{'fraction_non_alphanumeric': 0.03974662397327022, 'fraction_numerical': 0.04322706390087707, 'mean_word_length': 4.961410788381743, 'pattern_counts': {'":': 0, '<': 1, '<?xml version=': 0, '>': 2, 'https://': 0, 'lorem ipsum': 0, 'www.': 0, 'xml': 0}, 'pii_count': 0, 'substrings_counts': 0, 'word_list_counts': {'cursed_substrings.json': 1, 'profanity_word_list.json': 0, 'sexual_word_list.json': 0, 'zh_pornsignals.json': 0}}
Effectiveness of COVID-19 vaccines against hospitalization and death in Canada: A multiprovincial test-negative design study

Abstract Background A major goal of COVID-19 vaccination is to prevent severe outcomes (hospitalizations and deaths). We estimated the effectiveness of mRNA and ChAdOx1 COVID-19 vaccines against severe outcomes in four Canadian provinces between December 2020 and September 2021. Methods We conducted this multiprovincial retrospective test-negative study among community-dwelling adults aged ≥18 years in Ontario, Quebec, British Columbia, and Manitoba using linked provincial databases and a common study protocol. Multivariable logistic regression was used to estimate province-specific vaccine effectiveness against COVID-19 hospitalization and/or death. Estimates were pooled using random effects models. Results We included 2,508,296 tested subjects, with 31,776 COVID-19 hospitalizations and 5,842 deaths. Vaccine effectiveness was 83% after a first dose, and 98% after a second dose, against both hospitalization and death (separately). Against severe outcomes (hospitalization or death), effectiveness was 87% (95%CI: 71%–94%) ≥84 days after a first dose of mRNA vaccine, increasing to 98% (95%CI: 96%–99%) ≥112 days after a second dose. Vaccine effectiveness against severe outcomes for ChAdOx1 was 88% (95%CI: 75%–94%) ≥56 days after a first dose, increasing to 97% (95%CI: 91%–99%) ≥56 days after a second dose. Lower one-dose effectiveness was observed for adults aged ≥80 years and those with comorbidities, but effectiveness became comparable after a second dose. Two doses of vaccines provided very high protection for both homologous and heterologous schedules, and against Alpha, Gamma, and Delta variants. Conclusions Two doses of mRNA or ChAdOx1 vaccines provide excellent protection against severe outcomes of hospitalization and death.

Data sources and definitions 6 We linked data from provincial SARS-CoV-2 laboratory testing, COVID-19 public health 7 surveillance, COVID-19 vaccination, and health administrative datasets using unique encoded 8 identifiers in each province at: ICES (Ontario), Institut National de Santé Publique du Québec, 9 BC Centre for Disease Control, and the University of Manitoba Vaccine and Drug Evaluation 10 Centre (Supplemental Tables S1 and S2). Our primary outcome was COVID-19 hospitalization or death identified from notifiable disease 14 reporting systems and/or other administrative databases. COVID-19 hospitalization was defined 15 as hospitalization or ICU admission with a positive SARS-CoV-2 test within 14 days prior to or 16 3 days after hospitalization. We excluded nosocomial cases flagged in notifiable disease 17 reporting systems and SARS-CoV-2-positive cases with specimen collection >3 days after 18 hospital admission. COVID-19 death was defined as death with a positive SARS-CoV-2 test 19 identified from notifiable disease reporting systems or deaths occurring within 30 days following 20 a positive SARS-CoV-2 test or within 7 days post-mortem. Subjects with COVID-19 21 hospitalizations and deaths were treated as test-positive cases using the earliest of the specimen 22 collection date, hospitalization date, or death date as the index date. We included outcomes occurring until 30 September 2021, and included only the first positive test. Symptomatic 1 subjects who tested negative during the study period were treated as test-negative controls using 2 specimen collection date as index date. For controls with multiple negative tests, we randomly 3 selected one symptomatic test-negative specimen collection date. SARS-CoV-2 lineage was 4 determined using whole genome sequencing or screening PCR tests for various mutations to 5 group test-positive specimens into mutually exclusive categories: Alpha, Beta, Gamma, 6 Beta/Gamma, Delta, non-VOC SARS-CoV-2 (Supplemental methods). Information on vaccine product, date of administration, and dose number were collected from 10 provincial COVID-19 vaccination information systems.

12
Covariates 13 Information on the following covariates were obtained from relevant data sources [5][6][7]: age 14 group, sex, geographic region (Supplemental Table S3), 2-week periods of test (to control for 15 temporal changes in virus circulation and vaccine uptake), number of RT-PCR tests during the 3 16 months prior to the start of the study (as a proxy for frequently tested at-risk individuals),  [5]. All covariates except week of SARS-CoV-2 test were measured as of the start of 1 the study period. Baseline characteristics were summarized as means (standard deviation) for continuous variables 5 and frequencies and percentages for categorical variables. Logistic regression models were used 6 to estimate crude and adjusted odds ratios (OR) comparing the odds of being vaccinated versus 7 unvaccinated between test-positive cases and test-negative controls separately in each province.

8
Adjusted models accounted for all covariates listed above.

10
We estimated overall ORs separately for hospitalization and death but for all vaccines combined 11 ≥14 days after a first dose (among those who had received only 1 dose at the time of testing) and 12 ≥7 days after a second dose. We also estimated ORs by time since the most recent dose for 13 mRNA vaccines and ChAdOx1 separately; follow-up periods were shorter after ChAdOx1 than 14 mRNA vaccines because of fewer ChAdOx1 recipients. We conducted subgroup analysis by 15 subject characteristics (age group, sex, presence of any comorbidity), vaccine product, and 16 SARS-CoV-2 lineage. We also estimated ORs for varying dosing intervals among subjects who 17 received 2 doses of mRNA vaccines.

19
Each province conducted analyses independently to estimate province-specific ORs. There were 20 some variations in data sources and analyses among the provinces (Supplemental methods). We 21 conducted a sensitivity analysis by also including hospitalizations and deaths from administrative 22 databases in Ontario. 2 We pooled the log OR estimates from each province using random-effects models with inverse 3 variance weighting [9]. We used random-effects models because provinces differed slightly in 4 population demographics and vaccination programs. We converted ORs to VE using the 5 formula: VE=(1-OR)*100. We assessed between-province heterogeneity using the I 2 statistic.

6
Pooled VE estimates were not presented if based on just one province. Meta-analyses were 7 conducted using the meta package in R version 4.1.2 [10].

10
Overall, we included 2,508,296 community-dwelling SARS-CoV-2-tested subjects (Table 1). 11 We identified 33,420 COVID-19-associated severe outcomes; receipt of ≥1 dose of a COVID-19 12 vaccine ranged from 13% to 20% among test-positive severe outcome cases, and from 40% to 13 46% among symptomatic test-negative controls (Supplemental Table S4). Cases were more 14 likely to be older, male, have had no SARS-CoV-2 tests during the 3 months before the 15 vaccination program, have a comorbidity, have received an influenza vaccine (Ontario, Quebec), 16 and more likely to reside in neighbourhoods with lower income/more material deprivation, more 17 people per dwelling, and greater proportions of essential workers (Ontario, BC), and greater 18 proportions of visible minorities than controls. Vaccinated subjects were more likely to be older, 19 have a comorbidity, have received influenza vaccination, and less likely to be male than 20 unvaccinated subjects (Supplemental Table S5). Most vaccinated subjects received BNT162b2 21 (Supplemental Table S6).  Against hospitalization or death, the pooled aVE for mRNA vaccines increased over time from 7 43% (95%CI: 25-57%) 0-13 days after a first dose to 87% (95%CI: 71-94%) ≥84 days after a 8 first dose; after receiving a second dose, pooled aVE increased from 93% (95%CI: 88-96%) at 9 0-6 days to 98% (95%CI: 96-99%) at ≥112 days ( Figure 2A, Supplemental Table 7). The pooled 10 aVE for ChAdOx1 increased from 37% (95%CI: 20-51%) 0-13 days after a first dose to 88% 11 (95%CI: 75-94%) ≥56 days after a first dose; aVE was 97% (95%CI: 91-99%) ≥56 days after a 12 second dose ( Figure 2B, Supplemental Table S8). 13 14 In subgroup analyses, the pooled aVE was lower for adults aged ≥80 years versus younger adults 15 aged 18-59 years, and in subjects with comorbidities versus those without comorbidities ≥14 16 days after a first dose; however, aVE became comparable across all subgroups ≥7 days after a 17 second dose ( Figure 3A, Supplemental Table S9). The pooled aVE against severe outcomes was 18 >80% ≥14 days after a first dose for all 3 vaccines, which increased to ≥97% ≥7 days after a 19 second dose. aVE was similar ≥7 days after a second dose of a mixed mRNA or 20 ChAdOx1/mRNA mixed schedule ( Figure 3B, Supplemental Table S10). aVE against severe 21 outcomes caused by VOCs was lowest against Beta at 61% and highest against Delta at 89% ≥14 days after a first dose, and increased to ≥97% against Alpha, Gamma, and Delta ≥7 days after a 1 second dose ( Figure 3C, Supplemental Table S11). The pooled aVE for mRNA vaccines 7-55 days after a second dose increased from 94% with a 4 dosing interval of 21-34 days to ≥98% with a longer dosing interval, although 95% confidence 5 intervals for aVE overlapped (Figure 4, Supplemental Table S12). aVE was maintained at ≥97% 6 with longer dosing intervals from 56 days through ≥112 days after a second dose. Although we observed heterogeneity between provinces, as reflected by I 2 statistics for most 9 models (Supplemental Table S13), all province-specific VE estimates suggest the vaccines were 10 significantly protective with some variation in the magnitude.

12
In sensitivity analyses including severe outcomes from administrative data in Ontario, we 13 identified 22,759 severe outcomes; pooled sensitivity analyses yielded VE estimates similar to 14 the primary analyses (Supplemental Table S14). We found high and very high effectiveness against hospitalization and death with 1 (83%) and 2 18 (98%) doses of COVID-19 vaccines, respectively. mRNA and ChAdOx1 vaccines had 19 comparable effectiveness after first and second doses; protection increased or remained relatively 20 stable over time after each dose without noticeable waning over this relatively short period of 21 observation. In subgroup analyses, we observed lower one-dose VE for adults aged ≥80 years 22 and those with comorbidities, but VE became comparable after a second dose. Two doses provided very high protection against Alpha, Gamma, and Delta variants. We observed very high 1 level of protection with both homologous and heterologous schedules. Finally, our findings 2 suggest that lengthening dosing intervals minimally impacted on VE against severe outcomes.

4
Our pooled aVE estimates against hospitalization and against death ≥14 days after a single dose 5 were higher than reported estimates in a systematic review and meta-analysis of studies waning of protection against hospitalizations and deaths after a second dose has been reported. In 7 England, VE against Delta variant-related hospitalization and death decreased from 99% at 2-9 8 weeks to 92% at ≥20 weeks for BNT162b2, with more pronounced decline for ChAdOx1 from 9 95% at 2-9 weeks to 80-85% at ≥20 weeks [13]. Protection against hospitalizations and deaths  Our finding of comparable VE against severe outcomes in older and younger adults and in 21 people with and without comorbidities after a second dose aligns with findings from previous 22 studies [5,[20][21][22]. However, a lower overall VE of 88% (95%CI: 82-92%) was also reported previously in older adults aged ≥80 years compared to ≥94% VE in adults aged <80 years [3]. 1 We found good overall protection against hospitalizations or deaths caused by Alpha and Delta 2 (≥84%) ≥14 days after a first dose, and excellent protection (≥98%) ≥7 days after a second dose.   hospitalization may vary between and within jurisdictions, hospital capacity was maintained to 20 admit patients requiring hospitalization and we do not expect differential under-or over-21 estimation of severe outcomes, particularly death, with respect to COVID-19 vaccination status.

22
Third, despite a common study protocol, there is likely heterogeneity among provinces in terms of differences in populations, vaccination programs (rollout logistics and priority groups), 1 SARS-CoV-2 testing criteria, data capture, and covariates adjusted; we used random-effects 2 models to account for statistical heterogeneity. Fourth, given the observational nature of the 3 study, residual confounding remains possible despite adjustment for a number of potential 4 confounders. Fifth, we were unable to differentiate hospitalizations due to COVID-19 from 5 hospitalizations with COVID-19 in all participating provinces; the latter is more common with 6 Omicron and tends to lower VE against severe outcomes [31]. We believe this bias was minimal 7 in our VE estimates from the pre-Omicron period. Finally, our VE estimates may not apply to 8 Omicron-related severe outcomes. Our results provide strong evidence of excellent protection against hospitalizations and deaths 11 with 2 doses of mRNA or ChAdOx1 vaccines during the pre-Omicron period. We found 12 relatively stable protection through ≥16 weeks for mRNA vaccines and ≥8 weeks for ChAdOx1.  We acknowledge Public Health Ontario for access to case-level data from CCM, COVID-19 9 laboratory data, and COVaxON. We also thank the staff of Ontario's public health units who are 10 responsible for COVID-19 case and contact management and data collection within CCM. We  Authority, BC Ministry of Health and Regional Health Authority staff involved in data access, 15 procurement, and management. We gratefully acknowledge the residents of British Columbia 16 whose data are integrated in the British Columbia COVID-19 Cohort (BCC19C). We thank Dr.   Force. This study was also supported by ICES, which is funded by an annual grant from the    Comparative single-dose mRNA and ChAdOx1 vaccine effectiveness against SARS-CoV-2, 20 including variants of concern: test-negative design, British Columbia, Canada. J Infect Dis.    10 h Proportions calculated using the total number of SARS-CoV-2 cases with severe outcomes as the denominator.

11
A C C E P T E D M A N U S C R I P T