Prior infection- and/or vaccine-induced protection against Omicron BA.1, BA.2 and BA.4/BA.5-related hospitalisations in older adults: a test-negative case-control study in Quebec, Canada (preprint)

Background. Due to severe outcomes, elderly adults 60 years or older are prioritized for COVID-19 vaccination but accumulated SARS-CoV-2 infection and vaccination likely modifies their risk. We estimated vaccine effectiveness against omicron-associated hospitalisation among elderly adults, by number of doses, prior infection history and time since last immunological event. Methods. We conducted a test-negative case-control study among symptomatic elderly adults tested for SARS-CoV-2 in Quebec, Canada during BA.1-, BA.2- and BA.4/5-dominant periods. Relative to unvaccinated, infection-naive participants, we compared COVID-19 hospitalisation risk by mRNA vaccine dose and/or prior infection (pre-omicron or omicron) history. Findings. During BA.1, BA.2 and BA.4/5 periods, two- vs. four-dose vaccine effectiveness alone against hospitalisation was: 78% (95%CI:75-80) vs. 96% (95%CI:93-98); 60% (95%CI:50-97) vs. 84% (95%CI:81-87); and 40% (95%CI:30-49) vs. 68% (95%CI:63-72), respectively, consistent with longer median time since second vs fourth dose. By respective period, effectiveness of pre-omicron vs. omicron infection alone against hospitalisation was: 93% (95%CI:80-97) vs. [not estimable]; 88% (95%CI:50-97) vs. 96% (95%CI:68-99); and 69% (95%CI:30-85) vs. 90% (95%CI:79-95). Regardless of doses (2-5) or prior infection type, hybrid protection was [≥]90%, lasting at least 6-8 months during the BA.4/5 period. Prior omicron infection alone reduced BA.4/5 hospitalisation risk by >80% for at least 6-8 months. Interpretation. Elderly adults with history of both prior SARS-CoV-2 infection and [≥]2 vaccine doses appear well-protected for a prolonged period against omicron hospitalisation, including BA.4/5. Ensuring infection-naive older adults remain up-to-date with vaccination may further reduce COVID-19 hospitalisations most efficiently. Funding. Ministere de la Sante et des Services sociaux du Quebec.

Impact of a vaccine passport on first-dose COVID-19 vaccine coverage by age and area-level social determinants in the Canadian provinces of Quebec and Ontario: an interrupted time series analysis (preprint)

Background: In Canada, all provinces implemented vaccine passports in 2021 to increase vaccine uptake and reduce transmission in non-essential indoor spaces. We evaluate the impact of vaccine passport policies on first-dose COVID-19 vaccination coverage by age, area-level income and proportion racialized. Methods: We performed interrupted time-series analyses using vaccine registry data linked to census information in Quebec and Ontario (20.5 million people [≥]12 years; unit of analysis: dissemination area). We fit negative binomial regressions to weekly first-dose vaccination, using a natural spline to capture pre-announcement trends, adjusting for baseline vaccination coverage (start: July 3rd; end: October 23rd Quebec, November 13th Ontario). We obtain counterfactual vaccination rates and coverage, and estimated vaccine passports' impact on vaccination coverage (absolute) and new vaccinations (relative). Results: In both provinces, pre-announcement first-dose vaccination coverage was 82% ([≥]12 years). The announcement resulted in estimated increases in vaccination coverage of 0.9 percentage points (p.p.;95% CI: 0.4-1.2) in Quebec and 0.7 p.p. (95% CI: 0.5-0.8) in Ontario. In relative terms, these increases correspond to 23% (95% CI: 10-36%) and 19% (95% CI: 15-22%) more vaccinations. The impact was larger among people aged 12-39 (1-2 p.p.). There was little variability in the absolute impact by area-level income or proportion racialized in either province. Conclusions: In the context of high baseline vaccine coverage across two provinces, the announcement of vaccine passports led to a small impact on first-dose coverage, with little impact on reducing economic and racial inequities in vaccine coverage. Findings suggest the need for other policies to further increase vaccination coverage among lower-income and more racialized neighbourhoods and communities.

Protection against Omicron BA.2 reinfection conferred by primary Omicron or pre-Omicron infection with and without mRNA vaccination (preprint)

BackgroundWe estimated the protection against the Omicron BA.2 variant associated with prior primary infection (PI) due to pre-Omicron or Omicron BA.1 virus, with and without mRNA vaccination. MethodsA test-negative case-control study was conducted among healthcare workers (HCWs) tested for SARS-CoV-2 in Quebec, Canada, between March 27 and June 4, 2022, when BA.2 predominated and was presumptively diagnosed. Logistic regression models compared the likelihood of BA.2 reinfection (second positive test [≥]30 days after PI) among HCWs with history of PI and none to three doses of mRNA vaccine versus infection-naive, unvaccinated HCWs. FindingsAmong 37,732 presumed BA.2 cases, 2,521 (6.7%) and 659 (1.7%) were reinfections following pre-Omicron or BA.1 PI, respectively. Among 73,507 controls, 7,360 (10.0%) and 12,315 (16.8%) had a pre-Omicron or BA.1 PI, respectively. Pre-Omicron PI was associated with 38% (95%CI:19-53) reduction in BA.2 infection risk, with higher BA.2 protection among those also vaccinated with one (56%), two (69%) or three (70%) vaccine doses. Omicron BA.1 PI was associated with greater protection against BA.2 (72%; 95%CI:65-78), higher among two-dose vaccinated at 96% (95%CI:95-96) but not improved with a third dose (96%; 95%CI:95-97). Hybrid Omicron BA.1 PI plus two or three dose vaccine-induced protection persisted for five months post-infection. InterpretationTwice-vaccinated individuals who experienced BA.1 infection were subsequently well-protected for a prolonged period against BA.2 reinfection and derived no meaningful added benefit against BA.2 from a third dose of mRNA vaccine.

Protection against Omicron re-infection conferred by prior heterologous SARS-CoV-2 infection, with and without mRNA vaccination (preprint)

Importance. Omicron is phylogenetically- and antigenically-distinct from earlier SARS-CoV-2 variants and the original vaccine strain. Protection conferred by prior SARS-CoV-2 infection against Omicron re-infection, and the added value of vaccination, require quantification. Objective. To estimate protection against Omicron re-infection and hospitalization conferred by prior heterologous SARS-CoV-2 (non-Omicron) infection and/or up to three doses of (ancestral, Wuhan-like) mRNA vaccine. Design. Test-negative study between December 26 (epi-week 52), 2021 and March 12 (epi-week 10), 2022. Setting. Population-based, province of Quebec, Canada Participants. Community-dwelling [≥]12-year-olds tested for SARS-CoV-2. Exposures. Prior laboratory-confirmed infection with/without mRNA vaccination. Outcomes. Laboratory-confirmed SARS-CoV-2 re-infection and hospitalization, presumed Omicron by genomic surveillance. The odds of prior non-Omicron infection with/without vaccination were compared among Omicron cases/hospitalizations versus test-negative controls (single randomly-selected per individual). Adjusted odds ratios controlled for age, sex, testing-indication and epi-week. Analyses were stratified by severity and time since last non-Omicron infection or vaccine dose. Results. Without vaccination, prior non-Omicron infection reduced the Omicron re-infection risk by 44% (95%CI:38-48), decreasing from 66% (95%CI:57-73) at 3-5 months to 35% (95%CI:21-47) at 9-11 months post-infection and <30% thereafter. The more severe the prior infection, the greater the risk reduction: 8% (95%CI:17-28), 43% (95%CI:37-49) and 68% (95%CI:51-80) for prior asymptomatic, symptomatic ambulatory or hospitalized infections. mRNA vaccine effectiveness against Omicron infection was consistently significantly higher among previously-infected vs. non-infected individuals at 65% (95%CI:63-67) vs. 20% (95%CI:16-24) for one-dose; 68% (95%CI:67-70) vs. 42% (95%CI:41-44) for two doses; and 83% (95%CI:81-84) vs. 73% (95%CI:72-73) for three doses. Infection-induced protection against Omicron hospitalization was 81% (95%CI: 66-89) increasing to 86% (95%CI:77-99) with one, 94% (95%CI:91-96) with two and 97%(95%CI:94-99) with three mRNA vaccine doses. Two-dose effectiveness against hospitalization among previously-infected individuals did not wane across 11 months and did not significantly differ from three-dose effectiveness despite longer follow-up (median 158 and 27 days, respectively). Conclusions and relevance. Prior heterologous SARS-CoV-2 infection provided substantial and sustained protection against Omicron hospitalization, greatest among those also vaccinated. In the context of program goals to prevent severe outcomes and preserve healthcare system capacity, >2 doses of ancestral Wuhan-like vaccine may be of marginal incremental value to previously-infected individuals.

Mortality trends and lengths of stay among hospitalized COVID-19 patients in Ontario and Quebec (Canada): a population-based cohort study of the first three epidemic waves (preprint)

BackgroundEpidemic waves of COVID-19 strained hospital resources. We describe temporal trends in mortality risk and length of stay in intensive cares units (ICUs) among COVID-19 patients hospitalized through the first three epidemic waves in Canada. MethodsWe used population-based provincial hospitalization data from Ontario and Quebec to examine mortality risk and lengths of ICU stay. For each province, adjusted estimates were obtained using marginal standardization of logistic regression models, adjusting for patient-level characteristics and hospital-level determinants. ResultsUsing all hospitalizations from Ontario (N=26,541) and Quebec (N=23,857), we found that unadjusted in-hospital mortality risks peaked at 31% in the first wave and was lowest at the end of the third wave at 6-7%. This general trend remained after controlling for confounders. The odds of in-hospital mortality in the highest hospital occupancy quintile was 1.2 (95%CI: 1.0-1.4; Ontario) and 1.6 (95%CI: 1.3-1.9; Quebec) times that of the lowest quintile. Variants of concerns were associated with an increased in-hospital mortality. Length of ICU stay decreased over time from a mean of 16 days (SD=18) to 15 days (SD=15) in the third wave but were consistently higher in Ontario than Quebec by 3-6 days. ConclusionIn-hospital mortality risks and lengths of ICU stay declined over time in both provinces, despite changing patient demographics, suggesting that new therapeutics and treatment, as well as improved clinical protocols, could have contributed to this reduction. Continuous population-based monitoring of patient outcomes in an evolving epidemic is necessary for health system preparedness and response.

Time trends in social contacts of individuals according to comorbidity and vaccination status, before and during the COVID-19 pandemic: repeated cross-sectional population-based surveys (preprint)

Objectives: To describe time trends in social contacts of individuals according to comorbidity and vaccination status before and during the first three waves of the COVID-19 pandemic in Quebec, Canada. Design: Repeated cross-sectional population-based surveys. Setting: General population. Participants: Non-institutionalized adults from Quebec, Canada, recruited by random digit dialling before (2018/2019) and during the pandemic (April 2020 to July 2021). A total of 1441 and 5185 participants with and without comorbidities, respectively, were included in the analyses. Main outcome measures: Number of social contacts (two-way conversation at a distance [≤]2 meters or a physical contact, irrespective of masking) documented in a self-administered web-based questionnaire. We compared the mean number of contacts according to the comorbidity status of participants (pre-existing medical conditions with symptoms/medication in the past 12 months) and 1-dose vaccination status during the third wave. All analyses were performed using weighted generalized linear models with a Poisson distribution and robust variance. Results: Contacts significantly decreased from a mean of 6.1 (95% confidence interval 4.9 to 7.3) before the pandemic to 3.2 (2.5 to 3.9) during the first wave among individuals with comorbidities, and from 8.1 (7.3 to 9.0) to 2.7 (2.2 to 3.2) among individuals without comorbidities. Individuals with comorbidities maintained fewer contacts than those without comorbidities in the second wave, with a significant difference before the Christmas 2020/2021 holidays (2.9 (2.5 to 3.2) v 3.9 (3.5 to 4.3); P<0.001). During the third wave, contacts were similar for individuals with (4.1, 3.4 to 4.7) and without comorbidities (4.5, 4.1 to 4.9; P=0.27). This could be partly explained by individuals with comorbidities vaccinated with their first dose who increased their contacts to the level of those without comorbidities. Conclusions: The lower level of contacts maintained by individuals with comorbidities could have influenced the burden of hospitalisations and deaths of the second wave in Quebec. It will be important to closely monitor COVID-19-related outcomes and social contacts by comorbidity and vaccination status to inform targeted or population-based interventions.

Two-dose SARS-CoV-2 vaccine effectiveness with mixed schedules and extended dosing intervals: test-negative design studies from British Columbia and Quebec, Canada (preprint)

Background The Canadian COVID-19 immunization strategy deferred second doses and allowed mixed schedules. We compared two-dose vaccine effectiveness (VE) by vaccine type (mRNA and/or ChAdOx1), interval between doses, and time since second dose in two of Canada's larger provinces. Methods Two-dose VE against infections and hospitalizations due to SARS-CoV-2, including variants of concern, was assessed between May 30 and October 2, 2021 using test-negative designs separately conducted among community-dwelling adults [≥]18-years-old in British Columbia (BC) and Quebec, Canada. Findings In both provinces, two doses of homologous or heterologous SARS-CoV-2 vaccines were associated with ~95% reduction in the risk of hospitalization. VE exceeded 90% against SARS-CoV-2 infection when at least one dose was an mRNA vaccine, but was lower at ~70% when both doses were ChAdOx1. Estimates were similar by age group (including adults [≥]70-years-old) and for Delta-variant outcomes. VE was significantly higher against both infection and hospitalization with longer 7-8-week vs. manufacturer-specified 3-4-week interval between doses. Two-dose mRNA VE was maintained against hospitalization for the 5-7-month monitoring period and while showing some decline against infection, remained [≥]80%. Interpretation Two doses of mRNA and/or ChAdOx1 vaccines gave excellent protection against hospitalization, with no sign of decline by 5-7 months post-vaccination. A 7-8-week interval between doses improved VE and may be optimal in most circumstances. Findings indicate prolonged two-dose protection and support the use of mixed schedules and longer intervals between doses, with global health, equity and access implications in the context of recent third-dose proposals.

Time trends in social contacts before and during the COVID-19 pandemic: the CONNECT study (preprint)

ABSTRACT Background: Since the beginning of the Covid-19 pandemic, many countries, including Canada, have adopted unprecedented physical distancing measures such as closure of schools and non-essential businesses, and restrictions on gatherings and household visits. We described time trends in social contacts for the pre-pandemic and pandemic periods in Quebec, Canada. Methods: CONNECT is a population-based study of social contacts conducted shortly before (2018/2019) and during the Covid-19 pandemic (April 2020 to February 2021), using the same methodology for both periods. We recruited participants by random-digit-dialing and collected data by self-administered web-based questionnaires. Questionnaires documented socio-demographic characteristics and social contacts for two assigned days. A contact was defined as a two-way conversation at a distance [≤]2 meters or as a physical contact, irrespective of masking. We used weighted generalized linear models with a Poisson distribution and robust variance (taking possible overdispersion into account) to compare the mean number of social contacts over time by characteristics. Results: A total of 1291 and 5516 Quebecers completed the study before and during the pandemic, respectively. Contacts significantly decreased from a mean of 8 contacts/day prior to the pandemic to 3 contacts/day during the spring 2020 lockdown. Contacts remained lower than the pre-Covid period thereafter (lowest=3 contacts/day during the Christmas 2020/2021 holidays, highest=5 in September 2020). Contacts at work, during leisure activities/other locations, and at home with visitors showed the greatest decreases since the beginning of the pandemic. All sociodemographic subgroups showed significant decreases of contacts since the beginning of the pandemic. Conclusion: Physical distancing measures in Quebec significantly decreased social contacts, which most likely mitigated the spread of Covid-19.

Geographical concentration of COVID-19 cases by social determinants of health in 16 large metropolitan areas in Canada - a cross-sectional study (preprint)

Background: There is a growing recognition that strategies to reduce SARS-CoV-2 transmission should be responsive to local transmission dynamics. Studies have revealed inequalities along social determinants of health, but little investigation was conducted surrounding geographic concentration within cities. We quantified social determinants of geographic concentration of COVID-19 cases across sixteen census metropolitan areas (CMA) in four Canadian provinces. Methods: We used surveillance data on confirmed COVID-19 cases at the level of dissemination area. Gini (co-Gini) coefficients were calculated by CMA based on the proportion of the population in ranks of diagnosed cases and each social determinant using census data (income, education, visible minority, recent immigration, suitable housing, and essential workers) and the corresponding share of cases. Heterogeneity was visualized using Lorenz (concentration) curves. Results: Geographic concentration was observed in all CMAs (half of the cumulative cases were concentrated among 21-35% of each city's population): with the greatest geographic heterogeneity in Ontario CMAs (Gini coefficients, 0.32-0.47), followed by British Columbia (0.23-0.36), Manitoba (0.32), and Quebec (0.28-0.37). Cases were disproportionately concentrated in areas with lower income, education attainment, and suitable housing; and higher proportion of visible minorities, recent immigrants, and essential workers. Although a consistent feature across CMAs was concentration by proportion visible minorities, the magnitude of concentration by social determinants varied across CMAs. Interpretation: The feature of geographical concentration of COVID-19 cases was consistent across CMAs, but the pattern by social determinants varied. Geographically-prioritized allocation of resources and services should be tailored to the local drivers of inequalities in transmission in response to SARS-CoV-2's resurgence.

Single-dose mRNA vaccine effectiveness against SARS-CoV-2 in healthcare workers extending 16 weeks post-vaccination: a test-negative design from Quebec, Canada (preprint)

IntroductionIn Canada, first and second doses of mRNA vaccines against SARS-CoV-2 were uniquely spaced 16 weeks apart, but the duration of single-dose protection remains uncertain. We estimated one- and two-dose mRNA vaccine effectiveness (VE) among healthcare workers (HCWs) in Quebec, Canada including protection against varying outcome severity, variants of concern (VOC), and the stability of single-dose protection out to 16 weeks post-vaccination. MethodsA test-negative design compared vaccination among SARS-CoV-2 test-positive and weekly-matched (10:1), randomly-sampled, test-negative HCWs using linked surveillance and immunization databases. Vaccine status was defined by one dose [≥]14 days or two doses [≥]7 days before illness onset or specimen collection. Adjusted VE was estimated by conditional logistic regression. ResultsPrimary analysis included 5,316 cases and 53,160 controls. Single-dose VE was 70% (95%CI: 68-73) against SARS-CoV-2 infection, 73% (95%CI: 71-75) against COVID-19 illness and 97% (95%CI: 92-99) against associated hospitalization. Two-dose VE was 86% (95%CI: 81-90) and 93% (95%CI: 89-95), respectively, with no associated hospitalizations. VE was higher for non-VOC than VOC (73% Alpha) among single-dose (77%, 95%CI: 73-81 versus 63%, 95%CI: 57-67) but not two-dose recipients (87%, 95%CI: 57-96 versus 94%, 95%CI: 89-96). Across 16 weeks, no decline in single-dose VE was observed with appropriate stratification based upon prioritized vaccination determined by higher versus lower likelihood of direct patient contact. ConclusionOne mRNA vaccine dose provided substantial and sustained protection to HCWs extending at least four months post-vaccination. In circumstances of vaccine shortage, delaying the second dose may be a pertinent public health strategy to consider.

Global impact and cost-effectiveness of one-dose versus two-dose human papillomavirus vaccination schedules: a comparative modelling analysis (preprint)

Background To eliminate cervical cancer as a public health problem, the World Health Organization currently recommends routine vaccination of adolescent girls with two doses of the human papillomavirus (HPV) vaccine before sexual initiation. However, many countries have yet to implement HPV vaccination because of financial or logistical barriers to delivering two doses outside the infant immunisation programme. Methods Using three independent HPV transmission models, we estimated the long-term health benefits and cost-effectiveness of one-dose versus two-dose HPV vaccination, in 188 countries, assuming that one dose of the vaccine gives either a shorter duration of full protection (20 or 30 years) or lifelong protection but lower vaccine efficacy (e.g., 80%) compared to two doses. We simulated routine vaccination with the 9-valent HPV vaccine in 10-year-old girls at 80% coverage for the years 2021–2120, with a one-year catch-up campaign of 11–14-year-old girls at 80% coverage in the first year of the programme. Results Over the years 2021–2120, one-dose vaccination at 80% coverage was projected to avert 112.9 million (range of medians: 75.8–176.2) and 148.0 million (111.6–187.6) cervical cancer cases assuming one dose of the vaccine confers 20 and 30 years of protection, respectively. Should one dose of the vaccine provide lifelong protection at 80% vaccine efficacy, 155.2 million (143.7–170.3) cervical cancer cases could be prevented. Around 65 to 889 additional girls would need to be vaccinated with the second dose to prevent one cervical cancer case, depending on the epidemiological profiles of the country. Across all income groups, the threshold cost for the second dose was low: from 0.85 (0.07–3.82) USD in low-income countries to 18.08 (−3.62–85.64) USD in high-income countries, assuming one-dose confers 30-year protection. Conclusions Results: were consistent across the three independent models and suggest that one-dose vaccination has similar health benefits to a two-dose programme while simplifying vaccine delivery, reducing costs, and alleviating vaccine supply constraints. The second dose may be cost-effective if there is a shorter duration of protection from one dose, cheaper vaccine and vaccination delivery strategies, and high burden of cervical cancer.

Importation of SARS-CoV-2 following the "semaine de relache" and Quebec's (Canada) COVID-19 burden - a mathematical modeling study (preprint)

Background: The Canadian epidemics of COVID-19 exhibit distinct early trajectories, with Quebec bearing a very high initial burden. The semaine de relache, or March break, took place two weeks earlier in Quebec as compared to the rest of Canada. This event may have played a role in the spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We aimed to examine the role of case importation in the early transmission dynamics of SARS-CoV-2 in Quebec. Methods: Using detailed surveillance data, we developed and calibrated a deterministic SEIR-type compartmental model of SARS-CoV-2 transmission. We explored the impact of altering the number of imported cases on hospitalizations. Specifically, we investigated scenarios without case importation after March break, and as scenarios where cases were imported with the same frequency/timing as neighboring Ontario. Results: A total of 1,544 and 1,150 returning travelers were laboratory-confirmed in Quebec and Ontario, respectively (with symptoms onset before 2020-03-25). The cumulative number of hospitalizations could have been reduced by 55% (95% credible interval [95%CrI]: 51-59%) had no cases been imported after Quebec's March break. However, had Quebec experienced Ontario's number of imported cases, cumulative hospitalizations would have only been reduced by 12% (95%CrI: 8-16%). Interpretation: Our results suggest that case importation played an important role in the early spread of COVID-19 in Quebec. Yet, heavy importation of SARS-CoV-2 in early March could be insufficient to resolve interprovincial heterogeneities in cumulative hospitalizations. The importance of other factors -public health preparedness, responses, and capacity- should be investigated.