Safety of BNT162b2 mRNA COVID-19 vaccine batches: A nationwide cohort study (preprint)

Background: The safety of the BNT162b2 mRNA COVID-19 vaccine has been extensively evaluated since the global rollout began. While serious adverse events are rare, safety issues continue to arise. This study evaluates the claim that earlier small vaccine batches were associated with higher rates of serious adverse events compared to later batches. Methods: A nationwide cohort study was conducted in Denmark, comprising individuals vaccinated with the BNT162b2 vaccine from 52 pre-defined batches classified into three pre-defined groups. Vaccinated individuals were matched 1:1 between batch groups on age, sex, and vaccination priority group. The study outcomes, included 27 serious adverse events, 2 negative control outcomes and all-cause mortality. Cox regression was used to estimate hazard ratios (HRs) comparing rates between batch groups in the 28-days following vaccination. We conducted two comparisons of the early small batches to two groups of larger batches used later in the pandemic. Results: In the study period, 9,983,448 vaccinations were administered from batches in the three pre-defined groups. Slightly increased rates of arrhythmia were observed in both study comparisons, HRs 1.25 (95% CI,1.05-1.50) and 1.15 (1.00-1.31), respectively, but sensitivity analyses did not robustly support these associations. For the remaining outcomes, increased rates in both study comparisons were not observed. Conclusion: This nationwide cohort study provides reassurance regarding the safety of the BNT162b2 vaccine across different batches used in Denmark. The findings support the overall safety of the vaccine, with no clinically relevant variations in serious adverse event rates between batches.

SARS-CoV-2 infection and post-acute risk of non-Covid-19 infectious disease hospitalizations: a nationwide cohort study of Danish adults aged >=50 years (preprint)

Reports suggest that the potential long-lasting health consequences of SARS-CoV-2 infection may involve persistent dysregulation of some immune populations, but the potential clinical implications are unknown. In a nationwide cohort of 2,430,694 50+-year-olds, we compared the rates of non-Covid-19 infectious disease inpatient hospitalizations (of [≥]5 hours) following the acute phase of SARS-CoV-2 infection in 930,071 individuals with rates among SARS-CoV-2 uninfected from 1 January 2021 to 10 December 2022. The post-acute phase of SARS-CoV-2 infection was associated with an incidence rate ratio of 0.90 (95% confidence interval 0.88-0.92) for any infectious disease hospitalization. Findings were similar for upper- (1.08, 0.97-1.20), lower respiratory tract (0.90, 0.87-0.93), influenza (1.04, 0.94-1.15), gastrointestinal (1.28, 0.78-2.09), skin (0.98, 0.93-1.03), urinary tract (1.01, 0.96-1.08), certain invasive bacterial (0.96, 0.91-0.1.01), and other (0.96, 0.92-1.00) infectious disease hospitalizations and in subgroups. Our study does not support an increased susceptibility to non-Covid-19 infectious disease hospitalization following SARS-CoV-2 infection.

Covid-19 and post-acute sick leave: a hybrid register and questionnaire study in the adult Danish population (preprint)

Long covid follows 10-20% of first-time SARS-CoV-2 infections, but the societal burden of long covid and risk factors for the condition are not well-understood. Here, we report findings about self-reported sick leave and risk factors thereof from a hybrid survey and register study, which included 37,482 RT-PCR confirmed SARS-CoV-2 cases and 51,336 test-negative controls who were tested during the index and alpha waves. An additional 33 individuals per 1000 took substantial sick leave following acute infection compared to persons with no known history of infection, where substantial sick leave was defined as >1 month of sick leave within the period 1-9 months after the RT-PCR test date. Being female, [≥]50 years, and having certain pre-existing conditions such as fibromyalgia increased risks for taking substantial sick leave. Further research exploring this heterogeneity is urgently needed and may provide important evidence for more targeted preventative strategies.

Safety of bivalent omicron-containing mRNA-booster vaccines: a nationwide cohort study (preprint)

Background: Safety data to support bivalent omicron-containing mRNA-booster vaccination are lacking. Methods: In a Danish nationwide cohort study from 1 January 2021 to 10 December 2022, we examined the association between bivalent omicron-containing mRNA-booster vaccination as a fourth Covid-19 vaccine dose and risk of adverse events in individuals aged [≥]50 years. Using incidence rate ratios estimated with Poisson regression, we compared the rates of hospital visits for 27 different adverse events in a 28-day main risk period following vaccination with a bivalent omicron-containing mRNA-booster vaccine as a fourth dose to reference period rates from day 29 after the third or fourth vaccine dose and onward. Secondary analyses included stratifying by sex, age, and vaccine type and assessing the associations using self-controlled case series and observed vs. expected cohort analyses. Results: 1,740,417 individuals (mean age 67.8 years, standard deviation 10.7) received a bivalent omicron-containing mRNA-booster vaccine as a fourth dose. Fourth dose vaccination with a bivalent omicron-containing booster did not statistically significantly increase the rate of any of the 27 adverse outcomes within 28 days, nor when analyzed according to age, sex, vaccine type, or using alternative analytical approaches. However, post-hoc analysis detected signals for myocarditis (statistically significantly so in females), although the outcome was very rare and findings were based on few cases. No risk of cerebrovascular infarction was found. Conclusions: Bivalent omicron-containing mRNA-booster vaccination as a fourth dose was not associated with an increased risk of 27 different adverse events in 50+-year-olds.

Comparative effectiveness of the bivalent BA.4-5 and BA.1 mRNA-booster vaccines in the Nordic countries (preprint)

Background: Data on the comparative vaccine effectiveness (CVE) of the bivalent mRNA-booster vaccines containing the original SARS-CoV-2 and omicron BA.4-5 and BA.1 subvariants are limited. Methods: In a period of BA.4-5 subvariants predominance, we estimated the CVE of the bivalent Comirnaty (Pfizer-BioNTech) and Spikevax (Moderna) BA.4-5 and BA.1 mRNA-booster vaccines given as a fourth dose in Denmark, Finland, Norway, and Sweden. From 1 July 2022 to 12 December 2022, we conducted nationwide cohort analyses using target trial emulation to compare risks of Covid-19 hospitalization and death in four-dose (second booster) with three-dose (first booster) vaccinated and between four-dose vaccinated individuals. Results: Compared with having received three vaccine doses, receipt of a bivalent BA.4-5 booster as a fourth dose was associated with a country-combined CVE against Covid-19 hospitalization of 80.5% (95% confidence interval, 69.5% to 91.5%). The corresponding CVE for bivalent BA.1 boosters was 74.0% (68.6% to 79.4%). CVE against Covid-19 death was 77.8% (48.3% to 100%) and 80.1% (72.0% to 88.2%) for bivalent BA.4-5 and BA.1 boosters as a fourth dose, respectively. The CVE of bivalent BA.4-5 vs. BA.1 boosters were 32.3% (10.6% to 53.9%) for Covid-19 hospitalization and 12.3% (-36.1% to 60.7%) for death (the latter estimable in Denmark only). Conclusions: Vaccination with bivalent BA.4-5 or BA.1 mRNA-booster vaccines as a fourth dose was associated with increased protection against Covid-19 hospitalization and death during a period of BA.4-5 predominance. Bivalent BA.4-5 boosters conferred moderately greater vaccine effectiveness against Covid-19 hospitalization compared with bivalent BA.1 boosters.

Booster Vaccination with SARS-CoV-2 mRNA Vaccines and Myocarditis Risk in Adolescents and Young Adults: A Nordic Cohort Study of 8.9 Million Residents (preprint)

Importance The SARS-CoV-2 mRNA vaccines are associated with an increased risk of myocarditis. This association appears to be strongest in male adolescents and younger males and after the second dose. Few studies have evaluated the association after booster doses. Objective To evaluate the risk of myocarditis following SARS-CoV-2 mRNA booster vaccination in 12-to-39-year-olds. Design A multinational cohort study using nationwide register data. Setting Denmark, Finland, Norway, and Sweden. Participants Cohorts comprising all 8.9 million individuals residing in each of the four countries, born 1982-2009, and alive at start of study on December 27, 2020, without a previous diagnosis of myocarditis or pericarditis or laboratory-confirmed SARS-CoV-2 infection. Exposures The 28-day acute risk periods following the second and third dose of BNT162b2 and mRNA-1273, respectively, in a homologous schedule defines the exposures of interest. Main Outcomes and Measures Cohort participants were followed until an inpatient diagnosis of myocarditis, loss to follow-up, or end of study (latest data availability in each country), whichever occurred first. In each of the four countries, Poisson regression was used to estimate adjusted incidence rate ratios (IRRs) of myocarditis, with associated 95% confidence intervals (CIs), according to vaccination status. Country-specific results were combined in meta-analyses. Results A total of 8.9 million residents were followed for 12,271,861 person-years. We identified 1533 cases of myocarditis. In 12-to-39-year-old males, the 28-day acute risk period following the third dose of BNT162b2 or mRNA-1273 was associated with an increased incidence rate of myocarditis compared to the post-acute risk period 28 days or more after a second homologous dose (IRR, 2.08 [95% CI, 1.31 to 3.33] and 8.89 [95% CI, 2.26 to 35.03], respectively). The corresponding incidence rates following the third dose of BNT162b2 and mRNA-1273 were 0.86 and 1.95, respectively, within 28 days of follow-up among 100,000 individuals. Conclusions and Relevance Our results suggest that a booster dose is associated with increased myocarditis risk in male adolescents and young male adults.

Comparative effectiveness of heterologous booster schedules with AZD1222, BNT162b2, or mRNA-1273 vaccines against COVID-19 during omicron predominance in the Nordic countries (preprint)

Objective: To investigate the effectiveness of heterologous booster schedules with AZD1222 (Oxford-AstraZeneca, referred to as AZD), BNT162b2 (Pfizer-BioNTech, BNT), and mRNA-1273 (Moderna, MOD) vaccines compared with primary schedules and with homologous mRNA-vaccine booster schedules during a period of omicron predominance. Design: Population-based cohort analyses. Setting: Denmark, Finland, Norway, and Sweden, 27 December 2020 to 28 February 2022. Participants: Adults that had received at least a primary vaccination schedule (ie, two doses) of the AZD, BNT, and/or MOD vaccines during the study period. Main outcome measures: Using the Kaplan-Meier estimator, we compared country-specific risks of SARS-CoV-2 infection and severe COVID-19 outcomes in heterologous booster vaccinated with primary schedule vaccinated (matched analyses) and homologous booster vaccinated (weighted analyses) since emergence of omicron. Results: Heterologous booster schedules improved protection against all outcomes compared with primary schedules, with the largest and most robust effects observed for severe COVID-19. Risk differences for documented infection ranged from -22.4% to -3.1% (comparative vaccine effectiveness [CVE] 9.7% to 60.9%; >63.2% for COVID-19 hospitalisation) across countries for AZD1BNT2BNT3 (AZD as primary dose followed by two doses of BNT) vs AZD1BNT2 and -22.2% to -3.2% (CVE 37.4% to 67.8%; >34.6% for hospitalisation) for BNT1BNT2MOD3 vs BNT1BNT2, the two most common heterologous booster schedules. Heterologous- and homologous booster schedules had comparable effectiveness. Risk differences of documented infection ranged from -0.4% to 4.4% (CVE -20.0% to 2.4%) for AZD1BNT2BNT3 vs BNT1BNT2BNT3 and -19.8% to 1.7% (CVE -14.6% to 53.8%) for BNT1BNT2MOD3 vs BNT1BNT2BNT3; for most comparisons, risk differences for severe COVID-19 outcomes were smaller than 1 per 1000 vaccinated. Previous infection followed by a booster dose conferred the greatest protection. Conclusion: Heterologous booster vaccine schedules are associated with an increased protection against omicron-related COVID-19 outcomes that is comparable to that afforded by homologous booster schedules.

THE IMPACT OF THE COVID-19 LOCKDOWN ON BIRTH WEIGHT AMONG SINGLETON TERM BIRTHS IN DENMARK (preprint)

In Denmark, a nationwide COVID-19 lockdown was implemented on March 12, 2020 and eased on April 14, 2020. The COVID-19 lockdown featured reduced prevalence of extremely preterm or extremely low birth weight births. Here we explore the impact of this COVID-19 lockdown on term birth weights in Denmark. We conducted a nationwide register-based cohort study on 27,870 live singleton infants, born at term (weeks 37-41), between March 12 and April 14, 2015-2020, using data from the Danish Neonatal Screening Biobank. Primary outcomes, corrected for confounders, were birth weight, small-for-gestational-age (SGA), and large-for-gestational-age (LGA), comparing the COVID-19 lockdown to the previous five years. Data were analysed using linear regression to assess associations with birth weight. Multinomial logistic regression was used to assess associations with size-for-gestational-age (xGA) categories. Adjusted mean birth weight was significantly increased by 16.9 g (95% CI = 4.1 - 31.3) during the lockdown period. A dip in mean birth weight was found in gestational weeks 37 and 38 balanced by an increase in weeks 40 and 41. The 2020 lockdown period was associated with an increased LGA prevalence (aOR 1.13, 95% CI = 1.05 - 1.21). No significant changes in proportions of xGA groups were found between 2015 and 2019. Conclusion: The nationwide COVID-19 lockdown resulted in a small but significant increase in birth weight and proportion of LGA infants, driven by an increase in birth weight in gestational weeks 40 and 41.

Brief report: Preterm birth rates among twins during the Danish COVID-19 lockdown and mitigation period. (preprint)

Denmarks response to the COVID-19 pandemic was to issue guidelines on containment, isolation, and surveillance. Subsequently, Denmark entered a period with variable mitigation measures including closures of schools and workplaces, travel restrictions, and restrictions on public gatherings. A Danish study covering the lockdown period (March 12 - April 14, 2020) as well as a period of mitigation measures (February 27 - September 30, 2020) showed that the reduction in extremely preterm births was not associated with an increase in singleton stillbirth rate. Subsequent studies examining the impacts of COVID-19 mitigation measures on preterm birth have combined singleton with multifetal pregnancies. However, multifetal pregnancies have a different set of risk factors for preterm birth, as well as, increased risk of adverse outcomes, and a shorter expected pregnancy length. We assessed the impact of the Danish lockdown period, or the mitigation period on multifetal births and found no significant difference in the proportion of preterm twin births among all twin births, either within gestational age groups or in total, for either period.

Post-acute symptoms, new onset diagnoses and health problems 6 to 12 months after SARS-CoV-2 infection: a nationwide questionnaire study in the adult Danish population (preprint)

Background. A considerable number of individuals infected with SARS-CoV-2 continue to experience symptoms after the acute phase. More information on duration and prevalence of these symptoms in non-hospitalized populations is needed. Methods. We conducted a nationwide cross-sectional study including 152 880 individuals aged 15-years or older, consisting of RT-PCR confirmed SARS-CoV-2 cases between September 2020-April 2021 (N=61 002) and a corresponding test-negative control group (N=91 878). Data were collected 6, 9 or 12 months after the test using web-based questionnaires. The questionnaire covered acute and post-acute symptoms, selected diagnoses, sick leave and general health, together with demographics and life style at baseline. Risk differences (RDs) between test-positives and -negatives were reported, adjusted for age, sex, single comorbidities, Charlson comorbidity score, obesity and healthcare-occupation. Findings. Six to twelve months after the test date, the risks of 18 out of 21 physical symptoms were elevated among test-positives and one third (29.6%) of the test-positives experienced at least one physical post-acute symptom. The largest risk differences were observed for dysosmia (RD = 10.92%, 95%CI 10.68-11.21%), dysgeusia (RD=8.68%, 95%CI 8.43-8.93%), fatigue/exhaustion (RD=8.43%, 95%CI 8.14-8.74%), dyspnea (RD=4.87%, 95%CI 4.65-5.09%) and reduced strength in arms/legs (RD=4.68%, 95%CI 4.45-4.89%). More than half (53.1%) of test-positives reported at least one of the following conditions: concentration difficulties (RD=28.34%, 95%CI 27.34-28.78%), memory issues (RD=27.25%, 95%CI 26.80-27.71%), sleep problems (RD=17.27%, 95%CI 16.81-17.73%), mental (RD=32.58%, 95%CI 32.11-33.09%) or physical exhaustion (RD=40.45%, 95%CI 33.99-40.97%), compared to 11.5% of test-negatives. New diagnoses of anxiety (RD=1.15%, 95%CI 0.95-1.34%) or depression (RD=1.00%, 95%CI 0.81-1.19%) were also more common among test-positives. Interpretation. At the population-level, where the majority of test-positives (96.0%) were not hospitalized during acute infection, a considerable proportion experience post-acute symptoms and sequelae 6-12 months after infection. Funding. None

A nationwide study of Chlamydia trachomatis infections in Denmark during the COVID-19 pandemic (preprint)

Objectives: COVID-19 policies have been employed in Denmark since March 2020. We examined whether COVID-19 restrictions had an impact on Chlamydia trachomatis infections compared with 2018 and 2019. Methods: This retrospective nation-wide Danish observational study was performed using monthly incidences of laboratory confirmed chlamydia cases and number of tests, obtained from nation-wide surveillance data. Additionally, Oxford COVID-19 Government Response Tracker data, and Google COVID-19 Community Mobility Reports were used to contextualise the behavioural adaptions seen as a result of COVID-19 policies. Testing rates were compared using Poisson regression and test positivity rates were compared using logistic regression. Results: The crude incidence rate (IR) of laboratory confirmed chlamydia infections was reduced to 66.5 per 105 during the first (March-April 2020) lockdown period as compared to 88.3 per 105 in March-April 2018-2019, but the testing rate was also reduced (Rate ratio 0.72 95% CI 0.71-0.73), whereas the odds ratio for a positive test between the two periods was 0.98 (95% CI 0.96-1.00). The period of eased COVID 19 restrictions (May-December 2020) and the second lockdown period (December 2020-March 2021) were characterised by marginally increased crude IRs, while the number of tests performed, and test positivity rates returned very close to the levels seen in 2018-2019. These results were independent of sex, age group, and geographical location. Conclusion: The first Danish COVID-19 lockdown resulted in a reduction in the number of chlamydia tests performed and a consequent reduction in the number of laboratory-identified cases. This period was followed by a return of testing and test positivity close to the level seen in 2018-2019. Altogether the Danish COVID-19 restrictions have had negligible effects on laboratory confirmed C. trachomatis transmission.

Preterm birth, stillbirth, and early neonatal mortality during the Danish COVID-19 lockdown (preprint)

Importance Using provisional or opportunistic data, three nationwide studies (The Netherlands, USA, and Denmark) have identified a reduction in preterm or extremely preterm births during periods of COVID-19 restrictions. However, these findings have been challenged as none of the studies accounted for perinatal deaths. Objective To determine whether the reduction in extremely preterm births, observed in Denmark during the COVID-19 lockdown, could be a result of an increase in number of perinatal deaths; and to assess the impact of extended COVID-19 restrictions on the prevalence of preterm birth and perinatal death. Design The study is a nationwide Danish register-based prevalence proportion study using detailed data to capture all births (induced abortions were excluded) throughout Denmark. We assessed the prevalence of stillbirth, preterm birth, and early neonatal death. Setting Population-based study Participants All singleton pregnancies delivered in Denmark, between February 27, and September 30, 2015-2020. COVID-19 lockdown was studied in 31,164 births and the extended period of COVID-19 restrictions in 214,862 births. Exposure COVID-19 restrictions broadly (February 27, – September 30, 2020) or COVID-19 lockdown specifically (March 12, – April 14, 2020). Main Outcome Prevalence of preterm births, stillbirths and early neonatal deaths across the periods under study. Results The extremely preterm birth rate was reduced (OR 0.27, 95% CI 0.07 to 0.86) during the strict lockdown period, while perinatal mortality was not significantly different. During the extended period of restrictions, the extremely preterm birth rate was marginally reduced, and a significant reduction in the stillbirth rate (OR 0.69, 0.50 to 0.95) was observed. No changes in early neonatal mortality rates were found. Conclusion and Relevance Stillbirth and extremely preterm birth rates were reduced in Denmark during the period of COVID-19 restrictions and lockdown, respectively, suggesting that aspects of these containment and control measures confer an element of protection. The present observational study does not allow for causal inference; however, the results support design of studies to ascertain whether behavioural or social changes for pregnant women may improve pregnancy outcomes. Funding None Key points Question Can changes in stillbirth and early neonatal mortality rates during the COVID-19 lockdown explain the reduction in extremely preterm birth seen in Denmark? Findings In this nationwide register-based study that included data pertaining to 245,999 pregnancies, the statistically significant reduction in extremely preterm birth during the COVID-19 lockdown was confirmed. The stillbirth and early neonatal mortality rates were unchanged during lockdown, while the stillbirth rate was reduced over the extended period of COVID-19 restrictions. Meaning The reduction in extremely preterm births seen during the COVID-19 lockdown in Denmark is not a result of increased stillbirth or early neonatal death.