Social inequalities in COVID-19 deaths by area-level income: patterns over time and the mediating role of vaccination in a population of 11.2 million people in Ontario, Canada (preprint)

ImportanceSocial inequalities in COVID-19 deaths were evident early in the pandemic. Less is known about how vaccination may have influenced inequalities in COVID-19 deaths. ObjectivesTo examine patterns in COVID-19 deaths by area-level income over time and to examine the impact of vaccination on inequality patterns in COVID-19 deaths. Design, setting, and participantsPopulation-based retrospective cohort study including community-living individuals aged [≥]18 years residing in Ontario, Canada, as of March 1, 2020 who were followed through to January 30, 2022 (five pandemic waves). ExposureArea-level income derived from the 2016 Census at the level of dissemination area categorized into quintiles. Vaccination defined as receiving [≥] 1 dose of Johnson-Johnson vaccine or [≥] 2 doses of other vaccines. Main outcome measuresCOVID-19 death defined as death within 30 days following, or 7 days prior to a positive SARS-CoV-2 PCR test. Cause-specific hazard models were used to examine the relationship between income and COVID-19 deaths in each wave. We used regression-based causal mediation analyses to examine the impact of vaccination in the relationship between income and COVID-19 deaths during waves four and five. ResultsOf 11,248,572 adults, 7044 (0.063%) experienced a COVID-19 death. After accounting for demographics, baseline health, and area-level social determinants of health, inequalities in COVID-19 deaths by income persisted over time (adjusted hazard ratios (aHR) [95% confidence intervals] comparing lowest-income vs. highest-income quintiles were 1.37[0.98-1.92] for wave one, 1.21[0.99-1.48] for wave two, 1.55[1.22-1.96] for wave three, and 1.57[1.15-2.15] for waves four and five). Of 11,122,816 adults alive by the start of wave four, 7,534,259(67.7%) were vaccinated, with lower odds of vaccination in the lowest-income compared to highest-income quintiles (0.71[0.70-0.71]). This inequality in vaccination accounted for 57.9%[21.9%-94.0%] of inequalities in COVID-19 deaths between individuals in the lowest-income vs. highest-income quintiles. ConclusionsInequalities by income persisted in COVID-19 deaths over time. Efforts are needed to address both vaccination gaps and residual heightened risks associated with lower income to improve health equity in COVID-19 outcomes. Summary boxO_ST_ABSSection 1: What is already known on this topicC_ST_ABSO_LIEmerging data suggest social inequalities in COVID-19 deaths might have persisted over time, but existing studies were limited by their ecological design and/or inability to account for potential confounders. C_LIO_LIVaccination has contributed to reducing COVID-19 deaths but there were social inequalities in vaccination coverage. C_LIO_LIThe impact of inequalities in vaccination on inequalities in COVID-19 deaths has not yet been well-studied. C_LI Section 2: What this study addsO_LIAcross five pandemic waves (2020-2021) in Ontario, Canada, COVID-19 deaths remained higher in individuals living in lower-income neighbourhoods, even after accounting for individual-level demographics and baseline health, and other area-level social determinants of health. C_LIO_LIDuring later waves (following the vaccination roll-out), over half (57.9%) of the inequalities in COVID-19 deaths between individuals living in the lowest and highest income neighbourhoods could be attributed to differential vaccination coverage by income. This means that if vaccine equality was achieved, inequalities in deaths would persist but be reduced. C_LIO_LIAddressing vaccination gaps, as well as addressing the residual heightened risks of COVID-19 associated with lower income could improve health equity in COVID-19 outcomes. C_LI

Protection conferred by COVID-19 vaccination, prior SARS-CoV-2 infection, or hybrid immunity against Omicron-associated severe outcomes among community-dwelling adults (preprint)

Introduction: We assessed protection conferred by COVID-19 vaccines and/or prior SARS-CoV-2 infection against Omicron-associated severe outcomes during successive sublineage-predominant periods. Methods: We used a test-negative design to estimate protection by vaccines and/or prior infection against hospitalization/death among community-dwelling, PCR-tested adults aged >50 years in Ontario, Canada between January 2, 2022 and June 30, 2023. Multivariable logistic regression was used to estimate the relative change in the odds of hospitalization/death with each vaccine dose (2-5) and/or prior PCR-confirmed SARS-CoV-2 infection (compared with unvaccinated, uninfected subjects) up to 15 months since the last vaccination or infection. Results: We included 18,526 cases with Omicron-associated severe outcomes and 90,778 test-negative controls. Vaccine protection was high during BA.1/BA.2 predominance, but was generally <50% during periods of BA.4/BA.5 and BQ/XBB predominance without boosters. A third/fourth dose transiently increased protection during BA.4/BA.5 predominance (third-dose, 6-month: 68%, 95%CI 63%-72%; fourth-dose, 6-month: 80%, 95%CI 77%-83%), but was lower and waned quickly during BQ/XBB predominance (third-dose, 6-month: 59%, 95%CI 48%-67%; 12-month: 49%, 95%CI 41%-56%; fourth-dose, 6-month: 62%, 95%CI 56%-68%, 12-months: 51%, 95%CI 41%-56%). Hybrid immunity conferred nearly 90% protection throughout BA.1/BA.2 and BA.4/BA.5 predominance, but was reduced during BQ/XBB predominance (third-dose, 6-month: 60%, 95%CI 36%-75%; fourth-dose, 6-month: 63%, 95%CI 42%-76%). Protection was restored with a fifth dose (bivalent; 6-month: 91%, 95%CI 79%-96%). Prior infection alone did not confer lasting protection. Conclusion: Protection from COVID-19 vaccines and/or prior SARS-CoV-2 infections against severe outcomes is reduced when immune-evasive variants/subvariants emerge and may also wane over time. Our findings support a variant-adapted booster vaccination strategy with periodic review.

mRNA-1273 vaccine effectiveness against symptomatic SARS-CoV-2 infection and COVID-19-related hospitalization in children aged 6 months to 5 years (preprint)

Importance: Data on mRNA-1273 (Moderna) vaccine effectiveness in children aged 6 months to 5 years are limited. Objective: To assess mRNA-1273 vaccine effectiveness against symptomatic SARS-CoV-2 infection and COVID-19-related hospitalization among children aged 6 months to 5 years. Design, Setting, and Participants: A test-negative study using linked health administrative data in Ontario, Canada. Participants included symptomatic children aged 6 months to 5 years who were tested by RT-PCR. Exposures: mRNA-1273 vaccination. Main Outcomes and Measures: Symptomatic SARS-CoV-2 infection and COVID-19-related hospitalization. Results: We included 3467 test-negative controls and 572 test-positive cases. Receipt of mRNA-1273 was associated with reduced symptomatic SARS-CoV-2 infection (VE=90%; 95%CI: 53, 99%) and COVID-19-related hospitalization (VE=82%; 95%CI: 4, 99%) [≥]7 days after the second dose. Conclusions and Relevance: Our findings suggest mRNA-1273 vaccine effectiveness is initially strong against symptomatic SARS-CoV-2 infection and hospitalization in children aged 6 months to 5 years. Further research is needed to understand long-term effectiveness and the need for booster doses.

Effectiveness of mRNA COVID-19 monovalent and bivalent vaccine booster doses against Omicron severe outcomes among adults aged >=50 years in Ontario, Canada (preprint)

Objective: We estimated the effectiveness of booster doses of monovalent and bivalent mRNA COVID-19 vaccines against Omicron-associated severe outcomes among adults aged [≥]50 years in Ontario, Canada. Methods: We used a test-negative design to estimate vaccine effectiveness (VE), with unvaccinated adults as the comparator, against hospitalization or death among SARS-CoV-2-tested adults aged [≥]50 years between June 19, 2022 and January 28, 2023 stratified by time since vaccination. We explored VE by vaccine product (Moderna Spikevax (R) monovalent; Pfizer-BioNTech Comirnaty(R) monovalent; Moderna Spikevax(R) BA.1 bivalent; Pfizer-BioNTech Comirnaty(R) BA.4/BA.5 bivalent). Results: We included 3,755 Omicron cases and 14,338 test-negative controls. For the Moderna and Pfizer-BioNTech monovalent vaccines, VE 7-29 days after vaccination was 85% (95% confidence interval [CI], 72-92%) and 88% (95%CI, 82-92%), respectively, and was 82% (95%CI, 76-87%) and 82% (95%CI, 77-86%) 90-119 days after vaccination. For the Moderna BA.1 bivalent vaccine, VE was 86% (95%CI, 82-90%) 7-29 days after vaccination and was 76% (95%CI, 66-83%) 90-119 days after vaccination. For the Pfizer-BioNTech BA.4/BA.5 bivalent vaccine, VE 7-29 days after vaccination was 83% (95%CI, 77-88%) and was 81% (95%CI 72-87%) 60-89 days after vaccination. Conclusions: Booster doses of monovalent and bivalent mRNA COVID-19 vaccines provided similar, strong initial protection against severe outcomes in community-dwelling adults aged [≥]50 years in Ontario. Nonetheless, uncertainty remains around waning protection of these vaccines.

Effectiveness and Duration of Protection of a Fourth Dose of COVID-19 mRNA Vaccine among Long-Term Care Residents in Ontario, Canada (preprint)

Background: As of December 30, 2021, Ontario long-term care (LTC) residents who received a third dose of COVID-19 vaccine [≥]84 days previously were offered a fourth dose to prevent a surge in COVID-19-related morbidity and mortality due to the Omicron variant. Seven months have passed since fourth doses were implemented, allowing for the examination of fourth dose protection over time. Methods: We used a test-negative design and linked databases to estimate the marginal effectiveness (4 versus 3 doses) and vaccine effectiveness (VE; 2, 3, or 4 doses versus no doses) of mRNA vaccines among Ontario LTC residents aged [≥]60 years who were tested for SARS-CoV-2 between December 30, 2021 and August 3, 2022. Outcome measures included any Omicron infection, symptomatic infection, and severe outcomes (hospitalization or death). Results: We included 21,275 Omicron cases and 273,466 test-negative controls. The marginal effectiveness of a fourth dose <84 days ago compared to a third dose received [≥]84 days ago was 23% (95% Confidence Interval [CI] 17-29%), 36% (95%CI 26-44%), and 37% (95%CI 24-48%) against SARS-CoV-2 infection, symptomatic infection, and severe outcomes, respectively. Additional protection provided by a fourth dose compared to a third dose was negligible against all outcomes [≥]168 days after vaccination. Compared to unvaccinated individuals, vaccine effectiveness (VE) of a fourth dose decreased from 49% (95%CI 44%-54%) to 18% (95%CI 5-28%) against infection, 69% (95%CI 62-75%) to 44% (95%CI 24-59%) against symptomatic infection, and 82% (95%CI 77-86%) to 74% (95%CI 62-82%) against severe outcomes <84 days versus [≥]168 days after vaccination. Conclusions: Our findings suggest that fourth doses of mRNA COVID-19 vaccines provide additional protection against Omicron-related outcomes in LTC residents, but the protection wanes over time, with more waning seen against infection than severe outcomes.

Predictors of all-cause mortality among patients hospitalized with influenza, respiratory syncytial virus, or SARS-CoV-2 (preprint)

Background: Identification of shared and divergent predictors of clinical severity across respiratory viruses may support clinical decision-making and resource planning in the context of a novel or re-emergent respiratory pathogen. Methods: We conducted a retrospective cohort study to identify predictors of 30-day all-cause mortality following hospitalization with influenza (N=45,749; 2011-09 to 2019-05), respiratory syncytial virus (RSV, N=24,345; 2011-09 to 2019-04), or SARS-CoV-2 (N=8,988; 2020-03 to 2020-12; pre-vaccine) using population-based health administrative data from Ontario, Canada. Multivariable modified Poisson regression was used to assess associations between potential predictors and mortality. We compared the direction, magnitude and confidence intervals of risk ratios to identify shared and divergent predictors of mortality. Results: 3,186 (7.0%), 697 (2.9%) and 1,880 (20.9%) patients died within 30 days of hospital admission with influenza, RSV, and SARS-CoV-2, respectively. Common predictors of increased mortality included: older age, male sex, residence in a long-term care home, and chronic kidney disease. Positive associations between age and mortality were largest for patients with SARS-CoV-2. Few comorbidities were associated with mortality among patients with SARS-CoV-2 as compared to those with influenza or RSV. Conclusions: Our findings may help identify patients at highest risk of illness secondary to a respiratory virus, anticipate hospital resource needs, and prioritize local preventions and therapeutics to communities with high prevalence of risk factors.

Background incidence rates of adverse events of special interest related to COVID-19 vaccines in Ontario, Canada, 2015 to 2020, to inform COVID-19 vaccine safety surveillance (preprint)

Background: Background 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. Methods: We 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 Bells palsy, idiopathic thrombocytopenia, febrile convulsions, acute disseminated encephalomyelitis, myocarditis, pericarditis, Kawasaki disease, Guillain-Barre syndrome, and transverse myelitis during five pre-pandemic years (2015-2019) and 2020. Results: The 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 Bells 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-Barre 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-Barre syndrome. Bells palsy, acute disseminated encephalomyelitis, and Guillain-Barre 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 and older for pericarditis. Febrile convulsions and Kawasaki disease were predominantly childhood diseases and generally decreased with age. Conclusions: Our estimated background rates will permit estimating numbers of expected events for these conditions and facilitate detection of potential safety signals following COVID-19 vaccination.

Effectiveness of COVID-19 vaccines against variants of concern, Canada (preprint)

Objectives: To estimate the effectiveness of BNT162b2 (Pfizer-BioNTech), mRNA-1273 (Moderna), and ChAdOx1 (AstraZeneca) vaccines against symptomatic SARS-CoV-2 infection and severe outcomes (COVID-19 hospitalization or death) caused by the Alpha (B.1.1.7), Beta (B.1.351), Gamma (P.1), and Delta (B.1.617.2) variants of concern (VOCs) during December 2020 to May 2021. Methods: We conducted a test-negative design study using linked population-wide vaccination, laboratory testing, and health administrative databases in Ontario, Canada. Results: Against symptomatic infection caused by Alpha, vaccine effectiveness with partial vaccination ([≥]14 days after dose 1) was higher for mRNA-1273 than BNT162b2 and ChAdOx1. Full vaccination ([≥]7 days after dose 2) increased vaccine effectiveness for BNT162b2 and mRNA-1273 against Alpha. Protection against symptomatic infection caused by Beta/Gamma was lower with partial vaccination for ChAdOx1 than mRNA-1273. Against Delta, vaccine effectiveness after partial vaccination tended to be lower than against Alpha for BNT162b2 and mRNA-1273, but was similar to Alpha for ChAdOx1. Full vaccination with BNT162b2 increased protection against Delta to levels comparable to Alpha and Beta/Gamma. Vaccine effectiveness against hospitalization or death caused by all studied VOCs was generally higher than for symptomatic infection after partial vaccination with all three vaccines. Conclusions: Our findings suggest that even a single dose of these 3 vaccine products provide good to excellent protection against symptomatic infection and severe outcomes caused by the 4 currently circulating variants of concern, and that 2 doses are likely to provide even higher protection.

Effectiveness of BNT162b2 and mRNA-1273 COVID-19 vaccines against symptomatic SARS-CoV-2 infection and severe COVID-19 outcomes in Ontario, Canada (preprint)

Objectives: To estimate the effectiveness of one and two doses of mRNA COVID-19 vaccines against symptomatic infection and severe outcomes. Design: Using a test-negative design study and linked laboratory, vaccination, and health administrative databases, we estimated adjusted vaccine effectiveness (aVE) against symptomatic infection and severe outcomes (hospitalization or death) using multivariable logistic regression. Setting: Ontario, Canada between 14 December 2020 and 19 April 2021. Participants: Community-dwelling adults aged [≥]16 years who were tested for SARS-CoV-2 and had COVID-19 symptoms. Interventions: Pfizer-BioNTech's BNT162b2 or Moderna's mRNA-1273 vaccine. Main outcome measures: Laboratory-confirmed SARS-CoV-2 identified by RT-PCR; hospitalization or death associated with SARS-CoV-2 infection. Results: Among 324,033 symptomatic individuals, 53,270 (16.4%) were positive for SARS-CoV-2 and 21,272 (6.6%) received 1 or more vaccine dose. Among test-positive cases, 2,479 (4.7%) had a severe outcome. aVE against symptomatic infection 14 days or more after receiving only 1 dose was 60% (95%CI, 57 to 64%), increasing from 48% (95%CI, 41 to 54%) at 14-20 days after the first dose to 71% (95%CI, 63 to 78%) at 35-41 days. aVE 7 days or more after receiving 2 doses was 91% (95%CI, 89 to 93%). Against severe outcomes, aVE 14 days or more after receiving 1 dose was 70% (95%CI, 60 to 77%), increasing from 62% (95%CI, 44 to 75%) at 14-20 days to 91% (95%CI, 73 to 97%) at 35 days or more, whereas aVE 7 days or more after receiving 2 doses was 98% (95%CI, 88 to 100%). For adults aged 70 years and older, aVE estimates were lower after receiving 1 dose, but were comparable to younger adults after 28 days. After 2 doses, we observed high aVE against E484K-positive variants. Conclusions: Two doses of BNT162b2 and mRNA-1273 vaccines are highly effective against both symptomatic infection and severe outcomes. Effectiveness is lower after only a single dose, particularly for older adults shortly after the first dose.

Neighbourhood characteristics associated with the geographic variation in laboratory confirmed COVID-19 in Ontario, Canada: a multilevel analysis (preprint)

Purpose: There is limited information on the role of individual and neighbourhood level characteristics in explaining the geographic variation in the novel coronavirus 2019 (COVID-19) between regions. This study quantified the magnitude of the variation in COVID-19 rates between neighbourhoods in Ontario, Canada, and examined the extent to which neighbourhood-level differences are explained by census-based neighbourhood measures, after adjusting for individual-level covariates (i.e., age, sex, and chronic conditions). Methods: We conducted a multilevel population-based study of individuals nested within neighbourhoods. COVID-19 laboratory testing data were obtained from a centralized laboratory database and linked to health administrative data. The median rate ratio and the variance partition coefficient were used to quantify the magnitude of the neighbourhood-level characteristics on the variation of COVID-19 rates. Results: The unadjusted median rate ratio for the between-neighbourhood variation in COVID-19 was 2.22 (95% CI, 2.41 to 2.77). In the fully adjusted regression models, the individual and neighbourhood level covariates accounted for about 44% of the variation in COVID-19 between neighbourhoods, with 43% attributable to neighbourhood-level census-based characteristics. Conclusion: Neighbourhood-level characteristics could explain almost half of the observed geographic variation in COVID-19. Understanding how neighbourhood-level characteristics influence COVID-19 rates can support jurisdictions in creating effective and equitable intervention strategies.

Heterogeneity in risk, testing and outcome of COVID-19 across outbreak settings in the Greater Toronto Area, Canada: an observational study (preprint)

BackgroundWe compared the risk of, testing for, and death following COVID-19 infection across three settings (long-term care homes (LTCH), shelters, the rest of the population) in the Greater Toronto Area (GTA), Canada. MethodsWe sourced person-level data from COVID-19 surveillance and reporting systems in Ontario, and examined settings with population-specific denominators (LTCH residents, shelters, and the rest of the population). We calculated cumulatively, the diagnosed cases per capita, proportion tested for COVID-19, daily and cumulative positivity, and case fatality proportion. We estimated the age- and sex-adjusted relative rate ratios for test positivity and case fatality using quasi-Poisson regression. ResultsBetween 01/23/2020-05/25/2020, we observed a shift in the proportion of cases: from travel-related and into LTCH and shelters. Cumulatively, compared to the rest of the population, the number of diagnosed cases per 100,000 was 59-fold and 18-fold higher among LTCH and shelter residents, respectively. By 05/25/2020, 77.2% of LTCH residents compared to 2.4% of the rest of the population had been tested. After adjusting for age and sex, LTCH residents were 2.5 times (95% confidence interval (CI): 2.3-2.8) more likely to test positive. Case fatality was 26.3% (915/3485), 0.7% (3/402), and 3.6% (506/14133) among LTCH residents, shelter population, and others in the GTA, respectively. After adjusting for age and sex, case fatality was 1.4-fold (95%CI: 1.1-1.9) higher among LTCH residents than the rest of the population. InterpretationHeterogeneity across micro-epidemics among specific populations in specific settings may reflect underlying heterogeneity in transmission risks, necessitating setting-specific COVID-19 prevention and mitigation strategies.