Adverse Events After XBB.1.5-Containing COVID-19 mRNA Vaccines.

This study examines the association between XBB.1.5-containing vaccines administered as a fifth COVID-19 vaccine dose and the risk of 28 adverse events.

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.

Association between atopic disease and vaccination granulomas: A nested case-control study.

BACKGROUND: Vaccination granulomas are observed in 1% of all children vaccinated with an aluminium-adsorbed vaccine. Most children with granulomas also have aluminium contact allergy (CA). CA and atopic diseases are both highly prevalent among children and may be associated. OBJECTIVE: To investigate the association between vaccination granulomas and atopic dermatitis (AD), asthma and rhinitis in children. METHODS: We sourced a cohort of all Danish children born from 2009 to 2017 and conducted a nested case-control study, with cases defined as children with vaccination granulomas, matched to controls 1:10 on sex, socioeconomic class, gestational age and season of birth. All cases and controls were vaccinated with aluminium-adsorbed vaccines and followed until their second birthday. We used conditional logistic regression to estimate the odds ratios (ORs). RESULTS: The study included 2171 cases with vaccination granulomas, and 21 710 controls. Children with a diagnosis of AD had a significantly higher risk of a vaccination granuloma (OR 1.50, 95% confidence intervals [CI] 1.25-1.80). No significant association was found between granulomas and asthma or rhinitis. The association between granulomas and AD was even higher in an additional sensitivity-analysis, following the children until their fourth birthday (OR 2.71, 95% CI 2.36-3.11). CONCLUSION: AD was significantly associated with vaccination granulomas, but not with other atopic diseases, within both the first 2 and 4 years of life.

SARS-CoV-2 Infection and Postacute Risk of Non-Coronavirus Disease 2019 Infectious Disease Hospitalizations: A Nationwide Cohort Study of Danish Adults Aged ≥50 Years.

BACKGROUND: Reports suggest that the potential long-lasting health consequences of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection may involve persistent dysregulation of some immune populations, but the potential clinical implications are unknown. We investigated the associated risk of hospitalization due to non-coronavirus disease 2019 (COVID-19) infectious diseases following the postacute phase of SARS-CoV-2 infection. METHODS: By cross-linking data from the comprehensive Danish test and surveillance system for COVID-19 together with nationwide healthcare and demographic registers, we established a study cohort of 2 430 694 individuals aged ≥50 years, from 1 January 2021 to 10 December 2022, with no evidence of SARS-CoV-2 infection prior to study entry. Using Poisson regression, we compared the outcome rates of non-COVID-19 infectious disease hospitalizations following the acute phase of (a first) SARS-CoV-2 infection (defined as ≥29 days since the day of infection) in recovered individuals with rates among SARS-CoV-2-uninfected individuals. RESULTS: Among 2 430 694 included individuals (mean age, 66.8 [standard deviation, 11.3] years), 930 071 acquired SARS-CoV-2 infection during follow-up totaling 4 519 913 person-years. The postacute phase of SARS-CoV-2 infection was associated with an incidence rate ratio (IRR) of 0.90 (95% confidence interval [CI]: .88-.92) for any infectious disease hospitalization. Findings (IRR [95% CI]) were similar for upper respiratory tract (1.08 [.97-1.20]), lower respiratory tract (0.90 [.87-.93]), influenza (1.04 [.94-1.15]), gastrointestinal (1.28 [.78-2.09]), skin (0.98 [.93-1.03]), urinary tract (1.01 [.96-1.08]), certain invasive bacterial (0.96 [.91-1.01]), and other (0.96 [.92-1.00]) infectious disease hospitalizations and in subgroups. CONCLUSIONS: Our study does not support an increased susceptibility to non-COVID-19 infectious disease hospitalization following SARS-CoV-2 infection.

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 (

Safety of BA.4-5 or BA.1 bivalent mRNA booster vaccines: nationwide cohort study.

OBJECTIVE: To examine the association between the omicron adapted bivalent mRNA covid-19 booster vaccines received as a fourth dose and risk of adverse events. DESIGN: Nationwide cohort study. SETTING: Denmark. PARTICIPANTS: 2 225 567 adults aged ≥50 years who received three covid-19 vaccine doses during the study period, 1 January 2021 to 10 December 2022. MAIN OUTCOME MEASURES: The main outcome measure was rates of hospital visits for 27 different adverse events in a 28 day main risk period after vaccination with a bivalent omicron adapted mRNA booster vaccine as a fourth dose compared with reference period rates from day 29 after the third or fourth vaccine dose and onward. RESULTS: 1 740 417 adults (mean age 67.8 years, standard deviation 10.7 years) received a bivalent mRNA vaccine as a fourth dose. Fourth dose vaccination with a bivalent mRNA vaccine was not associated with a statistically significant increased rate of any of the 27 adverse outcomes within 28 days (eg, incidence rate ratio of 0.95, 95% confidence interval of 0.87 to 1.04 for ischaemic cardiac events based on 672 v 9992 events during the compared 28 day risk and reference period, respectively), nor when analysed according to age, sex, or vaccine type, or when using alternative analytical approaches. However, post hoc analysis detected signals for myocarditis (statistically significant in female participants), although the outcome was rare and findings were based on few cases. No risk of cerebrovascular infarction was found (incidence rate ratio 0.95, 95% confidence interval 0.87 to 1.05; 644 v 9687 events). CONCLUSIONS: The use of bivalent mRNA vaccines as a fourth vaccine dose against covid-19 was not associated with an increased risk of 27 different adverse events in adults aged ≥50 years.

Risk factors for granulomas in children following immunization with aluminium-adsorbed vaccines: A Danish population-based cohort study.

BACKGROUND: Aluminium-adsorbed vaccines may in some children cause severely itching nodules at the injection site, known as vaccination granulomas. OBJECTIVE: To investigate vaccine-, child- and maternal-level risk factors for the development of vaccination granulomas following immunization with aluminium-adsorbed vaccines. METHODS: A Danish population-based cohort study with 553 932 children born in Denmark from 1 January 2009 to 31 December 2018, vaccinated with an aluminium-adsorbed vaccine during the first year of life, followed until 31 December 2020. Poisson regression was used to estimate granuloma rate ratios according to the type of adjuvant, accumulated dose of aluminium, timing of vaccination appointments, sex, gestational age, having siblings with granulomas, maternal age and maternal ethnicity. RESULTS: We identified 1901 vaccination granuloma cases (absolute risk, 0.34%). Among vaccine level factors, revaccination (third vs. first vaccination appointment, adjusted rate ratio [RR] 1.26, 95% confidence interval [CI] 1.03-1.55), the specific adjuvant used (aluminium phosphate vs. hydroxide, RR 0.58, 95% CI 0.48-0.70) and dosage (≥1.0 mg vs. <1.0 mg, RR 1.34, 95% CI 1.19-1.52) were associated with risk of granulomas; the timing of vaccination appointments was not. Among child-level factors, female sex (vs. males, RR 1.12, 95% CI, 1.02-1.22), prematurity (vs. term birth, RR 0.71, 95% CI, 0.54-0.93) and having sibling(s) with granulomas (vs. no siblings with granulomas, RR 46.15, 95% CI, 33.67-63.26) were associated with risk of granulomas. Among maternal-level factors, non-Danish ethnicity (vs. Danish, RR 0.51, 95% CI, 0.42-0.63) and young maternal age (<20 years vs. 20-39 years, RR 0.46, 95% CI 0.25-0.83) were associated with risk of granulomas. CONCLUSIONS: Several risk factors for vaccination granulomas at the vaccine, child and maternal levels, were identified. Reducing the dose of aluminium or replacing aluminium hydroxide with aluminium phosphate could reduce the risk of granulomas. However, this must be balanced against the potential for reduced immunogenicity.

Safety of heterologous primary and booster schedules with ChAdOx1-S and BNT162b2 or mRNA-1273 vaccines: nationwide cohort study.

OBJECTIVE: To assess the risk of adverse events associated with heterologous primary (two dose) and booster (three dose) vaccine schedules for covid-19 with Oxford-AstraZeneca's ChAdOx1-S priming followed by mRNA vaccines (Pfizer-BioNTech's BNT162b2 or Moderna's mRNA-1273) as compared with homologous mRNA vaccine schedules for covid-19. DESIGN: Nationwide cohort study. SETTING: Denmark, 1 January 2021 to 26 March 2022. PARTICIPANTS: Adults aged 18-65 years who received a heterologous vaccine schedule of priming with ChAdOx1-S and one or two mRNA booster doses (with either the BNT162b2 or mRNA-1273 vaccine) were compared with adults who received a homologous BNT162b2 or mRNA-1273 vaccine schedule (ie, two dose v two dose, and three dose v three dose schedule). MAIN OUTCOME MEASURES: The incidence of hospital contacts for a range of adverse cardiovascular and haemostatic events within 28 days after the second or third vaccine dose, comparing heterologous versus homologous vaccine schedules. Secondary outcomes included additional prioritised adverse events of special interest. Poisson regression was used to estimate incidence rate ratios with adjustment for selected covariates. RESULTS: Individuals who had had a heterologous primary vaccine (n=137 495) or a homologous vaccine (n=2 688 142) were identified, in addition to those who had had a heterologous booster (n=129 770) or a homologous booster (n=2 197 213). Adjusted incidence rate ratios of adverse cardiovascular and haemostatic events within 28 days for the heterologous primary and booster vaccine schedules in comparison with the homologous mRNA vaccine schedules were 1.22 (95% confidence interval 0.79 to 1.91) and 1.00 (0.58 to 1.72) for ischaemic cardiac events, 0.74 (0.40 to 1.34) and 0.72 (0.37 to 1.42) for cerebrovascular events, 1.12 (0.13 to 9.58) and 4.74 (0.94 to 24.01) for arterial thromboembolisms, 0.79 (0.45 to 1.38) and 1.09 (0.60 to 1.98) for venous thromboembolisms, 0.84 (0.18 to 3.96) and 1.04 (0.60 to 4.55) for myocarditis or pericarditis, 0.97 (0.45 to 2.10) and 0.89 (0.21 to 3.77) for thrombocytopenia and coagulative disorders, and 1.39 (1.01 to 1.91) and 1.02 (0.70 to 1.47) for other bleeding events, respectively. No associations with any of the outcomes were found when restricting to serious adverse events defined as stay in hospital for more than 24 h. CONCLUSION: Heterologous primary and booster covid-19 vaccine schedules of ChAdOx1-S priming and mRNA booster doses as both second and third doses were not associated with increased risk of serious adverse events compared with homologous mRNA vaccine schedules. These results are reassuring but given the rarity of some of the adverse events, associations cannot be excluded.

Association of AZD1222 and BNT162b2 COVID-19 Vaccination With Thromboembolic and Thrombocytopenic Events in Frontline Personnel : A Retrospective Cohort Study.

BACKGROUND: In March 2021, several European countries suspended the use of the AZD1222 (Oxford-AstraZeneca) COVID-19 vaccine because of thromboembolic safety concerns. Reports from Norway and Germany subsequently described patients with venous thrombosis and thrombocytopenia within 5 to 16 days of vaccination. OBJECTIVE: To evaluate the risk for outcomes related to thrombosis and thrombocytopenia after AZD1222 or BNT162b2 (Pfizer-BioNTech) COVID-19 vaccination. DESIGN: Nationwide exploratory retrospective cohort study. SETTING: Danish linkable registers on vaccinations, hospitalizations, occupation, and other covariates. PARTICIPANTS: 355 209 Danish frontline personnel designated for priority COVID-19 vaccination followed from 27 December 2020 (the day of the first COVID-19 vaccination in Denmark) to 13 April 2021. MEASUREMENTS: Study outcomes were cerebral venous sinus thrombosis, splanchnic vein thrombosis, pulmonary embolism, deep venous thrombosis, arterial thrombosis, thrombocytopenia, and death. Cumulative incidences of study outcomes within 28 days of vaccination and unvaccinated risk time were compared using adjusted survival curves resulting in risk differences (RDs) at day 28 after vaccination. Adjustment for birth cohort, sex, calendar period, occupation, comorbid conditions, and prescription drug use was included. RESULTS: Vaccination with AZD1222 versus no vaccination was associated with a significant RD at day 28 for deep venous thrombosis (RD, 8.35 [95% CI, 0.21 to 16.49] per 100 000 vaccinations). The RDs for cerebral venous sinus thrombosis (RD, 1.68 [CI, -0.64 to 4.00] per 100 000 vaccinations) and thrombocytopenia (RD, 2.39 [CI, -1.09 to 5.87] per 100 000 vaccinations) were not significant. No adverse associations were seen for BNT162b2 vaccination. LIMITATION: No medical record review; surveillance bias. CONCLUSION: In this exploratory retrospective cohort study among frontline personnel in Denmark, receipt of the AZD1222 vaccine was associated with a small excess risk for deep venous thrombosis. Although the corresponding risks for the more rare and severe thrombotic outcomes (such as cerebral venous sinus thrombosis) were not statistically significantly increased, statistical precision was low, and clinically relevant risks could not be excluded with certainty. There was no statistically significant association of BNT162b2 vaccination with thrombotic or thrombocytopenic events. PRIMARY FUNDING SOURCE: Lundbeck Foundation.

SARS-CoV-2 vaccination and myocarditis or myopericarditis: population based cohort study.

OBJECTIVE: To investigate the association between SARS-CoV-2 vaccination and myocarditis or myopericarditis. DESIGN: Population based cohort study. SETTING: Denmark. PARTICIPANTS: 4 931 775 individuals aged 12 years or older, followed from 1 October 2020 to 5 October 2021. MAIN OUTCOME MEASURES: The primary outcome, myocarditis or myopericarditis, was defined as a combination of a hospital diagnosis of myocarditis or pericarditis, increased troponin levels, and a hospital stay lasting more than 24 hours. Follow-up time before vaccination was compared with follow-up time 0-28 days from the day of vaccination for both first and second doses, using Cox proportional hazards regression with age as an underlying timescale to estimate hazard ratios adjusted for sex, comorbidities, and other potential confounders. RESULTS: During follow-up, 269 participants developed myocarditis or myopericarditis, of whom 108 (40%) were 12-39 years old and 196 (73%) were male. Of 3 482 295 individuals vaccinated with BNT162b2 (Pfizer-BioNTech), 48 developed myocarditis or myopericarditis within 28 days from the vaccination date compared with unvaccinated individuals (adjusted hazard ratio 1.34 (95% confidence interval 0.90 to 2.00); absolute rate 1.4 per 100 000 vaccinated individuals within 28 days of vaccination (95% confidence interval 1.0 to 1.8)). Adjusted hazard ratios among female participants only and male participants only were 3.73 (1.82 to 7.65) and 0.82 (0.50 to 1.34), respectively, with corresponding absolute rates of 1.3 (0.8 to 1.9) and 1.5 (1.0 to 2.2) per 100 000 vaccinated individuals within 28 days of vaccination, respectively. The adjusted hazard ratio among 12-39 year olds was 1.48 (0.74 to 2.98) and the absolute rate was 1.6 (1.0 to 2.6) per 100 000 vaccinated individuals within 28 days of vaccination. Among 498 814 individuals vaccinated with mRNA-1273 (Moderna), 21 developed myocarditis or myopericarditis within 28 days from vaccination date (adjusted hazard ratio 3.92 (2.30 to 6.68); absolute rate 4.2 per 100 000 vaccinated individuals within 28 days of vaccination (2.6 to 6.4)). Adjusted hazard ratios among women only and men only were 6.33 (2.11 to 18.96) and 3.22 (1.75 to 5.93), respectively, with corresponding absolute rates of 2.0 (0.7 to 4.8) and 6.3 (3.6 to 10.2) per 100 000 vaccinated individuals within 28 days of vaccination, respectively. The adjusted hazard ratio among 12-39 year olds was 5.24 (2.47 to 11.12) and the absolute rate was 5.7 (3.3 to 9.3) per 100 000 vaccinated individuals within 28 days of vaccination. CONCLUSIONS: Vaccination with mRNA-1273 was associated with a significantly increased risk of myocarditis or myopericarditis in the Danish population, primarily driven by an increased risk among individuals aged 12-39 years, while BNT162b2 vaccination was only associated with a significantly increased risk among women. However, the absolute rate of myocarditis or myopericarditis after SARS-CoV-2 mRNA vaccination was low, even in younger age groups. The benefits of SARS-CoV-2 mRNA vaccination should be taken into account when interpreting these findings. Larger multinational studies are needed to further investigate the risks of myocarditis or myopericarditis after vaccination within smaller subgroups.