of participating physicians were tested for influenza virus by RT-PCR, and information on demographics, clinical outcomes, and vaccine status was collected. In this sentinel system, vaccine effectiveness may be measured by comparing vaccination status among influenza-positive “case” patients with influenza-negative “control” patients. This approach has produced accurate measures of vaccine effectiveness for TIV in the past, with estimates of protection in healthy adults higher when the vaccine is well-matched with circulating influenza strains and lower for mismatched seasons . The sentinel system was expanded to continue during April to July 2009, as the pH1N1 virus defied influenza seasonality and rapidly became dominant over seasonal influenza viruses in Canada.
The Canadian sentinel study showed that receipt of TIV in the previous season (autumn 2008) appeared to increase the risk of pH1N1 illness by 1.03- to 2.74-fold, even after adjustment for comorbidities, age, and geography . The investigators were prudent and conducted multiple sensitivity analyses to attempt to explain their perplexing findings. Importantly, TIV remained protective against seasonal influenza viruses circulating in April through May 2009, with an effectiveness estimated at 56% (41%–67%), suggesting that the system had not suddenly become flawed. TIV appeared as a risk factor in people under 50 y, but not in seniors—although senior estimates were imprecise due to lower rates of pandemic illness in that age group. Interestingly, if vaccine were truly a risk factor in younger adults, seniors may have fared better because their immune response to vaccination is less rigorous .
The Canadian authors quickly found themselves at odds with expert review committees who were not convinced by the data and largely dismissed the findings as due to confounding bias—a fair criticism of observational studies. To their credit, the authors had thoroughly assessed potential biases in their article , in particular relative to the selection of controls and differences in health care–seeking behavior, and repeated the study in different Canadian provinces. They also provided a full description of their study population and carefully compared vaccine coverage and prevalence of comorbidities in controls with national or province-level age-specific estimates—the best one can do short of a randomized study. In parallel, profound bias in observational studies of vaccine effectiveness does exist, as was amply documented in several cohort studies overestimating the mortality benefits of seasonal influenza vaccination in seniors .
The putative association between seasonal vaccination and 2009 pH1N1 illness remains an open question, given the conflicting evidence from available research. Canadian health authorities debated whether to postpone seasonal vaccination in the autumn of 2009 until after a second pandemic wave had occurred, but decided to follow normal vaccine recommendations instead, in part because of uncertainty about a resurgence of seasonal influenza viruses during the 2009–10 season . This illustrates the difficulty of making policy decisions in the midst of a public health crisis, when officials must rely on limited and possibly biased evidence from observational data, even in the best possible scenario of a well-established sentinel monitoring system already in place.