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.

Comparative analysis of pediatric Respiratory Syncytial Virus epidemiology and clinical severity before and during the COVID-19 pandemic in British Columbia, Canada (preprint)

BackgroundThe COVID-19 pandemic affected Respiratory Syncytial Virus (RSV) circulation and surveillance, causing logistical complexity for health systems. Our objective was to describe changes in epidemiology and clinical severity of RSV cases in British Columbia, Canada. MethodsComparative analysis of RSV detections in children <36 months at BC Childrens Hospital (BCCH) between September 1 and August 31 of 2017-18, 2018-19, 2019-20, 2020-21 and 2021-22. ResultsAbout one-fifth of children tested RSV positive on average across all periods. The median age of RSV cases was 11.8 [IQR: 3.8-22.3] months in 2021-22 versus 6.3 [IQR: 1.9-16.7] months in 2017-20 (p<0.001). Increased testing in 2021-22 (n=3,120) compared to 2017-20 (average n=1,222/period) detected milder infections with lower proportion hospitalized in all age subgroups <6 (26.0%), 6-11 (12.3%), 12-23 (12.2%) and 24-35 (16.0%) months versus 2017-20 (49.3%, 53.5%, 62.6%, 57.5%, respectively) (all p<0.001). Children <6 months consistently comprised most hospitalizations and those born prematurely <29 weeks or with chronic respiratory co-morbidities remained at highest hospitalization risk in 2021-22. Among hospitalized cases, intensive care, respiratory support or supplemental oxygen use did not differ between the 2017-20 and 2021-22 periods. ConclusionsRSV circulation halted during the pandemic, but with the lifting of mitigation measures a subsequent resurgence in children <36 months of age was accompanied by shift toward older (24-35 month) cases in 2021-22, without increased severity. For the 2022-23 period, increased circulation and residual vulnerability in additional birth cohorts spared from RSV infection during the pandemic could have marked cumulative healthcare impact, even without increase in proportion hospitalized.

Serial cross-sectional estimation of vaccine and infection-induced SARS-CoV-2 sero-prevalence in children and adults, British Columbia, Canada: March 2020 to August 2022 (preprint)

BackgroundWe chronicle SARS-CoV-2 sero-prevalence through eight cross-sectional sero-surveys (snapshots) in the Lower Mainland (Greater Vancouver and Fraser Valley), British Columbia, Canada from March 2020 to August 2022. MethodsAnonymized-residual sera were obtained from children and adults attending an outpatient laboratory network. Sera were tested with at least three immuno-assays per snapshot to detect spike (S1) and/or nucleocapsid protein (NP) antibodies. Sero-prevalence was defined by dual-assay positivity, including any or infection-induced, the latter requiring S1+NP antibody detection from January 2021 owing to vaccine availability. Infection-induced estimates were used to assess the extent to which surveillance case reports under-estimated infections. ResultsSero-prevalence was [≤]1% by the 3rd snapshot in September 2020 and <5% by January 2021 (4th). Following vaccine roll-out, sero-prevalence increased to >55% by May/June 2021 (5th), [~]80% by September/October 2021 (6th), and >95% by March 2022 (7th). In all age groups, infection-induced sero-prevalence remained <15% through September/October 2021, increasing through subsequent Omicron waves to [~]40% by March 2022 (7th) and [~]60% by July/August 2022 (8th). By August 2022, at least 70-80% of children [≤]19 years, 60-70% of adults 20-59 years, but [~]40% of adults [≥]60 years had been infected. Surveillance case reports under-estimated infections by 12-fold between the 6th-7th and 92-fold between the 7th-8th snapshots. InterpretationBy August 2022, most children and adults had acquired SARS-CoV-2 vaccine and infection exposures, resulting in more robust hybrid immunity. Conversely the elderly, still at greatest risk of severe outcomes, remain largely-dependent on vaccine-induced protection alone, and should be prioritized for additional doses.

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.

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.

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.

Comparative single-dose mRNA and ChAdOx1 vaccine effectiveness against SARS-CoV-2, including early variants of concern: a test-negative design, British Columbia, Canada (preprint)

IntroductionIn randomized controlled trials, single-dose efficacy against SARS-CoV-2 illness exceeded 90% for mRNA vaccines (BNT162b2 and mRNA-1273), and 75% for ChAdOx1. In British Columbia (BC), Canada second doses were deferred up to 16 weeks and ChAdOx1 was only initially recommended for adults 55 years of age and older. We compared single-dose vaccine effectiveness (VE) during the spring 2021 wave in BC when Alpha and Gamma variants of concern (VOC) predominated. MethodsVE was estimated against infection and hospitalization by test-negative design: cases were RT-PCR test-positive for SARS-CoV-2 and controls were test-negative. Adults 50-69 years old with specimen collection between April 4 and May 22 (weeks 14-20) were included. Variant-specific VE was estimated between weeks 17-20 when genetic characterization of all case viruses was performed, primarily through whole genome sequencing. ResultsVE analyses included 7,116 (10%) cases and 60,958 controls. Three-quarters of vaccinated participants received mRNA vaccine (60% BNT162b2, 15% mRNA-1273) and 25% received ChAdOx1. Half of genetically characterized viruses were Alpha, with 38% Gamma, 4% Delta and 8% non-VOCs. Single-dose VE against any infection was 75% (95%CI: 72-78) for BNT162b2, 82% (95%CI: 76-87) for mRNA-1273 and 61% (95%CI: 54-66) for ChAdOx1. VE against hospitalization was 83% (95%CI: 76-89), 85% (95%CI: 63-94) and 96% (95%CI: 86-99), respectively. VE against Alpha vs. Gamma infections did not differ among mRNA (78%;95%CI: 73-82 and 80%;95%CI: 74-85) or ChAdOx1 (66%;95%CI: 57-74 and 60%;95%CI: 48-69) recipients. ConclusionsA single dose of mRNA vaccine reduced the SARS-CoV-2 infection risk by at least 75%, including infections due to early VOC. Although effectiveness of a single dose of ChAdOx1 was lower at 60% against infection, just one dose of any vaccine reduced the hospitalization risk by more than 80%. In the context of constrained vaccine supplies, these findings have implications for global vaccine deployment to reduce the overall burden of infections and hospitalizations due to SARS-CoV-2.

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.

Single-dose mRNA vaccine effectiveness against SARS-CoV-2, including P.1 and B.1.1.7 variants: a test-negative design in adults 70 years and older in British Columbia, Canada (preprint)

Introduction: Randomized-controlled trials of mRNA vaccine protection against SARS-CoV-2 included relatively few elderly participants. We assess singe-dose mRNA vaccine effectiveness (VE) in adults [≥]70-years-old in British Columbia (BC), Canada where the second dose was deferred by up to 16 weeks and where a spring 2021 wave uniquely included co-dominant circulation of B.1.1.7 and P.1 variants of concern (VOC). Methods: Analyses included community-dwelling adults [≥]70-years-old with specimen collection between April 4 (epidemiological week 14) and May 1 (week 17). Adjusted VE was estimated by test-negative design through provincial laboratory and immunization data linkage. Cases were RT-PCR test-positive for SARS-CoV-2 and controls were test-negative. Vaccine status was defined by receipt of a single-dose [≥]21 days before specimen collection, but a range of intervals was assessed. In variant-specific analyses, test-positive cases were restricted to those genetically-characterized as B.1.1.7, P.1 or non-VOC. Results: VE analyses included 16,993 specimens: 1,226 (7.2%) test-positive cases and 15,767 test-negative controls. Of 1,131 (92%) viruses genetically categorized, 509 (45%), 314 (28%) and 276 (24%) were B.1.1.7, P.1 and non-VOC lineages, respectively. VE was negligible at 14% (95% CI 0-26) during the period 0-13 days post-vaccination but increased from 43% (95% CI 30-53) at 14-20 days to 75% (95% CI 63-83) at 35-41 days post-vaccination. VE at [≥]21 days was 65% (95% CI 58-71) overall: 72% (95% CI 58-81), 67% (95% CI 57-75) and 61% (95% CI 45-72) for non-VOC, B.1.1.7 and P.1, respectively. Conclusions: A single dose of mRNA vaccine reduced the risk of SARS-CoV-2 in adults [≥]70-years-old by about two-thirds, with protection only minimally reduced against B.1.1.7 and P.1 variants. Substantial single-dose protection in older adults reinforces the option to defer the second dose when vaccine supply is scarce and broader first-dose coverage is needed.

Low SARS-CoV-2 sero-prevalence based on anonymized residual sero-survey before and after first wave measures in British Columbia, Canada, March-May 2020 (preprint)

Background: The province of British Columbia (BC) has been recognized for successful SARS-CoV-2 control, with surveillance data showing amongst the lowest case and death rates in Canada. We estimate sero-prevalence for two periods flanking the start (March) and end (May) of first-wave mitigation measures in BC. Methods: Serial cross-sectional sampling was conducted using anonymized residual sera obtained from an outpatient laboratory network, including children and adults in the Greater Vancouver Area (population ~3 million) where community attack rates were expected to be highest. Screening used two chemiluminescent immuno-assays for spike (S1) and nucleocapsid antibodies. Samples sero-positive on either screening assay were assessed by a third assay targeting the S1 receptor binding domain plus a neutralization assay. Age-standardized sero-prevalence estimates were based on dual-assay positivity. The May sero-prevalence estimate was extrapolated to the source population to assess surveillance under-ascertainment, quantified as the ratio of estimated infections versus reported cases. Results: Serum collection dates spanned March 5-13 and May 15-27, 2020. In March, two of 869 specimens were dual-assay positive, with age-standardized sero-prevalence of 0.28% (95%CI=0.03-0.95). Neither specimen had detectable neutralizing antibodies. In May, four of 885 specimens were dual-assay positive, with age-standardized sero-prevalence of 0.55% (95%CI=0.15-1.37%). All four specimens had detectable neutralizing antibodies. We estimate ~8 times more infections than reported cases. Conclusions: Less than 1% of British Columbians had been infected with SARS-CoV-2 when first-wave mitigation measures were relaxed in May 2020. Our findings indicate successful suppression of community transmission in BC, but also substantial residual susceptibility. Further sero-survey snapshots are planned as the pandemic unfolds.