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

ObjectivesTo estimate the effectiveness of mRNA COVID-19 vaccines against symptomatic infection and severe outcomes. DesignWe applied a test-negative design study to linked laboratory, vaccination, and health administrative databases, and used multivariable logistic regression adjusting for demographic and clinical characteristics associated with SARS-CoV-2 and vaccine receipt to estimate vaccine effectiveness (VE) against symptomatic infection and severe outcomes. SettingOntario, Canada between 14 December 2020 and 19 April 2021. ParticipantsCommunity-dwelling adults aged [≥]16 years who had COVID-19 symptoms and were tested for SARS-CoV-2. InterventionsPfizer-BioNTechs BNT162b2 or Modernas mRNA-1273 vaccine. Main outcome measuresLaboratory-confirmed SARS-CoV-2 by RT-PCR; hospitalization/death associated with SARS-CoV-2 infection. ResultsAmong 324,033 symptomatic individuals, 53,270 (16.4%) were positive for SARS-CoV-2 and 21,272 (6.6%) received [≥]1 vaccine dose. Among test-positive cases, 2,479 (4.7%) had a severe outcome. VE against symptomatic infection [≥]14 days 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. VE [≥]7 days after 2 doses was 91% (95%CI, 89 to 93%). Against severe outcomes, VE [≥]14 days after 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, whereas VE [≥]7 days after 2 doses was 98% (95%CI, 88 to 100%). For adults aged [≥]70 years, VE estimates were lower for intervals shortly after receiving 1 dose, but were comparable to younger adults for all intervals after 28 days. After 2 doses, we observed high VE against E484K-positive variants. ConclusionsTwo doses of mRNA COVID-19 vaccines are highly effective against symptomatic infection and severe outcomes. Single-dose effectiveness is lower, particularly for older adults shortly after the first dose.

Background rates of hospitalizations and emergency department visits for selected thromboembolic and coagulation disorders in Ontario, Canada, 2015 to 2020, to inform COVID-19 vaccine safety surveillance

ObjectiveThe objective of this study was to estimate background rates of selected thromboembolic and coagulation disorders in Ontario, Canada. DesignPopulation-based retrospective observational study using linked health administrative databases. Records of hospitalizations and emergency department visits were searched to identify cases using diagnostic codes from the International Statistical Classification of Diseases and Related Health Problems, Tenth Revision, Canada (ICD-10-CA). ParticipantsAll Ontario residents. Primary outcome measuresIncidence rates of stroke, deep vein thrombosis, pulmonary embolism, idiopathic thrombocytopenia, disseminated intravascular coagulation, and cerebral venous thrombosis during five pre-pandemic years (2015-2019, annually, averaged, and monthly average) and 2020. ResultsThe average annual population was 14 million with 51% female. The mean annual rates during 2015-2019 were 127.1/100,000 population (95% confidence interval [CI], 126.2, 127.9) for ischemic stroke, 22.0/100,000 (95%CI, 21.6, 22.3) for intracerebral haemorrhage, 9.4 (95%CI, 9.2, 9.7) for subarachnoid haemorrhage, 86.8/100,000 (95%CI, 86.1, 87.5) for deep vein thrombosis, 63.7/100,000 (95%CI, 63.1, 64.3) for pulmonary embolism, 6.1/100,000 (95%CI, 5.9, 6.3) for idiopathic thrombocytopenia, 1.6/100,000 (95%CI, 1.5, 1.7) for disseminated intravascular coagulation, and 1.5/100,000 (95%CI, 1.4, 1.6) for cerebral venous thrombosis. Rates were lower in 2020 than during the pre-pandemic years for ischemic stroke, deep vein thrombosis, and idiopathic thrombocytopenia. Rates were generally consistent over time, except for pulmonary embolism, which increased from 57.1 to 68.5 per 100,000 between 2015 and 2019. Rates were higher for females than males for subarachnoid haemorrhage, pulmonary embolism, and cerebral venous thrombosis, and vice versa for ischemic stroke and intracerebral haemorrhage. Rates increased with age for most of these conditions, but idiopathic thrombocytopenia demonstrated a bimodal distribution with incidence peaks at 0-19 years and [≥]60 years. ConclusionsOur estimated background rates help to contextualize observed events of these potential adverse events of special interest and to detect potential safety signals related to COVID-19 vaccines. Strengths and limitations of this study[tpltrtarr] Recent background rates of selected thromboembolic and coagulation disorders that are potential adverse events special interest related to COVID-19 vaccine are estimated. [tpltrtarr]Background rates during five pre-pandemic (2015-2019) years and 2020 will provide context for these events to identify vaccine safety signals. [tpltrtarr]We used recorded diagnostic codes in administrative data without information on clinical and/or diagnostic confirmation, and the validity of these data are imperfect, which may result in under or overestimation.

Background rates of all-cause mortality, hospitalizations, and emergency department visits among nursing home residents in Ontario, Canada to inform COVID-19 vaccine safety assessments

BackgroundNursing home (NH) residents are prioritized for COVID-19 vaccination. We report monthly mortality, hospitalizations, and emergency department (ED) visit incidence rates (IRs) during 2010-2020 to provide context for COVID-19 vaccine safety assessments. MethodsWe observed outcomes among NH residents using administrative databases. IRs were calculated by month, sex, and age group. Comparisons between months were assessed using one-sample t-tests; comparisons by age and sex were assessed using chi-squared tests. ResultsFrom 2010-2019, there were 83,453 (SD: 652.4) NH residents per month, with an average of 2.3 (SD: 0.28) deaths, 3.1 (SD: 0.16) hospitalizations, and 3.6 (SD: 0.17) ED visits per 100 residents per month. From March to December 2020, mortality IRs were increased, but hospitalization and ED visit IRs were reduced (p<0.05). ConclusionWe identified consistent monthly mortality, hospitalization, and ED visit IRs during 2010-2019. Marked differences in these rates were observed during 2020, coinciding with the COVID-19 pandemic.

Saliva viral load is a dynamic unifying correlate of COVID-19 severity and mortality

While several clinical and immunological parameters correlate with disease severity and mortality in SARS-CoV-2 infection, work remains in identifying unifying correlates of coronavirus disease 2019 (COVID-19) that can be used to guide clinical practice. Here, we examine saliva and nasopharyngeal (NP) viral load over time and correlate them with patient demographics, and cellular and immune profiling. We found that saliva viral load was significantly higher in those with COVID-19 risk factors; that it correlated with increasing levels of disease severity and showed a superior ability over nasopharyngeal viral load as a predictor of mortality over time (AUC=0.90). A comprehensive analysis of immune factors and cell subsets revealed strong predictors of high and low saliva viral load, which were associated with increased disease severity or better overall outcomes, respectively. Saliva viral load was positively associated with many known COVID-19 inflammatory markers such as IL-6, IL-18, IL-10, and CXCL10, as well as type 1 immune response cytokines. Higher saliva viral loads strongly correlated with the progressive depletion of platelets, lymphocytes, and effector T cell subsets including circulating follicular CD4 T cells (cTfh). Anti-spike (S) and anti-receptor binding domain (RBD) IgG levels were negatively correlated with saliva viral load showing a strong temporal association that could help distinguish severity and mortality in COVID-19. Finally, patients with fatal COVID-19 exhibited higher viral loads, which correlated with the depletion of cTfh cells, and lower production of anti-RBD and anti-S IgG levels. Together these results demonstrated that viral load - as measured by saliva but not nasopharyngeal -- is a dynamic unifying correlate of disease presentation, severity, and mortality over time.

Kinetics of antibody responses dictate COVID-19 outcome

Recent studies have provided insights into innate and adaptive immune dynamics in coronavirus disease 2019 (COVID-19). Yet, the exact feature of antibody responses that governs COVID-19 disease outcomes remain unclear. Here, we analysed humoral immune responses in 209 asymptomatic, mild, moderate and severe COVID-19 patients over time to probe the nature of antibody responses in disease severity and mortality. We observed a correlation between anti-Spike (S) IgG levels, length of hospitalization and clinical parameters associated with worse clinical progression. While high anti-S IgG levels correlated with worse disease severity, such correlation was time-dependent. Deceased patients did not have higher overall humoral response than live discharged patients. However, they mounted a robust, yet delayed response, measured by anti-S, anti-RBD IgG, and neutralizing antibody (NAb) levels, compared to survivors. Delayed seroconversion kinetics correlated with impaired viral control in deceased patients. Finally, while sera from 89% of patients displayed some neutralization capacity during their disease course, NAb generation prior to 14 days of disease onset emerged as a key factor for recovery. These data indicate that COVID-19 mortality does not correlate with the cross-sectional antiviral antibody levels per se, but rather with the delayed kinetics of NAb production.

The Individual and Social Determinants of COVID-19 in Ontario, Canada: A Population-Wide Study

BackgroundOptimizing the public health response to reduce coronavirus disease 2019 (COVID-19) burden necessitates characterizing population-level heterogeneity of COVID-19 risks. However, heterogeneity in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) testing may introduce biased estimates depending on analytic design. MethodsWe explored the potential for collider bias and characterized individual, environmental, and social determinants of testing and diagnosis using cross-sectional analyses among 14.7 million community-dwelling people in Ontario, Canada. Among those diagnosed, we used separate analytic designs to compare predictors of: 1) individuals testing positive versus negative; 2) symptomatic individuals only testing positive versus testing negative; and 3) individuals testing positive versus individuals not testing positive (i.e., testing negative or not being tested). Analyses included tests conducted between March 1 and June 20, 2020. ResultsOf a total of 14,695,579 individuals, 758,691 were tested for SARS-CoV-2, of whom 25,030 (3.3%) tested positive. The further the odds of testing from the null, the more variability observed in the odds of diagnosis across analytic design, particularly among individual factors. There was less variability in testing by social determinants across analytic designs. Residing in areas with highest household density (adjusted odds ratio [aOR]: 1.86; 95%CI: 1.75-1.98), highest proportion of essential workers (aOR: 1.58; 95%CI: 1.48-1.69), lowest educational attainment (aOR: 1.33; 95%CI: 1.26-1.41), and highest proportion of recent immigrants (aOR: 1.10; 95%CI: 1.05-1.15) were consistently related to increased odds of SARS-CoV-2 diagnosis regardless of analytic design. InterpretationWhere testing is limited, risk factors may be better estimated using population comparators rather than test-negative comparators. Optimizing COVID-19 responses necessitates investment and sufficient coverage of structural interventions tailored to heterogeneity in social determinants of risk, including household crowding, occupation, and structural racism.

Longitudinal immunological analyses reveal inflammatory misfiring in severe COVID-19 patients

Recent studies have provided insights into the pathogenesis of coronavirus disease 2019 (COVID-19)1-4. Yet, longitudinal immunological correlates of disease outcome remain unclear. Here, we serially analysed immune responses in 113 COVID-19 patients with moderate (non-ICU) and severe (ICU) disease. Immune profiling revealed an overall increase in innate cell lineages with a concomitant reduction in T cell number. We identify an association between early, elevated cytokines and worse disease outcomes. Following an early increase in cytokines, COVID-19 patients with moderate disease displayed a progressive reduction in type-1 (antiviral) and type-3 (antifungal) responses. In contrast, patients with severe disease maintained these elevated responses throughout the course of disease. Moreover, severe disease was accompanied by an increase in multiple type 2 (anti-helminths) effectors including, IL-5, IL-13, IgE and eosinophils. Unsupervised clustering analysis of plasma and peripheral blood leukocyte data identified 4 immune signatures, representing (A) growth factors, (B) type-2/3 cytokines, (C) mixed type-1/2/3 cytokines, and (D) chemokines that correlated with three distinct disease trajectories of patients. The immune profile of patients who recovered with moderate disease was enriched in tissue reparative growth factor signature (A), while the profile for those with worsened disease trajectory had elevated levels of all four signatures. Thus, we identified development of a maladapted immune response profile associated with severe COVID-19 outcome and early immune signatures that correlate with divergent disease trajectories.