key: cord-0809756-bsiwkixj
authors: Fisman, D.; Tuite, A.
title: Progressive Increase in Virulence of Novel SARS-CoV-2 Variants in Ontario, Canada, February to June, 2021
date: 2021-07-07
journal: nan
DOI: 10.1101/2021.07.05.21260050
sha: fdde307f8146abc985a580270ee201fa78981d02
doc_id: 809756
cord_uid: bsiwkixj

The period from February to June 2021 was one during which initial wild-type SARS-CoV-2 strains were supplanted in Ontario, Canada, first by variants of concern (VOC) with the N501Y mutation (principally alpha, beta and gamma variants), and then by the delta variant. We demonstrate that these emerging VOCs were associated with an increase in virulence, as measured by risk of hospitalization, intensive care unit admission, and death. Compared to non-VOC SARS-CoV-2 strains, and adjusting for comorbidity, age and sex of cases, and temporal trends, the elevation in risk associated with N501Y-positive variants was 74% (62-86%) for hospitalization; 138% (105-176%) for ICU admission; and 83% (57-114%) for death. Increases with delta variant were even larger: 105% (80-133%) for hospitalization; 241% (163-344%) for ICU admission; and 121% (57-211%) for death. The progressive increase in transmissibility and virulence of SARS-CoV-2 variants will result in a significantly larger, and more deadly, pandemic.

Novel SARS-CoV-2 variants of concern (VOC), including viral strains carrying the N501Y and/or E484K mutations, were first identified in Ontario, Canada in December 2020 1 This serial replacement by emerging variants reflects progressively higher effective reproduction numbers which allow novel variants to outcompete previously dominant strains in the face of identical disease control interventions 4 . However, VOCs are also concerning because of an apparent increase in virulence, with increased risk of hospitalization, intensive care unit admission and death, after adjustment for age and other predictive factors [5] [6] [7] [8] . Although the increased virulence of strains with the N501Y mutation relative to strains which lack this mutation has been described [5] [6] [7] , only limited information is available on the virulence of infection with the delta variant, relative to earlier N501Y-positive variants (e.g., alpha, beta, and gamma variants) 8 . We sought to use Ontario's COVID-19 case data to evaluate the virulence of N501Y-positive variants relative to earlier SARS-CoV-2 strains, and also to evaluate the virulence of the delta variant of SARS-CoV-2 relative to N501Y-positive variants of concern.

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We created a retrospective cohort of people in Ontario testing positive for SARS-CoV-2 and screened for variants of concern, with dates of case report between February 3 and July 1, 2021.

Case information was extracted from the Ontario provincial Case and Contact Management (CCM) database as described elsewhere 9 . Although VOC cases were identified in Ontario beginning in December 2020, systematic screening was not implemented until Initially all specimens with the N501Y and/or E484K mutation and Ct value < 30 were sequenced; however, as of June 2021 routine WGS was no longer performed on specimens without E484K. By late April 2021, more than 90% of infections in Ontario were screen positive for N501Y( Figure 1 ); subsequently, N501Y mutations became less common, and N501Ynegative specimens subjected to WGS were demonstrated to be predominantly delta variant, with delta representing > 60% of new infections in Ontario on July 1, 2021 2, 3 . Analyses were restricted to individuals with infection episode dates from February 3, 2021 onwards, whose viral isolate had been screened for a VOC. Cases were classified as N501Y-positive (screening positive for N501Y or identified as alpha, beta, or gamma by WGS), probable delta variant (identified by WGS or negative for N501Y after May 1, 2021), or not VOC (all remaining . 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 July 7, 2021. ; https://doi.org/10.1101/2021.07.05.21260050 doi: medRxiv preprint cases). Individuals for whom VOC screening information was not available (N = 33,694), or for whom screening could not be completed (N = 13,841) were excluded from the analysis. We further restricted our analysis to individuals without a record of long-term care residence, as the epidemiology and severity of SARS-CoV-2 infection in long-term care home residents have been distinct in Ontario 10, 11 .

We constructed multivariable logistic regression models with hospitalization, intensive care admission, and death as dependent variables. Models adjusted for age (by 10-year increments), male sex, time (modeled as a week-on-week linear trend), documented major comorbidity (including documented asthma, COPD, hematological disease, liver disease, cardiac disease, diabetes, immune compromise, renal disease, neurological disease, or malignancy).

Hospitalization and ICU models were also adjusted for pregnancy, which was excluded from models evaluating death due to the rarity of fatalities among pregnant individuals. Due to geographic variation in prevalence of variants, health units were included as indicator variables.

In a separate analysis, we explored the apparent linear increase in virulence from non-VOC to N501Y-positive VOC to delta variant by modeling this progression as a 3-level ordinal variable.

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We included 216,678 cases in our analysis, with episode dates between February 3 and June 27, 2021. Changes over time in incidence of infections by VOC status, and in incidence of infections resulting in ICU admission, are presented in Figure 1 . Among all infections, 77%

were infections with N501Y-positive VOC; 2.2% were classified as probable delta variant infections. In crude comparisons, there were significant differences between variants in probability of hospitalization and ICU; individuals with N501Y-positive variants and probable delta infection were significantly younger and less likely to have comorbidities than individuals with non-VOC infections; VOC infections were more common in the Greater Toronto and Hamilton area (GTHA, the province's largest metropolitan area) than in the province as a whole; delta variant infections were less common in Ottawa (the province's second largest metropolitan area) than in the province as a whole ( Table 1) .

After adjustment for age, sex, comorbidities, and temporal trend, large and significant increases in the risk of hospitalization, ICU admission, and death were seen with both N501Y-positive VOC, and probable delta variant infections, relative to non-VOC ( Table 2) . Increases were larger with delta variant infection than with N501Y-positive VOC, with a relative increase in risk of hospitalization, ICU admission and death of 54%, 91% and 65%, respectively ( Table 3) .

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The emergence of novel SARS-CoV-2 variants of concern has slowed progress against the pandemic in three distinct ways: (i) by increasing transmissibility and the disease's reproduction number; (ii) by increasing immune escape and diminishing vaccine effectiveness; and (iii) by increasing the virulence of SARS-CoV-2 infection. Credible reports of enhanced virulence of VOC with the N501Y mutation have emerged over the past several months 5-7 , but to our knowledge this is one of the first analyses to demonstrate enhanced virulence of the delta variant 8 .

We show that in the Canadian province of Ontario, VOCs with the N501Y mutation were associated with a markedly increased risk of hospitalization, intensive care unit admission and death among infected individuals, but that the delta variant, which is now supplanting these other VOCs in Ontario, has increased these risks even further. Individuals infected with VOCs were, on average, younger and less likely to have comorbid conditions than those infected with non-VOC, but nonetheless had higher crude risks of hospitalization and ICU admission. Once we adjusted for confounding factors such as age, comorbidity, and temporal trends, elevated perinfection risk, including risk of death, remained markedly higher with VOCs, and with delta in particular. Indeed, given the relatively small number of delta infections in our time series, it is remarkable that a clear and significant elevation of risk of even uncommon, delayed outcomes, such as death, is readily visible in our analysis.

Canada is now one of the most widely vaccinated countries in the world with respect to SARS-CoV-2, and this vaccination has undoubtedly blunted the impact of emergence of these VOCs.

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A key limitation of our dataset is that it lacks data on individual-level vaccination status. We are indirectly modeling the impact of vaccination for prevention of severe illness by incorporating a linear trend term in our model. We do likely see a countervailing effect of vaccination in our data with a week-on-week reduced risk of hospitalization, ICU admission and death of approximately 2%, 4% and 6%, respectively. Inasmuch as SARS-CoV-2 vaccines in use in Canada appear to diminish the severity of infection even when vaccine fails to prevent infection, the differences in virulence we report here are most likely to represent a lower bound. This diminution of apparent effect is likely exacerbated by our likely having misclassified early delta variant infections as non-VOC due to the absence of routine screening for characteristic delta mutations; in other words, our estimates of excess risk for delta are likely biased towards the null.

In summary, we demonstrate that in the Canadian province of Ontario, despite widespread vaccination and VOC infections occurring more frequently in younger and healthier individuals, VOCs are associated with a substantial increase in virulence, including increased risk of death.

The emerging delta variant is more virulent than previously dominant N501Y-positive VOCs .

Combined with increased transmissibility and immune escape, these VOCs represent a significant escalation in risk to public health during the SARS-CoV-2 pandemic.

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The copyright holder for this preprint this version posted July 7, 2021. Cases of SARS-CoV-2 infection (left) and ICU admission (right) in Ontario, Canada by episode onset date (February 3 to June 27, 2021). Most infections during this period were with N501Y-positive variants of concern (VOC) (red); serial strain replacement occurred during this period with N501Y-positive VOCs supplanting non-VOC infections (blue), before increasingly being supplanted by probable delta VOC infections (green).

COVID-19 hospitalizations, ICU admissions and deaths associated with the new variants of concern

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

genome-sequencing-episummary.pdf?sc_lang=en. Last accessed

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

Epidemiologic summary: Estimating the prevalence and growth of SARS-CoV-2 variants in Ontario using mutation profiles

Estimated transmissibility and impact of SARS

CoV-2 lineage B.1.1.7 in England. Science

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

Risk of hospitalisation associated with infection with SARS-CoV-2 lineage B.1.1.7 in Denmark: an observational cohort study

Characteristics of SARS-CoV-2 variants of concern

1.351 or P.1: data from seven EU/EEA countries, weeks 38/2020 to 10/2021

demographics, risk of hospital admission, and vaccine effectiveness

COVID-19 Case-Age Distribution: Correction for Differential Testing by Age

For-profit long-term care homes and the risk of COVID-19 outbreaks and resident deaths

Risk Factors

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