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We examined the incremental protection and durability of infection-acquired immunity against Omicron infection in individuals with hybrid immunity in Ontario, Canada.We followed up six million Individuals with at least one RT-PCR test before November 21, 2021 until an Omicron infection. Protection via infection-acquired immunity was assessed by comparing Omicron infection risk between previously infected individuals and those without documented infection under different vaccination scenarios and stratified by time since last infection or vaccination.A prior infection was associated with 68% (95%CI 61-73) and 43% (95%CI 27-56) increased protection against Omicron infection in individuals with two and three doses, respectively. Among individuals with two-dose vaccination, the incremental protection of infection-induced immunity decreased from 79% (95%CI 75-81) within 3 months after vaccination or infection to 27% (95%CI 14-37) at 9-11 months. In individuals with three-dose vaccination, it decreased from 57% (95%CI 50-63) within 3 months to 37% (95%CI 19-51) at 3-5 months after vaccination or infection.Previous SARS-CovV-2 infections provide added cross-variant immunity to vaccination. Given the limited durability of infection-acquired protection in individuals with hybrid immunity, its influence on shield-effects at population level and reinfection risks at individual level may be limited.

Limited data exists on the effectiveness of a third COVID-19 vaccine dose in solid organ transplant recipients. We conducted a population-based cohort study using linked healthcare databases from Ontario, Canada to answer this question. We included solid organ transplant recipients (n = 12,842) as of December 14, 2020, with follow-up until November 28, 2021. We used an extended Cox proportional hazards model with vaccination status, including BNT162b2, mRNA-1273, and ChAdOx1 vaccines, modeled as a time-dependent exposure. Individuals started in the unvaccinated category (reference) and could contribute person-time to first, second, and third doses. Over a median follow-up of 349 days, 12.7% (n = 1632) remained unvaccinated, 54.1% (n = 6953) received 3 doses, and 488 (3.8%) tested positive for SARS-CoV-2 (of which 260 [53.3%] had a clinically important outcome [i.e., hospitalization or death]). Adjusted vaccine effectiveness against infection was 31% (95% CI: 2, 51%), 46% (95% CI: 21, 63%), and 72% (95% CI: 43, 86%) for one, two, and three doses. Vaccine effectiveness against clinically important outcomes was 38% (95% CI: 4, 61%), 54% (95% CI: 23, 73%), and 67% (95% CI: 11, 87%). Vaccine effectiveness in solid organ transplant recipients is lower than the general population, however, vaccine effectiveness improved following a third dose.

BackgroundBackground incidence rates are critical in pharmacovigilance to facilitate identification of vaccine safety signals. We estimated background incidence rates of nine adverse events of special interest related to COVID-19 vaccines in Ontario, Canada.MethodsWe conducted a population-based retrospective observational study using linked health administrative databases for hospitalizations and emergency department visits among Ontario residents. We estimated incidence rates of Bell’s palsy, idiopathic thrombocytopenia, febrile convulsions, acute disseminated encephalomyelitis, myocarditis, pericarditis, Kawasaki disease, Guillain-Barré syndrome, and transverse myelitis during five pre-pandemic years (2015– 2019) and 2020.ResultsThe average annual population was 14 million across all age groups with 51% female. The pre-pandemic mean annual rates per 100,000 population during 2015–2019 were 43.9 for idiopathic thrombocytopenia, 27.8 for Bell’s palsy, 25.0 for febrile convulsions, 22.8 for acute disseminated encephalomyelitis, 11.3 for myocarditis/pericarditis, 8.6 for pericarditis, 2.9 for myocarditis, 1.9 for Guillain-Barré syndrome, 1.7 for transverse myelitis, and 1.6 for Kawasaki disease. Females had higher rates of acute disseminated encephalomyelitis and transverse myelitis while males had higher rates of myocarditis, pericarditis, and Guillain-Barré syndrome. Bell’s palsy, acute disseminated encephalomyelitis, and Guillain-Barré syndrome increased with age. The mean rates of myocarditis and/or pericarditis increased with age up to 79 years; males had higher rates than females: from 12–59 years for myocarditis and ≥12 years for pericarditis. Febrile convulsions and Kawasaki disease were predominantly childhood diseases and generally decreased with age.ConclusionsOur estimated background rates will permit estimating numbers of expected events for these conditions and facilitate detection of potential safety signals following COVID-19 vaccination.

Background Nursing home (NH) residents are prioritized for COVID-19 vaccination. We report monthly mortality, hospitalizations, and emergency department (ED) visit incidence rates (IRs) during 2010–2020 to provide context for COVID-19 vaccine safety assessments. Methods We observed outcomes among all NH residents in Ontario using administrative databases. IRs were calculated by month, sex, and age group. Comparisons between months were assessed using one-sample t-tests; comparisons by age and sex were assessed using chi-squared tests. Results From 2010 to 2019, there were 83,453 (SD: 652.4) NH residents per month, with an average of 2.3 (SD: 0.28) deaths, 3.1 (SD: 0.16) hospitalizations, and 3.6 (SD: 0.17) ED visits per 100 residents per month. From March to December 2020, mortality IRs were increased, but hospitalization and ED visit IRs were reduced (p Conclusion We identified consistent monthly mortality, hospitalization, and ED visit IRs during 2010–2019. Marked differences in these rates were observed during 2020, coinciding with the COVID-19 pandemic.

Introduction In Ontario, Canada, parents have the responsibility to report their child’s routine infant and childhood vaccines to the provincial immunization registry (the Digital Health Immunization Repository; DHIR) without healthcare provider validation. Despite its use in routine immunization coverage monitoring, no study has previously examined the completeness of immunization data within the DHIR. Methods We assessed the completeness of DHIR immunizations, as compared to immunizations within the Electronic Medical Records—Primary Care (EMRPC) database, also known as EMRALD, a network of family physician electronic medical records (EMRs). We linked client records from the DHIR and EMRPC to a centralized population file. To create the study cohort, we examined children born during 2005–2008 and further defined the cohort based on those rostered to an EMRPC physician, visit criteria to ensure ongoing care by an EMRPC provider, and school attendance in Ontario at age 7. We calculated up-to-date (UTD) immunization coverage at age 7 for individual vaccines and overall using data from the DHIR and EMRPC separately, and compared the estimates. Results The analytic cohort to assess DHIR data completeness included 2,657 children. Overall UTD coverage (all vaccines assessed) was 82.0% in the DHIR and 67.6% in EMRPC. UTD coverage was higher in the DHIR for all vaccines assessed individually, with the exception of meningococcal C conjugate vaccine (difference = 0.3%). After excluding two EMRPC sites with irregularities in immunization data, the difference in overall UTD coverage between systems decreased from 14.4% to 6.6% Interpretation These results validate the use of DHIR for coverage assessment but also suggest that bidirectional exchange of immunization information has the potential to increase immunization data completeness in both systems.

Objectives Findings during the 2009 pandemic suggest severe maternal infection with pandemic influenza had adverse perinatal health consequences. Limited data exist evaluating the perinatal health effects of severe seasonal influenza and non-influenza infections during pregnancy. Methods A retrospective cohort of pregnant women from Australia, Canada, Israel, and the United States was established using birth records to identify pregnancies and birth outcomes and hospital and laboratory testing records to identify influenza and non-influenza associated acute respiratory or febrile illness (ARFI) hospitalizations. ARFI hospitalized women were matched to non-hospitalized women (1:4) by country and season of conception. Log-binomial regression was used to estimate the relative risk (aRR) of preterm birth (PTB), small-for-gestational-age (SGA), and low birthweight (LBW) birth, adjusting for pre-existing medical conditions, maternal age, and parity. Results 950 pregnant women hospitalized with an ARFI were matched with 3,800 non-hospitalized pregnant women. Compared to non-hospitalized women, risk of PTB was greater among women hospitalized with influenza-associated ARFI (aRR: 1.57; 95% CI: 1.15–2.15) and non-influenza ARFI (aRR: 2.78; 95% CI: 2.12–3.65). Similar results were observed for LBW; there were no associations with SGA birth. Conclusions ARFI hospitalization during pregnancy was associated with increased risk of PTB and LBW.

Background Pertussis persists in Manitoba despite the universal availability of pertussis vaccines. Recent cases have included previously vaccinated individuals, raising concerns about declining vaccine effectiveness (VE). We measured pertussis VE and duration of protection using Manitoba’s provincial immunization and communicable disease registries. Methods Using a nested case-control design, individuals with laboratory-confirmed pertussis in Manitoba diagnosed between April 1, 1992, and March 31, 2015, were matched to up to five population-based controls on age, gender, geography, and case physician or number of physician visits. Conditional logistic regression was used to estimate VE against pertussis for both the whole-cell (wP) and acellular (aP) pertussis vaccines. Duration of protection was assessed using time since last dose. Results Data on 534 eligible cases and 2614 controls were available for analysis. The adjusted VE estimate for aP-containing vaccines was 85% (95%CI: 74–91%); VE was 89% (66–96%) one to three years after the last vaccination. The adjusted VE of wP-containing vaccines was –15% (–91–31%) during a large outbreak in 1994 and 1995 compared to 35% (–26–66%) during non-outbreak years. Conclusions Our estimates suggest that the aP vaccine was effective in preventing pertussis since its introduction in Manitoba. VE was lower during a large outbreak, highlighting the importance of separately analyzing outbreak periods when estimating pertussis VE over time.

Background Influenza causes significant annual morbidity and mortality, particularly in older adults, for whom influenza vaccine effectiveness (VE) is also lower. Immunizing one group (e.g., children) against influenza may indirectly protect another group (e.g., older adults) against influenza and its complications. Methods We updated previous systematic reviews on indirect protection against influenza by searching MEDLINE and EMBASE for relevant human studies published until January 4, 2017. We abstracted and critically appraised English language publications that reported or provided information to calculate indirect VE against influenza, as a percentage, in non-institutional settings. We developed a term called ‘estimated actual protection’ to explore the relationship between indirect protection and the product of direct VE and relative vaccine coverage. We calculated estimated actual protection for a subset of studies that reported coverage and indirect VE for: laboratory-confirmed influenza; outpatient care for respiratory illness; influenza-associated emergency visits; or influenza-associated hospitalizations. We ran linear mixed models to compare estimated actual protection against indirect VE for the four outcomes, and graphed the data. Results Of 2320 unique records identified, we abstracted and appraised 26 articles describing 24 studies. The majority of included studies reported at least one outcome suggesting that immunizing one group reduced influenza-related outcomes in another group. Critical appraisal of the abstracted studies identified recurring methodological weaknesses, such as lack of laboratory-confirmed influenza. Our exploratory analyses of 18 studies indicated a positive but not statistically significant relationship between estimated actual protection and indirect protection for each of the four outcomes. Conclusions Our systematic review and exploratory analyses suggest influenza immunization provides some level of indirect protection. However, our critical appraisal highlights the need for a standardized and consistently applied approach to measuring indirect protection against influenza to fill existing knowledge gaps. Additionally, the concept of estimated actual protection requires validation.

Background Linking data on laboratory specimens collected during clinical practice with health administrative data permits highly powered vaccine effectiveness (VE) studies to be conducted at relatively low cost, but bias from using convenience samples is a concern. We evaluated the validity of using such data for estimating VE. Methods We created the Flu and Other Respiratory Viruses Research (FOREVER) Cohort by linking individual-level data on respiratory virus laboratory tests, hospitalizations, emergency department visits, and physician services. For community-dwelling adults aged > 65 years, we assessed the presence and magnitude of information and selection biases, generated VE estimates under various conditions, and compared our VE estimates with those from other studies. Results We included 65,648 unique testing episodes obtained from 54,434 individuals during the 2010–11 to 2015–16 influenza seasons. To examine information bias, we found the proportion testing positive for influenza for patients with unknown interval from illness onset to specimen collection was more similar to patients for whom illness onset date was ≤ 7 days before specimen collection than to patients for whom illness onset was > 7 days before specimen collection. To assess the presence of selection bias, we found the likelihood of influenza testing was comparable between vaccinated and unvaccinated individuals, although the adjusted odds ratios were significantly greater than 1 for some healthcare settings and during some influenza seasons. Over 6 seasons, VE estimates ranged between 36% (95%CI, 27–44%) in 2010–11 and 5% (95%CI, –2, 11%) in 2014–15. VE estimates were similar under a range of conditions, but were consistently higher when accounting for misclassification of vaccination status through a quantitative sensitivity analysis. VE estimates from the FOREVER Cohort were comparable to those from other studies. Conclusions Routinely collected laboratory and health administrative data contained in the FOREVER Cohort can be used to estimate influenza VE in community-dwelling older adults.

Background Resurgences of pertussis have occurred in several high-income countries, often linked to waning of immunity from acellular pertussis vaccines. The degree of waning observed has varied by study design and setting. In Ontario, pertussis has not shown a substantial resurgence in the past decade. The routine immunization schedule comprises three priming doses in infancy, toddler and pre-school doses, and an adolescent dose at 14–16 years of age. Methods We estimated pertussis vaccine effectiveness (VE) through a case-control study of 1335 cases statutorily reported to public health in Ontario and occurring between January 1, 2009 and March 31, 2015, compared with 5340 randomly selected population controls, frequency-matched by age, primary-care provider and year of diagnosis. Pertussis cases met provincial confirmed or probable case definitions. We used multivariable logistic regression to estimate crude and adjusted odds ratios (aOR). Results VE against pertussis was sustained between 92% (95% confidence interval (95%CI) 88–95%) in 2–3 year olds and 90% (95%CI: 80–95%) in 8–9 year olds, but fell rapidly to 49% (95%CI: 2–73%) in children 12–13 years of age. VE following the teenage booster given at 14–16 years in Ontario reached 76% (95%CI: 52–88%) in 14–16 year olds and 78% (95%CI: −31 to 96%) in those 16–22 years old. For children who were up-to-date with the immunization schedule, VE declined from 87% (95%CI: 84–90%) during the first year to 74% (95%CI: 63–82%) after 8 or more years following their last dose of immunization. Conclusions VE is high during the first decade of life but then falls rapidly. Protection is not fully restored by the teenage booster. Our findings are consistent with the localized outbreaks we observe in high school children and underline the importance of additional policies to protect infants.

Many studies have examined the effectiveness of non-pharmaceutical interventions (NPIs) on SARS-CoV-2 transmission worldwide. However, less attention has been devoted to understanding the limits of NPIs across the course of the pandemic and along a continuum of their stringency. In this study, we explore the relationship between the growth of SARS-CoV-2 cases and an NPI stringency index across Canada before the accelerated vaccine roll-out.We conducted an ecological time-series study of daily SARS-CoV-2 case growth in Canada from February 2020 to February 2021. Our outcome was a back-projected version of the daily growth ratio in a stringency period (i.e., a 10-point range of the stringency index) relative to the last day of the previous period. We examined the trends in case growth using a linear mixed-effects model accounting for stringency period, province, and mobility in public domains.Case growth declined rapidly by 20-60% and plateaued within the first month of the first wave, irrespective of the starting values of the stringency index. When stringency periods increased, changes in case growth were not immediate and were faster in the first wave than in the second. In the first wave, the largest decreasing trends from our mixed effects model occurred in both early and late stringency periods, depending on the province, at a geometric mean index value of 30⋅1 out of 100. When compared with the first wave, the stringency periods in the second wave possessed little association with case growth.The minimal association in the first wave, and the lack thereof in the second, is compatible with the hypothesis that NPIs do not, per se, lead to a decline in case growth. Instead, the correlations we observed might be better explained by a combination of underlying behaviors of the populations in each province and the natural dynamics of SARS-CoV-2. Although there exist alternative explanations for the equivocal relationship between NPIs and case growth, the onus of providing evidence shifts to demonstrating how NPIs can consistently have flat association, despite incrementally high stringency.

Background: We estimated the effectiveness of BNT162b2 and mRNA-1273 vaccines among residents of Ontario, Canada, where a policy to use an up to 16-week interval between doses was adopted in March 2021. Methods: We conducted a test-negative design study using linked province-wide laboratory, vaccination, and health administrative datasets. We included symptomatic individuals tested for SARS-CoV-2 by RT-PCR between 14 December 2020 and 19 April 2021. Study outcomes included symptomatic infection and associated severe outcomes (hospitalization or death). We estimated adjusted vaccine effectiveness (aVE) using multivariable logistic regression. Findings: Among 324,033 symptomatic tested individuals, 53,270 (16·4%) were positive for SARS-CoV-2 and 21,272 (6·6%) had received ≥1 dose of mRNA vaccine. Among test-positive cases, 2,479 (4·7%) had a severe outcome. aVE against symptomatic infection ≥14 days after receiving only 1 dose was 60% (95%CI, 57–64%), increasing from 48% (95%CI, 41–54%) at 14–20 days after the first dose to 71% (95%CI, 63–78%) at 35–41 days. aVE ≥7 days after receiving 2 doses was 91% (95%CI, 89–93%). Against severe outcomes, aVE ≥14 days after receiving 1 dose was 70% (95%CI, 60–77%) and aVE ≥7 days after receiving 2 doses was 98% (95%CI, 88–100%). We observed lower aVE against both outcomes after receiving 1 dose for adults aged ≥70 years, but aVE estimates for older adults were comparable to younger adults after 28 days. After 2 doses, we observed high aVE against E484K-positive variants. Interpretation: Our findings suggest that 2 doses of BNT162b2 and mRNA-1273 vaccines are highly effective against both symptomatic infection and associated severe outcomes for all circulating variants, with effectiveness lower after only a single dose, particularly for older adults shortly after the first dose. Funding Information: Canadian Institutes of Health Research, Public Health Agency of Canada, Ontario Ministries of Health and Long-Term Care. Declaration of Interests: KW is CEO of CANImmunize and serves on the data safety board for the Medicago COVID-19 vaccine trial. SMM has received unrestricted research grants from Merck, GlaxoSmithKline, Sanofi Pasteur, Pfizer, and Roche-Assurex for unrelated studies. SMM has received fees as an advisory board member for GlaxoSmithKline, Merck, Pfizer, Sanofi Pasteur, and Seqirus. CHR has received an unrestricted research grant from Pfizer for an unrelated study. The other authors declare no conflicts of interest. Ethics Approval Statement: ICES is a prescribed entity under Ontario’s Personal Health Information Protection Act (PHIPA). Section 45 of PHIPA authorizes ICES to collect personal health information, without consent, for the purpose of analysis or compiling statistical information with respect to the management of, evaluation or monitoring of, the allocation of resources to or planning for all or part of the health system. Projects that use data collected by ICES under section 45 of PHIPA, and use no other data, are exempt from REB review. The use of the data in this project is authorized under section 45 and approved by ICES’ Privacy and Legal Office.

Background: Cirrhosis is often diagnosed once complications such as ascites, encephalopathy and variceal bleeding have occurred. Current non-invasive tests to detect cirrhosis have limited performance, with many patients falling into the indeterminate category. Objectives: To identify patients with well-compensated liver cirrhosis of all-causes using machine learning algorithms (MLAs) trained on routinely measured clinical and laboratory parameters. Design, Setting, and Participants: Retrospective, cross-sectional study on patients with F0, F1, and F4 fibrosis staged via biopsy at the Toronto Liver Clinic, validated on 508 patients with F0 to F4 fibrosis staged via biopsy locally as well as at the McGill University Health Centre. Patients with decompensated cirrhosis were excluded. We trained 7 MLAs to identify patients with compensated cirrhosis. Performance was benchmarked against the Aspartate aminotransferase (AST)-to-Platelet Ratio Index (APRI), Fibrosis-4 index (FIB-4), nonalcoholic fatty liver disease (NAFLD) fibrosis score (NFS), Transient Elastography (TE), and an independent panel of 5 experts. Results: The best MLA achieved a cross-validation area under the receiver operating characteristic curve (AUROC) of 0.88 for identifying patients with well-compensated cirrhosis, with less than 8% indeterminate classifications. The MLA achieved higher or comparable AUROC to FIB-4 on both validation sets with 20% fewer indeterminate classifications. Additionally, we show that by altering cutoffs, the MLA outperformed expert hepatologists and the NFS score and achieved superior specificity to transient elastography. Conclusion: In this study, we have demonstrated that an MLA outperforms non-imaging based methods in detecting well-compensated cirrhosis across multiple etiologies of liver disease. Our MLA was superior to APRI, FIB-4, and NFS with significantly fewer indeterminate classifications, while achieving performance comparable to an independent panel of experts. MLAs using routinely collected data could flag patients with well-compensated liver cirrhosis among patients with chronic liver disease, allowing intervention prior to onset of decompensation and associated complications. Funding Statement: This study was supported by ICES, which is funded by an annual grant from the Ontario Ministry of Health and Long-Term Care (MOHLTC). Declaration of Interests: We have no competing interests to declare. Ethics Approval Statement: Ethics approval was obtained from the Research Ethics Boards at the University Health Network, SickKids Research Institute, and MUHC.

Introduction: Emerging studies have implicated air pollution in the neurodegenerative processes. Less is known about the influence of air pollution, especially at the relatively low levels, on developing dementia. We conducted a population-based cohort study in Ontario, Canada, where the concentrations of pollutants are among the lowest in the world, to assess whether air pollution exposure is associated with incident dementia. Methods: The study population comprised all Ontario residents who, on 1 April 2001, were 55–85years old, Canadian-born, and free of physician-diagnosed dementia (~2.1 million individuals). Follow-up extended until 2013. We used population-based health administrative databases with a validated algorithm to ascertain incident diagnosis of dementia as well as prevalent cases. Using satellite observations, land-use regression model, and an optimal interpolation method, we derived long-term average exposure to fine particulate matter (≤2.5μm in diameter) (PM2.5), nitrogen dioxide (NO2), and ozone (O3), respectively at the subjects' historical residences based on a population-based registry. We used multilevel spatial random-effects Cox proportional hazards models, adjusting for individual and contextual factors, such as diabetes, brain injury, and neighborhood income. We conducted various sensitivity analyses, such as lagging exposure up to 10years and considering a negative control outcome for which no (or weaker) association with air pollution is expected. Results: We identified 257,816 incident cases of dementia in 2001–2013. We found a positive association between PM2.5 and dementia incidence, with a hazard ratio (HR) of 1.04 (95% confidence interval (CI): 1.03–1.05) for every interquartile-range increase in exposure to PM2.5. Similarly, NO2 was associated with increased incidence of dementia (HR=1.10; 95% CI: 1.08–1.12). No association was found for O3. These associations were robust to all sensitivity analyses examined. These estimates translate to 6.1% of dementia cases (or 15,813 cases) attributable to PM2.5 and NO2, based on the observed distribution of exposure relative to the lowest quartile in concentrations in this cohort. Discussion: In this large cohort, exposure to air pollution, even at the relative low levels, was associated with higher dementia incidence. Keywords: Fine particulate matter, Nitrogen dioxides, Ozone, Dementia, Cohort

Background Seasonal influenza vaccine (SIV) uptake in the United States remains suboptimal, requiring new and innovative strategies. Objective To evaluate the impact of a behavioral peer comparison (PC) intervention on SIV uptake in community pharmacies across the United States. Methods A cluster randomized study was conducted across a national network of Walmart community pharmacies (> 4500 sites) during the 2019-2020 influenza season. The clusters consisted of 416 markets, each containing an average of 11 pharmacies. All pharmacies in a market were randomly assigned to either no intervention or the PC intervention, a software-delivered communication informing on-site staff, including pharmacists and pharmacy technicians, of their pharmacy’s weekly performance, measured as SIV doses administered, compared with that of peer pharmacies within their market. The outcome was the pharmacy-level cumulative SIV doses administered during the intervention period (September 1, 2019,-February 29, 2020). Linear regression models were used to estimate the PC impact, with multiway cluster-robust SEs estimated by market and state. Results A total of 4589 pharmacies were enrolled in the study, with 2297 (50.1%) randomized to the control group and 2292 (49.9%) randomized to the PC intervention group. Overall, compared with the control pharmacies, the PC pharmacies administered 3.7% (95% CI –0.3% to 7.9%) additional SIV doses. Among large-format pharmacies, the PC pharmacies administered 4.1% (95% CI 0.1%–8.3%) additional SIV doses compared with the controls. Historically low-performing large-format PC pharmacies administered 6.1% (95% CI 0.5%–11.9%) additional SIV doses compared with the controls. No statistically significant treatment effects were observed among small-format pharmacies. Conclusion Our findings demonstrate that PCs can improve SIV uptake among large-format community pharmacies, with historically low-performing pharmacies potentially exhibiting the greatest relative impact. Wide-scale implementation of PCs in community pharmacies may help to further improve SIV uptake in these settings.

Background: Streptococcus pneumoniae is the most commonly identified cause of bacterial pneumonia, and invasive pneumococcal disease (IPD) has a high case fatality rate. The wintertime co-seasonality of influenza and IPD in temperate countries has suggested that pathogen-pathogen interaction or environmental conditions contribute to IPD risk. We evaluated the contribution of influenza and environmental conditions, using standardized methodology, across multiple geographical regions. Methods: Case data for 25,292 cases from jurisdictions in Canada, the United States and Australia were available. Associations between influenza, temperature, absolute humidity and ultraviolet radiation and IPD were evaluated using a case-crossover design. Identical models were used in all jurisdictions; heterogeneity of effects was explored using meta-analytic methods. Findings: In adjusted models, elevated influenza activity at a 2-week lag was associated with increases in IPD risk (adjusted OR (aOR) per standard deviation increase 1.07, 95% CI: 1.01-1.13). Increased humidity decreased IPD risk at a 1-week lag (aOR per gram.m-3 of water 0.98, 95% CI 0.96-1.00). Other effects were heterogeneous; meta-regression suggested that combinations of environmental factors might represent unique local "risk signatures". Interpretation: Influenza drives IPD risk in temperate countries. This association is not explained by co-seasonality or case characteristics and appears generalizable. Absolute humidity attenuates IPD risk in the same jurisdictions. The generalizable nature of these associations has important implications for influenza control and advances the understanding of seasonality of this important disease. Funding Statement: Supported by Canadian Institutes for Health Research Operating Grants (#222287 and #337516) and by the Canadian Immunization Research Network. Declaration of Interests: The authors state: "None." Ethics Approval Statement: Ethical approval for this study was obtained by the University of Toronto Research Ethics Board.

Background: Streptococcus pneumoniae is the most commonly identified cause of bacterial pneumonia, and invasive pneumococcal disease (IPD) has a high case fatality rate. The wintertime co-seasonality of influenza and IPD in temperate countries has suggested that pathogen-pathogen interaction or environmental conditions contribute to IPD risk. We evaluated the contribution of influenza and environmental conditions, using standardized methodology, across multiple geographical regions. Methods: Case data for 25,292 cases from jurisdictions in Canada, the United States and Australia were available. Associations between influenza, temperature, absolute humidity and ultraviolet radiation and IPD were evaluated using a case-crossover design. Identical models were used in all jurisdictions; heterogeneity of effects was explored using meta-analytic methods. Findings: In adjusted models, elevated influenza activity at a 2-week lag was associated with increases in IPD risk (adjusted OR (aOR) per standard deviation increase 1.07, 95% CI: 1.01-1.13). Increased humidity decreased IPD risk at a 1-week lag (aOR per gram.m-3 of water 0.98, 95% CI 0.96-1.00). Other effects were heterogeneous; meta-regression suggested that combinations of environmental factors might represent unique local "risk signatures". Interpretation: Influenza drives IPD risk in temperate countries. This association is not explained by co-seasonality or case characteristics and appears generalizable. Absolute humidity attenuates IPD risk in the same jurisdictions. The generalizable nature of these associations has important implications for influenza control and advances the understanding of seasonality of this important disease. Funding Statement: Supported by Canadian Institutes for Health Research Operating Grants (#222287 and #337516) and by the Canadian Immunization Research Network. Declaration of Interests: The authors state: "None." Ethics Approval Statement: This study was approved by the Research Ethics Board of the University of Toronto (protocol #: 00036083. Protocol Title: Wintertime Seasonality of Influenza and Invasive Bacterial Disease: Influence of Environment, Pathogen Interactions, Time Scales, and Geography).

Objectives Invasive meningococcal disease (IMD) is a severe bacterial infection that displays wintertime seasonality in temperate countries. Mechanisms driving seasonality are poorly understood and may include environmental conditions and/or respiratory virus infections. We evaluated the contribution of influenza and environmental conditions to IMD risk, using standardized methodology, across multiple geographical regions. Methods We evaluated 3276 IMD cases occurring between January 1999 and December 2011 in 11 jurisdictions in Australia, Canada, France and the United States. Effects of environmental exposures and normalized weekly influenza activity on IMD risk were evaluated using a case-crossover design. Meta-analytic methods were used to evaluate homogeneity of effects and to identify sources of between-region heterogeneity. Results After adjustment for environmental factors, elevated influenza activity at a 2-week lag was associated with increased IMD risk (adjusted odds ratio (OR) per standard deviation increase 1.29; 95% confidence interval, 1.04–1.59). This increase was homogeneous across the jurisdictions studied. By contrast, although associations between environmental exposures and IMD were identified in individual jurisdictions, none was generalizable. Conclusions Using a self-matched design that adjusts for both coseasonality and case characteristics, we found that surges in influenza activity result in an acute increase in population-level IMD risk. This effect is seen across diverse geographic regions in North America, France and Australia. The impact of influenza infection on downstream meningococcal risk should be considered a potential benefit of influenza immunization programmes.

Introduction It is unknown whether urban green space is associated with reduced risk of major neurological conditions, especially dementia and stroke. Methods Retrospective, population-based cohorts were created for each study outcome, including 1.7 and 4.3 million adults in Ontario, Canada for dementia and stroke, respectively. Residential green space was quantified using the satellite-derived Normalized Difference Vegetation Index. Incidence was ascertained using health administrative data with validated algorithms. Mixed-effects Cox models were used to estimate hazard ratios per interquartile range increase in green space exposure. Results Between 2001 and 2013, 219,013 individuals were diagnosed with dementia and 89,958 had a stroke. The hazard ratio per interquartile range increase in green space was 0.97 (95% CI: 0.96–0.98) for dementia and 0.96 (0.95–0.98) for stroke. Estimates remained generally consistent in sensitivity analyses. Discussion Increased exposure to urban green space was associated with reduced incidence of dementia and stroke. To our knowledge, this is the first population-based cohort study to assess these relationships.

Long-term exposure to ambient air pollution has been linked to cardiovascular mortality, but the associations with incidence of major cardiovascular diseases are not fully understood, especially at low concentrations. We aimed to investigate the associations between exposure to fine particulate matter (PM2.5), nitrogen dioxide (NO2), ozone (O3), redox-weighted average of NO2 and O3 (Ox) and incidence of congestive heart failure (CHF) and acute myocardial infarction (AMI). Our study population included all long-term residents aged 35–85 years who lived in Ontario, Canada, from 2001 to 2015 (~5.1 million). Incidence of CHF and AMI were ascertained from validated registries. We assigned estimates of annual concentrations of pollutants to the residential postal codes of subjects for each year during follow-up. We estimated hazard ratios (HRs) and 95% CIs for each pollutant separately using Cox proportional hazards models. We examined the shape of concentration-response associations using shape-constrained health impact functions. From 2001 to 2015, there were 422,625 and 197,628 incident cases of CHF and AMI, respectively. In the fully adjusted analyses, the HRs of CHF corresponding to each interquartile range increase in exposure were 1.05 (95% CI: 1.04–1.05) for PM2.5, 1.02 (95% CI: 1.01–1.04) for NO2, 1.03 (95% CI: 1.02–1.03) for O3, and 1.02 (95% CI: 1.02–1.03) for Ox, respectively. Similarly, exposure to PM2.5, O3, and Ox were positively associated with AMI. The concentration-response relationships were different for individual pollutant and outcome combinations (e.g., for PM2.5 the relationship was supralinear with CHF, and linear with AMI). Keywords: Ambient air pollution, Incidence, Cardiovascular events, Congestive heart failure, Acute myocardial infarction, Concentration-response curves

Background Children are key drivers of influenza transmission. Vaccinating school age children decreases influenza in the community. Objective To pilot-test the methods for a future trial to compare the direct and indirect benefits of inactivated influenza vaccine (IIV) vs. live attenuated influenza vaccine (LAIV) in preventing influenza infection. Methods During the 2013–14 influenza vaccination campaign, we piloted an open-label cluster randomized trial involving 10 elementary schools in Peterborough, Ontario, Canada. We randomized schools on a 1:1 basis to have students receive IIV or LAIV. We invited a subset of vaccinated students and their households to participate in a surveillance sub-study, which involved completing daily symptom diaries during influenza season and collecting mid-turbinate swabs from symptomatic individuals to detect influenza infection. The main outcome measure was confirmed influenza infection using a real-time reverse transcriptase polymerase chain reaction (PCR) assay. Results One hundred and nineteen households (166 students and 293 household members) participated. During 15 weeks of surveillance, we detected 22 episodes of PCR-confirmed influenza (21 influenza A/H1N1 and 1 influenza B). The incidence of influenza per 1000 person-days was 1.24 (95% CI, 0.40–2.89) for IIV-vaccinated students, compared to 0.13 (95% CI, 0.003–0.72) for LAIV-vaccinated students; the incidence rate ratio was 0.10 (95% CI, 0.002–0.94). Similarly, the incidence of influenza per 1000 person-days was 1.33 (95% CI, 0.64–2.44) for IIV household members, compared to 0.47 (95% CI, 0.17–1.03) for LAIV household members; the incidence rate ratio was 0.36 (95% CI, 0.11–1.08). The overall incidence rate ratio (combining students and household members) was 0.27 (95% CI, 0.09–0.69). Conclusions Household surveillance involving participant monitoring and reporting of symptoms and self-collection of mid-turbinate swabs is feasible. A larger study is required to validate the suggestion that vaccinating children with LAIV might confer more protection against influenza for both children and their household contacts, compared to IIV. Trial registration: ClinicalTrials.gov NCT01995851 .

Background School-based influenza immunization can effectively address accessibility barriers, but injected inactivated influenza vaccines (IIV) may not be acceptable to some children and parents in school settings. Objectives To better understand the feasibility of offering intranasal live attenuated influenza vaccines (LAIV) through schools, we assessed uptake, stakeholder acceptability, and cost of school-based delivery of LAIV compared to IIV. Methods We piloted an open-label cluster randomized trial involving 10 elementary schools in Peterborough, Ontario during the 2013–2014 influenza vaccination campaign. Schools were randomized to having students receive IIV or LAIV at publicly-funded school-based clinics organized by the local public health department. We measured the percentage of students vaccinated with at least one dose of influenza vaccine at school. Stakeholder acceptability was evaluated through a questionnaire of parents and interviews of public health department personnel and school principals. We compared the costs per dose of vaccine administered, including staff time and costs of vaccines and supplies. Results Single-dose influenza vaccine uptake was higher for the five schools offering LAIV than for the five offering IIV (19.3% vs. 12.2%, p = 0.02). Interviews with nine school principals and five public health department personnel suggested that the clinics ran smoothly with little disruption to school routines, and that LAIV was associated with increased efficiency and calmer children. All interviewees cited unfamiliarity with LAIV and the study recruitment package length as potential reasons for low uptake. The cost per vaccine dose administered was $38.67 for IIV and $43.50 for LAIV. Conclusions Use of LAIV in school-based clinics was associated with increased vaccine uptake and the perception among immunizing staff of reduced child anxiety, but also slightly higher vaccine administration costs, compared to IIV. However, uptake was low for both groups. More effective strategies to promote influenza vaccines and to obtain parent consent may improve vaccine uptake. Trial registration ClinicalTrials.gov NCT01995851. Funding Public Health Agency of Canada/Canadian Institutes of Health Research Influenza Research Network.

OBJECTIVE Patients with rheumatoid arthritis (RA) are at increased risk of TB. Little is known about the risk of nontuberculous mycobacteria (NTM) disease in these patients. We sought to ascertain the rate of NTM infection and TB in all residents of Ontario, Canada, with and without RA. METHODS In a cohort study, all Ontarians aged ≥ 15 years in January 2001 were followed until December 2010. Individuals with RA were identified using a validated algorithm to search hospitalization and physician billing claims. We linked Public Health Ontario Laboratory data to identify all cases of laboratory-confirmed TB and NTM disease. Analysis was performed using Cox proportional hazards regression. RESULTS We identified 113,558 Ontarians with RA and 9,760,075 Ontarians without RA. Relative to the non-RA group, adjusted hazard ratios (HRs) and 95% CIs for TB (1.92, [1.50-2.47]) and NTM disease (2.07, [1.84-2.32]) demonstrated increased risks in the RA group. Among those with RA, per 100,000 person-years, NTM disease (HR, 41.6; 95% CI, 37.1-46.5) was more common than TB (HR, 8.5; 95% CI, 6.5-10.8). After full adjustment, people with RA who developed NTM disease were 1.81 times as likely to die than uninfected people with RA. CONCLUSIONS Mycobacterial infections are more common in Ontarians with RA, with NTM disease more likely than TB. NTM disease is associated with an increased risk of death in patients with RA. Given the rising rates of NTM disease worldwide, determining whether this risk is due to the use of immunosuppressive medications vs RA itself is an important objective for future research.

Summary Background The possible risk of Guillain-Barre syndrome from influenza vaccines remains a potential obstacle to achieving high vaccination coverage. However, influenza infection might also be associated with Guillain-Barre syndrome. We aimed to assess the risk of Guillain-Barre syndrome after seasonal influenza vaccination and after influenza-coded health-care encounters. Methods We used the self-controlled risk interval design and linked universal health-care system databases from Ontario, Canada, with data obtained between 1993 and 2011. We used physician billing claims for influenza vaccination and influenza-coded health-care encounters to ascertain exposures. Using fixed-effects conditional Poisson regression, we estimated the relative incidence of hospitalisation for primary-coded Guillain-Barre syndrome during the risk interval compared with the control interval. Findings We identified 2831 incident admissions for Guillain-Barre syndrome; 330 received an influenza vaccine and 109 had an influenza-coded health-care encounter within 42 weeks before hospitalisation. The risk of Guillain-Barre syndrome within 6 weeks of vaccination was 52% higher than in the control interval of 9–42 weeks (relative incidence 1·52; 95% CI 1·17–1·99), with the greatest risk during weeks 2–4 after vaccination. The risk of Guillain-Barre syndrome within 6 weeks of an influenza-coded health-care encounter was greater than for vaccination (15·81; 10·28–24·32). The attributable risks were 1·03 Guillain-Barre syndrome admissions per million vaccinations, compared with 17·2 Guillain-Barre syndrome admissions per million influenza-coded health-care encounters. Interpretation The relative and attributable risks of Guillain-Barre syndrome after seasonal influenza vaccination are lower than those after influenza illness. Patients considering immunisation should be fully informed of the risks of Guillain-Barre syndrome from both influenza vaccines and influenza illness. Funding Canadian Institutes of Health Research.

Background Immunization rates are used to assess the level of protection against influenza, but limited data exist on how such rates are measured in health care organizations. We conducted key informant interviews with campaign planners to learn about processes for collecting immunization data, including barriers and facilitating factors for measuring and reporting rates. Methods We conducted telephone interviews with 23 influenza immunization program planners across Canada working in 7 acute care hospitals, 6 continuing care facilities, and 8 public health organizations in 2012. We used content analysis to examine the interview data. Results The methods used to collect immunization data varied by the size and type of health care organization. Immunization data from different personnel groups were included in immunization rate calculations depending on the local public health reporting requirements and the organization's size. Challenges associated with collecting immunization data and calculating rates included lack of resources for identifying personnel immunized off-site, tracking personnel who declined immunization, identifying non-payroll staff, and interpreting unclear public health reporting requirements. Conclusion Support from other vaccine providers, public health, employers, and professional and external bodies is needed to provide the necessary information and resources to calculate accurate and complete rates. Further work is needed to refine and standardize the collection of HCW influenza immunization data so that it may be used for surveillance and quality assessment purposes.

Background In response to the need for improved quality of vaccine inventory and client immunization records, barcodes containing a unique identifier and lot number will be placed on all vaccine vials in Canada. We conducted feasibility studies to examine integration of barcode scanning into inventory recording workflow for mass immunization clinics. Methods During the 2010–2011 seasonal influenza vaccination campaign, Ontario public health units (PHUs) using an electronic immunization system were randomized to record clinic inventory data (including vaccine lot number and expiry date) through: (i) barcode scanning of vials; or (ii) drop-down menus. A third group of PHUs recording vaccine inventory on paper served as an observation arm. We visited a sample of clinics within each PHU to assess barcode readability, method efficiency and data quality. Clinic staff completed a survey examining method perceptions. Results We observed 20 clinics using barcode scanning to record inventory data (eight PHUs), 20 using drop-down menus (eight PHUs), and 21 using paper forms (five PHUs). Mean time spent recording data per vial was 4.3 s using barcode scanners with 1.3 scan attempts per vial, 0.5 s using drop-down menus, and 1.7 s using paper. Few errors were observed. Sixty-four perception surveys were completed by inventory staff; barcode scanning users indicated fairly strong overall satisfaction with the method (74%), and the majority agreed that barcode scanning improved client safety (84%) and inventory record accuracy (77%). However, 38% of barcode scanning users felt that individually scanning vials took longer than the other approaches and 26% indicated that this increased time would discourage them from adopting the method. Conclusions Our study demonstrated good readability of barcodes but scanning individual vials for high-volume clinics was time-consuming; modifying the process will improve feasibility to facilitate adoption in Canada, while serving as an example for other countries considering this technology.

Background Past varicella infection (chicken pox) may reactivate into herpes zoster (shingles). Varicella vaccination leads to a reduction in cases of varicella that may in turn increase herpes zoster rates due to reduction in the immune boosting effect of exposure to varicella zoster virus against varicella reactivation. We assessed the impact of childhood varicella vaccination in Ontario, Canada on zoster incidence and healthcare visits, and established baseline zoster rates prior to zoster vaccine introduction. Methods We used population-based, administrative databases to identify zoster incidence and healthcare use from April 1992 to March 2010. Results After routine varicella vaccination, zoster incidence rates decreased 29% for children aged 0–9 and changed minimally for other ages. Age-standardized rates of hospitalizations during the study period declined by 53%, while outpatient rates declined by 9%. The annual zoster incidence for those 60 or older was 740 per 100,000. Conclusions In the early post-varicella vaccination period, incidence rates of medically attended herpes zoster did not increase for the overall population and decreased moderately for children 9 years and younger, the age group targeted for varicella vaccination.

Birth weight of children born at term may theoretically be associated with risk of adverse events from immunization.We analyzed data on children born between April 1st 2002 and March 31st 2009 in the province of Ontario. Using the self-controlled case series design, we examined the risk of the combined endpoint of emergency room visit and hospital admission in the immediate three days post vaccination at 2 months of age compared to a control period 9-18 days after vaccination. In term children, we conducted 4 comparisons of relative incidence (RI) of events: (1) 4 lower birth weight quintiles compared to the largest quintile (2) SGA10 infants compared to non SGA10 infants, (3) low birth weight infants (2500g) compared to non low birth weight infants and (4) SGA10 infants vaccinated before 60 days compared to those vaccinated after 60 days.There was a significant trend towards increasing relative incidence of the combined endpoint with decreasing birth weight quintile (p=0.016). There was an increased relative incidence of events in SGA10 versus non SGA10 infants (RI 1.25 (95% CI 1.09-1.44)) and in SGA10 children vaccinated before 60 days of age compared to after 60 days of age (RI 1.57 (95% CI 1.14-2.18)). No significant effect was observed in low birth weight children. The impact of birth weight was primarily mediated through an increase in ER visits in the 24h following vaccination.Lower birth weight appears to be correlated with an increased risk of emergency room visits within 24h of vaccination. The absolute risk is small and there was no impact on admissions or death.

During the pandemic (H1N1) 2009 vaccination campaign, vaccine providers collected immunization data using hybrid (paper-based and electronic methods) and electronic data systems. We measured staff time in seconds spent on data collection tasks to compare system efficiencies. The sample consisted of 38 organizations across nine Canadian provinces/territories. The total mean data collection times per client were 104 s (electronic system), 143 s (hybrid system with electronic registration) and 172 s (hybrid system with paper registration). Electronic registration and record keeping were faster than paper-based methods; these findings should be used to improve data collection for future influenza seasons.

Varicella vaccines have been available for private purchase in Canada since 1998. Ontario introduced publicly funded varicella vaccination in 2004. We assessed the effects of private availability of varicella vaccines and subsequent implementation of a publicly funded vaccination program on varicella-related hospitalizations, emergency department (ED) use, and visits to physicians' offices in Ontario. Rates of hospitalizations, ED use, and office visits decreased 53% (95% CI, 48-58%), 43% (95% CI, 41-44%), and 45% (95% CI, 44-45%) after publicly funded vaccination, compared to only 9% (95% CI, 4-14%), 23% (95% CI, 22-24%), and 29% (95% CI, 28-29%) after private availability. Varicella vaccination is effective at reducing varicella-related health care use, with benefits extending beyond those who receive the vaccine. Publicly funded vaccination programs may be more effective than private vaccine availability.

The objective of this study was to validate physician billing claims against self-reported influenza vaccination to assess individual-level vaccination status. We compared responses to the Canadian Community Health Survey 1.1 (CCHS) and Ontario Health Insurance Plan (OHIP) physician billing claims and found moderate agreement. Using self-report as the gold standard, OHIP claims based on using both influenza-specific and general vaccination codes have high specificity and positive predictive value (PPV), reasonable negative predictive value (NPV), but only fair sensitivity. OHIP physician billing claims are suboptimal for ascertaining the vaccination status of individuals because many individuals receive their vaccinations outside doctor's offices, but may be used as the backbone for the creation of an immunization registry.

Groll and Thomson's evaluation of the effectiveness of Ontario's Universal Influenza Immunization Campaign used per capita cases of laboratory-confirmed influenza. We argue that these data are susceptible to various biases and should not be used as an outcome measure. Laboratory data are traditionally used to identify the presence of influenza activity rather than to identify levels of influenza activity. A better measure of viral activity is the proportion of influenza tests positive; whereas the weekly proportion of tests positive was relatively consistent, a marked increase over time in the numbers of laboratory-confirmed cases paralleled an increase in the number of tests performed. Regardless, for evaluating universal influenza immunization program effectiveness, other established and available measures employed in previous studies describing the epidemiology of influenza should be used instead of laboratory data.