key: cord-1021294-rricccz8 authors: Nasreen, S.; Febriani, Y.; Garcia, H. A. V.; Zhang, G.; Tadrous, M.; Buchan, S. A.; Righolt, C.; Mahmud, S. M.; Janjua, N. Z.; Krajden, M.; Serres, G. D.; Kwong, J. Z. title: Effectiveness of COVID-19 vaccines against hospitalization and death in Canada: A multiprovincial test-negative design study date: 2022-04-13 journal: nan DOI: 10.1101/2022.04.13.22273825 sha: b4a4bf546e3eaf27cc8f07fd71e1254782fb5f8e doc_id: 1021294 cord_uid: rricccz8 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. SARS-CoV-2 infection is associated with high morbidity and mortality [1] . A major goal of COVID-19 vaccination is to prevent hospitalizations and deaths. Provincial vaccination programs in Canada have involved extended intervals between first and second doses due to vaccine supply constraints, and use of heterologous (i.e., 'mix-and-match') vaccine schedules due to concerns regarding vaccine-induced immune thrombotic thrombocytopenia associated with ChAdOx1 (AstraZeneca Vaxzevria and COVISHIELD) and variable supplies of specific vaccine products [2, 3] . Assessing COVID-19 vaccine effectiveness (VE) against severe outcomes with longer follow-up after each dose will inform our understanding of the duration of protection. There are limited data on real-world effectiveness of heterologous vaccine schedules and extended dosing intervals against severe outcomes [4] . The aim of this study was to estimate the effectiveness of mRNA Using a common study protocol across 4 Canadian provinces, we conducted a test-negative design study [5] involving Ontario, Quebec, British Columbia (BC), and Manitoba (total population 30 million, comprising approximately 79% of the Canadian population) among community-dwelling residents who sought SARS-CoV-2 testing. We included all residents aged . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted April 13, 2022. ; https://doi.org/10.1101/2022.04.13.22273825 doi: medRxiv preprint ≥ 18 years, eligible for provincial health insurance (virtually everyone), not living in long-term care, and tested for SARS-CoV-2 between the start of vaccine availability in a province (14 December 2020 in Ontario and Quebec, 15 December 2020 in BC, 16 December 2020 in Manitoba) and 30 September 2021 and met our case or control definitions. We excluded recipients of non-Health Canada-authorized vaccines or Ad26.COV2.S (Johnson & Johnson's Janssen) vaccine. We linked data from provincial SARS-CoV-2 laboratory testing, COVID-19 public health surveillance, COVID-19 vaccination, and health administrative datasets using unique encoded identifiers in each province at: ICES (Ontario), Institut National de Santé Publique du Québec, BC Centre for Disease Control, and the University of Manitoba Vaccine and Drug Evaluation Centre (Supplemental Tables S1 and S2). Our primary outcome was COVID-19 hospitalization or death identified from notifiable disease reporting systems and/or other administrative databases. COVID-19 hospitalization was defined as hospitalization or ICU admission with a positive SARS-CoV-2 test within 14 days prior to or 3 days after hospitalization. We excluded nosocomial cases flagged in notifiable disease reporting systems and SARS-CoV-2-positive cases with specimen collection >3 days after hospital admission. COVID-19 death was defined as death with a recent positive SARS-CoV-2 test identified from notifiable disease reporting systems or deaths occurring within 30 days following a positive SARS-CoV-2 test or within 7 days post-mortem. Subjects with COVID-19 . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted April 13, 2022. ; https://doi.org/10.1101/2022.04.13.22273825 doi: medRxiv preprint hospitalizations and deaths were treated as test-positive cases using the earliest of the specimen collection date, hospitalization date, or death date as the index date. We included COVID-19 hospitalizations and deaths occurring until 30 September 2021, and included only the first positive test. Symptomatic subjects who tested negative during the study period were treated as test-negative controls using the specimen collection date as the index date. For controls with multiple negative tests, we randomly selected one symptomatic test-negative specimen collection date. SARS-CoV-2 lineage was determined using whole genome sequencing or screening PCR tests for various mutations to group test-positive specimens into the following mutually exclusive categories: Alpha, Beta, Gamma, Beta/Gamma, Delta, and non-VOC SARS-CoV-2 (Supplemental methods). Information on COVID-19 vaccination, including vaccine product, date of administration, and dose number were collected from each province's COVID-19 vaccination information system. Information on the following covariates were obtained from relevant data sources [6] [7] [8] : age group, sex, geographic region (Supplemental Table S3 ), 2-week periods of test (to control for temporal changes in virus circulation and vaccine uptake), number of RT-PCR tests during the 3 months prior to the start of the study (as a proxy for frequently tested at-risk individuals), comorbidities that increase the risk of severe COVID-19 [9] , receipt of 2019-2020 and/or 2020-2021 influenza vaccination (as a proxy for health behaviours), and 4 area-level social determinants of health (median neighbourhood income, proportion of the working population . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted April 13, 2022. ; https://doi.org/10.1101/2022.04.13.22273825 doi: medRxiv preprint employed as non-health essential workers [i.e., those unable to work from home], average number of persons per dwelling, and proportion of the population who self-identify as a visible minority) [6] . All covariates were measured as of the start of the study period, except week of SARS-CoV-2 test. Baseline characteristics were summarized as means (standard deviation, SD) for continuous variables and frequencies and percentages for categorical variables. Logistic regression models were used to estimate crude and adjusted odds ratios (OR) comparing the odds of being vaccinated versus unvaccinated between test-positive cases and test-negative controls separately in each province. Adjusted models accounted for all the covariates listed above. We estimated overall ORs separately for hospitalization and death but for all vaccines combined ≥ 14 days after a first dose among those who had received only 1 dose at the time of testing and ≥ 7 days after a second dose among those who had received 2 doses. We also estimated the ORs by time since their most recent dose for mRNA vaccines and ChAdOx1separately; follow-up periods were shorter after ChAdOx1 than mRNA vaccines because there were fewer recipients of ChAdOx1. We conducted subgroup analysis by subject characteristics (age group, sex, and presence of any comorbidity), vaccine product, and SARS-CoV-2 lineage. We also estimated ORs for varying dosing intervals among individuals who received 2 doses of mRNA vaccines. Each province conducted these analyses independently to estimate province-specific ORs. There were some variations in data sources and analyses among the provinces. Details are provided in . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted April 13, 2022. ; https://doi.org/10.1101/2022.04.13.22273825 doi: medRxiv preprint Supplemental methods. We conducted a sensitivity analysis by also including hospitalizations and deaths from administrative databases in Ontario. We pooled the log OR estimates from each province using random-effects models with inverse variance weighting [10] . We used random-effects models because provinces differed slightly in population demographics and vaccination programs that may introduce some variability. We converted province-specific and pooled ORs to VE using the formula: VE=(1-OR)*100. We assessed between-province heterogeneity using the I 2 statistic. Pooled VE estimates were not presented if a single province contributed to the meta-analysis. Meta-analyses were conducted using meta package in R version 4.1.2 [11] . Overall, we included 2,508,296 community-dwelling SARS-CoV-2-tested subjects (Table 1) . We identified 33,420 COVID-19-associated severe outcomes; receipt of at least 1 dose of a COVID-19 vaccine ranged from 13% to 20% among test-positive severe outcome cases, and from 40% to 46% among symptomatic test-negative controls (Supplemental Table S4 ). Cases were more likely to be older, male, have had no SARS-CoV-2 tests during the 3 months before the vaccination program, have a comorbidity, have received an influenza vaccine (in Ontario and Quebec), and more likely to reside in neighbourhoods with lower income/more material deprivation, more people per dwelling, and greater proportions of essential workers (in Ontario and BC), and greater proportions of visible minorities than controls. Vaccinated subjects were more likely to be older, have a comorbidity, have received an influenza vaccine, and less likely . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) 1 0 to be male than unvaccinated subjects (Supplemental Table S5 ). Most vaccinated subjects received BNT162b2 (Supplemental Table S6 ). In pooled analyses, the adjusted VE (aVE) was 83% (95% confidence interval [CI]: 78%-87%) against hospitalization and 83% (95%CI: 72%-90%) against death after a first dose; aVE increased to 98% against both hospitalization (95%CI: 96%-99%) and death (95%CI: 95%-99%) after receiving a second dose ( Figure 1 , Supplemental Table S7 ). Against severe outcomes of hospitalization or death, the pooled aVE increased over time from 43% (95%CI: 25%-57%) 0-13 days after a first dose to 87% (95%CI: 71%-94%) ≥ 84 days after a first dose for an mRNA vaccine; after receiving a second dose, pooled aVE increased from 93% (95%CI: 88%-96%) at 0-6 days to 98% (95%CI: 96%-99%) at Table 7 ). The pooled aVE against severe outcomes for ChAdOx1 increased from 37% (95%CI: 20%-51%) 0-13 days after a first dose to 88% (95%CI: 75%-94%) ≥ 56 days after a first dose; aVE increased to 97% (95%CI: 91%-99%) ≥ 56 days after receiving a second dose ( Figure 2B , Supplemental Table S8 ). In subgroup analyses, the pooled aVE against severe outcomes was lower for adults aged Table S9 ). The pooled aVE against severe outcomes was >80% ≥ 14 days after a first dose for BNT162b2, . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) 1 1 mRNA-1273, or ChAdOx1 vaccines, which increased to ≥ 97% ≥ 7 days after receipt of a second dose. aVE against severe outcomes was similar ≥ 7 days after receiving a second dose of a mixed mRNA or ChAdOx1/mRNA mixed schedule ( Figure 3B , Supplemental Table S10 ). aVE against severe outcomes caused by VOCs was lowest against Beta at 61% and highest against Delta at 89% ≥ 14 days after a first dose, and aVE increased to ≥ 97% against Alpha, Gamma, and Delta ≥ 7 days after a second dose ( Figure 3C , Supplemental Table S11 ). The pooled aVE against severe outcomes for mRNA vaccines 7-55 days after a second dose increased from 94% with a dosing interval of 21-34 days to ≥ 98% with a longer dosing interval, although 95% confidence intervals for aVE overlapped ( Figure 4 , Supplemental Table S12 ). aVE was maintained at ≥ 97% with longer between dose intervals from 56 days through ≥ 112 days after receiving a second dose. Although heterogeneity between the provinces was observed, as reflected by the I 2 statistics for most of the models (Supplemental Table S13 ), all province-specific VE estimates suggest the vaccines were significantly protective with some variation in the magnitude. In sensitivity analyses with the inclusion of severe outcomes from administrative data in Ontario, we identified 22,759 severe outcomes; pooled sensitivity analyses yielded similar VE estimates to those obtained from the pooled primary analyses (Supplemental Table S14 ). . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted April 13, 2022 . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted April 13, 2022. ; https://doi.org/10.1101/2022.04.13.22273825 doi: medRxiv preprint (95%CI: 85%-95%) and 94% (95%CI: 83%-98%) against hospitalization and a composite of severe outcomes due to Delta, respectively, after receipt of a second dose [13] . Against hospitalization or death, we observed sustained pooled aVE of 87% for mRNA vaccines at ≥ 12 weeks, and 88% for ChAdOx1 at [14, 15] and Qatar [16] . A high VE of ≥ 95% at ≥ 28 weeks for mRNA vaccines and ≥ 93% at ≥ 12 weeks for ChAdOx1 was also maintained against hospitalizations in Quebec and BC [4] . However, some waning of immunity against hospitalizations and deaths after a second dose has been reported from other studies. VE against Delta variant-related hospitalization, and death decreased from 99% at 2-9 weeks to 92% at ≥ 20 weeks for BNT162b2 with more pronounced decline for ChAdOx1 from 95% at 2-9 weeks to 80-85% at ≥ 20 weeks in the UK [17] . Waning of protection against hospitalizations and deaths for BNT162b2 was observed at ≥ 7 months in Qatar [16] . VE against hospitalization for COVID-19 or all-cause 30-day mortality after confirmed infection for mRNA or ChAdOx1 declined from 89% (95%CI: 82%-93%) at 15-30 days to 64% (95%CI: 44% to 77%) at ≥ 121 days after a second dose in Sweden [18] . The cumulative VE within 6 months of receiving 2 doses of a COVID-19 vaccine (mainly mRNA and ChAdOx1) declined from 87% and 84% to 52% and 34% after 6 months against hospitalizations and deaths, respectively in Italy [19] . Confounding by indication resulting from . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted April 13, 2022. ; https://doi.org/10.1101/2022.04.13.22273825 doi: medRxiv preprint averaging VE across subgroups with different exposure and infection risk, vaccination priority, clinical risk, and increased transmission and/or shorter interval of 3 weeks between doses with longer follow-up and rapid uptake of vaccines may explain the waning of VE observed in these studies [17, 20] . Our finding of comparable VE against severe outcomes in older and younger adults and in people with and without comorbidities after receiving a second dose aligns with findings from previous studies [6, [21] [22] [23] . 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 [4] . We found good overall protection against hospitalizations or deaths caused by Alpha and Delta (≥84%) ≥ 14 days after the first dose, and excellent protection (≥98%) ≥ 7 days after a second dose. Similar high VEs against Alpha (84%-97%) and Delta (92%-98%) with a second dose have been reported from other studies [24] [25] [26] [27] . We observed similar high pooled aVE (≥97%) against severe outcomes ≥ 7 days after receiving a second dose of homologous BNT162b2, mRNA-1273, or ChAdOx1 vaccine series; these estimates were similar to our pooled aVE after receiving mixed mRNA (98%) or ChAdOx1/mRNA mixed schedule (99%), adding to the evidence of real-world effectiveness of heterologous dosing schedules. Our findings corroborate previously reported VE estimates against hospitalization using homologous and heterologous vaccine schedules from Quebec and BC [4] . Countries and jurisdictions with low 2-dose vaccine coverage and/or facing limited supplies of specific vaccine products could benefit from implementing heterologous vaccine schedules to increase population protection against severe outcomes. . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted April 13, 2022. [4] . This likely resulted from differences in methods and follow-up time between the studies. Deciding on the optimal interval between doses must weigh the benefits of delaying second doses against the risks of infection and subsequent severe outcomes in the context of local incidence, vaccine coverage, and vaccine supply. This study has some limitations. First, while the test-negative design accounts for differences in healthcare seeking behaviour, indications for testing and risks of exposure to SARS-CoV-2 infection between test-positive cases and test-negative controls may differ. Testing indications also varied between the provinces and over the study period. We adjusted for biweekly period of test and number of prior tests to account for these. Second, although healthcare utilization and thresholds for hospitalization may vary between and within jurisdictions, hospital capacity was maintained to admit patients requiring hospitalization and we do not expect differential under-or over-estimation of severe outcomes, particularly death, with respect to COVID-19 vaccination status. Third, despite a common study protocol, there is likely heterogeneity among provinces in . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted April 13, 2022. ; https://doi.org/10.1101/2022.04.13.22273825 doi: medRxiv preprint terms of differences in populations, vaccination programs (rollout logistics and priority groups), SARS-CoV-2 testing criteria, data capture, and covariates adjusted; we used random-effects models to account for statistical heterogeneity. Fourth, given the observational nature of the study, residual confounding remains possible despite adjustment for a number of potential confounders. Finally, our VE estimates may not apply to severe outcomes caused by Omicron. In conclusion, our results from this large multiprovincial study provide strong evidence of excellent protection against severe outcomes of hospitalizations and deaths with 2 doses of mRNA or ChAdOx1 vaccines during the pre-Omicron period. With 2 doses, we found relatively stable protection through 16 weeks and beyond for mRNA vaccines and 8 weeks and beyond for ChAdOx1. Our findings further support the interchangeability of homologous and heterologous vaccine schedules. Likewise, the sustained protection from extended dosing intervals observed in our study lends evidence to delay administration of second doses in settings faced with limited vaccine supply. . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. Data used in this article was derived from administrative health and social data as a secondary use. The dataset for Ontario from this study is held securely in coded form at ICES. While legal data sharing agreements between ICES and data providers (e.g., healthcare organizations and government) prohibit ICES from making the dataset publicly available, access may be granted to those who meet pre-specified criteria for confidential access, available at www.ices.on.ca/DAS (email: das@ices.on.ca). The full dataset creation plan and underlying analytic code are available from the authors upon request, understanding that the computer programs may rely upon coding templates or macros that are unique to ICES and are therefore either inaccessible or may require modification. The data was provided under specific data sharing agreements only for approved use at the Manitoba Centre for Health Policy (MCHP). The original source data is not owned by the researchers or MCHP and as such cannot be provided to a public repository. The original data source and approval for use has been noted in the acknowledgments of the article. Where . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted April 13, 2022. ; https://doi.org/10.1101/2022.04.13.22273825 doi: medRxiv preprint necessary, source data specific to this article or project may be reviewed at MCHP with the consent of the original data providers, along with the required privacy and ethical review bodies. This study was supported by ICES, which is funded by an annual grant from the Ontario We would like to acknowledge Public Health Ontario for access to case-level data from CCM, COVID-19 laboratory data, and COVaxON. We also thank the staff of Ontario's public health units who are responsible for COVID-19 case and contact management and data collection . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. BC Ministry of Health and Regional Health Authority staff involved in data access, procurement, and management. We gratefully acknowledge the residents of British Columbia whose data are integrated in the British Columbia COVID-19 Cohort (BCC19C). . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted April 13, 2022. ; https://doi.org/10.1101/2022.04.13.22273825 doi: medRxiv preprint . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted April 13, 2022 . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted April 13, 2022 g Percentage of people in the area who self-identified as a visible minority. Census counts for people are randomly rounded up or down to the nearest number divisible by 5, which causes some minor imprecision. h Proportions calculated using the total number of SARS-CoV-2 cases with severe outcomes as the denominator. . It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted April 13, 2022. is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted April 13, 2022. is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted April 13, 2022. is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted April 13, 2022. . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted April 13, 2022. ; https://doi.org/10.1101/2022.04.13.22273825 doi: medRxiv preprint Epidemiology of COVID-19: A systematic review and meta-analysis of clinical characteristics, risk factors, and outcomes NACI rapid response: Extended dose intervals for COVID-19 vaccines to optimize early vaccine rollout and population protection in Canada Government of Canada Two-dose SARS-CoV-2 vaccine effectiveness with mixed schedules and extended dosing intervals: test-negative design studies from British Columbia and Quebec Postlicensure Evaluation of COVID-19 Vaccines Effectiveness of BNT162b2 and mRNA-1273 covid-19 vaccines against symptomatic SARS-CoV-2 infection and severe covid-19 outcomes in Ontario, Canada: test negative design study Patterns and descriptors of COVID-19 testing and lab-confirmed COVID-19 incidence in Manitoba Mental Health and Substance Use Associated with Hospitalization among People with COVID-19: A Population-Based Cohort Study Underlying Medical Conditions Associated with High Risk for Severe COVID-19: Information for Healthcare Providers 2021 Meta-analysis in clinical trials How to perform a meta-analysis with R: a practical tutorial Effectiveness and safety of SARS-CoV-2 vaccine in real-world studies: a systematic review and meta-analysis Effectiveness of COVID-19 vaccines against SARS-CoV-2 infection with the Delta (B.1.617.2) variant: second interim results of a living systematic review and meta-analysis Sustained Effectiveness of Pfizer-BioNTech and Moderna Vaccines Against COVID-19 Associated Hospitalizations Among Adults -United States Effectiveness of mRNA BNT162b2 COVID-19 vaccine up to 6 months in a large integrated health system in the USA: a retrospective cohort study Waning of BNT162b2 Vaccine Protection against SARS-CoV-2 Infection in Qatar Duration of Protection against Mild and Severe Disease by Covid-19 Vaccines Risk of infection, hospitalisation, and death up to 9 months after a second dose of COVID-19 vaccine: a retrospective, total population cohort study in Sweden Primary COVID-19 vaccine cycle and booster doses efficacy: analysis of Italian nationwide vaccination campaign Single-Dose Messenger RNA Vaccine Effectiveness Against Severe Acute Respiratory Syndrome Coronavirus 2 in Healthcare Workers Extending 16 Weeks Postvaccination: A Test-Negative Design From Québec Impact and effectiveness of mRNA BNT162b2 vaccine against SARS-CoV-2 infections and COVID-19 cases, hospitalisations, and deaths following a nationwide vaccination campaign in Israel: an observational study using national surveillance data New COVID-19 Cases and Hospitalizations Among Adults, by Vaccination Status Effectiveness of Covid-19 Vaccines in Ambulatory and Inpatient Care Settings Effectiveness of COVID-19 vaccines against hospital admission with the Delta (B.1.617.2) variant