key: cord-0992379-2ixzxc94
authors: Grewal, R.; Kitchen, S. A.; Nguyen, L.; Buchan, S. A.; Wilson, S. E.; Costa, A. P.; Kwong, J. C.
title: Effectiveness of a Fourth Dose of COVID-19 Vaccine among Long-Term Care Residents in Ontario, Canada
date: 2022-04-18
journal: nan
DOI: 10.1101/2022.04.15.22273846
sha: ccbbeb16f8de508cf8cc851edaeb4e5c75235304
doc_id: 992379
cord_uid: 2ixzxc94

Background: As of December 30, 2021, Ontario long-term care (LTC) residents who received a third dose of COVID-19 vaccine [≥]84 days previously were offered a fourth dose to prevent a surge in COVID-19-related morbidity and mortality due to the Omicron variant. Methods: We used a test-negative design and linked databases to estimate the marginal effectiveness (4 versus 3 doses) and vaccine effectiveness (VE; 2, 3, or 4 doses versus no doses) of mRNA vaccines among Ontario LTC residents aged [≥]60 years who were tested for SARS-CoV-2 between December 30, 2021 and March 2, 2022. Outcome measures included any Omicron infection, symptomatic infection, and severe outcomes (hospitalization or death). Results: We included 9,957 Omicron cases and 46,849 test-negative controls. The marginal effectiveness of a fourth dose [≥]7 days after vaccination versus a third dose received [≥]84 days prior was 40% (95% Confidence Interval[CI], 34-45%) against infection, 63% (95%CI, 51-71%) against symptomatic infection, and 54% (95%CI, 31-70%) against severe outcomes. VE (compared to an unvaccinated group) increased with each additional dose, and for a fourth dose was 65% (95%CI, 60-70%), 87% (95%CI, 81-91%), and 92% (95%CI, 87-95%), against infection, symptomatic infection, and severe outcomes, respectively. Conclusions: Our findings suggest that compared to a third dose received [≥]84 days ago, a fourth dose recommendation for LTC residents improved protection against infection, symptomatic infection, and severe outcomes caused by Omicron. Compared to unvaccinated individuals, fourth doses provide strong protection against symptomatic infection and severe outcomes but the duration of protection remains unknown.

Residents of long-term care (LTC) facilities are at high risk of SARS-CoV-2 infection and severe outcomes for a range of reasons including risk of exposure due to their reliance on care from others within a congregate living setting, underlying comorbidities that increase the risk of clinical severity if infected, and age-related changes in the immune system (immunosenescence) that may impact the response to COVID-19 vaccines. 1, 2 In Ontario, Canada, LTC residents have been disproportionately affected by the COVID-19 pandemic, accounting for nearly two-thirds of deaths during the first two waves. 2 The arrival of COVID-19 vaccines drastically improved outcomes for LTC residents, with an 89% relative reduction in infections and 96% reduction in mortality compared to unvaccinated control populations within 8 weeks. 3 However, the effectiveness of a 2-dose primary series declines over time, and the emergence of new variants of concern (VOC) led to increased breakthrough infections and deaths. [4] [5] [6] [7] [8] [9] [10] On August 17, 2021, Ontario began offering third (first booster) doses to LTC residents.

The arrival of the Omicron variant in November 2021 raised significant concerns for the LTC population, with early evidence suggesting increased transmissibility, greater risk of reinfection, and reduced vaccine protection against Omicron compared to previous VOCs. [11] [12] [13] Additionally, susceptibility increased due to partial immune evasion by Omicron and waning immunity following third doses. 12, 14 To mitigate another surge in COVID-19-related morbidity and mortality, Ontario began offering fourth (second booster) doses on December 30, 2021 to LTC residents who had received their third dose 3 months (≥84 days) prior. 12 The preferred product was a 100mcg dose of mRNA-1273 (Moderna Spikevax). 12 Other jurisdictions have subsequently recommended fourth (second booster) doses for their LTC populations. Although evidence from Israel suggests that fourth doses compared to third doses provide additional protection against SARS-CoV-2 infection and severe COVID-19 among older adults, findings have been limited to the BNT162b2 (Pfizer-BioNTech Comirnaty) vaccine, 15, 16 . 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 18, 2022. ;  https://doi.org/10.1101/2022.04. 15.22273846 doi: medRxiv preprint and no studies to date have reported both marginal effectiveness and vaccine effectiveness (VE) of fourth doses in the LTC population.

The objectives of this study were: 1) to estimate the marginal effectiveness of a fourth dose of mRNA COVID-19 vaccine relative to a third dose received ≥ 84 days prior; and 2) to estimate VE of varying numbers of doses relative to an unvaccinated group. For both objectives, we examined SARS-CoV-2 infection, symptomatic infection, and severe outcomes among Ontario LTC residents.

We used a test-negative design and linked provincial databases to estimate marginal effectiveness and . 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 18, 2022. ; https://doi.org/10.1101/2022.04.15.22273846 doi: medRxiv preprint positive predictive value, and 99.7% negative predictive value. 20 If laboratory screening information was unavailable, we assumed cases were Omicron unless they were confirmed as B.1.617.2 (Delta).

We excluded Delta cases that were identified based on WGS or SGTF.

We linked provincial SARS-CoV-2 laboratory testing, COVID-19 vaccination, and health administrative datasets (Table S1) using unique encoded identifiers and analyzed them at ICES (formerly the Institute for Clinical Evaluative Sciences).

We created cohorts for three outcomes: any infection (SARS-CoV-2-positive individuals, irrespective of symptoms), symptomatic infection (individuals with ≥ 1 symptom consistent with COVID-19 disease that was recorded in the Ontario Laboratories Information System (OLIS) when tested [details on determinization of symptom status are available in Table S2 ]; many symptomatic, tested individuals may have been excluded because symptom information was not recorded in OLIS for various reasons), and severe outcomes (those with a recent positive test who were hospitalized or died). Individuals who tested positive at least once during the study period were considered cases and those testing negative throughout the study period were considered controls. Among cases with multiple occurrences of the same outcome, we selected the first occurrence. For controls, we randomly selected 1 negative test during the study period. For the infection outcomes, the index date was the date of specimen collection, and for severe outcomes, the index date was the earliest of specimen collection date, hospitalization, or death.

We used a centralized province-wide vaccine registry to identify receipt of COVID-19 vaccines. We classified LTC residents based on the number of doses received. We stratified groups based on time . 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 18, 2022 

From various databases described previously (Table S1 ), 22 we obtained information on each person's age, sex, public health unit region of residence, week of test, whether they had a SARS-CoV-2 infection >90 days prior, and whether there was an active SARS-CoV-2 outbreak in their LTC facility.

We calculated means (continuous variables) and frequencies (categorical variables) and compared testnegative controls to test-positive Omicron cases using standardized differences. We also compared individuals vaccinated with a third dose ≥ 84 days prior to their index test to those who received no doses, 1 dose, 2 doses, 3 doses <84 days prior, 4 doses <7 days prior, or 4 doses ≥ 7 days prior.

We used multivariable logistic regression to estimate odds ratios comparing the odds of vaccination among cases with the odds of vaccination among controls, while adjusting for covariates.

We used the formula 1-ORx100% to estimate marginal effectiveness and VE.

In the primary analysis for marginal effectiveness, we compared the effectiveness <7 days and ≥ 7 days after a fourth dose to a third dose received ≥ 84 days prior, and included all covariates listed above except LTC facility outbreak. We conducted several secondary analyses: 1) adjusted for LTC facility outbreaks; 2) stratified by LTC facility outbreaks; 3) used a third dose received <84 days prior as the comparator (i.e., non-exposed) group; and 4) removed LTC facilities with ≥ 10% residents classified as unvaccinated to assess the impact of potential misclassification of vaccination status (e.g., due to incomplete reporting to the provincial vaccine registry) in these facilities.

. 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 18, 2022. ; https://doi.org/10.1101/2022.04. 15.22273846 doi: medRxiv preprint In the primary analysis for VE, we estimated the effectiveness of 2, 3, or 4 doses compared to unvaccinated individuals using the same covariates as the marginal effectiveness analysis. We also estimated VE for the most frequently reported vaccine product combinations among those who received a third dose (there was not enough variability by product to explore this for fourth doses): 1) 3 doses of mRNA-1273; 2) 3 doses of BNT162b2; and 3) 2 doses of BNT162b2 followed by mRNA-1273. In Ontario, for booster doses of mRNA-1273, a 100mcg dose is recommended for LTC residents or older adults in other congregate settings and community-dwelling individuals aged ≥ 70 years (50mcg is recommended for most other groups). 23 All analyses were conducted using SAS Version 9.4 (SAS Institute Inc., Cary, NC). All tests were 2-sided and we used a statistical significance level of p<0.05.

Section 45 of PHIPA authorizes ICES to collect personal health information, without consent, for the purpose of analysis or compiling statistical information with respect to the management of, evaluation or monitoring of, the allocation of resources to or planning for all or part of the health system. Projects 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 18, 2022. ; https://doi.org/10.1101/2022.04.15.22273846 doi: medRxiv preprint (69.2%) and controls (69.2%) had only received a third dose, and a greater proportion of controls (21.1%) than cases (14.7%) had received a fourth dose (Table 1 ). More cases resided in a facility with an active outbreak (64.0%) than controls (55.8%) and fewer had a prior positive SARS-CoV-2 test >90 days ago (7.7%) compared to controls (16.1%). We observed few differences between residents who received a third dose ≥ 84 days ago and residents who received a fourth dose (Table 2 ). Residents who received fewer doses were younger (Tables S3 and S4 ).

Relative to individuals who received a third dose ≥ 84 days prior to testing, the marginal effectiveness of a fourth dose was 40% (95% Confidence Interval[CI] 34-45%) against infection, 63%

(95%CI 51-71%) against symptomatic infection, and 54% (95%CI 31-70%) against severe outcomes ≥ 7 days following vaccination; estimates were lower <7 days since a fourth dose ( Figure 1 , Table S5 ).

Adjustment for outbreaks did not change estimates, whereas estimates for symptomatic infection and severe outcomes were higher when there was no outbreak compared to when facilities were experiencing an outbreak (Table S6 ). The marginal effectiveness of a fourth dose was lower for those who had a third dose <84 days prior to testing versus ≥ 84 days ago ( Figure S1 , Table S5 ). The estimates were similar when we removed LTC facilities with >10% unvaccinated residents (Table S7 ).

Compared to unvaccinated individuals, VE increased with each additional dose of vaccine but was lower for those whose third dose was ≥ 84 days prior to testing compared to those who received a third dose more recently (Figure 2 , 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 18, 2022. ; https://doi.org/10.1101/2022.04.15.22273846 doi: medRxiv preprint vaccination to testing was shorter for the latter (Table 3) . VE was lower among individuals who received 3 doses of BNT162b2. Almost all LTC residents (97%) who received a fourth dose received mRNA-1273.

In this study of LTC residents, we found that compared to a third mRNA dose received There are few studies exploring the effect of fourth doses. In Israel, among adults aged ≥ 60 years, the marginal effectiveness against any infection 7-13 days after a fourth dose versus a third dose of BNT162b2 received ≥ 4 months earlier was 46%, peaking 21-27 days after vaccination at 64%. 16 The marginal effectiveness against severe disease was 73% 7-27 days following a fourth dose and was highest 49-69 days after vaccination at 86%. 16 Similar to our study, there was considerable additional protection against infection and severe disease with a fourth dose relative to a third dose, though findings cannot be directly compared due to differences in study design, outcome definitions, population characteristics, settings, vaccine products, and dosing intervals. Very few individuals (3%) in the Israeli study were nursing home residents. 16 We observed a rise in VE with each dose for all outcomes, complementing the marginal differences observed between a third and fourth dose. VE was 23 percentage points higher against any . 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.

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important since the consequences of infection, including extended social isolation, risk of developing severe disease, and mortality, are higher compared to the general population. 1, 2, 24 Although the difference in VE against severe outcomes was lower at 10 percentage points (92% versus 82%), given the high baseline incidence of severe outcomes in this population, 25 suggest that effectiveness of fourth doses of BNT162b2 against infection may wane faster than third doses, but similar to third doses, there is a lower degree of waning against severe disease. 15, 16 Canadian studies have found that immune protection among LTC residents wanes much faster than younger, healthier adults after 2 doses; similar patterns may be expected for booster doses. 28, 29 Studies from the United Kingdom (UK) among adults suggest similar levels of protection from a third dose of either mRNA vaccine against symptomatic Omicron infection irrespective of the mRNA product used for the primary series. 13, 26 Among adults aged ≥ 65 years in the UK, VE against hospitalization was also similar for a third dose of either mRNA vaccine following 2 doses of BNT162b2. 30 We found that among Ontario LTC residents, a third dose of mRNA-1273 after a homologous 2-dose primary series of either mRNA vaccine was more effective against all outcomes than 3 doses of BNT162b2. For those receiving a primary course of BNT162b2 with an mRNA-1273 booster, the time between vaccination and testing was shorter compared to the other schedules, making it difficult to determine the relative impact of the booster product versus the shorter time period.

. 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 18, 2022 Additionally, as previously mentioned, a 100mcg dose of mRNA-1273 is recommended for LTC residents in Ontario for boosters, 12, 23 whereas most other jurisdictions (e.g., the UK 31 ) use a 50mcg dose for boosters, which may have influenced our findings.

This study has some limitations. First, our symptomatic cohort was limited to individuals who had symptoms recorded in OLIS and therefore may be incomplete. Second, Ontario laboratories discontinued routine SGTF screening of all positive samples on December 30, 2021, therefore there may be some misclassification of Delta cases as Omicron, potentially inflating VE. Nonetheless, it is unlikely this would significantly impact our estimates since the prevalence of Delta in Ontario was very low during our study period. Third, we classified outbreaks at the facility level since we did not have data on whether the outbreak was on a resident's floor or if it was more contained, therefore we may have overestimated the impact of outbreaks at the person level. Finally, we did not have access to LTC staff vaccination records. Staff vaccination strongly influences SARS-CoV-2 transmission in LTC facilities. 32 At the time of this study, all LTC staff in Ontario were required to be vaccinated with 2 doses, 33 but 2-dose VE against Omicron infection is low. 13, 27, 34 Although a mandate for required third doses was also implemented, staff had until March 14, 2022 (past our study period) to comply (though this may not have been enforced since the province shifted from a provincial LTC vaccination mandate to supporting employer-led policies on the same day). 33

Our findings indicate that a fourth dose of a COVID-19 mRNA vaccine (97% received mRNA-1273) 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 18, 2022. ; https://doi.org/10.1101/2022.04.15.22273846 doi: medRxiv preprint physical distancing may help optimize protection against SARS-CoV-2 for this highly vulnerable population.

The dataset 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 prespecified 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.

We would like to acknowledge Public Health Ontario for access to vaccination data from COVaxON, case-level data from CCM and COVID-19 laboratory data, as well as assistance with data interpretation. We also thank the staff of Ontario's public health units who are responsible for COVID-19 case and contact management and data collection within CCM. We thank IQVIA Solutions Canada Inc. for use of their Drug Information Database. The authors are grateful to the Ontario residents without whom this research would be impossible.

. 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 18, 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 18, 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 18, 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 18, 2022 is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)

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Risk factors for severity of COVID-19: a rapid review to inform vaccine prioritisation in Canada

Canadian Institute for Health Information. The Impact of COVID-19 on Long-Term Care in Canada: Focus on the First 6 Months. Ottawa, ON: CIHI

Early impact of Ontario's COVID-19 vaccine rollout on long-term care home residents and health care workers. Science Briefs of the Ontario COVID-19 Science Advisory Table

Neutralizing antibody responses to SARS-CoV-2 variants in vaccinated Ontario long-term care home residents and workers. medRxiv

Reduced BNT162b2 mRNA vaccine response in SARS-CoV-2-naive nursing home residents

Adverse outcomes associated with Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) variant B.1.351 infection in vaccinated residents of a long-term care home

COVID-19) outbreak associated with Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) P.1 lineage in a long-term care home after implementation of a vaccination program -Ontario

Effectiveness of mRNA BNT162b2 vaccine 6 months after vaccination among patients in large health maintenance organization

Effectiveness of Pfizer-BioNTech and Moderna vaccines in preventing SARS-CoV-2 infection among nursing home residents before and during widespread circulation of the SARS-CoV-2 B.1.617.2 (Delta) variant -National Healthcare Safety Network

Antibody responses 3-5 months post-vaccination with mRNA-1273 or BNT163b2 in nursing home residents

Relative instantaneous reproduction number of Omicron SARS-CoV-2 variant with respect to the Delta variant in Denmark

Recommendations: Fourth COVID-19 Vaccine Dose for Long-Term Care Home Residents and Older Adults in Congregate Settings

Covid-19 vaccine effectiveness against the Omicron (B.1.1.529) variant

Striking antibody evasion manifested by the Omicron variant of SARS-CoV-2

Protection by a fourth dose of BNT162b2 against Omicron in Israel

Relative effectiveness of four doses compared to three dose of the BNT162b2 vaccine in Israel

Government of Canada

Ontario Agency for Health Protection and Promotion (Public Health Ontario)

COVID-19 Variant of Concern Omicron (B.1.1.529): Risk Assessment

SARS-CoV-2 (COVID-19 Virus) Variant of Concern (VoC) Screening and Genomic Sequencing for Surveillance. Public Health Ontario. Last Updated

SARS-CoV-2 neutralization with BNT162b2 vaccine dose 3

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

Ontario Ministry of Health. COVID-19 Vaccine Third Dose and Booster Recommendations. Ontario, Canada: Government of Ontario

Excess mortality in long-term care residents with and without personal contact with family or friends during the COVID-19 pandemic

Efficacy of a fourth dose of Covid-19 mRNA vaccine against Omicron

COVID-19 Vaccine Surveillance Report: Week 12. United Kingdom: UK Health and Security Agency

Effectiveness of mRNA-1273 against SARS-CoV-2 Omicron and Delta variants

Protecting Canada's Long-Term Care Residents from COVID-19: The Evidence Behind the Policies. Canada: COVID-19 Immunity Task Force

Safety and efficacy of preventative COVID vaccines: The StopCoV Study

Effectiveness of COVID-19 vaccines against Omicron and Delta hospitalisation: test negative case-control study

JCVI statement regarding a COVID-19 booster vaccine programme for winter 2021 to 2022

Male sex