The impact of repeated vaccination using 10-year vaccination history on protection against influenza in older adults: a test-negative design study across the 2010/11 to 2015/16 influenza seasons in Ontario, Canada

Introduction Annual influenza vaccination is recommended for older adults, but evidence regarding the impact of repeated vaccination has been inconclusive. Aim We investigated vaccine effectiveness (VE) against laboratory-confirmed influenza and the impact of repeated vaccination over 10 previous seasons on current season VE among older adults. Methods We conducted an observational test-negative study in community-dwelling adults aged > 65 years in Ontario, Canada for the 2010/11 to 2015/16 seasons by linking laboratory and health administrative data. We estimated VE using multivariable logistic regression. We assessed the impact of repeated vaccination by stratifying by previous vaccination history. Results We included 58,304 testing episodes for respiratory viruses, with 11,496 (20%) testing positive for influenza and 31,004 (53%) vaccinated. Adjusted VE against laboratory-confirmed influenza for the six seasons combined was 21% (95% confidence interval (CI): 18 to 24%). Patients who were vaccinated in the current season, but had received no vaccinations in the previous 10 seasons, had higher current season VE (34%; 95%CI: 9 to 52%) than patients who had received 1–3 (26%; 95%CI: 13 to 37%), 4–6 (24%; 95%CI: 15 to 33%), 7–8 (13%; 95%CI: 2 to 22%), or 9–10 (7%; 95%CI: −4 to 16%) vaccinations (trend test p = 0.001). All estimates were higher after correcting for misclassification of current season vaccination status. For patients who were not vaccinated in the current season, residual protection rose significantly with increasing numbers of vaccinations received previously. Conclusions Although VE appeared to decrease with increasing numbers of previous vaccinations, current season vaccination likely provides some protection against influenza regardless of the number of vaccinations received over the previous 10 influenza seasons.


Supplementary Appendix
This supplementary material is hosted by Eurosurveillance as supporting information alongside the article, "The impact of repeated vaccination using 10-year vaccination history on protection against influenza in older adults: a test-negative design study across the 2010/11 to 2015/16 influenza seasons in Ontario, Canada," on behalf of the authors who remain responsible for the accuracy and appropriateness of the content. The same standards for ethics, copyright, attributions and permissions as for the article apply. Supplements are not edited by Eurosurveillance and Eurosurveillance is not responsible for the maintenance of any links or email addresses provided therein.  Table S1. Participating laboratories and research ethics approval numbers 4. Table S2. Descriptive characteristics of subtyped and unsubtyped influenza A specimens obtained from community-dwelling adults aged > 65 years, 2010/11 to 2015/16 influenza seasons 5. Supplementary Text. Sensitivity analysis involving manual reclassification of past vaccination status based on misclassification of current season vaccination status 6. Table S3. Descriptive characteristics of influenza test-positive and influenza testnegative community-dwelling adults aged > 65 years, 2010/11 to 2015/16 influenza seasons 7. Table S4. Descriptive characteristics of vaccinated and unvaccinated communitydwelling adults aged > 65 years, 2010/11 to 2015/16 influenza seasons 8. Table S5. Influenza vaccine effectiveness estimates for community-dwelling adults aged > 65 years, by influenza type/subtype and influenza season (2010/11 to 2015/16) 9. Figure S1. Forest plots of the estimates of current season vaccine effectiveness against influenza A(H3N2) for community-dwelling adults aged > 65 years, taking into account vaccination histories for one, five, and 10 previous seasons by stratifying by (i.e., conditioning on) vaccination history (panel a), and correcting for misclassification of current season vaccination status (panel b) 10. Figure S2. Forest plots of the estimates of current season vaccine effectiveness against influenza A(H1N1)pdm09 for community-dwelling adults aged > 65 years, taking into account vaccination histories for one, five, and 10 previous seasons by stratifying by (i.e., conditioning on) vaccination history (panel a), and correcting for misclassification of current season vaccination status (panel b) 11. Figure S3. Forest plots of the estimates of current season vaccine effectiveness against influenza B for community-dwelling adults aged > 65 years, taking into account vaccination histories for one, five, and 10 previous seasons by stratifying by (i.e., conditioning on) vaccination history (panel a), and correcting for misclassification of current season vaccination status (panel b) 12. Figure S4. Forest plots of the estimates of current season vaccine effectiveness against any influenza restricted to community-dwelling adults aged ≥ 75 years taking into account vaccination histories for one, five, and 10 previous seasons, by stratifying by (i.e., conditioning on) vaccination history (panel a), and correcting for misclassification of current season vaccination status (panel b) 13. Figure S5. Forest plots of the estimates of current season vaccine effectiveness against any influenza for community-dwelling adults aged > 65 years, taking into account vaccination histories for one, five, and 10 previous seasons by stratifying by (i.e., conditioning on) vaccination history and, based on misclassification of current season vaccination status, manually reclassifying vaccination status from unvaccinated to vaccinated for all previous seasons (panel a), and moving individuals 'up' a single category (panel b) 14. Figure S6. Forest plots of the estimates of current season vaccine effectiveness against any influenza for community-dwelling adults aged > 65 years, taking into account vaccination histories for one, five, and 10 previous seasons, using the standard approach of a common reference group (i.e., patients who were not vaccinated in the current or any previous seasons under consideration) (panel a), and correcting for misclassification of current season vaccination status (panel b)

Supplementary Text. Sensitivity analysis involving manual reclassification of past vaccination status based on misclassification of current season vaccination status
For each execution of the misclassification macro developed by Fox et al.,(1) thousands of iterations of exposure re-classification are performed on the observed data, with each iteration using a different combination of sensitivity and specificity values within the prespecified ranges to calculate an OR. Thus, some individuals could be deemed misclassified in one iteration but not the next. The reported misclassification-corrected adjusted vaccine effectiveness (VE) estimate is based on the median odds ratio (OR) calculated from all iterations.
We modified the macro to retain the re-classified current season vaccination status for each individual from each iteration, which we used to determine the overall proportion vaccinated separately among test-positive cases and test-negative controls for each iteration. After all iterations were completed, we calculated the proportion of iterations for which each individual was re-classified as vaccinated. We also calculated the median overall proportion vaccinated for cases and controls. If an individual's proportion was greater than the median for their case status, their current season vaccination status was set to vaccinated.
For those individuals whose current season vaccination status was re-classified, we created two scenarios to also change their past seasons' vaccination history. In the first scenario, we assumed that for all previous seasons where they were considered to be unvaccinated in the administrative data, we changed them to vaccinated. Consequently, these individuals were re-categorized to the highest past vaccination history group in each respective analysis (e.g., in the one previous season analysis, all were recategorized into the 'vaccinated in the previous season' group; in the five previous seasons analysis, all were re-categorized to the 'vaccinated in 4-5 previous seasons' group). In the second scenario, we assumed that only some of the previous seasons were misclassified as unvaccinated. To achieve this, we moved these individuals 'up' one past vaccination history category (e.g., for the analysis examining 5-year vaccination history, those initially considered vaccinated in none of the previous five seasons were re-categorized to the 'vaccinated in 1-3 of the previous five seasons' group). We conducted stratified analyses using these new past vaccination history groups for both scenarios.

Reference
Fox MP, Lash TL, Greenland S. A method to automate probabilistic sensitivity analyses of misclassified binary variables. Int J Epidemiol. 2005 Dec 1;34(6):1370-6.     Figure S5. Forest plots of current season vaccine effectiveness estimates against any influenza for community-dwelling adults aged > 65 years, taking into account vaccination histories for one, five, and 10 previous seasons and stratifying according to number of vaccinations received and, based on misclassification of current season vaccination status, (A) manually reclassifying vaccination status from unvaccinated to vaccinated for all previous seasons, and (B) moving individuals 'up' a single category a The model adjusted for age, sex, census area-level neighbourhood income quintile, number of hospitalisations in the past 3 years, number of outpatient visits in the past year, receipt of home care services in the past year, number of prescription medications in the past year, comorbidities that increase the risk of influenza complications (anaemia, cancer, cardiovascular disease, dementia, diabetes, frailty, immunodeficiency due to underlying disease and/or therapy, as well as renal disease and respiratory disease), calendar time, and influenza season. a b Figure S6. Forest plots of (A) current season vaccine effectiveness estimates against any influenza for community-dwelling adults aged > 65 years, taking into account vaccination histories for one, five, and 10 previous seasons, using the standard approach of a common reference group (i.e., patients who were not vaccinated in the current or any previous seasons under consideration), and (B) also correcting for misclassification of current season vaccination status a a