[Clinical Infectious Diseases, 1 February 2023]

Background: The rapid development of safe and effective vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been a singular scientific achievement. Confounding due to health-seeking behaviors, circulating variants, and differential testing by vaccination status may bias analyses toward an apparent increase in infection severity following vaccination.

Methods: We used data from the Ontario, Canada, Case and Contact Management Database and a provincial vaccination dataset (COVaxON) to create a time-matched cohort of individuals who were hospitalized with SARS-CoV-2 infection. Vaccinated individuals were matched to up to 5 unvaccinated individuals based on test date. Risk of intensive care unit (ICU) admission and death were evaluated using conditional logistic regression.

Results: In 20 064 individuals (3353 vaccinated and 16 711 unvaccinated) hospitalized with infection due to SARS-CoV-2 between 1 January 2021 and 5 January 2022, vaccination with 1, 2, or 3 doses significantly reduced the risk of ICU admission and death. An inverse dose–response relationship was observed between vaccine doses received and both outcomes (adjusted odds ratio [aOR] per additional dose for ICU admission, 0.66; 95% confidence interval [CI], .62 to .71; aOR for death, 0.78; 95% CI, .72 to .84).

Conclusions: We identified decreased virulence of SARS-CoV-2 infections in vaccinated individuals, even when vaccines failed to prevent infection sufficiently severe to cause hospitalization. Even with diminished efficacy of vaccines against infection with novel variants of concern, vaccines remain an important tool for reduction of ICU admission and mortality.

[Clinical Infectious Diseases, 1 February 2023]

Background: Pregnancy represents a physiological state associated with increased vulnerability to severe outcomes from infectious diseases, both for the pregnant person and developing infant. The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic may have important health consequences for pregnant individuals, who may also be more reluctant than nonpregnant people to accept vaccination.

Methods: We sought to estimate the degree to which increased severity of SARS-CoV-2 outcomes can be attributed to pregnancy using a population-based SARS-CoV-2 case file from Ontario, Canada. Because of varying propensity to receive vaccination, and changes in dominant circulating viral strains over time, a time-matched cohort study was performed to evaluate the relative risk of severe illness in pregnant women with SARS-CoV-2 compared to other SARS-CoV-2 infected women of childbearing age (10–49 years old). Risk of severe SARS-CoV-2 outcomes was evaluated in pregnant women and time-matched nonpregnant controls using multivariable conditional logistic regression.

Results: Compared with the rest of the population, nonpregnant women of childbearing age had an elevated risk of infection (standardized morbidity ratio, 1.28), whereas risk of infection was reduced among pregnant women (standardized morbidity ratio, 0.43). After adjustment for confounding, pregnant women had a markedly elevated risk of hospitalization (adjusted odds ratio, 4.96; 95% confidence interval, 3.86–6.37) and intensive care unit admission (adjusted odds ratio, 6.58; 95% confidence interval, 3.29–13.18). The relative increase in hospitalization risk associated with pregnancy was greater in women without comorbidities than in those with comorbidities (P for heterogeneity, .004).

Conclusions: Given the safety of SARS-CoV-2 vaccines in pregnancy, risk-benefit calculus strongly favors SARS-CoV-2 vaccination in pregnant women.

[Preventive Medicine Reports, December 2022]

The long-term dynamics of COVID-19 disease incidence and public health measures may impact individuals’ precautionary behaviours as well as support for measures. The objectives of this study were to assess longitudinal changes in precautionary behaviours and support for public health measures. Survey data were collected online from 1030 Canadians in each of 5 cycles in 2020: June 15-July 13; July 22-Aug 8; Sept 7–15; Oct 14–21; and Nov 12–17. Precautionary behaviour increased over the study period in the context of increasing disease incidence. When controlling for the stringency of public health measures and disease incidence, mixed effects logistic regression models showed these behaviours did not significantly change over time. Odds ratios for avoiding contact with family and friends ranged from 0.84 (95% CI 0.59–1.20) in September to 1.25 (95% CI 0.66–2.37) in November compared with July 2020. Odds ratios for attending an indoor gathering ranged from 0.86 (95% CI 0.62–1.20) in August to 1.71 (95% CI 0.95–3.09) in October compared with July 2020. Support for non-essential business closures increased over time with 2.33 (95% CI 1.14–4.75) times higher odds of support in November compared to July 2020. Support for school closures declined over time with lower odds of support in September (OR 0.66 [95% CI 0.45–0.96]), October (OR 0.48 [95% CI 0.26–0.87]), and November (OR 0.39 [95% CI 0.19–0.81]) compared with July 2020. In summary, respondents’ behaviour mirrored government guidance between July and November 2020 and supported individual precautionary behaviour and limitations on non-essential businesses over school closures.

[Clinical Infectious Diseases, 1 July 2022]

Background: Novel variants of concern (VOCs) have been associated with both increased infectivity and virulence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The virulence of SARS-CoV-2 is closely linked to age. Whether relative increases in virulence of novel VOCs are similar across the age spectrum or are limited to some age groups is unknown.

Methods: We created a retrospective cohort of people in Ontario, Canada, who tested positive for SARS-CoV-2 and were screened for VOCs (n = 259 984) between 7 February 2021 and 31 October 2021. Cases were classified as N501Y-positive VOC, probable Delta VOC, or VOC undetected. We constructed age-specific logistic regression models to evaluate associations between N501Y-postive or Delta VOC infections and infection severity using hospitalization, intensive care unit (ICU) admission, and death as outcome variables. Models were adjusted for sex, comorbidity, vaccination status, and temporal trends.

Results: Infection with either N501Y-positive or Delta VOCs was associated with significant elevations in risk of hospitalization, ICU admission, and death across age groups compared with infections where a VOC was not detected. The Delta VOC increased hospitalization risk in children aged <10 years by a factor of 2.5 (adjusted odds ratio; 95% confidence interval, 1.3 to 5.0) compared with non-VOCs. There was a significant inverse relationship between age and relative increase in risk of death with the Delta VOC, with younger age groups showing a greater relative increase in risk of death than older individuals.

Conclusions: SARS-CoV-2 VOCs appear to be associated with increased relative virulence of infection in all age groups, though low absolute numbers of outcomes in younger individuals make estimates in these groups imprecise.

[Clinical Infectious Diseases, 1 July 2022]

Background: People in prison are at increased risk of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. We examined the seroprevalence of SARS-CoV-2 and associated carceral risk factors among incarcerated adult men in Quebec, Canada.

Methods: We conducted a cross-sectional seroprevalence study in 2021 across 3 provincial prisons, representing 45% of Quebec’s incarcerated male provincial population. The primary outcome was SARS-CoV-2 antibody seropositivity (Roche Elecsys serology test). Participants completed self-administered questionnaires on sociodemographic, clinical, and carceral characteristics. The association of carceral variables with SARS-CoV-2 seropositivity was examined using Poisson regression models with robust standard errors. Crude and adjusted prevalence ratios (aPR) with 95% confidence intervals (95% CIs) were calculated.

Results: Between 19 January 2021 and 15 September 2021, 246 of 1100 (22%) recruited individuals tested positive across 3 prisons (range, 15%–27%). Seropositivity increased with time spent in prison since March 2020 (aPR, 2.17; 95% CI, 1.53–3.07 for “all” vs “little time”), employment during incarceration (aPR, 1.64; 95% CI, 1.28–2.11 vs not), shared meal consumption during incarceration (“with cellmates”: aPR, 1.46; 95% CI, 1.08–1.97 vs “alone”; “with sector”: aPR, 1.34; 95% CI, 1.03–1.74 vs “alone”), and incarceration post-prison outbreak (aPR, 2.32; 95% CI, 1.69–3.18 vs “pre-outbreak”).

Conclusions: The seroprevalence of SARS-CoV-2 among incarcerated individuals was high and varied among prisons. Several carceral factors were associated with seropositivity, underscoring the importance of decarceration and occupational safety measures, individual meal consumption, and enhanced infection prevention and control measures including vaccination during incarceration.

[Canada Communicable Disease Report, 31 May 2023]

Background: National responses to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic have been highly variable. We sought to explore the effectiveness of the Canadian pandemic response up to May 2022 relative to responses in four peer countries with similar political, economic and health systems, and with close historical and cultural ties to Canada.

Methods: We used reported age-specific mortality data to generate estimates of pandemic mortality standardized to the Canadian population. Age-specific case fatality, hospitalization, and intensive care admission probabilities for the Canadian province of Ontario were applied to estimated deaths, to calculate hospitalizations and intensive care admissions averted by the Canadian response. Health impacts were valued in both monetary terms, and in terms of lost quality-adjusted life years.

Results: We estimated that the Canadian pandemic response averted 94,492, 64,306 and 13,641 deaths relative to the responses of the United States, United Kingdom and France, respectively, and more than 480,000 hospitalizations relative to the United States. The United States pandemic response, if applied to Canada, would have resulted in more than $40 billion in economic losses due to healthcare expenditures and lost quality-adjusted life years. In contrast, an Australian pandemic response applied to Canada would have averted over 28,000 additional deaths and averted nearly $9 billion in costs.

Conclusion: Canada outperformed several peer countries that aimed for mitigation rather than elimination of SARS-CoV-2 in the first two years of the pandemic, with substantial numbers of lives saved and economic costs averted. However, a comparison with Australia demonstrated that an elimination focus would have saved Canada tens of thousands of lives as well as substantial economic costs.

Citerank: (11) 679746Steini BrownProfessor and Dean of the Dalla Lana School of Public Health at the University of Toronto.10019D3ABAB, 679755Ashleigh TuiteAshleigh Tuite is an Assistant Professor in the Epidemiology Division at the Dalla Lana School of Public Health at the University of Toronto.10019D3ABAB, 679757Beate SanderCanada Research Chair in Economics of Infectious Diseases and Director, Health Modeling & Health Economics and Population Health Economics Research at THETA (Toronto Health Economics and Technology Assessment Collaborative).10019D3ABAB, 679802Isaac BogochClinician Investigator, Toronto General Hospital Research Institute (TGHRI)10019D3ABAB, 679893Kumar MurtyProfessor Kumar Murty is in the Department of Mathematics at the University of Toronto. His research fields are Analytic Number Theory, Algebraic Number Theory, Arithmetic Algebraic Geometry and Information Security. He is the founder of the GANITA lab, co-founder of Prata Technologies and PerfectCloud. His interest in mathematics ranges from the pure study of the subject to its applications in data and information security.10019D3ABAB, 685230Doug ManuelDr. Manuel is a Medical Doctor with a Masters in Epidemiology and Royal College specialization in Public Health and Preventive Medicine. He is a Senior Scientist in the Clinical Epidemiology Program at Ottawa Hospital Research Institute, and a Professor in the Departments of Family Medicine and Epidemiology and Community Medicine.10019D3ABAB, 685420Hospitals16289D5D4, 701020CANMOD – PublicationsPublications by CANMOD Members144B5ACA0, 701037MfPH – Publications144B5ACA0, 704045Covid-19859FDEF6, 715390Mortality859FDEF6

[Science Briefs of the Ontario COVID-19 Science Advisory Table, 29 March 2021]

Background: As of March 28, 2021 new variants of concern (VOCs) account for 67% of all Ontario SARS-CoV-2 infections. The B.1.1.7 variant originally detected in Kent, United Kingdom accounts for more than 90% of all VOCs in Ontario, with emerging evidence that it is both more transmissible and virulent.

Questions: What are the risks of COVID-19 hospitalization, ICU admission and death caused by VOCs as compared with the early variants of SARS-CoV-2?

What is the early impact of new VOCs on Ontario’s healthcare system?

Findings: A retrospective cohort study of 26,314 people in Ontario testing positive for SARS-CoV-2 between February 7 and March 11, 2021, showed that 9,395 people (35.7%) infected with VOCs had a 62% relative increase in COVID-19 hospitalizations (odds ratio [OR] 1.62, 95% confidence interval [CI] 1.41 to 1.87), a 114% relative increase in ICU admissions (OR 2.14, 95% CI 1.52 to 3.02), and a 40% relative increase in COVID-19 deaths (OR 1.40, 95% CI 1.01 to 1.94), after adjusting for age, sex and comorbidities.

A meta-analysis including the Ontario cohort study and additional cohort studies in the United Kingdom and Denmark showed that people infected with VOCs had a 63% higher risk of hospitalization (RR 1.63, 95% CI 1.44 to 1.83), a doubling of the risk of ICU admission (RR 2.03, 95% CI 1.69 to 2.45), and a 56% higher risk of all-cause death (RR 1.56, 95% CI 1.30 to 1.87). Estimates observed in different studies and regions were completely consistent, and the B.1.1.7 variant was dominant in all three jurisdictions over the study periods.

The number of people hospitalized with COVID-19 on March 28, 2021, is 21% higher than at the start of the province-wide lockdown during the second wave on December 26, 2020, while ICU occupancy is 28% higher.

Between December 14 to 20, 2020, there were 149 new admissions to ICU; people aged 59 years and younger accounted for 30% of admissions. Between March 15, 2021 and March 21, 2021, there were 157 new admissions to ICU; people aged 59 years and younger accounted for 46% of admissions.

Interpretation: The new VOCs will result in a considerably higher burden to Ontario’s health care system during the third wave compared to the impact of early SARS-CoV-2 variants during Ontario’s second wave.

Since the start of the third wave on March 1, 2021, the number of new cases of SARS-CoV-2 infection, and the COVID-19 hospital and ICU occupancies have surpassed prior thresholds at the start of the province-wide lockdown on December 26, 2020.

[Annals of Internal Medicine, 18 July 2023]

Regarding their trial, Loeb and colleagues (1) state, “the overall estimates rule out a doubling in hazard”; however, no such conclusion is possible. The trial used an extraordinary threshold (a hazard ratio of 2, or a 100% relative increase in risk) for noninferiority and was underpowered to find smaller but still important risks. (We estimate that a 4-fold increase in sample size would have been needed to identify a 50% increase in relative hazard.) Power aside, design flaws biased the study toward the null result that was obtained.

The intervention under study was incorrect use of N95 respirators—intermittently rather than continuously. SARS-CoV-2 is an airborne pathogen (2). Infection occurs via inhalation of shared air, and infective aerosols accumulate over time in closed indoor settings. As such, only continuous use of N95 respirators protects health care workers against respiratory infection; intermittent use of medical masks and respirators is equally ineffective (3). Unplanned crossover (those randomly assigned to medical masks could reassign themselves to the N95 group on the basis of unrecorded risk assessment) and contamination due to failure to use a cluster design further biased study results toward the null (4).

Notwithstanding lack of power and multiple biases—and although only 21 infections developed among 301 participants recruited in Canada and Israel through May 2021—analysis according to the registered protocol reveals a doubling of risk for infection for medical masks (relative risk, 2.05 [95% CI, 0.85 to 4.95]; P = 0.10) in these participants. The study had come close to showing inferiority after recruiting only a fraction of its prespecified sample size. Around this time, the authors recalculated their required sample size (in July 2021) as 1010 participants and began recruiting participants in Pakistan at a site not mentioned in the trial's registered protocol. Six months later, recruitment in Pakistan was discontinued and was begun in Egypt (also not registered in the protocol). Final results were heavily influenced by the inclusion of the sites in Egypt, with more than 70% of infections originating there. As Altman and associates note, “when authors substitute other outcomes after the trial has started there must be concern that such changes were done with knowledge of the data. That casts doubt on the reliability and integrity of the results” (5).

Lastly, the performance of this trial lacked equipoise in the face of clear engineering evidence of the superiority of respirators for airborne pathogens. The fact that this trial was done in a flawed manner that could not provide valid results means that participants were endangered for no reason.

[PLoS ONE, 31 March 2023]

Background: Vaccines against SARS-CoV-2 have been shown to reduce risk of infection as well as severe disease among those with breakthrough infection in adults. The latter effect is particularly important as immune evasion by Omicron variants appears to have made vaccines less effective at preventing infection. Therefore, we aimed to quantify the protection conferred by mRNA vaccination against hospitalization due to SARS-CoV-2 in adolescent and pediatric populations.

Methods: We retrospectively created a cohort of reported SARS-CoV-2 case records from Ontario’s Public Health Case and Contact Management Solution among those aged 4 to 17 linked to vaccination records from the COVaxON database on January 19, 2022. We used multivariable logistic regression to estimate the association between vaccination and hospitalization among SARS-CoV-2 cases prior to and during the emergence of Omicron.

Results: We included 62 hospitalized and 27,674 non-hospitalized SARS-CoV-2 cases, with disease onset from May 28, 2021 to December 4, 2021 (Pre-Omicron) and from December 23, 2021 to January 9, 2022 (Omicron). Among adolescents, two mRNA vaccine doses were associated with an 85% (aOR = 0.15; 95% CI: [0.04, 0.53]; p<0.01) lower likelihood of hospitalization among SARS-CoV-2 cases caused by Omicron. Among children, one mRNA vaccine dose was associated with a 79% (aOR = 0.21; 95% CI: [0.03, 0.77]; p<0.05) lower likelihood of hospitalization among SARS-CoV-2 cases caused by Omicron. The calculation of E-values, which quantifies how strong an unmeasured confounder would need to be to nullify our findings, suggest that these effects are unlikely to be explained by unmeasured confounding.

Conclusions: Despite immune evasion by SARS-CoV-2 variants, vaccination continues to be associated with a lower likelihood of hospitalization among adolescent and pediatric Omicron (B.1.1.529) SARS-CoV-2 cases, even when the vaccines do not prevent infection. Continued efforts are needed to increase vaccine uptake among adolescent and pediatric populations.

[PNAS Nexus, 12 February 2024]

Mask use for prevention of respiratory infectious disease transmission is not new but has proven controversial during the SARS-CoV-2 pandemic. In Ontario, Canada, irregular regional introduction of community mask mandates in 2020 created a quasi-experiment useful for evaluating the impact of such mandates; however, Ontario SARS-CoV-2 case counts were likely biased by testing focused on long-term care facilities and healthcare workers. We developed a regression-based method that allowed us to adjust cases for under-testing by age and gender. We evaluated mask mandate effects using count-based regression models with either unadjusted cases, or testing-adjusted case counts, as dependent variables. Models were used to estimate mask mandate effectiveness, and the fraction of SARS-CoV-2 cases, severe outcomes, and costs, averted by mask mandates. Models using unadjusted cases as dependent variables identified modest protective effects of mask mandates (range 31–42%), with variable statistical significance. Mask mandate effectiveness in models predicting test-adjusted case counts was higher, ranging from 49% (95% CI 44–53%) to 76% (95% CI 57–86%). The prevented fraction associated with mask mandates was 46% (95% CI 41–51%), with 290,000 clinical cases, 3,008 deaths, and loss of 29,038 quality-adjusted life years averted from 2020 June to December, representing $CDN 610 million in economic wealth. Under-testing in younger individuals biases estimates of SARS-CoV-2 infection risk and obscures the impact of public health preventive measures. After adjustment for under-testing, mask mandates emerged as highly effective. Community masking saved substantial numbers of lives, and prevented economic costs, during the SARS-CoV-2 pandemic in Ontario, Canada.

[PLoS ONE, 4 April 2024]

Background: We previously demonstrated that when vaccines prevent infection, the dynamics of mixing between vaccinated and unvaccinated sub-populations is such that use of imperfect vaccines markedly decreases risk for vaccinated people, and for the population overall. Risks to vaccinated people accrue disproportionately from contact with unvaccinated people. In the context of the emergence of Omicron SARS-CoV-2 and evolving understanding of SARS-CoV-2 epidemiology, we updated our analysis to evaluate whether our earlier conclusions remained valid.

Methods: We modified a previously published Susceptible-Infectious-Recovered (SIR) compartmental model of SARS-CoV-2 with two connected sub-populations: vaccinated and unvaccinated, with non-random mixing between groups. Our expanded model incorporates diminished vaccine efficacy for preventing infection with the emergence of Omicron SARS-CoV-2 variants, waning immunity, the impact of prior immune experience on infectivity, “hybrid” effects of infection in previously vaccinated individuals, and booster vaccination. We evaluated the dynamics of an epidemic within each subgroup and in the overall population over a 10-year time horizon.

Results: Even with vaccine efficacy as low as 20%, and in the presence of waning immunity, the incidence of COVID-19 in the vaccinated subpopulation was lower than that among the unvaccinated population across the full 10-year time horizon. The cumulative risk of infection was 3–4 fold higher among unvaccinated people than among vaccinated people, and unvaccinated people contributed to infection risk among vaccinated individuals at twice the rate that would have been expected based on the frequency of contacts. These findings were robust across a range of assumptions around the rate of waning immunity, the impact of “hybrid immunity”, frequency of boosting, and the impact of prior infection on infectivity in unvaccinated people.

Interpretation: Although the emergence of the Omicron variants of SARS-CoV-2 has diminished the protective effects of vaccination against infection with SARS-CoV-2, updating our earlier model to incorporate loss of immunity, diminished vaccine efficacy and a longer time horizon, does not qualitatively change our earlier conclusions. Vaccination against SARS-CoV-2 continues to diminish the risk of infection among vaccinated people and in the population as a whole. By contrast, the risk of infection among vaccinated people accrues disproportionately from contact with unvaccinated people.