Comparative effectiveness of bivalent BA.4-5 or BA.1 mRNA booster vaccines among immunocompromised individuals across three Nordic countries: A nationwide cohort study.

OBJECTIVES: To estimate the effectiveness and waning of the bivalent BA.4-5 or BA.1 mRNA booster vaccine against Covid-19-related hospitalization and death in immunocompromised individuals. METHODS: Nationwide analyses across Nordic countries from 1 September 2022 to 31 October 2023 using a matched cohort design. Individuals boosted with a BA.4-5 or BA.1 vaccine were matched 1:1 with unboosted individuals. The outcomes of interest were country-combined vaccine effectiveness (VE) estimates against Covid-19-related hospitalization and death at day 270 of follow-up. Waning was assessed in 45-day intervals. RESULTS: A total of 352,762 BA.4-5 and 191,070 BA.1 booster vaccine doses were included. At day 270, the comparative VE against Covid-19-related hospitalization was 34.2% (95% CI, 7.1% to 61.3%) for the bivalent BA.4-5 vaccine and 42.6% (95% CI, 31.3% to 53.9%) for the BA.1 vaccine compared with matched unboosted. The comparative VE against Covid-19-related death was 53.9% (95% CI, 38.6% to 69.3%) for the bivalent BA.4-5 vaccine and 57.9% (95% CI, 48.5% to 67.4%) for the BA.1 vaccine. CONCLUSIONS: In immunocompromised individuals, vaccination with bivalent BA.4-5 or BA.1 booster lowered the risk of Covid-19-related hospitalization and death over a follow-up period of 9 months. The effectiveness was highest during the first months since vaccination with subsequent gradual waning.

Relative effectiveness of bivalent boosters against severe COVID-19 outcomes among people aged ≥ 65 years in Finland, September 2022 to August 2023.

BackgroundLong-term effectiveness data on bivalent COVID-19 boosters are limited.AimWe evaluated the long-term protection of bivalent boosters against severe COVID-19 among ≥ 65-year-olds in Finland.MethodsIn this register-based cohort analysis, we compared the risk of three severe COVID-19 outcomes among ≥ 65-year-olds who received a bivalent booster (Original/Omicron BA.1 or Original/BA.4-5; exposed group) between 1/9/2022 and 31/8/2023 to those who did not (unexposed). We included individuals vaccinated with at least two monovalent COVID-19 vaccine doses before 1/9/2022 and ≥ 3 months ago. The analysis was divided into two periods: 1/9/2022-28/2/2023 (BA.5 and BQ.1.X predominating) and 1/3/2023-31/8/2023 (XBB predominating). The hazards for the outcomes between exposed and unexposed individuals were compared with Cox regression.ResultsWe included 1,191,871 individuals. From 1/9/2022 to 28/2/2023, bivalent boosters were associated with a reduced risk of hospitalisation due to COVID-19 (hazard ratio (HR): 0.45; 95% confidence interval (CI): 0.37-0.55), death due to COVID-19 (HR: 0.49; 95% CI: 0.38-0.62), and death in which COVID-19 was a contributing factor (HR: 0.40; 95% CI: 0.31-0.51) during 14-60 days since vaccination. From 1/3/2023 to 31/8/2023, bivalent boosters were associated with lower risks of all three severe COVID-19 outcomes during 61-120 days since a bivalent booster (e.g. HR: 0.53; 95% CI: 0.39-0.71 for hospitalisation due to COVID-19); thereafter no notable risk reduction was observed. No difference was found between Original/Omicron BA.1 and Original/BA.4-5 boosters.ConclusionBivalent boosters initially reduced the risk of severe COVID-19 outcomes by ca 50% among ≥ 65-year-olds, but protection waned over time. These findings help guide vaccine development and vaccination programmes.

Estimated number of lives directly saved by COVID-19 vaccination programmes in the WHO European Region from December, 2020, to March, 2023: a retrospective surveillance study.

BACKGROUND: By March, 2023, 54 countries, areas, and territories (hereafter CAT) in the WHO European Region had reported more than 2·2 million COVID-19-related deaths to the WHO Regional Office for Europe. Here, we estimated how many lives were directly saved by vaccinating adults in the WHO European Region from December, 2020, to March, 2023. METHODS: In this retrospective surveillance study, we estimated the number of lives directly saved by age group, vaccine dose, and circulating variant-of-concern (VOC) period, regionally and nationally, using weekly data on COVID-19 mortality and infection, COVID-19 vaccination uptake, and SARS-CoV-2 virus characterisations by lineage downloaded from The European Surveillance System on June 11, 2023, as well as vaccine effectiveness data from the literature. We included data for six age groups (25-49 years, 50-59 years, ≥60 years, 60-69 years, 70-79 years, and ≥80 years). To be included in the analysis, CAT needed to have reported both COVID-19 vaccination and mortality data for at least one of the four older age groups. Only CAT that reported weekly data for both COVID-19 vaccination and mortality by age group for 90% of study weeks or more in the full study period were included. We calculated the percentage reduction in the number of expected and reported deaths. FINDINGS: Between December, 2020, and March, 2023, in 34 of 54 CAT included in the analysis, COVID-19 vaccines reduced deaths by 59% overall (CAT range 17-82%), representing approximately 1·6 million lives saved (range 1·5-1·7 million) in those aged 25 years or older: 96% of lives saved were aged 60 years or older and 52% were aged 80 years or older; first boosters saved 51% of lives, and 60% were saved during the Omicron period. INTERPRETATION: Over nearly 2·5 years, most lives saved by COVID-19 vaccination were in older adults by first booster dose and during the Omicron period, reinforcing the importance of up-to-date vaccination among the most at-risk individuals. Further modelling work should evaluate indirect effects of vaccination and public health and social measures. FUNDING: US Centers for Disease Control and Prevention.

Diagnostic performance of multiplex lateral flow tests in ambulatory patients with acute respiratory illness.

We assessed the performance of three different multiplex lateral flow assays manufactured by SureScreen, Microprofit and Goldsite which provide results for influenza, respiratory syncytial virus (RSV) and SARS-CoV-2. Between 4 April and 20 October 2023, 1646 patients 6 months and older presenting to an outpatient department of a hospital in Hong Kong with ≥2 symptoms or signs of an acute respiratory illness were enrolled. The point estimates for all three multiplex tests had sensitivity >80% for influenza A and SARS-CoV-2 compared to PCR, and the tests manufactured by Microprofit and Goldsite had sensitivity >84% to detect RSV. Specificity was >97% for all three tests except for the SureScreen test which had specificity 86.2% (95% CI: 83.9% to 88.3%) for influenza A. Sensitivity was lower than reported by the manufacturers, resulting in a higher risk of false negatives. The three multiplex tests performed better in patients with high viral loads.

COVID-19 Vaccine Effectiveness Among Adolescents.

BACKGROUND: For adolescents, data on the long-term effectiveness of the BNT162b2 and mRNA-1273 vaccines against severe COVID-19 outcomes are scarce. Additionally, only a few studies have evaluated vaccine effectiveness (VE) for mRNA-1273 or heterologous mRNA vaccine schedules (ie, mixing BNT162b2 and mRNA-1273). METHODS: Nationwide register-based 1-to-1 matched cohort analyses were conducted in Denmark, Finland, Norway, and Sweden between May 28, 2021, and April 30, 2023, to estimate VE for primary COVID-19 vaccine (2-dose) schedules among adolescents aged 12 to 17 years. Cumulative incidences of COVID-19-related hospitalization (primary outcome) and laboratory-confirmed SARS-CoV-2 infection (secondary outcome) were compared for vaccinated and unvaccinated at 6 months of follow-up using the Kaplan-Meier estimator. Country-specific VE (1-risk ratio) and risk differences (RD) were combined by random-effects meta-analyses. RESULTS: The study included 526 966 primary schedule vaccinated adolescents. VE against COVID-19-related hospitalization was 72.6% (95% confidence interval [CI], 62.5-82.7) and RD was -2.8 (95% CI, -4.5 to -1.0) per 10 000 vaccinated for BNT162b2 at 6 months of follow-up compared with unvaccinated. The corresponding VE and RD were 86.0% (95% CI, 56.8-100.0) and -2.1 (95% CI, -4.0 to -0.2) per 10 000 vaccinated for mRNA-1273 and 80.7% (95% CI, 58.0-100.0) and -5.5 (95% CI, -15.5 to 4.6) per 10 000 vaccinated for heterologous mRNA vaccine schedules. Estimates were comparable when restricting to a period of omicron predominance and extending follow-up to 12 months. CONCLUSIONS: Across 4 Nordic countries, severe COVID-19 in adolescents was a rare event. Compared with unvaccinated, BNT162b2, mRNA-1273, and heterologous mRNA vaccination schedules provided high protection against COVID-19-related hospitalization, including hospitalizations during the omicron period.

Effectiveness of Vaccines and Monoclonal Antibodies Against Respiratory Syncytial Virus: Generic Protocol for Register-Based Cohort Study.

Several immunization products are currently being developed against respiratory syncytial virus (RSV) for children, pregnant females, and older adults, and some products have already received authorization. Therefore, studies to monitor the effectiveness of these products are needed in the following years. To assist researchers to conduct postmarketing studies, we developed a generic protocol for register-based cohort studies to evaluate immunization product effectiveness against RSV-specific and nonspecific outcomes. To conduct a study on the basis of this generic protocol, the researchers can use any relevant databases or healthcare registers that are available at the study site.

Effectiveness of Immunization Products Against Medically Attended Respiratory Syncytial Virus Infection: Generic Protocol for a Test-Negative Case-Control Study.

Monitoring the real-life effectiveness of respiratory syncytial virus (RSV) products is of major public health importance. This generic protocol for a test-negative design study aims to address currently envisioned approaches for RSV prevention (monoclonal antibodies and vaccines) to study effectiveness of these products among target groups: children, older adults, and pregnant women. The generic protocol approach was chosen to allow for flexibility in adapting the protocol to a specific setting. This protocol includes severe acute respiratory infection (SARI) and acute respiratory infection (ARI), both due to RSV, as end points. These end points can be applied to studies in hospitals, primarily targeting patients with more severe disease, but also to studies in general practitioner clinics targeting ARI.

Comparative effectiveness of heterologous third dose vaccine schedules against severe covid-19 during omicron predominance in Nordic countries: population based cohort analyses.

OBJECTIVE: To investigate the comparative vaccine effectiveness of heterologous booster schedules (ie, three vaccine doses) compared with primary schedules (two vaccine doses) and with homologous mRNA vaccine booster schedules (three vaccine doses) during a period of omicron predominance. DESIGN: Population based cohort analyses. SETTING: Denmark, Finland, Norway, and Sweden, 27 December 2020 to 31 December 2022. PARTICIPANTS: All adults aged ≥18 years who had received at least a primary vaccination schedule of AZD1222 (Oxford-AstraZeneca) or monovalent SARS-CoV-2 wild type (ancestral) strain based mRNA vaccines BNT162b2 (Pfizer-BioNTech) or mRNA-1273 (Moderna), in any combination. MAIN OUTCOME MEASURES: The main outcome measure was country combined risks of covid-19 related hospital admission and death with covid-19 and additional outcomes of covid-19 related admission to an intensive care unit and SARS-CoV-2 infection. During a period of omicron predominance, these outcomes were compared in those who received a heterologous booster versus primary schedule (matched analyses) and versus those who received a homologous mRNA vaccine booster (weighted analyses). Follow-up was for 75 days from day 14 after the booster dose; comparative vaccine effectiveness was calculated as 1-risk ratio. RESULTS: Across the four Nordic countries, 1 086 418 participants had received a heterologous booster schedule of AZD1222+BNT162b2 or mRNA-1273 and 2 505 093 had received a heterologous booster schedule of BNT162b2+mRNA-1273. Compared with the primary schedule only (two doses), the vaccine effectiveness of heterologous booster schedules comprising AZD1222+BNT162b2 or mRNA-1273 and BNT162b2+mRNA-1273 was 82.7% (95% confidence interval 77.1% to 88.2%) and 81.5% (78.9% to 84.2%) for covid-19 related hospital admission and 95.9% (91.6% to 100.0%) and 87.5% (82.5% to 92.6%) for death with covid-19, respectively. Homologous mRNA booster schedules were similarly associated with increased protection against covid-19 related hospital admission (≥76.5%) and death with covid-19 (≥84.1%) compared with previous primary course vaccination only. When a heterologous booster schedule was compared with the homologous booster schedule, vaccine effectiveness was 27.2% (3.7% to 50.6%) for AZD1222+BNT162b2 or mRNA-1273 and 23.3% (15.8% to 30.8%) for BNT162b2+mRNA-1273 schedules against covid-19 related hospital admission and 21.7% (-8.3% to 51.7%) and 18.4% (-15.7% to 52.5%) against death with covid-19, respectively. CONCLUSION: Heterologous booster schedules are associated with increased protection against severe, omicron related covid-19 outcomes compared with primary course schedules and homologous booster schedules.

Comparative effectiveness of bivalent BA.4-5 and BA.1 mRNA booster vaccines among adults aged ≥50 years in Nordic countries: nationwide cohort study.

OBJECTIVE: To estimate the effectiveness of the bivalent mRNA booster vaccines containing the original SARS-CoV-2 and omicron BA.4-5 or BA.1 subvariants as the fourth dose against severe covid-19. DESIGN: Nationwide cohort analyses, using target trial emulation. SETTING: Denmark, Finland, Norway, and Sweden, from 1 July 2022 to 10 April 2023. PARTICIPANTS: People aged ≥50 years who had received at least three doses of covid-19 vaccine (that is, a primary course and a first booster). MAIN OUTCOME MEASURES: The Kaplan-Meier estimator was used to compare the risk of hospital admission and death related to covid-19 in people who received a bivalent Comirnaty (Pfizer-BioNTech) or Spikevax (Moderna) BA.4-5 or BA.1 mRNA booster vaccine as a fourth dose (second booster) with three dose (first booster) vaccinated people and between four dose vaccinated people. RESULTS: A total of 1 634 199 people receiving bivalent BA.4-5 fourth dose booster and 1 042 124 receiving bivalent BA.1 fourth dose booster across the four Nordic countries were included. Receipt of a bivalent BA.4-5 booster as a fourth dose was associated with a comparative vaccine effectiveness against admission to hospital with covid-19 of 67.8% (95% confidence interval 63.1% to 72.5%) and a risk difference of -91.9 (95% confidence interval -152.4 to -31.4) per 100 000 people at three months of follow-up compared with having received three doses of vaccine (289 v 893 events). The corresponding comparative vaccine effectiveness and risk difference for bivalent BA.1 boosters (332 v 977 events) were 65.8% (59.1% to 72.4%) and -112.9 (-179.6 to -46.2) per 100 000, respectively. Comparative vaccine effectiveness and risk difference against covid-19 related death were 69.8% (52.8% to 86.8%) and -34.1 (-40.1 to -28.2) per 100 000 for bivalent BA.4-5 booster (93 v 325 events) and 70.0% (50.3% to 89.7%) and -38.7 (-65.4 to -12.0) per 100 000 for BA.1 booster (86 v 286) as a fourth dose. Comparing bivalent BA.4-5 and BA.1 boosters as a fourth dose directly resulted in a three month comparative vaccine effectiveness and corresponding risk difference of -14.9% (-62.3% to 32.4%) and 10.0 (-14.4 to 34.4) per 100 000 people for admission to hospital with covid-19 (802 v 932 unweighted events) and -40.7% (-123.4% to 42.1%) and 8.1 (-3.3 to 19.4) per 100 000 for covid-19 related death (229 v 243 unweighted events). The comparative vaccine effectiveness did not differ across sex and age (

High vaccine effectiveness against severe COVID-19 in the elderly in Finland before and after the emergence of Omicron.

BACKGROUND: The elderly are highly vulnerable to severe COVID-19. Waning immunity and emergence of Omicron have caused concerns about reduced effectiveness of COVID-19 vaccines. The objective was to estimate vaccine effectiveness (VE) against severe COVID-19 among the elderly. METHODS: This nationwide, register-based cohort analysis included all residents aged 70 years and over in Finland. The follow-up started on December 27, 2020, and ended on March 31, 2022. The outcomes of interest were COVID-19-related hospitalization and intensive care unit (ICU) admission timely associated with SARS-CoV-2 infection. VE was estimated as one minus the hazard ratio comparing the vaccinated and unvaccinated and taking into account time since vaccination. Omicron-specific VE was evaluated as the effectiveness observed since January 1, 2022. RESULTS: The cohort included 896,220 individuals. Comirnaty (BioNTech/Pfizer) VE against COVID-19-related hospitalization was 93% (95% CI 89-95%) and 85% (95% CI 82-87%) 14-90 and 91-180 days after the second dose; VE increased to 95% (95% CI 94-96%) 14-60 days after the third dose. VE of other homologous and heterologous three dose series was similar. Protection against severe COVID-19 requiring ICU treatment was even better. Since January 1, 2022, Comirnaty VE was 98% (95% CI 92-99%) and 92% (95% CI 87-95%) 14-90 and 91-180 days after the second and 98% (95% CI 95-99%) 14-60 days after the third dose. CONCLUSIONS: VE against severe COVID-19 is high among the elderly. It waned slightly after two doses, but a third restored the protection. VE against severe COVID-19 remained high even after the emergence of Omicron.

Cohort study of Covid-19 vaccine effectiveness among healthcare workers in Finland, December 2020 - October 2021.

Recently, Covid-19 vaccine effectiveness has decreased especially against mild disease due to emergence of the Delta variant and waning protection. In this register-based study among healthcare workers in Finland, the vaccine effectiveness of two-dose mRNA vaccine series against SARS-CoV-2 infection decreased from 82% (95% CI 79-85%) 14-90 days after vaccination to 53% (43-62%) after 6 months. Similar trend was observed for other series. Waning was not observed against Covid-19 hospitalization. These results facilitate decision-making of booster doses for healthcare workers.

Initial assessment of the COVID-19 vaccination's impact on case numbers, hospitalisations and deaths in people aged 80 years and older, 15 EU/EEA countries, December 2020 to May 2021.

Prioritisation of elderly people in COVID-19 vaccination campaigns aimed at reducing severe outcomes in this group. Using EU/EEA surveillance and vaccination uptake, we estimated the risk ratio of case, hospitalisation and death notifications in people 80 years and older compared with 25-59-year-olds. Highest impact was observed for full vaccination uptake 80% or higher with reductions in notification rates of cases up to 65% (IRR: 0.35; 95% CI: 0.13-0.99), hospitalisations up to 78% (IRR: 0.22; 95% CI: 0.13-0.37) and deaths up to 84% (IRR: 0.16; 95% CI: 0.13-0.20).

Effectiveness of vaccination against SARS-CoV-2 infection and Covid-19 hospitalisation among Finnish elderly and chronically ill-An interim analysis of a nationwide cohort study.

BACKGROUND: In Finland, both mRNA and adenovirus vector (AdV) Covid-19 vaccines have been used after the vaccination campaign started on December 27, 2020. Vaccination of the elderly and chronically ill was prioritized and the interval between doses set to 12 weeks. The objective of this interim analysis was to evaluate first and second dose vaccine effectiveness (VE) in a real-world setting. METHODS: During the first five months of the campaign, a register-based cohort study was conducted in the Finnish elderly aged 70+ years and those aged 16-69 years with medical conditions predisposing to severe Covid-19 (chronically ill). Using Cox regression, VE against SARS-CoV-2 infection and Covid-19 hospitalisation was estimated comparing the hazard in the vaccinated with that in the unvaccinated. RESULTS: The cohorts included 901092 elderly (89% vaccinated) and 774526 chronically ill (69% vaccinated) individuals. Three weeks after the first dose, mRNA VE against infection was 45% (95% confidence interval, 36-53%) and 40% (26-51%) in elderly and chronically ill; mRNA VE against hospitalisation was 63% (49-74%) and 82% (56-93%). In chronically ill, AdV VE was 42% (32-50) and 62% (42-75%) against infection and hospitalisation, respectively. One week after the second dose, mRNA VE against infection was 75% (65-82%) and 77% (65-85%) in elderly and chronically ill; mRNA VE against hospitalisation was 93% (70-98%) and 90% (29-99%). CONCLUSIONS: Covid-19 vaccines protect against SARS-CoV-2 infection and Covid-19 hospitalisation. A single dose provides moderate protection in elderly and chronically ill, although two doses are clearly superior.

Detection of SARS-CoV-2 Infection in Gargle, Spit, and Sputum Specimens.

The gold standard for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection diagnosis is reverse transcription (RT)-PCR from a nasopharyngeal swab specimen (NPS). Its collection involves close contact between patients and health care workers, requiring a significant amount of workforce and putting them at risk of infection. We evaluated self-collection of alternative specimens and compared their sensitivity and cycle threshold (CT) values to those of NPS. We visited acute coronavirus disease 2019 (COVID-19) outpatients to collect concomitant NPS and gargle specimens and had patients self-collect gargle and either sputum or spit specimens the next morning. We included 40 patients and collected 40 concomitant NPS and gargle specimens, as well as 40 gargle, 22 spit, and 16 sputum specimens the next day (2 patients could not produce sputum). All specimens were as sensitive as NPS. Gargle specimens had a sensitivity of 0.97 (95% confidence interval [CI], 0.92 to 1.00), whether collected concomitantly with NPS or the next morning. Next-morning spit and sputum specimens showed sensitivities of 1.00 (95% CI, 1.00 to 1.00) and 0.94 (95% CI, 0.87 to 1.00]), respectively. The gargle specimens had significantly higher mean CT values of 29.89 (standard deviation [SD], 4.63; P < 0.001) and 29.25 (SD, 3.99; P < 0.001) when collected concomitantly and the next morning, respectively, compared to NPS (22.07 [SD, 4.63]). CT values obtained with spit (23.51 [SD, 4.57]; P = 0.11) and sputum (25.82 [SD, 9.21]; P = 0.28) specimens were close to those of NPS. All alternative specimen collection methods were as sensitive as NPS, but spit collection appeared more promising, with a low CT value and ease of collection. Our findings warrant further investigation. IMPORTANCE Control of the COVID-19 pandemic relies heavily on a test-trace-isolate strategy. The most commonly used specimen for diagnosis of SARS-CoV-2 infection is a nasopharyngeal swab. However, this method is quite uncomfortable for the patient, requires specific equipment (nose swabs and containers), and requires close proximity to health care workers, putting them at risk of infection. Developing alternative sampling strategies could decrease the burden for health care workers, help overcome potential shortages of equipment, and improve acceptability of testing by reducing patient discomfort.