Jeffrey C. Kwong

Importance: Influenza causes substantial morbidity in children, yet Canadian data on influenza vaccine effectiveness (VE) in preventing emergency department (ED) visits and hospitalizations are limited. Objective: To estimate VE against influenza-associated ED visits and hospitalizations among children during the 2024-2025 and 2025-2026 seasons. Design: Test-negative case-control design. Setting: Fourteen Canadian pediatric tertiary-care hospitals participating in the Surveillance Program for the Rapid IdeNtification and TracKing of Infectious Diseases in kidS (SPRINT-KIDS) network. Participants: Symptomatic children aged 6 months to <18 years tested for influenza from October 27, 2024, to June 7, 2025, and from November 2, 2025, to June 13, 2026. Exposure: At least one dose of current-season influenza vaccine. Main Outcomes and Measures: VE against laboratory-confirmed influenza A or B associated with an ED visit or hospitalization. VE was estimated using multivariable logistic regression adjusted for age, epidemiologic week, site, and high-risk comorbidity. Results: The 2024-2025 season included 17,316 encounters (median [IQR] age=41.0 [18.5–82.3] months; 54.0% male), with 4,760 influenza-positive cases (8.9% vaccinated) and 12,556 influenza-negative controls (15.9% vaccinated). The 2025-2026 season included 13,417 encounters (median [IQR] age=33.5 [16.7–74.8] months; 54.1% male), with 4,798 cases (7.6% vaccinated) and 8,619 controls (18.1% vaccinated). VE against any influenza was 47% (95%CI, 40–53%) and 53% (95%CI, 46–59%) in 2024-2025 and 2025-2026, respectively. VE against ED visits was 53% (95%CI, 45–59%) and 57% (95%CI, 49–63%), and VE against hospitalization was 33% (95%CI, 16–47%) and 48% (95%CI, 33–59%) in 2024-2025 and 2025-2026, respectively. VE was lower against influenza A as compared to B in both seasons: 31% (95%CI, 22–39%) vs. 75% (95%CI, 64– 82%) (p<0.001) in 2024-2025; and 42% (95%CI, 32–50%) vs. 64% (95%CI, 55–72%) (p=0.001) in 2025-2026. VE was lower in children aged 10 to <18 years than in those <10 years, particularly among children with comorbidities. Protection against influenza A lasted up to 90 days, whereas it persisted beyond 120 days for influenza B. Conclusions and Relevance: Influenza vaccines were moderately effective against pediatric ED visits and hospitalizations in both seasons. Routine vaccination should continue to be recommended to prevent hospital-attended influenza. Key Points: Question: How effective were influenza vaccines against influenza-associated emergency department visits and hospitalizations among Canadian children during the 2024-2025 and 2025-2026 seasons? Findings: In this test-negative case-control study of 30,733 encounters at 14 pediatric hospitals, vaccine effectiveness against any influenza was 47% in 2024-2025 and 53% in 2025-2026, despite antigenically drifted A(H3N2) subclade K predominance. Effectiveness was lower against influenza A than B and among adolescents. Meaning: These findings support continued annual influenza vaccination of children, even when substantial antigenic mismatch is anticipated.

Rapid cycle analysis (RCA) enables near real-time post-licensure safety monitoring of vaccines using large-scale health data. However, implementation across multinational, federated surveillance systems presents substantive challenges, including heterogeneity in data sources, coding systems, data lags, analytic capacity, and data-sharing constraints. Challenges are amplified during public health emergencies, when timely, coordinated signal detection that can achieve sufficient sample size for detecting rare adverse events is required across diverse populations. We describe the design and statistical methodology of an innovative analytic framework that supports collaborative, multinational implementation of RCA across a global network. The framework explicitly accommodates federated environments and inclusivity, enabling countries to contribute according to their available data assets, governance setting, and analytic capacity. Key features include innovative use of multiple complementary study designs, tiered participation levels aligned to minimum data requirements, and harmonised analytic protocols that ensure methodological consistency while preserving local data sovereignty. Central to the framework is the purpose-built rapidcycler R package, delivering a standardised pipeline for local data aggregation, formatting, sequential analysis, and sharing of de-identified summary statistics. This approach enables scalable, privacy-preserving signal detection inclusive of low- and middle-income countries. The framework’s modular design allows rapid adaptation to emergent vaccines, platforms, variants, coadministration scenarios, or changing immunisation policies, with minimal redevelopment effort. By integrating harmonised study designs, sequential hypothesis testing, and data-driven analytic pipelines within a federated architecture, this RCA framework provides a robust, flexible platform for collaborative, adaptive monitoring using real-world data, enhancing future global capacity to monitor vaccine safety at scale and speed.

Background: Older adults hospitalized for major cardiovascular events may have reduced influenza vaccine effectiveness (VE) due to function immunosenescence, multimorbidity, frailty, and chronic medication use. Despite their high burden of cardiovascular disease (CVD), influenza VE has not been specifically evaluated in this population. We estimated influenza VE against laboratory-confirmed influenza infection among older adults hospitalized with cardiovascular conditions and assessed whether VE differed by sex or age. Methods: Using linked health administrative datasets in Ontario, Canada, we applied a test-negative design across six influenza seasons (2010−11 to 2015−16). Adults aged >65 years hospitalized within three days of an acute cardiovascular event (acute myocardial infarction, unstable angina) were included. Multivariable logistic regression models estimated the adjusted odds ratios (ORs) of vaccination among cases versus controls, adjusting for demographic and clinical covariates. VE was derived as (1 − OR) ×100%. Effect modification analysis by sex (male vs. female) and age (≤80 vs. >80 years) was conducted separately. Results: Among 1,159 patients, 50% were vaccinated,14% tested positive for influenza, while 20% of unvaccinated patients tested positive for influenza (p-value 0.013). Adjusted VE was 43% [95% CI, 20% 60%]. No effect modification was observed. Conclusion: Influenza vaccination provided moderate protection comparable to the general population, supporting its use in high-risk older adults hospitalized for cardiovascular events.

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Background: COVID-19 vaccines can cause rare but serious adverse events such as myocarditis and immune thrombotic thrombocytopenia. Despite a lack of strong evidence, concerns have been expressed that COVID-19 vaccination might lead to sudden death in younger healthy adults. We studied the association between COVID-19 vaccination and sudden death in apparently healthy people aged 12–50 years. Methods and findings: We conducted a population-based case-control study using linked administrative datasets of residents of Ontario, Canada who were alive as of April 1, 2021. We excluded individuals aged >50 years and those with documented cardiovascular disease, mental illness, or diseases that predispose to adverse outcomes from COVID-19. We defined cases as those with out-of-hospital death, or death within 24 hours of presentation to hospital with a final diagnosis of cardiac arrest between April 1, 2021 and June 30, 2023. We matched each case with five controls on age, sex, region of residence, and neighborhood income quintile. We used conditional logistic regression to assess the association between sudden death and previous COVID-19 vaccination after adjusting for multiple potential confounders (positive severe acute respiratory syndrome coronavirus 2 [SARS-CoV-2] tests, number of SARS-CoV-2 polymerase chain reaction (PCR) tests, influenza vaccination, common comorbidities). Sensitivity analyses were conducted with different definitions of the exposure and subsets of cases (with their matched controls). Another sensitivity analysis utilized a modified self-controlled case series (SCCS) of vaccinated individuals meeting the case definition during the study period with up to three doses of any COVID-19 vaccine. Of 6,365,451 eligible individuals, we identified 4,963 (0.08%) cases meeting our definition of sudden death (median age 36 years, 74.4% male). In the primary analysis, COVID-19 vaccination was associated with a lower risk of sudden death (adjusted odds ratio [aOR] = 0.57; 95% confidence interval (CI) [0.53,0.61]; p < 0.001). The findings were consistent for COVID-19 vaccination within six weeks before death (aOR = 0.63; 95%CI [0.55,0.72]; p < 0.001) and in sensitivity analyses limited to people aged p < 0.001), those who died in hospital or in the emergency department (aOR = 0.71; 95%CI [0.55,0.91]; p = 0.006), and after exclusion of opioid-related deaths (aOR = 0.57; 95%CI [0.51,0.64]; p < 0.001). The SCCS sensitivity analysis showed no significant difference in the rate of sudden death in the 6 weeks following first (relative incidence (RI) 0.87; 95%CI [0.54,1.40]; p = 0.57), second (RI 0.94; 95%CI [0.57,1.57]; p = 0.82), or third (RI 0.87; 95%CI [0.37,2.05]; p = 0.10) dose of the COVID-19 vaccine. Study limitations include the inability to confirm the cause of out-of-hospital deaths and residual confounding due to differences in health-seeking behaviors for the case-control analysis. Conclusions: These findings do not support the hypothesis that COVID-19 vaccines increase the risk of sudden cardiac death in young healthy adults.

Empirical evidence on the indirect herd benefits of COVID-19 vaccination and/or prior infection is limited. We examined how area-level immunity interacts with individual-level immunity to affect COVID-19 diagnoses and deaths. Ontario residents aged ≥18 years were followed from August 1, 2021, to January 30, 2022. Individual-level immunity was defined as receipt of a primary series of COVID-19 vaccines or a positive SARS-CoV-2 test in the past 165 days. Area-level immunity was based on the proportion of immune individuals in an individual's residing area. Logistic regression and cause-specific hazard models were used to examine the relationship between immunity and COVID-19 diagnosis, and between immunity and COVID-19 death, with an interaction term between individual-level and area-level immunity. Of 11 122 816 adults, 7 518 015 (67.6%) were classified as having individual-level immunity at baseline. After accounting for potential confounders, area-level immunity (highest vs. lowest quintiles) was associated with lower odds of COVID-19 diagnosis. Higher area-level immunity (highest vs. lowest quintiles) was also associated with lower hazard of COVID-19 death among non-immune individuals (hazard ratio, 0.77 [0.60, 1.00]). Findings provide evidence supporting the herd benefits of vaccination or prior infection on COVID-19 diagnosis and deaths, and provide insights for interpreting vaccine effectiveness estimates in the context of herd immunity.

Background: Indirect vaccine effectiveness (IVE) estimates are vulnerable to bias, and high-quality evidence on influenza IVE remains limited. We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) estimating influenza IVE. Methods: We searched MEDLINE and EMBASE through 9 December 2025, for RCTs conducted in non-institutional settings estimating IVE by comparing reverse transcription-polymerase chain reaction-confirmed influenza illness among unvaccinated individuals in vaccinated versus unvaccinated households or communities. Searches were restricted to English-language publications. Results: Eight articles describing twelve RCTs were included, comprising 10 cluster-randomized trials designed to estimate IVE and 2 individual-randomized trials assessing IVE among household contacts. Risk of bias was low. Across trials conducted between 2008 and 2013, estimates of direct vaccine effectiveness (DVE) were moderate, whereas IVE estimates were lower and often centered near no effect, with the CIs for 9 of 12 trials including zero. The pooled DVE was 44.1% (95% CI: 29.6%, 55.6%), and the pooled IVE was 13.7% (95% CI: 1.5%, 24.5%). Sensitivity analyses excluding pandemic outcomes yielded minimally higher point estimates and did not materially change the findings. Between-study heterogeneity was moderate. There was no evidence of publication bias. Certainty of evidence was rated as moderate. Conclusions: This review provides a methodologically rigorous benchmark of IVE measurable under randomized conditions. While pooled DVE was moderate, pooled IVE was lower, and most individual trials did not demonstrate statistically significant indirect effects. The findings indicate that individual vaccination is the most reliable means of preventing influenza, rather than depending on indirect or community-level protection.

Background: Hepatitis C virus (HCV) infections have increased among younger populations, including pregnant people. While universal screening guidelines have improved case-finding, studies suggest low postpartum linkage-to-care rates. Better understanding of the peripartum HCV care cascade at the population level is needed to inform optimal management, including the role of treatment in pregnancy. Methods: A retrospective cohort study linking pregnant individuals with HCV test records to health administrative data in Ontario, Canada. We examined the HCV care continuum, including during subsequent pregnancies. We used Andersen-Gill models to examine predictors of missed opportunities for treatment, defined as pregnancies occurring before/in absence of treatment, and initiating treatment. Results: From 2003 to 2021, we identified 42 797 pregnancies in 16 888 people who tested HCV antibody-positive between 1999 and 2021. Of antibody-positive individuals, 14 538 (86.1%) had RNA testing and 7457 (51.3%) tested RNA-positive. Treatment uptake was 1.1%, 2.5%, and 5.2% at 1, 2, and 5 years after RNA positivity. Ultimately, 3861 (51.8%) initiated treatment and 2277 (30.5%) demonstrated sustained virologic response. Among those with confirmed chronic HCV, 47.5% (n = 3025) experienced a missed opportunity for treatment, with 19.2% (n = 1221) having multiple missed opportunities. Numbers of pregnancies and diagnosis year pre-2012 were associated with higher likelihood of a missed opportunity for treatment, while diagnoses of substance use disorder, HIV, and chronic disease were associated with lower likelihood. Conclusions: Despite diagnosis, <10% initiated treatment within 5 years of RNA positivity and multiple pregnancies occurred before treatment, resulting in repeated exposures. Additional efforts will be required to ensure linkage-to-care and treatment either during pregnancy or postpartum.