Key Points Question Is SARS-CoV-2 messenger RNA (mRNA) vaccination associated with risk of myocarditis? Findings In a cohort study of 23.1 million residents across 4 Nordic countries, risk of myocarditis after the first and second doses of SARS-CoV-2 mRNA vaccines was highest in young males aged 16 to 24 years after the second dose. For young males receiving 2 doses of the same vaccine, data were compatible with between 4 and 7 excess events in 28 days per 100 000 vaccinees after second-dose BNT162b2, and between 9 and 28 per 100 000 vaccinees after second-dose mRNA-1273. Meaning The risk of myocarditis in this large cohort study was highest in young males after the second SARS-CoV-2 vaccine dose, and this risk should be balanced against the benefits of protecting against severe COVID-19 disease.

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.

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 (</≥70 years) and seemed to be sustained up to six months from the day of vaccination with modest waning. Conclusion Vaccination with bivalent BA.4-5 or BA.1 mRNA booster vaccines as a fourth dose was associated with reduced rates of covid-19 related hospital admission and death among adults aged ≥50 years. The protection afforded by the bivalent BA.4-5 and BA.1 boosters did not differ significantly when directly compared, and any potential difference would most likely be very small in absolute numbers.

ObjectiveTo investigate the clinical outcomes of myocarditis associated with mRNA vaccines against the SARS-CoV-2 virus compared with other types of myocarditis.DesignPopulation based cohort study.SettingNationwide register data from four Nordic countries (Denmark, Finland, Norway, and Sweden), from 1 January 2018 to the latest date of follow-up in 2022.ParticipantsThe 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 measuresHeart 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.ResultsIn 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).ConclusionsCompared 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.

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.