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Figure.  Estimates of Vaccine Effectiveness Against Symptomatic Omicron and Delta Infections and Severe Outcomes Associated With These Infections From December 6 to 26, 2021, by Time Since Latest Dose
Estimates of Vaccine Effectiveness Against Symptomatic Omicron and Delta Infections and Severe Outcomes Associated With These Infections From December 6 to 26, 2021, by Time Since Latest Dose

A and B, Markers indicate estimates, with vertical lines indicating 95% CIs. B, Severe outcomes included hospitalization and death. Omicron vaccine effectiveness estimates for 7 to 59 days, 60 to 119 days, and 240 days or more after the second dose are not presented owing to imprecision in the estimates and wide 95% CIs (ie, ≥100 percentage points). Vaccine effectiveness of the mRNA-1273 vaccine (Moderna) 0 to 6 days after the third dose was estimated as 100% based on 0 vaccinated test-positive hospitalized cases and therefore is not presented.

Table 1.  Characteristics of Omicron and Delta Cases and SARS-CoV-2–Negative Controlsa
Characteristics of Omicron and Delta Cases and SARS-CoV-2–Negative Controlsa
Table 2.  Characteristics of Vaccinated and Unvaccinated Omicron Cases and SARS-CoV-2–Negative Controlsa
Characteristics of Vaccinated and Unvaccinated Omicron Cases and SARS-CoV-2–Negative Controlsa
Table 3.  Estimates of Vaccine Effectiveness Against Symptomatic Omicron and Delta Infection or Severe Outcomes Associated With These Infections From December 6 to 26, 2021, by Time Since Latest Dosea
Estimates of Vaccine Effectiveness Against Symptomatic Omicron and Delta Infection or Severe Outcomes Associated With These Infections From December 6 to 26, 2021, by Time Since Latest Dosea
1.
World Health Organization. Classification of Omicron (B.1.1.529): SARS-CoV-2 variant of concern. November 26, 2021. Accessed December 30, 2021. https://www.who.int/news/item/26-11-2021-classification-of-omicron-(b.1.1.529)-sars-cov-2-variant-of-concern
2.
Public Health Ontario. COVID-19 vaccine uptake and program impact in Ontario: December 14, 2020 to December 19, 2021. Accessed December 30, 2021. https://www.publichealthontario.ca/-/media/documents/ncov/epi/covid-19-vaccine-uptake-ontario-epi-summary.pdf?sc_lang=en
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Government of Ontario. Data catalogue: COVID-19 vaccinations data. Accessed December 25, 2021. https://data.ontario.ca/en/dataset?groups=2019-novel-coronavirus
4.
Nemet  I, Kliker  L, Lustig  Y,  et al.  Third BNT162b2 vaccination neutralization of SARS-CoV-2 Omicron infection.   N Engl J Med. 2021;86:492-494. doi:10.1056/NEJMc2119358PubMedGoogle ScholarCrossref
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Cele  S, Jackson  L, Khoury  DS,  et al.  SARS-CoV-2 Omicron has extensive but incomplete escape of Pfizer BNT162b2 elicited neutralization and requires ACE2 for infection.  medRxiv. Preprint posted online December 17, 2021. doi:10.1101/2021.12.08.21267417
6.
Dejnirattisai  W, Shaw  RH, Supasa  P,  et al.  Reduced neutralisation of SARS-CoV-2 Omicron B.1.1.529 variant by post-immunisation serum.   Lancet. Published online December 20, 2021. doi:10.1101/2021.12.10.21267534PubMedGoogle Scholar
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Rössler  A, Riepler  L, Bante  D, von Laer  D, Kimpel  J.  SARS-CoV-2 Omicron variant neutralization in serum from vaccinated and convalescent persons.   N Engl J Med. 2022;386(7):698-700. doi:10.1056/NEJMc2119236 PubMedGoogle ScholarCrossref
8.
Ferguson  N, Ghani  A, Cori  A, Hogan A, Hinsley W, Volz E; Imperial College COVID-19 Response Team. Report 49: growth, population distribution and immune escape of Omicron in England. Imperial College London. December 16, 2021. Accessed December 30, 2021. https://www.imperial.ac.uk/mrc-global-infectious-disease-analysis/covid-19/report-49-omicron/
9.
UK Health Security Agency. COVID-19 vaccine surveillance report: week 3. January 20, 2022. Accessed January 21, 2022. https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/1049160/Vaccine-surveillance-report-week-3-2022.pdf
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Tartof  SY, Slezak  JM, Puzniak  L,  et al.  BNT162b2 (Pfizer–Biontech) mRNA COVID-19 vaccine against Omicron-related hospital and emergency department admission in a large US health system: a test-negative design.  Preprints with The Lancet. Preprint posted online January 18, 2022. doi:10.2139/ssrn.4011905
11.
Andrews  N, Stowe  J, Kirsebom  F,  et al.  Effectiveness of COVID-19 vaccines against the Omicron (B.1.1.529) variant of concern.  medRxiv. Preprint posted online December 14, 2021. doi:10.1101/2021.12.14.21267615
12.
Hansen  CH, Schelde  AB, Moustsen-Helm  IR,  et al.  Vaccine effectiveness against SARS-CoV-2 infection with the Omicron or Delta variants following a two-dose or booster BNT162b2 or mRNA-1273 vaccination series: a Danish cohort study.  medRxiv. Preprint posted online December 23, 2021. doi:10.1101/2021.12.20.21267966
13.
Sheikh  A, Kerr  S, Woolhouse  M,  et al.  Severity of Omicron variant of concern and vaccine effectiveness against symptomatic disease: national cohort with nested test negative design study in Scotland.  Edinburgh Research Explorer. Preprint posted online 2021. https://www.pure.ed.ac.uk/ws/portalfiles/portal/245818096/Severity_of_Omicron_variant_of_concern_and_vaccine_effectiveness_against_symptomatic_disease.pdf
14.
Collie  S, Champion  J, Moultrie  H,  et al.  Effectiveness of BNT162b2 vaccine against Omicron variant in South Africa.   N Engl J Med. 2022;386(5):494-496. doi:10.1056/NEJMc2119270PubMedGoogle ScholarCrossref
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Thompson  MG, Natarajan  K, Irving  SA,  et al. Effectiveness of a third dose of mRNA vaccines against COVID-19–associated emergency department and urgent care encounters and hospitalizations among adults during periods of Delta and Omicron variant predominance—VISION Network, 10 states, August 2021–January 2022. MMWR Morb Mortal Wkly Rep. 2022;71(4):139-145. doi:10.15585/mmwr.mm7104e3Crossref
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Tseng  HF, Ackerson  BK, Luo  Y,  et al.  Effectiveness of mRNA-1273 against SARS-CoV-2 Omicron and Delta variants.   medRxiv. Preprint posted online February 18, 2022. doi:10.1101/2022.01.07.22268919 Google Scholar
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ICES. Home page. Accessed August 9, 2022. https://www.ices.on.ca/
18.
von Elm  E, Altman  DG, Egger  M, Pocock  SJ, Gøtzsche  PC, Vandenbroucke  JP; STROBE Initiative.  The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies.   PLoS Med. 2007;4(10):e296. doi:10.1371/journal.pmed.0040296 PubMedGoogle ScholarCrossref
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Government of Ontario. Updated eligibility for PCR testing and case and contact management guidance in Ontario. December 30, 2021. Accessed January 25, 2022. https://news.ontario.ca/en/backgrounder/1001387/updated-eligibility-for-pcr-testing-and-case-and-contact-management-guidance-in-ontario
20.
Skowronski  DM, Setayeshgar  S, Febriani  Y,  et al.  Two-dose SARS-CoV-2 vaccine effectiveness with mixed schedules and extended dosing intervals: test-negative design studies from British Columbia and Quebec, Canada.   medRxiv. Preprint posted online October 26, 2021. doi:10.1101/2021.10.26.21265397 Google Scholar
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Public Health Agency of Canada. Canadian COVID-19 vaccination coverage report. January 21, 2022. Accessed January 25, 2022. https://health-infobase.canada.ca/covid-19/vaccination-coverage/
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Chung  H, He  S, Nasreen  S,  et al; Canadian Immunization Research Network (CIRN) Provincial Collaborative Network (PCN) Investigators.  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.   BMJ. Published online August 20, 2021. doi:10.1136/bmj.n1943 PubMedGoogle ScholarCrossref
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Public Health Ontario. Coronavirus Disease 2019 (COVID-19)—variant of concern screening and whole genome sequencing surveillance. 2021. Accessed December 28, 2021. https://www.publichealthontario.ca/en/laboratory-services/test-information-index/covid-19-voc
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McGrath  JM. Here’s Ontario’s booster-shot plan. TVO Today. Accessed January 25, 2022. https://www.tvo.org/article/heres-ontarios-booster-shot-plan
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Government of Ontario. Ontario accelerating booster eligibility to adults aged 50+. December 2, 2021. Accessed January 25, 2022. https://news.ontario.ca/en/release/1001269/ontario-accelerating-booster-eligibility-to-adults-aged-50
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Government of Ontario. All Ontarians 18+ eligible for COVID-19 booster appointments at three-month interval. December 15, 2021. Accessed January 25, 2022. https://news.ontario.ca/en/release/1001352/all-ontarians-18-eligible-for-covid-19-booster-appointments-at-three-month-interval
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Kahn  R, Schrag  SJ, Verani  JR, Lipsitch  M.  Identifying and alleviating bias due to differential depletion of susceptible people in postmarketing evaluations of COVID-19 vaccines.   Am J Epidemiol. 2022;191(5):800-811. doi:10.1093/aje/kwac015 PubMedGoogle ScholarCrossref
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Statistics Canada. Dictionary, census population, 2016: visible minority. Accessed August 22, 2022. https://www12.statcan.gc.ca/census-recensement/2016/ref/dict/pop127-eng.cfm
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Gao  Y, Cai  C, Grifoni  A,  et al.  Ancestral SARS-CoV-2-specific T cells cross-recognize the Omicron variant.   Nat Med. 2022;28(3):472-476. doi:10.1038/s41591-022-01700-x PubMedGoogle ScholarCrossref
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Wu  M, Wall  EC, Carr  EJ,  et al.  Three-dose vaccination elicits neutralising antibodies against Omicron.   Lancet. 2022;399(10326):715-717. doi:10.1016/S0140-6736(22)00092-7 PubMedGoogle ScholarCrossref
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Garcia-Beltran  WF, St. Denis  KJ, Hoelzemer  A,  et al.  mRNA-based COVID-19 vaccine boosters induce neutralizing immunity against SARS-CoV-2 Omicron variant.   medRxiv. Preprint posted online December 14, 2021. doi:10.1101/2021.12.14.21267755Google Scholar
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Pfizer. Pfizer and BioNTech provide update on Omicron variant. December 8, 2021. Accessed December 22, 2021. https://www.pfizer.com/news/press-release/press-release-detail/pfizer-and-biontech-provide-update-omicron-variant
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Muik  A, Lui  BG, Wallisch  AK,  et al.  Neutralization of SARS-CoV-2 Omicron by BNT162b2 mRNA vaccine-elicited human sera.   Science. 2022;375(6581):678-680. doi:10.1126/science.abn7591 PubMedGoogle ScholarCrossref
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Redd  AD, Nardin  A, Kared  H,  et al.  Minimal cross-over between mutations associated with Omicron variant of SARS-CoV-2 and CD8+ T cell epitopes identified in COVID-19 convalescent individuals.   bioRxiv. Preprint posted online December 9, 2021. doi:10.1101/2021.12.06.471446 Google Scholar
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Lipsitch  M, Krammer  F, Regev-Yochay  G, Lustig  Y, Balicer  RD.  SARS-CoV-2 breakthrough infections in vaccinated individuals: measurement, causes and impact.   Nat Rev Immunol. 2022;22(1):57-65. doi:10.1038/s41577-021-00662-4 PubMedGoogle ScholarCrossref
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Accorsi  EK, Britton  A, Fleming-Dutra  KE,  et al.  Association between 3 doses of mRNA COVID-19 vaccine and symptomatic infection caused by the SARS-CoV-2 Omicron and Delta variants.   JAMA. 2022;327(7):639-651. doi:10.1001/jama.2022.0470 PubMedGoogle ScholarCrossref
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Glasziou  P, McCaffery  KJ, Cvejic  E,  et al.  Testing behaviour may bias observational studies of vaccine effectiveness.   medRxiv. Preprint posted online January 21, 2022. doi:10.1101/2022.01.17.22269450Google Scholar
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    Original Investigation
    Public Health
    September 22, 2022

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

    Author Affiliations
    • 1Public Health Ontario, Toronto, Ontario, Canada
    • 2ICES, Toronto, Ontario, Canada
    • 3Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada
    • 4Centre for Vaccine Preventable Diseases, University of Toronto, Toronto, Ontario, Canada
    • 5Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto, Ontario, Canada
    • 6School of Epidemiology and Public Health, University of Ottawa, Ottawa, Ontario, Canada
    • 7Children’s Hospital of Eastern Ontario Research Institute, Ottawa, Ontario, Canada
    • 8Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada
    • 9Center for Clinical Epidemiology and Population Health, Marshfield Clinic Research Institute, Marshfield, Wisconsin
    • 10Women’s College Hospital, Toronto, Ontario, Canada
    • 11Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada
    • 12Department of Medicine, University of Ottawa, Ottawa, Ontario, Canada
    • 13Bruyère Research Institute, Ottawa, Ontario, Canada
    • 14Ottawa Hospital Research Institute, Ottawa, Ontario, Canada
    • 15Department of Family and Community Medicine, University of Toronto, Toronto, Ontario, Canada
    • 16University Health Network, Toronto, Ontario, Canada
    JAMA Netw Open. 2022;5(9):e2232760. doi:10.1001/jamanetworkopen.2022.32760
    Key Points

    Question  What is the estimated effectiveness of COVID-19 vaccines for preventing symptomatic infections due to the Omicron and Delta variants and severe outcomes (hospitalization or death) associated with these infections?

    Findings  In this test-negative case-control study of 134 435 adults in Ontario, Canada, the estimated effectiveness of 2 doses of COVID-19 vaccine was high against symptomatic Delta infection and severe outcomes and was lower against symptomatic Omicron infection. After a third dose, estimated vaccine effectiveness against Omicron was 61% for symptomatic infection and 95% for severe outcomes.

    Meaning  The findings suggest that 3 doses of COVID-19 vaccine may protect against symptomatic Omicron infection and severe outcomes, but other measures are also likely needed to prevent Omicron infection.

    Abstract

    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.

    Introduction

    The World Health Organization declared Omicron a COVID-19 variant of concern on November 26, 2021, owing to its highly transmissible nature and risk of immune evasion.1 In Ontario, Canada, the first detected case of Omicron was identified on November 22, 2021; within weeks, Omicron accounted for most new cases. Despite high 2-dose COVID-19 vaccine coverage in Ontario (88% among individuals aged ≥18 years by mid-December 2021),2 the rate of cases among fully vaccinated individuals increased substantially during this period.3

    A reduction in neutralizing antibodies against Omicron following second and third doses of mRNA vaccines has been established,4-7 but clinical data evaluating vaccine performance are still emerging.8-16 The objective of this study was to estimate vaccine effectiveness (VE) against symptomatic infection due to the Omicron or Delta variants and severe outcomes (hospitalization or death) associated with these infections in Ontario.

    Methods
    Study Population, Setting, Design, and Data Sources

    In this case-control study, we used a test-negative study design and linked provincial databases in Ontario, Canada, to estimate VE. We linked provincial SARS-CoV-2 laboratory testing, reportable disease, COVID-19 vaccination, and health administrative databases using unique encoded identifiers and analyzed them at ICES, a not-for-profit provincial research institute.17 ICES is a prescribed entity under Ontario’s Personal Health Information Protection Act, section 45 of which authorizes ICES to collect personal health information without consent for analysis or compiling statistical information with respect to the management of, evaluation or monitoring of, allocation of resources to, or planning for all or part of the health system. Projects that use data collected by ICES under section 45 of the Personal Health Information Protection Act and use no other data are exempt from research ethics board review. The use of the data in this study was authorized under section 45 and was approved by the ICES Privacy and Legal Office. We followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline for case-control studies.18

    We included individuals in Ontario who had COVID-19 symptoms, were aged 18 years or older, had provincial health insurance, and had a SARS-CoV-2 real-time reverse transcription–polymerase chain reaction (PCR) test between December 6 and 26, 2021. Our study period aligned with a provincial initiative to universally screen positive specimens to differentiate Omicron and Delta cases and was before restrictions in laboratory-based PCR test eligibility announced on December 30, 2021.19 We excluded long-term care residents, individuals who had received only 1 dose or 4 doses of COVID-19 vaccine or who had received a second dose less than 7 days before being tested, individuals who tested positive for SARS-CoV-2 within the previous 90 days, individuals who had received 2 or 3 doses of ChAdOx1 vaccine (AstraZeneca) because estimated VE for that primary schedule is known to be lower and the product has rarely been used as a third dose,20 individuals who had received a vaccine not authorized by Health Canada for any dose, and individuals who had received the Ad.26.COV2.S vaccine (Janssen/Johnson & Johnson; although approved for use, <0.1% of the Ontario population received this vaccine21) (eFigure in the Supplement).

    Outcomes

    We identified individuals with confirmed SARS-CoV-2 infection using reportable disease and laboratory data. To estimate VE against symptomatic infection, we restricted our analysis to individuals who had at least 1 COVID-19–related symptom (self-reported or measured) at the time of testing, as identified in the laboratory testing data.22 The specimen collection date was used as the index date. We used reportable disease data to identify severe outcomes, defined as hospital admission or death. Public health units were directed to record hospitalizations and deaths associated with COVID-19 in the reportable disease system. For symptomatic individuals who tested negative for SARS-CoV-2 repeatedly during the study period and were considered controls (for both outcomes), we randomly selected 1 test with a negative result.

    Specimens positive for SARS-CoV-2 identified through whole genome sequencing as B.1.1.529 lineage or found to have S-gene target failure (SGTF; a proxy measure for Omicron, resulting from the amino acid 69-70 spike deletion that does not occur with Delta) were considered to be infected with Omicron. Specimens sequenced as B.1.617 lineage or found to be negative for SGTF were considered to be infected with Delta. Individuals with unknown or inconclusive SGTF results were excluded.23 Between December 6 and 24, 2021, all specimens with a positive PCR result (and a cycle threshold value ≤35) should have been sent for testing using ThermoFisher TaqPath COVID-19 PCR to identify SGTF; as such, we selected our primary study period to approximate the period of universal screening for SGTF. Before December 20, 2021, SGTF-positive specimens with cycle threshold values of 30 or less also underwent whole genome sequencing. In Ontario, the estimated sensitivity of SGTF compared with whole genome sequencing for detecting Omicron among samples with a cycle threshold value of 30 or less was 98.9%, and the specificity was 99.9%.23

    COVID-19 Vaccination

    To date, Ontario has primarily used 3 products (BNT162b2 [Pfizer-BioNTech], mRNA-1273 [Moderna], and ChAdOx1) in its COVID-19 vaccination program. Owing to fluctuating vaccine supply, varying dosing intervals and mixed vaccine schedules were used. We classified individuals based on the number of doses received and the timing of these doses relative to the index date. We included individuals who received at least 1 mRNA vaccine for the primary 2-dose series (because a mixed schedule consisting of ChAdOx1 and an mRNA vaccine was demonstrated to have similar estimated VE as 2 mRNA vaccines).20 For the third dose, we included individuals who received any mRNA vaccine and also stratified by the specific third-dose product. All comparisons included individuals who had not yet received any doses (ie, unvaccinated) by the index date as the reference group.

    Third-dose eligibility in Ontario began in August 2021 and expanded gradually.24 Initially, only moderately or severely immunocompromised individuals were eligible to receive a third dose as part of an extended primary series. Third doses (ie, boosters) were then provided to residents of higher-risk, congregate settings for older adults (eg, long-term care homes, high-risk retirement homes). In early October 2021, older adults living in other congregate care settings, including all remaining retirement homes, became eligible. All individuals aged 70 years or older and health care workers became eligible on November 6, 2021; individuals aged 50 years or older, on December 13, 2021; and those aged 18 years or older, on December 18, 2021.25 The standard interval for third-dose eligibility was generally 168 or more days following a second dose but was shortened to 84 or more days on December 15, 2021.26

    Covariates

    We obtained information on each individual’s age (in 10-year age bands); sex; public health unit region of residence; number of SARS-CoV-2 PCR tests during the 3 months before December 14, 2020 (as a proxy for health care worker status based on the start date of the provincial COVID-19 vaccine program); SARS-CoV-2 infection more than 90 days before the index date (to account for protection conferred from past infection)27; comorbidities associated with increased risk of severe COVID-19; influenza vaccination status during the 2019-2020 and/or 2020-2021 influenza seasons (as a proxy for health behaviors); and neighborhood-level information on median household income, proportion of the working population employed as nonhealth essential workers, mean number of persons per dwelling, and proportion of the population who self-identified as belonging to a visible minority group (non-Aboriginal peoples who are not White, consisting mainly of Arab, Black, Chinese, Filipino, Korean, Japanese, Latin American, South Asian, Southeast Asian, and West Asian groups).28 These data were included owing to potential confounding. These definitions and the databases used are described elsewhere.22

    Statistical Analysis

    We calculated means (continuous variables) and frequencies (categorical variables) of baseline characteristics and compared test-positive cases (separately for Omicron and Delta) with test-negative controls using standardized differences. We used multivariable logistic regression to estimate adjusted odds ratios (aORs) comparing the odds of vaccination in each time-since-second-or-third-dose interval among cases with the odds among controls while adjusting for all aforementioned covariates and a categorical variable representing the week of the test. Estimated VE was calculated using the formula VE = (1 – aOR) × 100%. We did not report VE estimates when the width of the 95% CI was 100 percentage points or greater.

    We performed a sensitivity analysis for severe outcomes using a less specific definition of Omicron infection to allow for a larger sample size. In this analysis, cases diagnosed from December 21, 2021, onward (when the prevalence of SGTF in the province was >90%) with no or inconclusive SGTF results were considered to be Omicron infection.

    All analyses were conducted using SAS, version 9.4 (SAS Institute Inc). All tests were 2-sided and used P < .05 as the level of statistical significance.

    Results

    Between December 6 and 26, 2021, the study population included 134 435 adults, of whom 16 087 were Omicron-positive cases (mean [SD] age, 36.0 [14.1] years; 8249 [51.3%] female; 7838 [48.7%] male), 4261 were Delta-positive cases (mean [SD] age, 44.2 [16.8] years; 2199 [51.6%] female; 2062 [48.4%] male), and 114 087 were test-negative controls (mean [SD] age, 42.0 [16.5] years; 67 884 [59.5%] female; 46 203 [40.5%] male). Compared with controls, Omicron cases were younger, more likely to be male, less likely to have any comorbidities, less likely to have received an influenza vaccine, less likely to have previously tested positive for SARS-CoV-2, and less likely to have received a third vaccine dose. Cases of Omicron infection were also more likely to have occurred during the last week of the study period compared with controls (Table 1).

    In contrast, Delta cases had some characteristics more similar to those of controls than to those of Omicron cases (eg, age, presence of comorbidities) and other characteristics more different from those of controls than those of Omicron cases, such as being more likely to be unvaccinated (Delta cases: 1251 [29.4%]; controls: 4681 [4.1%]; Omicron cases: 790 [4.9%]).

    In the Omicron VE analyses, vaccinated individuals (ie, 2 or 3 doses) were more likely to be older, female, influenza vaccine recipients, and residents of neighborhoods with higher income and fewer essential workers than were unvaccinated individuals (Table 2). Recipients of a third dose were more likely to have comorbidities and to have been tested in the last week of the study period. We observed similar patterns for individuals in the Delta VE analyses (eTable 1 in the Supplement).

    After 2 doses of COVID-19 vaccine (with at least 1 mRNA vaccine), estimated VE against symptomatic Delta infection decreased steadily over time from 89% (95% CI, 86%-92%) 7 to 59 days after a second dose to 80% (95% CI, 74%-84%) after 240 days or longer but increased to 97% (95% CI, 96%-98%) 7 or more days after a third dose (Table 3 and Figure, A). Estimated VE was lower against symptomatic Omicron infection compared with Delta infection for the entire period and waned more rapidly from 36% (95% CI, 24%-45%) 7 to 59 days after a second dose to 1% (95% CI, –8% to 10%) 180 to 239 days after a second dose. Estimated VE against symptomatic Omicron infection was 61% (95% CI, 56%-65%) 7 or more days after a third dose and was similar regardless of the mRNA product administered.

    Estimated VE was higher against severe outcomes compared with symptomatic infection and did not have the same degree of waning (Figure, B). Estimated VE was also higher against severe outcomes associated with Delta than with Omicron in the time following a second dose, but 95% CIs were wide for some Omicron estimates. Estimated VE against severe outcomes 7 or more days following a third dose was slightly higher for Delta (99%; 95% CI, 98%-99%) than for Omicron (95%; 95% CI, 87%-98%). Model estimates for VE against Omicron or Delta symptomatic infection or severe outcomes are provided in eTables 2 and 3 in the Supplement.

    When using a less specific definition for Omicron (eTable 4 in the Supplement), VE estimates against severe outcomes were higher and substantially more stable (eTable 5 in the Supplement).

    Discussion

    In Ontario, Canada, between December 6 and 26, 2021, we found the estimated effectiveness of 2 doses of COVID-19 vaccines against symptomatic infection to be substantially lower for Omicron than for Delta; estimated VE against symptomatic Omicron infection was minimal starting at 60 days after a second dose, and there was no significant protection beyond 180 days. However, the estimated VE against symptomatic Omicron infection was 61% at 7 or more days following a third dose. Against severe outcomes, including hospitalization and death, the estimated VE shortly following a third dose was slightly lower for Omicron than for Delta.

    Substantial waning of 2-dose VE against symptomatic infection was observed in England, with lower estimated VE against Omicron infection than Delta infection at each interval following 2 or 3 doses9,11; our results demonstrated a similar pattern, with a marked reduction in 2-dose (with at least 1 being an mRNA vaccine) and 3-dose estimated effectiveness against symptomatic Omicron infection compared with Delta infection. In data from the UK Health Security Agency, estimated VE against symptomatic Omicron infection after 2 doses of BNT162b2 or mRNA-1273 vaccine decreased to less than 20% starting at 20 weeks after a second dose.9 After a third dose of mRNA vaccine, estimated VE increased to approximately 60% to 75% during the first 4 weeks,9 consistent with our finding of 61% estimated VE 7 or more days after a third dose. Although the UK data suggest that waning VE also occurs after a third dose, insufficient time elapsed for enough third-dose recipients in Ontario to assess this in our study. In Scotland, a third dose was associated with a two-thirds reduction in the odds of symptomatic Omicron infection compared with the odds 25 or more weeks after a second dose in the early Omicron period.13

    Although prior studies have demonstrated reduced neutralizing antibodies against Omicron compared with other variants following receipt of 2 mRNA vaccine doses4,5,7,29,30 (but with potent neutralization following a third dose31-33), CD8+ cytotoxic T cells are less affected by sequence variations in the Omicron variant and likely continue to provide protection against severe disease.32,34 Emerging clinical data have demonstrated that vaccine protection is more preserved against severe outcomes than against infection in the Omicron era. In South Africa, estimated VE against hospitalization was 93% in the pre-Omicron period and 70% in the Omicron period.14 In England, estimated VE against hospitalization associated with Omicron also appeared to be better maintained compared with VE against symptomatic infection with Omicron.8,9,35 In an analysis of the BNT162b2, mRNA-1273, and ChAdOx1 vaccines, estimated VE against Omicron-related hospitalization decreased over time after a second dose but to a lesser extent than against symptomatic infection.9 After a third dose, estimated VE was restored to 85% to 95% during the first 3 months.9 In California, estimated VE against Omicron-related hospitalization was 89% in the first 3 months following 3 doses of the BNT162b2 vaccine.10 In another study in the US, 3-dose VE against hospitalization when Omicron was predominant was estimated at 90%.15 Our 3-dose VE estimates against severe outcomes were similar to these results from England and the US. Although our 2-dose estimates against severe Omicron-related outcomes were challenging to compare given the wide 95% CIs, they suggest less waning against hospitalization than has been observed elsewhere, and this finding is consistent with surveillance data in Ontario.36,37

    Direct comparisons with other jurisdictions are challenging38 owing to differences in study methods, outcome definitions (ie, identification of Omicron and Delta based on laboratory confirmation vs time-based criteria), intervals following the latest dose, vaccination policies (eg, homologous vs heterologous vaccine schedules, third-dose eligibility criteria, and product-specific policies [eg, use of mRNA vs viral vector vaccines and a preferential recommendation in Ontario for the BNT162b2 vaccine for young adults]),39 population age structures, public health measures implemented during the study period (eg, vaccine certificates, mask mandates40), testing patterns, and use of antivirals and other therapies. Furthermore, Ontario has experienced a lower cumulative incidence of reported infections and has attained higher vaccine coverage than other countries that have estimated VE against Omicron to date,41 and thus, it has a potentially dissimilar distribution of infection-induced vs vaccine-induced immunity.41,42 Despite this, the general trends across the studies are similar and suggest immune evasion, in particular in relation to infection, by Omicron.8-10,13,15,16,43

    Limitations

    This study has limitations. First, we were unable to differentiate individuals who received a third vaccine dose as part of an extended primary series (ie, severely or moderately immunocompromised individuals) as well as individuals at higher risk for infection and severe infection who were eligible for a third dose earlier (eg, residents of retirement homes). Because third-dose eligibility did not expand to all adults until mid-December 2021, a proportion of third-dose recipients in this study may reflect these populations that were at higher risk; thus, our 3-dose VE estimates may be lower than what would be expected for the general population. Third-dose eligibility and timing of primary series completion may have resulted in differing characteristics of individuals by interval since last dose. Second, not all specimens were screened for SGTF owing to the rapid increase in case volumes and eligibility criteria for screening, and whole genome sequencing results identified during our study period may not have been available at the time of analysis owing to processing delays. In a sensitivity analysis for severe outcomes, we obtained higher VE estimates when we classified all cases after a certain date as Omicron. However, this less specific outcome may overestimate VE if there was differential misclassification of the variant based on vaccination status (ie, if Delta circulated at a higher level in unvaccinated individuals, VE would be overestimated). Third, changes in testing patterns, including increased use of rapid antigen tests (which were not captured in our data) and decreased PCR testing availability, may have impacted our estimates, but the direction of any resulting bias is uncertain. However, if vaccinated individuals were more likely than unvaccinated individuals to be tested, VE would be underestimated.44 Fourth, symptom information was not available for all laboratories submitting to Ontario’s centralized system; as such, symptomatic individuals who were tested but did not have this information recorded would have been excluded from our study.22 Fifth, we were unable to estimate VE for extended periods following a third dose. Sixth, there may be residual confounding that was not accounted for in our analysis. This includes an inability to control for previous undocumented infections, which may have been differential by vaccination status, and confounding due to behavioral patterns.

    Conclusions

    In this test-negative case-control study, estimated VE was high against symptomatic Delta infection and severe outcomes after 2 doses of COVID-19 vaccine but was lower and more short term against symptomatic Omicron infection and 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 associated with both variants. These results suggest that a third vaccine dose is important to bolster protection against both Omicron infection and severe outcomes associated with Omicron infection, although the duration of this protection is uncertain. Our work adds to a rapidly evolving body of evidence that suggests that vaccine-induced protection depends on a variety of factors—in particular, time since latest dose and circulating variant. Tools beyond the currently available vaccines, such as public health measures, antivirals or other therapies, and new formulations of COVID-19 vaccines, are likely needed to prevent Omicron infection, although protection against severe outcomes appears to be maintained with current vaccines.

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    Article Information

    Accepted for Publication: July 19, 2022.

    Published: September 22, 2022. doi:10.1001/jamanetworkopen.2022.32760

    Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2022 Buchan SA et al. JAMA Network Open.

    Corresponding Author: Jeffrey C. Kwong, MD, ICES, G1 06, 2075 Bayview Ave, Toronto, ON M4N 3M5, Canada (jeff.kwong@utoronto.ca).

    Author Contributions: Ms Chung and Dr Kwong had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

    Concept and design: Buchan, Chung, Brown, Fell, Schwartz, Kwong.

    Acquisition, analysis, or interpretation of data: Buchan, Chung, Austin, Fell, Gubbay, Nasreen, Schwartz, Sundaram, Tadrous, K. Wilson, S.E. Wilson, Kwong.

    Drafting of the manuscript: Buchan, Chung, Kwong.

    Critical revision of the manuscript for important intellectual content: Chung, Brown, Austin, Fell, Gubbay, Nasreen, Schwartz, Sundaram, Tadrous, K. Wilson, S.E. Wilson, Kwong.

    Statistical analysis: Chung, Brown.

    Obtained funding: Fell, Kwong.

    Administrative, technical, or material support: Buchan, Schwartz, Sundaram.

    Supervision: Brown, Kwong.

    Conflict of Interest Disclosures: Dr Buchan reported receiving grants from the Canadian Institutes of Health Research and the Public Health Agency of Canada during the conduct of the study. Dr Austin reported being supported by a Mid-Career Investigator Award from the Heart and Stroke Foundation. Dr Gubbay reported being a consultant scientific editor for the Global Infectious Diseases Epidemiology Online Network. Dr Sundaram reported receiving grants from GSK outside the submitted work. Dr K. Wilson reported being the chief executive officer and cofounder of CANImmunize Inc, being a member of the independent data monitoring committee of Medicago, and serving on the data safety board for the Medicago COVID-19 vaccine trial outside the submitted work. Dr S. E. Wilson reported receiving grants from the Public Health Agency of Canada COVID-19 Immunity Task Force and the Canadian Immunization Research Network during the conduct of the study. Dr Kwong reported receiving grants from the Public Health Agency of Canada and the Canadian Institutes of Health Research during the conduct of the study and being supported by a Clinician-Scientist Award from the University of Toronto Department of Family and Community Medicine. No other disclosures were reported.

    Funding/Support: This work was supported by the Canadian Immunization Research Network (CIRN) through grant CNF 151944 from the Public Health Agency of Canada and the Canadian Institutes of Health Research and CITF-VSRG-01 from the Public Health Agency of Canada through the Vaccine Surveillance Reference Group and the COVID-19 Immunity Task Force. This study was also supported by ICES (which is funded by an annual grant from the Ontario Ministry of Health [MOH] and the Ministry of Long-Term Care [MLTC]), Public Health Ontario, and the Ontario Health Data Platform (OHDP), a Province of Ontario initiative to support Ontario’s ongoing response to COVID-19 and its related impacts. Parts of this study were based on data and/or information compiled and provided by the Canadian Institute for Health Information (CIHI) and by Ontario Health (OH).

    Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

    Disclaimer: The analyses, conclusions, opinions, and statements expressed herein are solely those of the authors and do not reflect those of the funding or data sources. No endorsement by ICES, the MOH, the MLTC, the OHDP, or their partners; the Province of Ontario; the CIHI; or OH is intended or should be inferred.

    Additional Contributions: Public Health Ontario provided access to vaccination data from COVaxON, case-level data from the Public Health Case and Contact Management System (CCM), and COVID-19 laboratory data as well as assistance with data interpretation. The staff of Ontario’s public health units were responsible for COVID-19 case and contact management and data collection within the CCM. IQVIA Solutions Canada Inc permitted use of its Drug Information File. The CIRN provided networking support. We thank the Ontario residents, without whom this research would be impossible.

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