Booster vaccination with SARS-CoV-2 mRNA vaccines and myocarditis in adolescents and young adults: a Nordic cohort study.

BACKGROUND AND AIMS: 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. The aim was to evaluate the risk of myocarditis following SARS-CoV-2 mRNA booster vaccination in 12-to-39-year-olds. METHODS: A multinational cohort study was conducted using nationwide register data in Denmark, Finland, Norway, and Sweden and comprising all 8.9 million individuals residing in each of the four countries. Participants were followed for an inpatient diagnosis of myocarditis. In each of the four countries, Poisson regression was used to estimate adjusted incidence rate ratios (IRRs) of myocarditis comparing vaccination schedules, with associated 95% confidence intervals (CIs). Country-specific results were combined in meta-analyses. RESULTS: A total of 8.9 million residents were followed for 12 271 861 person-years and 1533 cases of myocarditis were identified. 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 the second dose [IRR 2.08 (95% CI 1.31-3.33) and 8.89 (2.26-35.03), respectively]. For females, the corresponding IRR was only estimable for BNT162b2, 3.99 (0.41-38.64). The corresponding absolute risks following the third dose of BNT162b2 and mRNA-1273 in males were 0.86 (95% CI 0.53-1.32) and 1.95 (0.53-4.99) myocarditis events within 28 days per 100 000 individuals vaccinated, respectively. In females, the corresponding absolute risks following the third dose of BNT162b2 were 0.15 (0.04-0.39) events per 100 000 individuals vaccinated. No deaths occurred within 30 days of vaccine-related cases. CONCLUSIONS: The results suggest that a booster dose is associated with increased myocarditis risk in adolescents and young adults. However, the absolute risk of myocarditis following booster vaccination is low.

Postvaccination immune responses and risk of primary total hip arthroplasty-A population-based cohort study.

OBJECTIVE: To investigate the relationship between individual postvaccination immune responses and subsequent risk of total hip arthroplasty (THA) due to idiopathic osteoarthritis (OA) or rheumatoid arthritis (RA). METHOD: Results of tuberculin skin tests (TSTs) following the Bacille Calmette-Guerin (BCG) vaccination were used as a marker of individual immune responses. TST results from the mandatory mass tuberculosis screening program 1948-1975 (n = 236 770) were linked with information on subsequent THA during 1987-2020 from the Norwegian Arthroplasty Register. The multivariable Cox proportional hazard regression was performed. RESULTS: A total of 10 698 individuals received a THA during follow-up. In men, there was no association between TST and risk of THA due to OA (Hazard ratio [HR] 1.01, 95% confidence interval [CI] 0.92-1.12 for positive versus negative TST and HR 1.06, 95% CI 0.95-1.18 for strong positive vs negative TST), while the risk estimates increased with increasingly restrictive sensitivity analyses. In women, there was no association with THA due to OA for positive versus negative TST (HR 0.98, 95% CI 0.92-1.05), while a strong positive TST was associated with reduced risk of THA (HR 0.90, 95% CI 0.84-0.97). No significant associations were observed in the sensitivity analysis for women or for THA due to RA. CONCLUSION: Our results suggest that an increased postvaccination immune response is associated with a nonsignificant trend of increased risk of THA among men and a decreased risk among women, although risk estimates were small.

A combined effect of anti-HPA-1a and anti-HLA Class I in pregnancy?

BACKGROUND: Maternal anti-human leukocyte antigen (HLA) Class I is commonly detected alongside anti-human platelet antigen (HPA)-1a in fetal and neonatal alloimmune thrombocytopenia (FNAIT). Little is known regarding whether the presence of anti-HLA Class I may exert an additive effect on the risk and severity of FNAIT. METHODS AND MATERIALS: We reanalyzed samples originally collected as part of a large Norwegian screening study on FNAIT during 1995-2004. This study identified and managed 170 pregnancies where the mother was HPA-1a negative and had detectable anti-HPA-1a during pregnancy. Maternal samples from 166 of these pregnancies were rescreened for anti-HLA Class I, revealing 111 (67%) that were antibody positive. Various regression models were used to assess if and how maternal anti-HLA Class I influenced the neonatal platelet count. RESULTS AND CONCLUSIONS: Unadjusted neonatal platelet counts and the frequency of neonatal thrombocytopenia was not significantly affected by the presence of anti-HLA Class I alongside anti-HPA-1a, but results from regression analyses revealed a possible increased risk when the mother was nulliparous. These results warrant further investigation.

Covid-19 and influenza vaccine effectiveness against associated hospital admission and death among individuals over 65 years in Norway: A population-based cohort study, 3 October 2022 to 20 June 2023.

BACKGROUND: Co-circulation of SARS-CoV-2 and influenza virus can lead to double epidemics and increased pressure on health systems. To evaluate the effect of both vaccines, we estimated the adjusted vaccine effectiveness (aVE) of influenza and Covid-19 vaccines against related severe disease in the elderly population in Norway during the 2022/2023 season. METHODS: In this population-based cohort study, we included data from the Emergency preparedness register for Covid-19 (Beredt C19) on all individuals ≥ 65 years living in Norway between 3 October 2022 and 20 June 2023. Using Cox-proportional hazard models, we estimated aVE of both influenza and Covid-19 vaccines (bivalent BA.1 and BA.4-5) against associated hospitalisation and death. Vaccine status was included as a time-varying covariate and all models were adjusted for potential confounders, including the other vaccine. RESULTS: We identified 2,437 influenza-associated hospitalisations and 178 deaths, alongside 5,824 Covid-19-associated hospitalisations and 621 deaths. The aVE was highest in the first three months after receiving either vaccine. Against influenza-associated hospitalisation the aVE was 34 % (26 %-42 %) among 65-79-year-olds and 40 % (30 %-48 %) among ≥ 80-year-olds, and 6.6 % (-64 %-47 %) and 37 % (0.5 %-61 %) against influenza-associated death, respectively. The aVE against Covid-19-associated hospitalisation was 65 % (61 %-69 %) among 65-79-year-olds and 55 % (49 %-60 %) among ≥ 80-year-olds (compared to having received the vaccine ≥ 180 days ago). Similarly, the aVE against Covid-19-associated death was 68 % (48 %-80 %) and 78 % (65 %-86 %), respectively. For Covid-19 we show a reduction in aVE with time since dose. CONCLUSION: Covid-19 and influenza vaccines reduced the risk of severe disease in the same high-risk population. Ensuring high uptake of both vaccines could thus limit the overall health care burden.

Dietary inflammatory pattern and risk of hip fracture in the Nurses' Health Study.

Our immune system activity is impacted by what we eat and can influence fracture risk under certain conditions. In this article, we show that postmenopausal women with a pro-inflammatory dietary pattern have an increased risk of hip fracture. PURPOSE: The immune system influences bone homeostasis and can increase the risk of fracture under certain pro-inflammatory conditions. Immune system activity is impacted by dietary patterns. Using the empirical dietary inflammatory pattern (EDIP), we investigated whether postmenopausal women with a pro-inflammatory dietary pattern had an increased risk of hip fracture. METHODS: The study population consisted of postmenopausal women participating in the Nurses' Health Study from 1980 to 2014, who reported information on lifestyle and health, including hip fractures, on biennial questionnaires, while semiquantitative food frequency questionnaires (FFQs) were completed every fourth year. Hazard ratios (HR) for hip fracture were computed using Cox proportional hazards models, adjusting for potential confounders. RESULTS: EDIP was calculated using intake information from the FFQ for 87,955 postmenopausal participants, of whom 2348 sustained a non-traumatic hip fracture during follow-up. After adjustment for confounders, there was a 7% increase in the risk of hip fracture per 1 SD increase in EDIP (HR 1.07, 95% CI 1.02-1.12), and the uppermost quintile had a 22% greater risk compared to the lowest (HR 1.22, 95% CI 1.06-1.40). For the separate components of the EDIP, we found that higher intakes of low-energy beverages (diet sodas) were independently associated with an increased risk of hip fracture, while higher intakes of green leafy vegetables were associated with a reduced risk. CONCLUSION: A pro-inflammatory dietary pattern was associated with an increased risk of hip fracture among postmenopausal women.

Clinical outcomes of myocarditis after SARS-CoV-2 mRNA vaccination in four Nordic countries: population based cohort study.

Objective: To investigate the clinical outcomes of myocarditis associated with mRNA vaccines against the SARS-CoV-2 virus compared with other types of myocarditis. Design: Population based cohort study. Setting: Nationwide register data from four Nordic countries (Denmark, Finland, Norway, and Sweden), from 1 January 2018 to the latest date of follow-up in 2022. Participants: The Nordic myocarditis cohort; 7292 individuals aged ≥12 years who had an incident diagnosis of myocarditis as a main or secondary diagnosis, in a population of 23 million individuals in Denmark, Finland, Norway, and Sweden. Main outcome measures: Heart failure, or death from any cause within 90 days of admission to hospital for new onset myocarditis, and hospital readmission within 90 days of discharge to hospital for new onset myocarditis. Clinical outcomes of myocarditis associated with SARS-CoV-2 mRNA vaccination, covid-19 disease, and conventional myocarditis were compared. Results: In 2018-22, 7292 patients were admitted to hospital with new onset myocarditis, with 530 (7.3%) categorised as having myocarditis associated with SARS-CoV-2 mRNA vaccination, 109 (1.5%) with myocarditis associated with covid-19 disease, and 6653 (91.2%) with conventional myocarditis. At the 90 day follow-up, 62, nine, and 988 patients had been readmitted to hospital in each group (vaccination, covid-19, and conventional myocarditis groups, respectively), corresponding to a relative risk of readmission of 0.79 (95% confidence interval 0.62 to 1.00) and 0.55 (0.30 to 1.04) for the vaccination type and covid-19 type myocarditis groups, respectively, compared with the conventional myocarditis group. At the 90 day follow-up, 27, 18, and 616 patients had a diagnosis of heart failure or died in the vaccination type, covid-19 type, and conventional myocarditis groups, respectively. The relative risk of heart failure within 90 days was 0.56 (95% confidence interval 0.37 to 0.85) and 1.48 (0.86 to 2.54) for myocarditis associated with vaccination and covid-19 disease, respectively, compared with conventional myocarditis; the relative risk of death was 0.48 (0.21 to 1.09) and 2.35 (1.06 to 5.19), respectively. Among patients aged 12-39 years with no predisposing comorbidities, the relative risk of heart failure or death was markedly higher for myocarditis associated with covid-19 disease than for myocarditis associated with vaccination (relative risk 5.78, 1.84 to 18.20). Conclusions: Compared with myocarditis associated with covid-19 disease and conventional myocarditis, myocarditis after vaccination with SARS-CoV-2 mRNA vaccines was associated with better clinical outcomes within 90 days of admission to hospital.

Short-term safety of COVID-19 mRNA vaccines with respect to all-cause mortality in the older population in Norway.

BACKGROUND: There have been concerns about COVID-19 vaccination safety among frail older individuals. We investigated the relationship between COVID-19 mRNA vaccination and mortality among individuals aged ≥ 70 years and whether mortality varies across four groups of health services used. METHODS: In this nationwide cohort study, we included 688,152 individuals aged ≥ 70 years at the start of the Norwegian vaccination campaign (December 27, 2020). We collected individual-level data from theNorwegian Emergency Preparedness Register for COVID-19. Vaccinated and unvaccinated individuals were matched (1:1 ratio) on the date of vaccination based on sociodemographic and clinical characteristics. The main outcome was all-cause mortality during 21 days after first dose of COVID-19 mRNA vaccination. Kaplan-Meier survival functions were estimated for the vaccinated and unvaccinated groups. We used Cox proportional-hazards regression to estimate hazard ratios (HRs) of death between vaccinated and unvaccinated individuals, with associated 95% confidence intervals (CIs), overall and by use of health services (none, home-based, short- and long-term nursing homes) and age group. RESULTS: Between December 27, 2020, and March 31, 2021, 420,771 older individuals (61.1%) were vaccinated against COVID-19. The Kaplan-Meier estimates based on the matched study sample showed a small absolute risk difference in all-cause mortality between vaccinated and unvaccinated individuals, with a lower mortality in the vaccinated group (overall HR 0.28 [95% CI: 0.24-0.31]). Similar results were obtained in analyses stratified by use of health services and age group. CONCLUSION: We found no evidence of increased short-term mortality among vaccinated individuals in the older population after matching on sociodemographic and clinical characteristics affecting vaccination and mortality.

Strong tuberculin response after BCG vaccination is associated with low multiple sclerosis risk: a population-based cohort study.

BACKGROUND: Multiple sclerosis (MS) is characterized by inflammatory lesions in the central nervous system involving pro-inflammatory T-cells. Immune dysregulation is well described in prevalent disease, but it is not known whether this precedes disease development. Bacillus Calmette-Guérin (BCG) vaccination ameliorates MS-like disease in mice. In people vaccinated with BCG, the tuberculin skin test (TST) offers a standardized measure of a T-cell-mediated immune response. We therefore hypothesized that the strength of the TST response after BCG vaccination is associated with subsequent MS risk. METHODS: Using data from a Norwegian tuberculosis screening programme (1963-1975), we designed a population-based cohort study and related the size of TST reactions in individuals previously vaccinated with BCG to later MS disease identified through the Norwegian MS registry. We fitted Cox proportional hazard models and flexible parametric survival models to investigate the association between TST reactivity, MS risk and its temporal relationship. RESULTS: Among 279 891 participants (52% females), 679 (69% females) later developed MS. Larger TST reactivity was associated with decreased MS risk. The hazard ratio for MS per every 4-mm increase in skin induration size was 0.86 (95% confidence interval 0.76-0.96) and similar between sexes. The strength of the association persisted for >30 years after the TST. CONCLUSION: A strong in vivo vaccine response to BCG is associated with reduced MS risk >30 years later. The immunological mechanisms determining TST reactivity suggest that skewed T-cell-mediated immunity precedes MS onset by many decades.

Risk of hip and forearm fracture in subjects with type 2 diabetes mellitus and latent autoimmune diabetes of adults. The HUNT Study, Norway.

Type 1 and type 2 diabetes mellitus incur an increased risk of fracture, with a generally higher risk among individuals with type 1 diabetes. The fracture risk among individuals with latent autoimmune diabetes of adulthood (LADA) is not known. The present cohort study aimed to estimate the risk of hip and forearm fracture among individuals with LADA, alongside type 1 and type 2 diabetes, using data from the second survey of the Trøndelag Health Study (HUNT2) in 1995-97. All inhabitants aged 20 years or older (N = 92,936) were invited to attend, of whom 65,234 (70%) participated. A total of 1972 (3%) reported to have diabetes; 1399 were found to have type 2 diabetes, 144 to have LADA, and 138 to have type 1 diabetes. All participants were followed prospectively with respect to hip- and forearm fractures by linkage to the local fracture registry. During a median follow-up of 16.2 years, 2695 persons with hip fractures and 3533 persons with forearm fractures were identified. There was an increased risk of hip fracture in women with type 2 diabetes (HR = 1.51, 95% CI 1.24-1.85) and LADA (HR = 2.15, 95% CI 1.25-3.72), whereas women with type 1 diabetes did not have a significantly increased risk (HR = 2.13, 95% CI 0.89-5.14). Among men, only LADA was associated with an increased risk of hip fracture (HR = 2.69, 95% CI 1.34-5.41). There was no statistically significant association between any of the diabetes types and forearm fracture. In women with type 2 diabetes, the highest risks of hip fracture were observed among those with highest HbA1c level at baseline, longest time since diagnosis, and most visual and movement impairment. We found that individuals with LADA had an increased risk of hip fracture similar to that previously reported for individuals with type 1 diabetes, and no increased risk of forearm fracture.

Arterial events, venous thromboembolism, thrombocytopenia, and bleeding after vaccination with Oxford-AstraZeneca ChAdOx1-S in Denmark and Norway: population based cohort study.

OBJECTIVE: To assess rates of cardiovascular and haemostatic events in the first 28 days after vaccination with the Oxford-AstraZeneca vaccine ChAdOx1-S in Denmark and Norway and to compare them with rates observed in the general populations. DESIGN: Population based cohort study. SETTING: Nationwide healthcare registers in Denmark and Norway. PARTICIPANTS: All people aged 18-65 years who received a first vaccination with ChAdOx1-S from 9 February 2021 to 11 March 2021. The general populations of Denmark (2016-18) and Norway (2018-19) served as comparator cohorts. MAIN OUTCOME MEASURES: Observed 28 day rates of hospital contacts for incident arterial events, venous thromboembolism, thrombocytopenia/coagulation disorders, and bleeding among vaccinated people compared with expected rates, based on national age and sex specific background rates from the general populations of the two countries. RESULTS: The vaccinated cohorts comprised 148 792 people in Denmark (median age 45 years, 80% women) and 132 472 in Norway (median age 44 years, 78% women), who received their first dose of ChAdOx1-S. Among 281 264 people who received ChAdOx1-S, the standardised morbidity ratio for arterial events was 0.97 (95% confidence interval 0.77 to 1.20). 59 venous thromboembolic events were observed in the vaccinated cohort compared with 30 expected based on the incidence rates in the general population, corresponding to a standardised morbidity ratio of 1.97 (1.50 to 2.54) and 11 (5.6 to 17.0) excess events per 100 000 vaccinations. A higher than expected rate of cerebral venous thrombosis was observed: standardised morbidity ratio 20.25 (8.14 to 41.73); an excess of 2.5 (0.9 to 5.2) events per 100 000 vaccinations. The standardised morbidity ratio for any thrombocytopenia/coagulation disorders was 1.52 (0.97 to 2.25) and for any bleeding was 1.23 (0.97 to 1.55). 15 deaths were observed in the vaccine cohort compared with 44 expected. CONCLUSIONS: Among recipients of ChAdOx1-S, increased rates of venous thromboembolic events, including cerebral venous thrombosis, were observed. For the remaining safety outcomes, results were largely reassuring, with slightly higher rates of thrombocytopenia/coagulation disorders and bleeding, which could be influenced by increased surveillance of vaccine recipients. The absolute risks of venous thromboembolic events were, however, small, and the findings should be interpreted in the light of the proven beneficial effects of the vaccine, the context of the given country, and the limitations to the generalisability of the study findings.

Individual Variation in Adaptive Immune Responses and Risk of Hip Fracture-A NOREPOS Population-Based Cohort Study.

Immune-mediated bone loss significantly impacts fracture risk in patients with autoimmune disease, but to what extent individual variations in immune responses affect fracture risk on a population level is unknown. To examine how immune responses relate to risk of hip fracture, we looked at the individual variation in a post-vaccination skin test response that involves some of the immune pathways that also drive bone loss. From 1963 to 1975, the vast majority of the Norwegian adult population was examined as part of the compulsory nationwide Norwegian mass tuberculosis screening. These examinations included standardized tuberculin skin tests (TSTs). Our study population included young individuals (born 1940 to 1960 and aged 14 to 30 years at examination) who had all received Bacille Calmette-Guerin (BCG) vaccination after a negative TST at least 1 year prior and had no signs of tuberculosis upon clinical examination. The study population ultimately included 244,607 individuals, whose data were linked with a national database of all hospitalized hip fractures in Norway from 1994 to 2013. There were 3517 incident hip fractures during follow-up. Using a predefined Cox model, we found that men with a positive or a strong positive TST result had a 20% (hazard ratio [HR] = 1.20, 95% confidence interval [CI] 1.01-1.44) and 24% (HR = 1.24, 95% CI 1.03-1.49) increased risk of hip fracture, respectively, compared with men with a negative TST. This association was strengthened in sensitivity analyses. Total hip bone mineral density (BMD) was available for a limited subsample and similarly revealed a non-significantly reduced BMD among men with a positive TST. Interestingly, no such clear association was observed in women. An increased immune response after vaccination is associated with an increased risk of hip fracture decades later among men, possibly because of increased immune-mediated bone loss. © 2020 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Unraveling the role of maternal anti-HLA class I antibodies in fetal and neonatal thrombocytopenia-Antibody specificity analysis using epitope data.

Anti-HLA class I antibodies have been suggested as a possible cause of fetal and neonatal alloimmune thrombocytopenia (FNAIT). The aim of this study was to characterize maternal anti-HLA class I alloantibodies in suspected cases of FNAIT. The study population consisted of all nationwide referrals of neonates with suspected FNAIT to the National Unit for Platelet Immunology in Tromsø, Norway, during 1998-2009 (cases), and 250 unselected pregnancies originally included in a prospective study (controls). Inclusion criterion was a positive screening for maternal anti-HLA class I antibodies. Neonates with other identifiable causes of thrombocytopenia, including maternal anti-human platelet antigens (HPA) antibodies, were excluded. Ultimately, 50 cases with suspected FNAIT were compared with 60 controls. The median neonatal platelet count nadir among cases was 24×109/L (range 4-98×109/L). Five children (10%) were reported to have intracranial hemorrhage. Maternal and neonatal HLA class I genotype was available for 33 mother/child pairs (66%). Immunization was not tied to any particular HLA class I antigen. Using epitope mapping, we could demonstrate that the maternal anti-HLA class I antibodies were specific towards mismatched paternally-inherited fetal epitopes, with little reactivity towards any third-party epitopes. Antibody reactivity patterns were similar to those found among controls, although the mean fluorescence intensities (MFI) among cases were significantly higher. This study demonstrates the value of using data on HLA epitope expression, instead of HLA antigens, to examine alloimmune responses in connection with neonatal thrombocytopenia. Our findings support the idea that maternal anti-HLA class I antibodies are involved in FNAIT.