The safety of seasonal influenza vaccination among adults prescribed immune checkpoint inhibitors: A self-controlled case series study using administrative data.

BACKGROUND: Immune checkpoint inhibitor (ICI) therapy for patients undergoing cancer treatment carries a risk of severe immune-related adverse events (IRAEs). Questions remain about whether seasonal influenza vaccination might increase the risk of developing IRAEs among these patients given that vaccines are immunomodulatory. Previous vaccine safety studies on patients with cancer prescribed ICI therapy have demonstrated conflicting results. METHODS: Using health administrative data from Ontario, Canada among adults diagnosed with cancer who had been prescribed ICI therapy and who had received an influenza vaccine from 2012 to 2019, we conducted a self-controlled case series study. The pre-vaccination control period started 42-days post-ICI initiation until 14-days prior to vaccination, the risk period was 1-42 days post-vaccination, and the post-vaccination control period was after the risk period until ICI discontinuation or a maximum period of two years. Emergency department (ED) visit(s) and/or hospitalization for any cause after ICI initiation was used to identify severe IRAEs. We fitted a fixed-effects Poisson regression model accounting for seasonality and calendar time to estimate relative incidence of IRAEs between risk and control periods. RESULTS: We identified 1133 records of cancer patients who received influenza vaccination while prescribed ICI therapy. Most were aged ≥ 66 years (73 %), were male (63 %), had lung cancer (54 %), and had received ICI therapy with a programmed cell death protein 1(PD-1) inhibitor (91 %). A quarter (26 %) experienced an ED visit and/or hospitalization during the observation period. Rates of ED visits and/or hospitalizations in the risk vs. control periods were similar, with an incidence rate ratio of 1.04 (95 % CI: 0.75-1.45). Subgroup and sensitivity analyses yielded similar results. CONCLUSION: Seasonal influenza vaccination was not associated with an increased incidence of ED visit or hospitalization among adults with cancer treated with ICI therapy and our results support further evidence of vaccine safety.

Measuring waning protection from seasonal influenza vaccination during nine influenza seasons, Ontario, Canada, 2010/11 to 2018/19.

BackgroundWaning immunity from seasonal influenza vaccination can cause suboptimal protection during peak influenza activity. However, vaccine effectiveness studies assessing waning immunity using vaccinated and unvaccinated individuals are subject to biases.AimWe examined the association between time since vaccination and laboratory-confirmed influenza to assess the change in influenza vaccine protection over time.MethodsUsing linked laboratory and health administrative databases in Ontario, Canada, we identified community-dwelling individuals aged ≥ 6 months who received an influenza vaccine before being tested for influenza by RT-PCR during the 2010/11 to 2018/19 influenza seasons. We estimated the adjusted odds ratio (aOR) for laboratory-confirmed influenza by time since vaccination (categorised into intervals) and for every 28 days.ResultsThere were 53,065 individuals who were vaccinated before testing for influenza, with 10,264 (19%) influenza-positive cases. The odds of influenza increased from 1.05 (95% CI: 0.91-1.22) at 42-69 days after vaccination and peaked at 1.27 (95% CI: 1.04-1.55) at 126-153 days when compared with the reference interval (14-41 days). This corresponded to 1.09-times increased odds of influenza every 28 days (aOR = 1.09; 95% CI: 1.04-1.15). Individuals aged 18-64 years showed the greatest decline in protection against influenza A(H1N1) (aORper 28 days = 1.26; 95% CI: 0.97-1.64), whereas for individuals aged ≥ 65 years, it was against influenza A(H3N2) (aORper 28 days = 1.20; 95% CI: 1.08-1.33). We did not observe evidence of waning vaccine protection for individuals aged < 18 years.ConclusionsInfluenza vaccine protection wanes during an influenza season. Understanding the optimal timing of vaccination could ensure robust protection during seasonal influenza activity.

Incorporating Efficacy Data from Initial Trials Into Subsequent Evaluations: Application to Vaccines Against Respiratory Syncytial Virus.

BACKGROUND: When a randomized controlled trial fails to demonstrate statistically significant efficacy against the primary endpoint, a potentially costly new trial would need to be conducted to receive licensure. Incorporating data from previous trials might allow for more efficient follow-up trials to demonstrate efficacy, speeding the availability of effective vaccines. METHODS: Based on the outcomes from a failed trial of a maternal vaccine against respiratory syncytial virus (RSV), we simulated data for a new Bayesian group-sequential trial. We analyzed the data either ignoring data from the previous trial (i.e., weakly informative prior distributions) or using prior distributions incorporating the historical data into the analysis. We evaluated scenarios where efficacy in the new trial was the same, greater than, or less than that in the original trial. For each scenario, we evaluated the statistical power and type I error rate for estimating the vaccine effect following interim analyses. RESULTS: When we used a stringent threshold to control the type I error rate, analyses incorporating historical data had a small advantage over trials that did not. If control of type I error is less important (e.g., in a postlicensure evaluation), the incorporation of historical data can provide a substantial boost in efficiency. CONCLUSIONS: Due to the need to control the type I error rate in trials used to license a vaccine, incorporating historical data provides little additional benefit in terms of stopping the trial early. However, these statistical approaches could be promising in evaluations that use real-world evidence following licensure.

Urban and rural healthcare providers' perspectives on HPV vaccination in Minnesota.

Human papillomavirus (HPV) vaccination can dramatically reduce the incidence of HPV-associated cancers. However, HPV vaccination coverage in rural areas is lower than in urban areas, and overall HPV vaccination coverage in the United States remains lower than other adolescent vaccines. We conducted 20 qualitative interviews with adolescent healthcare providers and clinic staff in urban and rural Minnesota and assessed their perspectives on HPV vaccination. Guiding interview topics included: strategies to persuade families to vaccinate their children, the impact of the patient-provider relationship and the clinical environment on vaccination uptake, and provider perceptions of parents' vaccine attitudes. In thematic analysis, all participants reported using common vaccination strategies, such as framing the HPV vaccine in terms of cancer prevention. The analysis also revealed three themes described as occurring uniquely or more intensely in rural communities than urban communities: the rural value of choice or independence, the spread of misinformation, and close-knit, multifaceted patient-provider relationships in clinical practice. Interventions aimed at increasing HPV vaccination should consider the distinctive circumstances of rural healthcare providers and patients.

Comprehensive profiling of social mixing patterns in resource poor countries: a mixed methods research protocol.

Background: Low-and-middle-income countries (LMICs) bear a disproportionate burden of communicable diseases. Social interaction data inform infectious disease models and disease prevention strategies. The variations in demographics and contact patterns across ages, cultures, and locations significantly impact infectious disease dynamics and pathogen transmission. LMICs lack sufficient social interaction data for infectious disease modeling. Methods: To address this gap, we will collect qualitative and quantitative data from eight study sites (encompassing both rural and urban settings) across Guatemala, India, Pakistan, and Mozambique. We will conduct focus group discussions and cognitive interviews to assess the feasibility and acceptability of our data collection tools at each site. Thematic and rapid analyses will help to identify key themes and categories through coding, guiding the design of quantitative data collection tools (enrollment survey, contact diaries, exit survey, and wearable proximity sensors) and the implementation of study procedures.We will create three age-specific contact matrices (physical, nonphysical, and both) at each study site using data from standardized contact diaries to characterize the patterns of social mixing. Regression analysis will be conducted to identify key drivers of contacts. We will comprehensively profile the frequency, duration, and intensity of infants' interactions with household members using high resolution data from the proximity sensors and calculating infants' proximity score (fraction of time spent by each household member in proximity with the infant, over the total infant contact time) for each household member. Discussion: Our qualitative data yielded insights into the perceptions and acceptability of contact diaries and wearable proximity sensors for collecting social mixing data in LMICs. The quantitative data will allow a more accurate representation of human interactions that lead to the transmission of pathogens through close contact in LMICs. Our findings will provide more appropriate social mixing data for parameterizing mathematical models of LMIC populations. Our study tools could be adapted for other studies.

Comparison of socio-economic determinants of COVID-19 testing and positivity in Canada: A multi-provincial analysis.

BACKGROUND: The effects of the COVID-19 pandemic have been more pronounced for socially disadvantaged populations. We sought to determine how access to SARS-CoV-2 testing and the likelihood of testing positive for COVID-19 were associated with demographic factors, socioeconomic status (SES) and social determinants of health (SDH) in three Canadian provinces. METHODS: An observational population-based cross-sectional study was conducted for the provinces of Ontario, Manitoba and New Brunswick between March 1, 2020 and April 27, 2021, using provincial health administrative data. After excluding residents of long-term care homes, those without current provincial health insurance and those who were tested for COVID-19 out of province, records from provincial healthcare administrative databases were reviewed for 16,900,661 healthcare users. Data was modelled separately for each province in accordance to a prespecified protocol and follow-up consultations among provincial statisticians and collaborators. We employed univariate and multivariate regression models to examine determinants of testing and test results. RESULTS: After adjustment for other variables, female sex and urban residency were positively associated with testing, while female sex was negatively associated with test positivity. In New Brunswick and Ontario, individuals living in higher income areas were more likely to be tested, whereas in Manitoba higher income was negatively associated with both testing and positivity. High ethnocultural composition was associated with lower testing rates. Both high ethnocultural composition and high situational vulnerability increased the odds of testing positive for SARS-CoV-2. DISCUSSION: We observed that multiple demographic, income and SDH factors were associated with SARS-CoV-2 testing and test positivity. Barriers to healthcare access identified in this study specifically relate to COVID-19 testing but may reflect broader inequities for certain at-risk groups.

Incorporating efficacy data from initial trials into subsequent evaluations: Application to vaccines against respiratory syncytial virus.

Background: When a randomized controlled trial fails to demonstrate statistically significant efficacy against the primary endpoint, a potentially costly new trial would need to be conducted to receive licensure. Incorporating data from previous trials might allow for the conduct of more efficient follow-up trials to demonstrate efficacy, speeding the availability of effective vaccines. Methods: Based on the outcomes from a failed trial of a maternal vaccine against respiratory syncytial virus (RSV), we simulated data for a new Bayesian group-sequential trial. The data were analyzed either ignoring data from the previous trial (i.e., weakly informative prior distributions) or using prior distributions that incorporate the historical data into the analysis. We evaluated scenarios where the efficacy in the new trial was the same, greater than, or less than the efficacy in the original trial. For each scenario, we evaluated the statistical power and type I error rate for estimating the vaccine effect following interim analyses. Results: If a stringent threshold is used to control the type I error rate, the analyses that incorporated historical data had a small advantage over trials that did not. If control of type I error is less important (e.g., in a post-licensure evaluation), the incorporation of historical data can provide a substantial boost in efficiency. Conclusions: Due to the need to control the type I error rate in trials used to license a vaccine, the incorporation of historical data provides little additional benefit in terms of stopping the trial early. However, these statistical approaches could be promising in evaluations that use real-world evidence following licensure.

Your Outpatient has Coronavirus Disease 2019: What Are the Treatment Options in the Current Severe Acute Respiratory Syndrome Coronavirus 2 Variant Climate?

Mutations accumulated by novel Severe Acute Respiratory Syndrome Coronavirus 2 Omicron sublineages contribute to evasion of previously effective monoclonal antibodies for treatment or prevention of Coronavirus Disease 2019 (COVID-19). Other authorized or approved antiviral drugs such as nirmatrelvir/ritonavir, remdesivir, and molnupiravir are, however, predicted to maintain activity against these sublineages and are key tools to reduce severe COVID-19 outcomes in vulnerable populations. A stepwise approach may be taken to target the appropriate antiviral drug to the appropriate patient, beginning with identifying whether a patient is at high risk for hospitalization or other complications of COVID-19. Among higher risk individuals, patient profile (including factors such as age, organ function, and comedications) and antiviral drug access inform suitable antiviral drug selection. When applied in targeted fashion, these therapies serve as a complement to vital ongoing nonpharmaceutical interventions and vaccination strategies that reduce morbidity and maximize protection against COVID-19.

COVID-19 vaccine coverage disparities in rural and farm children.

BACKGROUND: The risks of severe outcomes associated with SARS-CoV-2 (COVID-19) are elevated in unvaccinated individuals. It remains crucial to understand patterns of COVID-19 vaccination, particularly in younger and remote populations where coverage often lags. This study examined disparities in COVID-19 vaccine coverage in farm children and adolescents. METHODS: A cross-sectional analysis was conducted in patients of the Marshfield Clinic Health System (MCHS) in Wisconsin. The sample included children/adolescents age 5-17 years who were eligible for COVID-19 vaccine initiation for ≥ 90 days (as of September 30, 2022), stratified by those who lived vs did not live on a farm. Outcomes included COVID-19 vaccine initiation, series completion, and booster receipt. Multivariable regression was used to examine associations between COVID-19 vaccination and farm, as well as rural and non-rural, residence. RESULTS: There were 47,104 individuals (5% farm residents) in the sample. Overall, 33% of participants initiated and 31% completed the COVID-19 vaccine series. After adjustment, farm residence was associated with significantly lower odds of COVID-19 vaccine initiation (aOR [95% CI] = 0.68 [0.61, 0.75], p < 0.001), series completion (aOR = 0.67 [0.60, 0.75], p < 0.001), and booster receipt (aOR = 0.73 [0.61, 0.88], p = 0.001). Secondary analyses found COVID-19 vaccine coverage was lowest in young children who lived on dairy farms. CONCLUSIONS: COVID-19 vaccine coverage is low in north-central Wisconsin children and adolescents. Those who live on farms have significantly lower likelihood of COVID-19 vaccine initiation, series completion, and booster receipt compared to non-farm counterparts. Farm families are an underserved group and require more effective public health interventions designed to prevent COVID-19.

Extended surveillance to assess safety of 9-valent human papillomavirus vaccine.

The safety of 9-valent HPV vaccine (9vHPV) has been established with regard to common and uncommon adverse events. However, investigation of rare and severe adverse events requires extended study periods to capture rare outcomes. This observational cohort study investigated the occurrence of three rare and serious adverse events following 9-valent human papillomavirus (9vHPV) vaccination compared to other vaccinations, in US individuals 9-26 years old, using electronic health record data from the Vaccine Safety Datalink (VSD). We searched for occurrences of Guillain-Barré syndrome (GBS), chronic inflammatory demyelinating polyneuropathy (CIDP), and stroke following 9vHPV vaccination from October 4, 2015, through January 2, 2021. We compared the risks of GBS, CIDP, and stroke following 9vHPV vaccination to risks of those outcomes following comparator vaccines commonly given to this age group (Td, Tdap, MenACWY, hepatitis A, and varicella vaccines) from January 1, 2007, through January 2, 2021. We observed 1.2 cases of stroke, 0.3 cases of GBS, and 0.1 cases of CIDP per 100,000 doses of 9vHPV vaccine. After observing more than 1.8 million doses of 9vHPV, we identified no statistically significant increase in risks associated with 9vHPV vaccination for any of these adverse events, either combined or stratified by age (9-17 years of age vs. 18-26 years of age) and sex (males vs. females). Our findings provide additional evidence supporting 9vHPV vaccine safety, over longer time frames and for more serious and rare adverse events.

Estimated Effectiveness of COVID-19 Vaccines Against Omicron or Delta Symptomatic Infection and Severe Outcomes.

Importance: The incidence of SARS-CoV-2 infection, including among individuals who have received 2 doses of COVID-19 vaccine, increased substantially following the emergence of the Omicron variant in Ontario, Canada. Understanding the estimated effectiveness of 2 or 3 doses of COVID-19 vaccine against outcomes associated with Omicron and Delta infections may aid decision-making at the individual and population levels. Objective: To estimate vaccine effectiveness (VE) against symptomatic infections due to the Omicron and Delta variants and severe outcomes (hospitalization or death) associated with these infections. Design, Setting, and Participants: This test-negative case-control study used linked provincial databases for SARS-CoV-2 laboratory testing, reportable disease, COVID-19 vaccination, and health administration in Ontario, Canada. Participants were individuals aged 18 years or older who had COVID-19 symptoms or severe outcomes (hospitalization or death) and were tested for SARS-CoV-2 between December 6 and 26, 2021. Exposures: Receipt of 2 or 3 doses of the COVID-19 vaccine and time since last dose. Main Outcomes and Measures: The main outcomes were symptomatic Omicron or Delta infection and severe outcomes (hospitalization or death) associated with infection. Multivariable logistic regression was used to estimate the effectiveness of 2 or 3 COVID-19 vaccine doses by time since the latest dose compared with no vaccination. Estimated VE was calculated using the formula VE = (1 - [adjusted odds ratio]) × 100%. Results: Of 134 435 total participants, 16 087 were Omicron-positive cases (mean [SD] age, 36.0 [14.1] years; 8249 [51.3%] female), 4261 were Delta-positive cases (mean [SD] age, 44.2 [16.8] years; 2199 [51.6%] female), and 114 087 were test-negative controls (mean [SD] age, 42.0 [16.5] years; 67 884 [59.5%] female). Estimated VE against symptomatic Delta infection decreased from 89% (95% CI, 86%-92%) 7 to 59 days after a second dose to 80% (95% CI, 74%-84%) after 240 or more days but increased to 97% (95% CI, 96%-98%) 7 or more days after a third dose. Estimated VE against symptomatic Omicron infection was 36% (95% CI, 24%-45%) 7 to 59 days after a second dose and 1% (95% CI, -8% to 10%) after 180 days or longer, but 7 or more days after a third dose, it increased to 61% (95% CI, 56%-65%). Estimated VE against severe outcomes was high 7 or more days after a third dose for both Delta (99%; 95% CI, 98%-99%) and Omicron (95%; 95% CI, 87%-98%). Conclusions and Relevance: In this study, in contrast to high estimated VE against symptomatic Delta infection and severe outcomes after 2 doses of COVID-19 vaccine, estimated VE was modest and short term against symptomatic Omicron infection but better maintained against severe outcomes. A third dose was associated with improved estimated VE against symptomatic infection and with high estimated VE against severe outcomes for both variants. Preventing infection due to Omicron and potential future variants may require tools beyond the currently available vaccines.

Effectiveness of COVID-19 Vaccines Over Time Prior to Omicron Emergence in Ontario, Canada: Test-Negative Design Study.

Background: Waning protection from 2 doses of coronavirus disease 2019 (COVID-19) vaccines led to third dose availability in multiple countries even before the emergence of the Omicron variant. Methods: We used the test-negative study design to estimate vaccine effectiveness (VE) against any severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, any symptomatic infection, and severe outcomes (COVID-19-related hospitalizations or death) by time since second dose of any combination of BNT162b2, mRNA-1273, and ChAdOx1 between January 11, and November 21, 2021, for subgroups based on patient and vaccine characteristics. Results: We included 261 360 test-positive cases (of any SARS-CoV-2 lineage) and 2 783 699 individuals as test-negative controls. VE of 2 mRNA vaccine doses decreased from 90% (95% CI, 90%-90%) 7-59 days after the second dose to 75% (95% CI, 72%-78%) after ≥240 days against infection, decreased from 94% (95% CI, 84%-95%) to 87% (95% CI, 85%-89%) against symptomatic infection, and remained stable (98% [95% CI, 97%-98%] to 98% [95% CI, 96%-99%]) against severe outcomes. Similar trends were seen with heterologous ChAdOx1 and mRNA vaccine schedules. VE estimates for dosing intervals <35 days were lower than for longer intervals (eg, VE of 2 mRNA vaccines against symptomatic infection at 120-179 days was 86% [95% CI, 85%-88%] for dosing intervals <35 days, 92% [95% CI, 91%-93%] for 35-55 days, and 91% [95% CI, 90%-92%] for ≥56 days), but when stratified by age group and subperiod, there were no differences between dosing intervals. Conclusions: Before the emergence of Omicron, VE of any 2-dose primary series, including heterologous schedules and varying dosing intervals, decreased over time against any infection and symptomatic infection but remained high against severe outcomes.

Estimating the number of US children susceptible to measles resulting from COVID-19-related vaccination coverage declines.

Measles elimination hinges on vaccination coverage remaining above 95% to retain sufficient community protection. Recent declines in routine measles vaccinations due to the COVID-19 pandemic coupled with prior models indicating the country was close to the 92% herd immunity benchmark are a cause for concern. We evaluated population-level measles susceptibility in the US, including sensitivity analyses accounting for pandemic-related impacts on immunization. We estimated the number of children aged 0-18 currently susceptible to measles and modeled susceptibility proportions in decreased vaccination scenarios. Participants were respondents to the NIS-Teen survey between 2008 and 2017 that also had provider-verified vaccination documentation. The exposure of interest was vaccination with a measles-containing vaccine (MCV), and the age at which they were vaccinated for all doses given. Using age at vaccination, we estimated age-based probabilities of vaccination and modeled population levels of MCV immunization and immunity vs. susceptibility. Currently, 9,145,026 children (13.1%) are estimated to be susceptible to measles. With pandemic level vaccination rates, 15,165,221 children (21.7%) will be susceptible to measles if no attempt at catch-up is made, or 9,454,436 children (13.5%) if catch-up vaccinations mitigate the decline by 2-3%. Models based on increased vaccine hesitancy also show increased susceptibility at national levels, with a 10% increase in hesitancy nationally resulting in 14,925,481 children (21.37%) susceptible to measles, irrespective of pandemic vaccination levels. Current levels of measles immunity remain below herd immunity thresholds. If pandemic-era reductions in childhood immunization are not rectified, population-level immunity to measles is likely to decline further.

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

BACKGROUND: Shared and divergent predictors of clinical severity across respiratory viruses may support clinical and community responses in the context of a novel 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; 2010-09 to 2019-05), respiratory syncytial virus (RSV; N = 24 345; 2010-09 to 2019-04), or severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2; N = 8988; 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: A total of 3186 (7.0%), 697 (2.9%), and 1880 (20.9%) patients died within 30 days of hospital admission with influenza, RSV, and SARS-CoV-2, respectively. Shared 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 with those with influenza or RSV. CONCLUSIONS: Our findings may help identify patients at greatest risk of illness secondary to a respiratory virus, anticipate hospital resource needs, and prioritize local prevention and therapeutic strategies to communities with higher prevalence of risk factors.

Effectiveness of COVID-19 vaccines against symptomatic SARS-CoV-2 infection and severe outcomes with variants of concern in Ontario.

SARS-CoV-2 variants of concern (VOC) are more transmissible and may have the potential for increased disease severity and decreased vaccine effectiveness. We estimated the effectiveness of BNT162b2 (Pfizer-BioNTech Comirnaty), mRNA-1273 (Moderna Spikevax) and ChAdOx1 (AstraZeneca Vaxzevria) vaccines against symptomatic SARS-CoV-2 infection and 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) VOC in Ontario, Canada, using a test-negative design study. We identified 682,071 symptomatic community-dwelling individuals who were tested for SARS-CoV-2, and 15,269 individuals with a COVID-19 hospitalization or death. Effectiveness against symptomatic infection ≥7 d after two doses was 89-92% against Alpha, 87% against Beta, 88% against Gamma, 82-89% against Beta/Gamma and 87-95% against Delta across vaccine products. The corresponding estimates ≥14 d after one dose were lower. Effectiveness estimates against hospitalization or death were similar to or higher than against symptomatic infection. Effectiveness against symptomatic infection was generally lower for older adults (≥60 years) than for younger adults (<60 years) for most of the VOC-vaccine combinations. Our findings suggest that jurisdictions facing vaccine supply constraints may benefit from delaying the second dose in younger individuals to more rapidly achieve greater overall population protection; however, older adults would likely benefit most from minimizing the delay in receiving the second dose to achieve adequate protection against VOC.

Stringency of containment and closures on the growth of SARS-CoV-2 in Canada prior to accelerated vaccine roll-out.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.