Timing and Predictors of Loss of Infectivity among Healthcare Workers with Primary and Recurrent COVID-19: a Prospective Observational Cohort Study (preprint)

Background: There is a need to understand the duration of infectivity of primary and recurrent COVID-19 and identify predictors of loss of infectivity. Methods: Prospective observational cohort study with serial viral culture, rapid antigen detection test (RADT) and RT-PCR on nasopharyngeal specimens of healthcare workers with COVID-19. The primary outcome was viral culture positivity as indicative of infectivity. Predictors of loss of infectivity were determined using multivariate regression model. The performance of the US CDC criteria (fever resolution, symptom improvement and negative RADT) to predict loss of infectivity was also investigated. Results: 121 participants (91 female [79.3%]; average age, 40 years) were enrolled. Most (n=107, 88.4%) had received [≥]3 SARS-CoV-2 vaccine doses, and 20 (16.5%) had COVID-19 previously. Viral culture positivity decreased from 71.9% (87/121) on day 5 of infection to 18.2% (22/121) on day 10. Participants with recurrent COVID-19 had a lower likelihood of infectivity than those with primary COVID-19 at each follow-up (day 5 OR, 0.14; p<0.001]; day 7 OR, 0.04; p=0.003]) and were all non-infective by day 10 (p=0.02). Independent predictors of infectivity included prior COVID-19 (adjusted OR [aOR] on day 5, 0.005; p=0.003), a RT-PCR Ct value <23 (aOR on day 5, 22.75; p<0.001), but not symptom improvement or RADT result. The CDC criteria would identify 36% (24/67) of all non-infectious individuals on Day 7. However, 17% (5/29) of those meeting all the criteria had a positive viral culture. Conclusions: Infectivity of recurrent COVID-19 is shorter than primary infections. Loss of infectivity algorithms could be optimized.

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.

Humoral responses against BQ.1.1 elicited after breakthrough infection and SARS-CoV-2 mRNA vaccination (preprint)

The Omicron BQ.1.1 variant is now the major SARS-CoV-2 circulating strain in many countries. Because of the many mutations present in its Spike glycoprotein, this variant is resistant to humoral responses elicited by monovalent mRNA vaccines. With the goal to improve immune responses against Omicron subvariants, bivalent mRNA vaccines have recently been approved in several countries. In this study, we measure the capacity of plasma from vaccinated individuals, before and after a fourth dose of mono- or bivalent mRNA vaccine, to recognize and neutralize the ancestral (D614G) and the BQ.1.1 Spikes. Before and after the fourth dose, we observe a significantly better recognition and neutralization of the ancestral Spike. We also observe that fourth-dose vaccinated individuals who have been recently infected recognize and neutralize better the BQ.1.1 Spike, independently of the mRNA vaccine used, than donors who have never been infected or have an older infection. Our study supports that hybrid immunity, generated by vaccination and a recent infection, induces higher humoral responses than vaccination alone, independently of the mRNA vaccine used.

Seroprevalence, seroconversion, and seroreversion of infection-induced SARS-CoV-2 antibodies among a cohort of children and adolescents in Montreal, Canada (preprint)

Importance: Repeated serological testing for SARS-CoV-2 allows the monitoring of antibody dynamics in populations, including detecting infections that are missed by RT-PCR or antigen testing. Understanding the factors associated with seroconversion and seroreversion as well as the duration of infection-induced antibodies can also inform public health recommendations regarding disease prevention and mitigation efforts. Objective: To use serological testing to assess the prevalence, seroconversion, and seroreversion of infection-induced SARS-CoV-2 antibodies in children and adolescents in Montreal, Canada. Design: This analysis reports on three rounds of data collection from a prospective cohort study (Enfants et COVID-19: Etude de seroprevalence [EnCORE]). The study rounds occurred as follows: Round 1 October 2020-March 2021, Round 2 May to July 2021, and Round 3 November 2021 to January 2022. Most Round 3 samples were collected prior to the spread of the Omicron BA.1 variant in Quebec. Setting: Population-based sample. Participants: Children and adolescents aged 2 to 17 years in Montreal, Canada. Exposure: Potential exposure to SARS-CoV-2. Main Outcomes and Measures: Participants provided dried blood spots (DBS) for antibody detection and parents completed online questionnaires for sociodemographics and COVID-19 symptoms and testing history. The serostatus of participants was determined by enzyme-linked immunosorbent assays (ELISAs) using the receptor-binding domain (RBD) from the spike protein and the nucleocapsid protein (N) as antigens. We estimated seroprevalence for each round of data collection and by participant and household characteristics. Seroconversion rates were calculated as were the likelihoods of remaining seropositive at six months and one year. Results: The study included DBS samples from 1 632, 936, and 723 participants in the first, second, and third rounds of data collection, respectively. The baseline seroprevalence was 5.8% (95% CI 4.8-7.1), which increased to 10.5% and 10.9% for the respective follow-ups (95% CI 8.6-12.7; 95% CI 8.8-13.5). The overall average crude rate of seroconversion over the study period was 12.7 per 100 person-years (95% CI 10.9-14.5). Adjusted hazard rates of seroconversion by child and household characteristics showed higher rates in children who were female, whose parent identified as a racial or ethnic minority, and in households with incomes less than 100K. The likelihood of remaining seropositive at six months was 67% (95% CI 59-76) and dropped to 19% (95% CI 11%-33%) at one year. Conclusions and Relevance: The data reported here provide estimates of pre-Omicron seroprevalence, seroconversion rates and time to seroreversion in a population-based cohort of children and adolescents. Serological studies continue to provide valuable contributions for infection prevalence estimates and help us better understand the dynamics of antibody levels following infection. Continued study of seroconversion and seroreversion can inform public health recommendations such as COVID-19 vaccination and booster schedules.

SARS-CoV-2 BA.4/5 Spike recognition and neutralization elicited after the third dose of mRNA vaccine (preprint)

The SARS-CoV-2 Omicron BA.4 and BA.5 subvariants have recently emerged, with BA.5 becoming the dominant circulating strain in many countries. Both variants share the same Spike glycoprotein sequence which contains a large number of mutations, raising concerns about vaccine efficacy. In this study, we evaluated the ability of plasma from a cohort of individuals that received three doses of mRNA vaccine to recognize and neutralize the BA.4/5 Spike. We observed that BA.4/5 Spike is markedly less recognized and neutralized compared to the D614G and Omicron BA.2 Spike variants. Individuals who have been infected before or after vaccination present better humoral responses than SARS-CoV-2 naive vaccinated individuals, thus indicating that hybrid immunity generates better humoral responses against this subvariant.

BNT162b2 effectiveness against Delta & Omicron variants in teens by dosing interval and duration (preprint)

Background and Objectives Two- and three-dose BNT162b2 (Pfizer-BioNTech) mRNA vaccine effectiveness (VE) against SARS-CoV-2 infection, including Delta and Omicron variants, was assessed among adolescents in two Canadian provinces where first and second doses were spaced longer than the manufacturer-specified 3-week interval. Methods Test-negative design estimated VE against laboratory-confirmed SARS-CoV-2 infection among adolescents 12-17 years old in Quebec and British Columbia, Canada between September 5, 2021 (epi-week 36), and April 30, 2022 (epi-week 17). Delta-dominant and Omicron-dominant periods spanned epi-weeks 36-47 and 51-17, respectively. VE was assessed from 14 days and explored by interval between first and second doses, time since second dose, and with administration of a third dose. Results Median first-second dosing-interval was ~8 weeks and second-third dosing-interval was ~28-31 weeks. Median follow-up post-second-dose was ~10-11 weeks for Delta-dominant and ~21-22 weeks for Omicron-dominant periods, and ~3-9 weeks post-third dose. VE against Delta was [≥]90% to at least the 5th month post-second dose. VE against Omicron declined from ~65-75% at 2-3 weeks to [≤]50% by the 3rd month post-vaccination, restored to ~60-65% shortly following a third dose. VE exceeded 90% against Delta regardless of dosing-interval but appeared improved against Omicron with [≥]8 weeks between first and second doses. Conclusion In adolescents, two BNT162b2 doses provided strong and sustained protection against Delta but reduced and rapidly-waning VE against Omicron. Longer interval between first and second doses and a third dose improved Omicron protection. Updated vaccine antigens, increased doses and/or dosing-intervals may be needed to improve adolescent VE against immunological-escape variants.

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.

A boost with SARS-CoV-2 BNT162b2 mRNA vaccine elicits strong humoral responses independently of the interval between the first two doses (preprint)

SUMMARY Due to the recrudescence of SARS-CoV-2 infections worldwide, mainly caused by Omicron BA.1 and BA.2 variants of concern, several jurisdictions are administering a mRNA vaccine boost. Here, we analyzed humoral responses induced after the second and third doses of mRNA vaccine in naïve and previously-infected donors who received their second dose with an extended 16-week interval. We observed that the extended interval elicited robust humoral responses against VOCs, but this response was significantly diminished 4 months after the second dose. Administering a boost to these individuals brought back the humoral responses to the same levels obtained after the extended second dose. Interestingly, we observed that administering a boost to individuals that initially received a short 3-4 weeks regimen elicited humoral responses similar to those elicited in the long interval regimen. Nevertheless, humoral responses elicited by the boost in naïve individuals did not reach those present in previously-infected vaccinated individuals.

Effectiveness of COVID-19 vaccines against hospitalization and death in Canada: A multiprovincial test-negative design study (preprint)

ABSTRACT Background A major goal of COVID-19 vaccination is to prevent severe outcomes (hospitalizations and deaths). We estimated the effectiveness of mRNA and ChAdOx1 COVID-19 vaccines against severe outcomes in four Canadian provinces between December 2020 and September 2021. Methods We conducted this multiprovincial retrospective test-negative study among community-dwelling adults aged ≥18 years in Ontario, Quebec, British Columbia, and Manitoba using linked provincial databases and a common study protocol. Multivariable logistic regression was used to estimate province-specific vaccine effectiveness against COVID-19 hospitalization and/or death. Estimates were pooled using random effects models. Results We included 2,508,296 tested subjects, with 31,776 COVID-19 hospitalizations and 5,842 deaths. Vaccine effectiveness was 83% after a first dose, and 98% after a second dose, against both hospitalization and death (separately). Against severe outcomes (hospitalization or death), effectiveness was 87% (95%CI: 71%–94%) ≥84 days after a first dose of mRNA vaccine, increasing to 98% (95%CI: 96%–99%) ≥112 days after a second dose. Vaccine effectiveness against severe outcomes for ChAdOx1 was 88% (95%CI: 75%–94%) ≥56 days after a first dose, increasing to 97% (95%CI: 91%–99%) ≥56 days after a second dose. Lower one-dose effectiveness was observed for adults aged ≥80 years and those with comorbidities, but effectiveness became comparable after a second dose. Two doses of vaccines provided very high protection for both homologous and heterologous schedules, and against Alpha, Gamma, and Delta variants. Conclusions Two doses of mRNA or ChAdOx1 vaccines provide excellent protection against severe outcomes of hospitalization and death.

Immunogenicity of Pfizer-BioNTech COVID-19 mRNA Primary Vaccination Series in Recovered Individuals Depends on Symptoms at Initial Infection (preprint)

ABSTRACT Importance Public health vaccination recommendations for COVID-19 primary series and boosters in previously infected individuals differ worldwide. As infection with SARS-CoV-2 is often asymptomatic, it remains to be determined if vaccine immunogenicity is comparable in all previously infected subjects. We present detailed immunological evidence to clarify the requirements for one-or two-dose primary vaccination series for naturally primed individuals. Objective Evaluate the immune response to COVID-19 mRNA vaccines in healthcare workers (HCWs) who recovered from a SARS-CoV-2 infection. Design Multicentric observational prospective cohort study of HCWs with a PCR-confirmed SARS-CoV-2 infection designed to evaluate the dynamics of T and B cells immune responses to primary infection and COVID-19 mRNA vaccination over 12 months. Participants Unvaccinated HCWs with PCR-confirmed SARS-CoV-2 infection were selected based on the presence or absence of symptoms at infection and serostatus at enrollment. Age- and sex-matched adults not infected with SARS-CoV-2 prior to vaccination were included as naïve controls. Exposure Vaccination with Pfizer BioNTech BNT162b2 mRNA vaccine. Main Outcome(s) and Measure(s) Immunity score (zero to three), before and after vaccination, based on anti-RBD IgG ratio, serum capacity to neutralize live virus and IFN-γ secretion capacity in response to SARS-CoV-2 peptide pools above the positivity threshold for each of the three assays. We compared the immunity score between groups based on subjects’ symptoms at diagnosis and/or serostatus prior to vaccination. Results None of the naïve participants (n=14) showed a maximal immunity score of three following one dose of vaccine compared to 84% of the previously infected participants (n=55). All recovered individuals who did not have an immunity score of three were seronegative prior to vaccination, and 67% had not reported symptoms resulting from their initial infection. Following one dose of vaccine, their immune responses were comparable to naïve individuals, with significantly weaker responses than those who were symptomatic during infection. Conclusions and Relevance Individuals who did not develop symptoms during their initial SARS-CoV-2 infection and were seronegative prior to vaccination present immune responses comparable to that of naïve individuals. These findings highlight the importance of administering the complete two-dose primary regimen and following boosters of mRNA vaccines to individuals who experienced asymptomatic SARS-CoV-2 infection. KEY POINTS Question Is a single dose of COVID-19 mRNA vaccine sufficient to induce robust immune responses in individuals with prior SARS-CoV-2 infection? Findings In this cohort of 55 health care workers previously infected with SARS-CoV-2, we show that the absence of symptoms during initial infection and negative serostatus prior to vaccination predict the strength of immune responses to COVID-19 mRNA vaccine. Lack of symptoms and a negative serostatus prior to vaccination leads to immune responses comparable to naïve individuals. Meaning Our results support a two-dose primary series requirement for any individual with prior history of asymptomatic SARS-CoV-2 infection.

Physical, psychological and cognitive profile of post-COVID condition in healthcare workers, Quebec, Canada (preprint)

Importance. Most adults with COVID-19 do not require hospitalization, but the subsequent risk of post-COVID condition, including associated psychological and cognitive dysfunction, remains poorly understood among non-hospitalized versus hospitalized cases. Objective. To assess the prevalence and duration of post-COVID condition, including physical, psychological and cognitive symptoms. Design. Case series and case-control study between December 2020 and May 2021 Setting. Healthcare workers in Quebec, Canada Participants. Eligible cases were symptomatic healthcare workers with PCR-confirmed COVID-19 between July 2020 and May 2021. Among 17,717 contacted cases, 6061 (34%) participated. A random sample of symptomatic healthcare workers with negative PCR result between November 2020 and May 2021 served as controls. Among 11,498 contacted controls, 4390 (38%) participated. Exposures. In multivariable models, sociodemographic and clinical characteristics, as well as vaccine history, were evaluated as potential risk factors. Prevalence ratios compared self-reported cognitive dysfunctions (difficulty concentrating; difficulty organizing oneself; forgetfulness; loss of necessary items) among cases with post-COVID condition to controls, adjusting for psychological distress and fatigue. Outcomes. Post-COVID condition was defined by symptoms persisting [≥]4 weeks or [≥]12 weeks after COVID-19 onset. Results. Four-week and 12-week post-COVID condition prevalences of 46% (2,746/5,943) and 40% (653/1,746), respectively, were observed among non-hospitalized cases and 76% (90/118) and 68% (27/37), respectively, among hospitalized cases. Hospitalization, female sex and age were associated with higher risk. A substantial proportion of non-hospitalized cases with 4-week post-COVID condition often or very often reported cognitive dysfunction, including concentration (33%) or organizing (23%) difficulties, forgetfulness (20%) and loss of necessary items (10%), with no decline at 12 weeks. All four aspects of cognitive dysfunction were 2.2 to 3.0 times more prevalent among cases with post-COVID condition than in controls, but also independently associated with psychological distress and fatigue. Conclusions and relevance. Post-COVID condition may be a frequent sequela of ambulatory COVID-19 in working-age adults, with important effects on cognition. With so many healthcare workers infected since the beginning of the COVID-19 pandemic, the ongoing implications for quality healthcare delivery could be profound should cognitive dysfunction and other severe post-COVID symptoms persist in a professionally-disabling way over the longer term.

Safety of COVID-19 vaccines in pregnancy: a Canadian National Vaccine Safety (CANVAS) Network study (preprint)

BackgroundPregnant individuals have been receiving COVID-19 vaccines following pre-authorization clinical trials in non-pregnant people. This study aimed to determine significant health events amongst pregnant females after COVID-19 vaccination, compared with unvaccinated pregnant controls and vaccinated non-pregnant individuals. MethodsStudy participants were pregnant and non-pregnant females aged 15-49 years who had received any COVID-19 vaccine, and pregnant unvaccinated controls. Participants reported significant health events occurring within seven days of vaccination. We employed multivariable logistic regression to examine significant health events associated with mRNA vaccines. FindingsOverall 226/5,597(4.0%) vaccinated pregnant females reported a significant health event after dose one of an mRNA vaccine, and 227/3,108(7.3%) after dose two, compared with 11/339(3.2%) pregnant unvaccinated females. Pregnant vaccinated females had an increased odds of a significant health event after dose two of mRNA-1273 (aOR 4.4,95%CI 2.4-8.3) compared to pregnant unvaccinated controls, but not after dose one of mRNA-1273 or any dose of BNT162b2. Pregnant females had decreased odds of a significant health event compared to non-pregnant females after both dose one (aOR 0.63,95%CI 0.55-0.72) and dose two (aOR 0.62,95%CI 0.54-0.71) of mRNA vaccination. There were no significant differences in any analyses when restricted to events which led to medical attention. InterpretationCOVID-19 mRNA vaccines have a good safety profile in pregnancy. Rates of significant health events were higher after dose two of mRNA-1273 compared with unvaccinated controls, with no difference when considering events leading to medical consultation. Rates of significant health events were lower in pregnant females than similarly aged non-pregnant individuals. FundingThis work was supported by the COVID-19 Vaccine Readiness funding from the Canadian Institutes of Health Research and the Public Health Agency of Canada CANVAS grant number CVV-450980 and by funding from the Public Health Agency of Canada, through the Vaccine Surveillance Reference Group and the COVID-19 Immunity Task Force.

The REinfection in COVID-19 Estimation of Risk (RECOVER) study: Reinfection and serology dynamics in a cohort of Canadian healthcare workers. (preprint)

Background : Understanding the immune response to natural infection by SARS-CoV-2 is key to pandemic management, especially in the current context of emerging variants. Uncertainty remains regarding the efficacy and duration of natural immunity against reinfection. Method : We conducted an observational prospective cohort study in Canadian healthcare workers (HCWs) with a history of PCR-confirmed SARS-CoV-2 infection to : (i) measure the average incidence rate of reinfection and (ii), describe the serological immune response to the primary infection. Results : We detected 5 cases of reinfection over 14 months of follow-up, for a reinfection incidence rate of 3.3 per 100 person-years. Median duration of seropositivity was 420 days in symptomatics at primary infection compared to 213 days in asymptomatics (p<0.0001). Other variables associated with prolonged seropositivity for IgG against the spike protein included age 55 and above, obesity, and non-Caucasian ethnicity. Summary : Among healthcare workers, the incidence of reinfection with SARS-CoV-2 following a primary infection remained rare, although our analysis predates the circulation of the Omicron variant.

SARS-CoV-2 Omicron Spike recognition by plasma from individuals receiving BNT162b2 mRNA vaccination with a 16-weeks interval between doses (preprint)

Continuous emergence of SARS-CoV-2 variants of concern (VOC) is fueling the COVID-19 pandemic. Omicron (B.1.1.529), is rapidly spreading worldwide. The large number of mutations in its Spike raised concerns about a major antigenic drift that could significantly decrease vaccine efficacy and infection-induced immunity. A long interval between BNT162b2 mRNA doses was shown to elicit antibodies that efficiently recognize Spikes from different VOCs. Here we evaluated the recognition of Omicron Spike by plasma from a cohort of SARS-CoV-2 naive and previously-infected individuals that received their BNT162b2 mRNA vaccine 16-weeks apart. Omicron Spike was recognized less efficiently than D614G, Alpha, Beta, Gamma and Delta Spikes. We compared to plasma activity from participants receiving a short (4-weeks) interval regimen. Plasma from individuals of the long interval cohort neutralized better the Omicron Spike compared to those that received a short interval. Whether this difference confers any clinical benefit against Omicron remains unknown.

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.

Psychological distress of healthcare workers in Québec (Canada) during the second and the third pandemic waves (preprint)

Objective We aimed to measure the prevalence of psychological distress among Quebec healthcare workers (HCWs) during the second and third pandemic waves and to assess the effect of psychosocial risk factors (PSRs) on work-related psychological distress among SARS-CoV-2 infected (cases) and non-infected (controls) HCWs. Methods A self-administered survey was used to measure validated indicators of psychological distress (K6 scale) and PSR (questions based on Karasek and Siegrist models, value conflicts and work-life balance). Adjusted robust Poisson models were used to estimate prevalence ratios. Results 4068 cases and 4152 controls completed the survey. Prevalence of high work-related psychological distress was 42%; it was associated with PSRs (mainly work-life balance, value conflicts and high psychological demands) but not with SARS-CoV-2 infection. Conclusion Primary prevention measures targeting PSRs are needed to reduce mental health risks of HCWs.

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.

Strong humoral immune responses against SARS-CoV-2 Spike after BNT162b2 mRNA vaccination with a sixteen-week interval between doses (preprint)

While the standard regimen of the BNT162b2 mRNA vaccine includes two doses administered three weeks apart, some public health authorities decided to space them, raising concerns about vaccine efficacy. Here, we analyzed longitudinal humoral responses including antibody binding, Fc-mediated effector functions and neutralizing activity against the D614G strain but also variants of concern and SARS-CoV-1 in a cohort of SARS-CoV-2 naive and previously infected individuals, with an interval of sixteen weeks between the two doses. While the administration of a second dose to previously infected individuals did not significantly improve humoral responses, we observed a significant increase of humoral responses in naive individuals after the 16-weeks delayed second shot, achieving similar levels as in previously infected individuals. Our results highlight strong vaccine-elicited humoral responses with an extended interval BNT162b2 vaccination for naive individuals.