SARS-CoV-2 mRNA Vaccine Effectiveness in Health Care Workers by Dosing Interval and Time Since Vaccination: Test-Negative Design, British Columbia, Canada.

Background: One- and two-dose mRNA vaccine effectiveness (VE) estimates against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection by dosing interval and time since vaccination were assessed among healthcare workers (HCWs) in publicly funded acute and community (nonresidential) healthcare facilities in British Columbia, Canada. Methods: A test-negative design was used with controls matched to cases (6:1) on epidemiological week of SARS-CoV-2 test date. mRNA vaccination was defined by receipt of the first dose ≥21 days or second dose ≥14 days before the test date. HCWs ≥18 years old tested for SARS-CoV-2 between epi-weeks 3 and 39 (January 17-October 2, 2021) were included, when varying dosing intervals and a mix of circulating variants of concern contributed, including Delta dominance provincially from epi-week 31 (August 1). Results: Single- and two-dose analyses included 1265 and 1246 cases, respectively. The median follow-up period (interquartile range) was 49 (34-69) days for single-dose and 89 (61-123) days for two-dose recipients, with 12%, 31%, and 58% of second doses given 3-5, 6, or ≥7 weeks after the first. Adjusted mRNA VE against SARS-CoV-2 was 71% (95% CI, 66%-76%) for one dose and 90% (95% CI, 88%-92%) for two doses, similar to two heterologous mRNA doses (92%; 95% CI, 86%-95%). Two-dose VE remained >80% at ≥28 weeks post-second dose. Two-dose VE was consistently 5%-7% higher with a ≥7-week vs 3-5-week interval between doses, but with overlapping confidence intervals. Conclusions: Among HCWs, we report substantial single-dose and strong and sustained two-dose mRNA vaccine protection, with the latter maintained for at least 7 months. These findings support a longer interval between doses, with global health and equity implications.

Two-Dose Severe Acute Respiratory Syndrome Coronavirus 2 Vaccine Effectiveness With Mixed Schedules and Extended Dosing Intervals: Test-Negative Design Studies From British Columbia and Quebec, Canada.

BACKGROUND: The Canadian coronavirus disease 2019 (COVID-19) immunization strategy deferred second doses and allowed mixed schedules. We compared 2-dose vaccine effectiveness (VE) by vaccine type (mRNA and/or ChAdOx1), interval between doses, and time since second dose in 2 of Canada's larger provinces. METHODS: Two-dose VE against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection or hospitalization among adults ≥18 years, including due to Alpha, Gamma, and Delta variants of concern (VOCs), was assessed ≥14 days postvaccination by test-negative design studies separately conducted in British Columbia and Quebec, Canada, between 30 May and 27 November (epi-weeks 22-47) 2021. RESULTS: In both provinces, all homologous or heterologous mRNA and/or ChAdOx1 2-dose schedules were associated with ≥90% reduction in SARS-CoV-2 hospitalization risk for ≥7 months. With slight decline from a peak of >90%, VE against infection was ≥80% for ≥6 months following homologous mRNA vaccination, lower by ∼10% when both doses were ChAdOx1 but comparably high following heterologous ChAdOx1 + mRNA receipt. Findings were similar by age group, sex, and VOC. VE was significantly higher with longer 7-8-week versus manufacturer-specified 3-4-week intervals between mRNA doses. CONCLUSIONS: Two doses of any mRNA and/or ChAdOx1 combination gave substantial and sustained protection against SARS-CoV-2 hospitalization, spanning Delta-dominant circulation. ChAdOx1 VE against infection was improved by heterologous mRNA series completion. A 7-8-week interval between first and second doses improved mRNA VE and may be the optimal schedule outside periods of intense epidemic surge. Findings support interchangeability and extended intervals between SARS-CoV-2 vaccine doses, with potential global implications for low-coverage areas and, going forward, for children.

Comparative Single-Dose mRNA and ChAdOx1 Vaccine Effectiveness Against Severe Acute Respiratory Syndrome Coronavirus 2, Including Variants of Concern: Test-Negative Design, British Columbia, Canada.

BACKGROUND: In British Columbia, Canada, most adults 50-69 years old became eligible for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine in April 2021, with chimpanzee adenoviral vectored vaccine (ChAdOx1) restricted to ≥55-year-olds and second doses deferred ≥6 weeks to optimize single-dose coverage. METHODS: Among adults 50-69 years old, single-dose messenger RNA (mRNA) and ChAdOx1 vaccine effectiveness (VE) against SARS-CoV-2 infection and hospitalization, including variant-specific, was assessed by test-negative design between 4 April and 2 October 2021. RESULTS: Single-dose VE included 11 861 cases and 99 544 controls. Median of postvaccination follow-up was 32 days (interquartile range, 15-52 days). Alpha, Gamma, and Delta variants comprised 23%, 18%, and 56%, respectively, of genetically characterized viruses. At 21-55 days postvaccination, single-dose mRNA and ChAdOx1 VE (95% confidence interval [CI]) was 74% (71%-76%) and 59% (53%-65%) against any infection and 86% (80%-90%) and 94% (85%-97%) against hospitalization, respectively. VE (95% CI) was similar against Alpha and Gamma infections for mRNA (80% [76%-84%] and 80% [75%-84%], respectively) and ChAdOx1 (69% [60%-76%] and 66% [56%-73%], respectively). mRNA VE was lower at 63% (95% CI, 56%-69%) against Delta but 85% (95% CI, 71%-92%) against Delta-associated hospitalization (nonestimable for ChAdOx1). CONCLUSIONS: A single mRNA or ChAdOx1 vaccine dose gave important protection against SARS-CoV-2, including early variants of concern. ChAdOx1 VE was lower against infection, but 1 dose of either vaccine reduced the hospitalization risk by >85% to at least 8 weeks postvaccination. Findings inform program options, including longer dosing intervals.

Influenza Vaccine Effectiveness by A(H3N2) Phylogenetic Subcluster and Prior Vaccination History: 2016-2017 and 2017-2018 Epidemics in Canada.

BACKGROUND: The influenza A(H3N2) vaccine was updated from clade 3C.3a in 2015-2016 to 3C.2a for 2016-2017 and 2017-2018. Circulating 3C.2a viruses showed considerable hemagglutinin glycoprotein diversification and the egg-adapted vaccine also bore mutations. METHODS: Vaccine effectiveness (VE) in 2016-2017 and 2017-2018 was assessed by test-negative design, explored by A(H3N2) phylogenetic subcluster and prior season's vaccination history. RESULTS: In 2016-2017, A(H3N2) VE was 36% (95% confidence interval [CI], 18%-50%), comparable with (43%; 95% CI, 24%-58%) or without (33%; 95% CI, -21% to 62%) prior season's vaccination. In 2017-2018, VE was 14% (95% CI, -8% to 31%), lower with (9%; 95% CI, -18% to 30%) versus without (45%; 95% CI, -7% to 71%) prior season's vaccination. In 2016-2017, VE against predominant clade 3C.2a1 viruses was 33% (95% CI, 11%-50%): 18% (95% CI, -40% to 52%) for 3C.2a1a defined by a pivotal T135K loss of glycosylation; 60% (95% CI, 19%-81%) for 3C.2a1b (without T135K); and 31% (95% CI, 2%-51%) for other 3C.2a1 variants (with/without T135K). VE against 3C.2a2 viruses was 45% (95% CI, 2%-70%) in 2016-2017 but 15% (95% CI, -7% to 33%) in 2017-2018 when 3C.2a2 predominated. VE against 3C.2a1b in 2017-2018 was 37% (95% CI, -57% to 75%), lower at 12% (95% CI, -129% to 67%) for a new 3C.2a1b subcluster (n = 28) also bearing T135K. CONCLUSIONS: Exploring VE by phylogenetic subcluster and prior vaccination history reveals informative heterogeneity. Pivotal mutations affecting glycosylation sites, and repeat vaccination using unchanged antigen, may reduce VE.

Single-dose mRNA Vaccine Effectiveness Against Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), Including Alpha and Gamma Variants: A Test-negative Design in Adults 70 Years and Older in British Columbia, Canada.

BACKGROUND: Randomized-controlled trials of messenger RNA (mRNA) vaccine protection against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) included relatively few elderly participants. We assess single-dose mRNA vaccine effectiveness (VE) in adults ≥ 70 years old in British Columbia, Canada, where second doses were deferred by up to 16 weeks and where a spring 2021 wave uniquely included codominant circulation of Alpha (B.1.1.7) and Gamma (P.1) variants of concern (VOC). METHODS: Analyses included community-dwelling adults ≥ 70 years old with specimen collection between 4 April (epidemiological week 14) and 1 May (week 17) 2021. Adjusted VE was estimated by test-negative design. Cases were reverse-transcription polymerase chain reaction (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. Variant-specific VE was estimated against viruses genetically characterized as Alpha, Gamma or non-VOC lineages. RESULTS: VE analyses included 16 993 specimens: 1226 (7%) test-positive cases and 15 767 test-negative controls. Of 1131 (92%) genetically characterized viruses, 509 (45%), 314 (28%), and 276 (24%) were Alpha, Gamma, and non-VOC lineages, respectively. At 0-13 days postvaccination, VE was negligible at 14% (95% confidence interval [CI], 0-26) but increased from 43% (95% CI, 30-53) at 14-20 days to 75% (95% CI, 63-83) at 35-41 days postvaccination. VE at ≥ 21 days postvaccination 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, Alpha, and Gamma variants, respectively. CONCLUSIONS: A single dose of mRNA vaccine reduced the risk of SARS-CoV-2 by about two-thirds in adults ≥ 70 years old, with protection only minimally reduced against Alpha and Gamma variants.

Influenza Vaccine Does Not Increase the Risk of Coronavirus or Other Noninfluenza Respiratory Viruses: Retrospective Analysis From Canada, 2010-2011 to 2016-2017.

Influenza vaccine effectiveness against influenza and noninfluenza respiratory viruses (NIRVs) was assessed by test-negative design using historic datasets of the community-based Canadian Sentinel Practitioner Surveillance Network, spanning 2010-2011 to 2016-2017. Vaccine significantly reduced the risk of influenza illness by >40% with no effect on coronaviruses or other NIRV risk.

A Computerized Frailty Assessment Tool at Points-of-Care: Development of a Standalone Electronic Comprehensive Geriatric Assessment/Frailty Index (eFI-CGA).

Background: Frailty is characterized by loss of biological reserves and is associated with an increased risk of adverse health outcomes. Frailty can be operationalized using a Frailty Index (FI) based on the accumulation of health deficits; items under health evaluation in the well-established Comprehensive Geriatric Assessment (CGA) have been used to generate an FI-CGA. Traditionally, constructing the FI-CGA has relied on paper-based recording and manual data processing. As this can be time-consuming and error-prone, it limits widespread uptake of this proven type of frailty assessment. Here, we report the development of an electronic tool, the eFI-CGA, for use on personal computers by frontline healthcare providers, to collect CGA data and automate FI-CFA calculation. The ultimate goal is to support early identification and management of frailty at points-of-care, and make uptake in Electronic Medical Records (EMR) feasible and transparent. Methods: An electronic CGA (eCGA) form was implemented to operate on Microsoft's WinForms platform and coded using C# programming language. Users complete the eCGA form, from which items under the CGA evaluation are automatically retrieved and processed to output an eFI-CGA score. A user-friendly interface and secured data saving methods were implemented. The software was debugged and tested using systematically designed simulation data, addressing different logic, syntax, and application errors, and then tested with clinical assessment. The user manual and manual scoring were used as ground truth to compare eFI-CGA input and automated eFI score calculations. Frontline health-provider user feedback was incorporated to improve the end-user experience. Results: The Standalone eFI-CGA software tool was developed and optimized for use on personal computers. The user interface adapted the design of paper-based CGA form to facilitate familiarity for clinical users. Compared to known scores, the software tool generated eFI-CGA scores with 100% accuracy to four decimal places. The eFI-CGA allowed secure data storage and retrieval of multiple types, including user input, completed eCGA form, coded items, and calculated eFI-CGA scores. It also permitted recording of actions requiring clinical follow-up, facilitating care planning. Application bugs were identified and resolved at various stages of the implementation, resulting in efficient system performance. Discussion: Accurate, robust, and reliable computerized frailty assessments are needed to promote effective frailty assessment and management, as a key tool in health care systems facing up to frailty. Our research has enabled the delivery of the standalone eFI-CGA software technology to empower effective frailty assessment and management by various healthcare providers at points-of-care, facilitating integrated care of older adults.

Interim estimates of 2019/20 vaccine effectiveness during early-season co-circulation of influenza A and B viruses, Canada, February 2020.

Interim results from Canada's Sentinel Practitioner Surveillance Network show that during a season characterised by early co-circulation of influenza A and B viruses, the 2019/20 influenza vaccine has provided substantial protection against medically-attended influenza illness. Adjusted VE overall was 58% (95% confidence interval (CI): 47 to 66): 44% (95% CI: 26 to 58) for A(H1N1)pdm09, 62% (95% CI: 37 to 77) for A(H3N2) and 69% (95% CI: 57 to 77) for influenza B viruses, predominantly B/Victoria lineage.

Paradoxical clade- and age-specific vaccine effectiveness during the 2018/19 influenza A(H3N2) epidemic in Canada: potential imprint-regulated effect of vaccine (I-REV).

IntroductionThe Canadian Sentinel Practitioner Surveillance Network reports vaccine effectiveness (VE) for the 2018/19 influenza A(H3N2) epidemic.AimTo explain a paradoxical signal of increased clade 3C.3a risk among 35-54-year-old vaccinees, we hypothesise childhood immunological imprinting and a cohort effect following the 1968 influenza A(H3N2) pandemic.MethodsWe assessed VE by test-negative design for influenza A(H3N2) overall and for co-circulating clades 3C.2a1b and 3C.3a. VE variation by age in 2018/19 was compared with amino acid variation in the haemagglutinin glycoprotein by year since 1968.ResultsInfluenza A(H3N2) VE was 17% (95% CI: -13 to 39) overall: 27% (95% CI: -7 to 50) for 3C.2a1b and -32% (95% CI: -119 to 21) for 3C.3a. Among 20-64-year-olds, VE was -7% (95% CI: -56 to 26): 6% (95% CI: -49 to 41) for 3C.2a1b and -96% (95% CI: -277 to -2) for 3C.3a. Clade 3C.3a VE showed a pronounced negative dip among 35-54-year-olds in whom the odds of medically attended illness were > 4-fold increased for vaccinated vs unvaccinated participants (p < 0.005). This age group was primed in childhood to influenza A(H3N2) viruses that for two decades following the 1968 pandemic bore a serine at haemagglutinin position 159, in common with contemporary 3C.3a viruses but mismatched to 3C.2a vaccine strains instead bearing tyrosine.DiscussionImprinting by the first childhood influenza infection is known to confer long-lasting immunity focused toward priming epitopes. Our findings suggest vaccine mismatch may negatively interact with imprinted immunity. The immunological mechanisms for imprint-regulated effect of vaccine (I-REV) warrant investigation.