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. 2023 Feb 21;20(2):e1004127. doi: 10.1371/journal.pmed.1004127

Safety and effectiveness of monovalent COVID-19 mRNA vaccination and risk factors for hospitalisation caused by the omicron variant in 0.8 million adolescents: A nationwide cohort study in Sweden

Peter Nordström 1,2,*, Marcel Ballin 2, Anna Nordström 3,4
PMCID: PMC9990916  PMID: 36802397

Abstract

Background

Real-world evidence on the safety and effectiveness of Coronavirus Disease 2019 (COVID-19) vaccination against severe disease caused by the omicron variant among adolescents is sparse. In addition, evidence on risk factors for severe COVID-19 disease, and whether vaccination is similarly effective in such risk groups, is unclear. The aim of the present study was therefore to examine the safety and effectiveness of monovalent COVID-19 mRNA vaccination against COVID-19 hospitalisation, and risk factors for COVID-19 hospitalisation in adolescents.

Methods and findings

A cohort study was conducted using Swedish nationwide registers. The safety analysis included all individuals in Sweden born between 2003 and 2009 (aged 11.3 to 19.2 years) given at least 1 dose of monovalent mRNA vaccine (N = 645,355), and never vaccinated controls (N = 186,918). The outcomes included all-cause hospitalisation and 30 selected diagnoses until 5 June 2022. The vaccine effectiveness (VE) against COVID-19 hospitalisation, and risk factors for hospitalisation, were evaluated in adolescents given 2 doses of monovalent mRNA vaccine (N = 501,945), as compared to never vaccinated controls (N = 157,979), for up to 5 months follow-up during an omicron predominant period (1 January 2022 to 5 June 2022). Analyses were adjusted for age, sex, baseline date, and whether the individual was born in Sweden. The safety analysis showed that vaccination was associated with 16% lower (95% confidence interval (CI) [12, 19], p < 0.001) risk of all-cause hospitalisation, and with marginal differences between the groups regarding the 30 selected diagnoses. In the VE analysis, there were 21 cases (0.004%) of COVID-19 hospitalisation among 2-dose recipients and 26 cases (0.016%) among controls, resulting in a VE of 76% (95% CI [57, 87], p < 0.001). Predominant risk factors for COVID-19 hospitalisation included previous infections (bacterial infection, tonsillitis, and pneumonia) (odds ratio [OR]: 14.3, 95% CI [7.7, 26.6], p < 0.001), and cerebral palsy/development disorders (OR: 12.7, 95% CI [6.8, 23.8], p < 0.001), with similar estimates of VE in these subgroups as in the total cohort. The number needed to vaccinate with 2 doses to prevent 1 case of COVID-19 hospitalisation was 8,147 in the total cohort and 1,007 in those with previous infections or developmental disorders. None of the individuals hospitalised due to COVID-19 died within 30 days. Limitations of this study include the observational design and the possibility of unmeasured confounding.

Conclusions

In this nationwide study of Swedish adolescents, monovalent COVID-19 mRNA vaccination was not associated with an increased risk of any serious adverse events resulting in hospitalisation. Vaccination with 2 doses was associated with a lower risk of COVID-19 hospitalisation during an omicron predominant period, also among those with certain predisposing conditions who should be prioritised for vaccination. However, COVID-19 hospitalisation in the general population of adolescents was extremely rare, and additional doses in this population may not be warranted at this stage.

In a nationwide cohort study of 0.8 million adolescents in Sweden, Peter Nordström and colleagues report the safety and effectiveness of monovalent COVID-19 mRNA vaccination and risk factors for hospitalisation caused by the omicron variant.

Author summary

Why was this study done?

Evidence before this study

  • ➢ There is limited evidence on the effectiveness of Coronavirus Disease 2019 (COVID-19) vaccination against severe outcomes during the omicron era among adolescents.

  • ➢ In addition, there is lack of data on whether certain groups of adolescents are at greater risk of severe COVID-19 and should be prioritised in vaccination programs, and whether vaccination is equally effective in such risk groups.

  • ➢ Regarding safety, some studies have indicated a link between COVID-19 mRNA vaccination and increased risk of myocarditis and pericarditis in young men.

What did the researchers do and find?

  • ➢ Using Swedish nationwide health registers, a nationwide cohort of adolescents were followed for up to 5 months during the omicron era to evaluate the safety and effectiveness of monovalent COVID-19 mRNA vaccination against COVID-19 hospitalisation, and risk factors for COVID-19 hospitalisation.

  • ➢ Adolescents vaccinated with at least 1 dose of a monovalent COVID-19 mRNA vaccine did not have a higher risk of hospitalisation for any diagnosis, as compared to unvaccinated adolescents.

  • ➢ In contrast, individuals vaccinated with 2 doses of vaccine had 76% lower risk of being hospitalised due to COVID-19, although only about 7 individuals in 100,000 were hospitalised due to COVID-19 during follow-up.

  • ➢ There were specific risk factors for COVID-19 hospitalisation, including previous infections and different development disorders, which increased the risk of COVID-19 hospitalisation more than 10-fold. Vaccine effectiveness among these individuals was similar as in the rest of the cohort.

What do these findings mean?

  • ➢ Although monovalent COVID-19 mRNA vaccination appears safe and associated with reduced risk of COVID-19 hospitalisation, the risk of severe COVID-19 seems to be extremely low in the general population of adolescents.

  • ➢ Administration of additional vaccine doses to the general population of adolescents may not be warranted at this stage of the pandemic.

  • ➢ In contrast, individuals with a high risk for severe COVID-19 should be prioritised for vaccination.

Introduction

The omicron variant of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) led to a surge in cases among young people during 2022 when several countries lifted or alleviated their restrictions [1]. Although clinical trials showed that the BNT162b2 and mRNA-1273 vaccines had acceptable safety profiles in adolescents and reduced the risk of infection in the short term [2,3], these trials were conducted before the emergence of omicron. Limited sample sizes also hindered the evaluation of the level of protection against severe Coronavirus Disease 2019 (COVID-19), such as hospitalisation, which could be estimated using large-scale observational studies. These studies also offer the possibility of investigating any potential links between vaccination and rare serious adverse events, such as myocarditis [4,5].

Currently, there is limited data on vaccine effectiveness (VE) against severe COVID-19 caused by the omicron variant among adolescents. Two case–control studies found that 2 doses of the BNT162b2 mRNA vaccine had about 80% VE against COVID-19 hospitalisation or death in adolescents during the omicron era [6,7]. However, given their study design, it is difficult to determine how common severe disease is during the omicron era. In addition, little is known about whether certain groups of adolescents should be prioritised for vaccination because of a higher risk of severe COVID-19, and whether vaccination has a similarly protective effect in such risk groups. Moreover, although a third dose, also known as a booster dose, may increase protection against symptomatic omicron infection in adolescents [8,9], the risk of severe COVID-19 after a third dose relative to after the second dose is unclear.

In the present study, we used Swedish nationwide registers to evaluate, among adolescents, (1) the risk of hospitalisation from any cause following monovalent COVID-19 mRNA vaccination, and (2) the effectiveness of monovalent COVID-19 mRNA vaccination against hospitalisation due to COVID-19 and risk factors for COVID-19 hospitalisation during an omicron predominant period.

Methods

Study design and cohorts

This nationwide, retrospective cohort study was approved by the Swedish Ethical Review Authority (number 00094/2021). There was no prospective written analysis plan for the present study, and the construction of the models and analyses were data driven. This study is reported as per the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guideline (S1 STROBE Checklist).

The cohort considered for inclusion was compiled by Statistics Sweden (www.SCB.se); the government agency in charge of nationwide statics in different areas and covering the total population of Sweden. The Public Health Agency of Sweden provided data for all individuals born 2003 to 2009 who were given at least 1 dose of monovalent COVID-19 mRNA vaccine or had a documented SARS-CoV-2 infection until March 2022 (N = 692,419). To vaccinated individuals, Statistics Sweden matched 1 control individual on birth year, sex, and municipality. Controls could not have received a first dose of vaccine at the date when the corresponding vaccinated individual had received 2 doses of vaccine. The cohort was updated with vaccination data and SARS-CoV-2 infections until 2 June 2022. Because 1 control could be matched to several vaccinated individuals, the total eligible cohort consisted of 832,273 individuals, of whom 645,355 had been vaccinated with at least 1 dose, 600,721 had been vaccinated with 2 doses, and 60,391 had been vaccinated with at least 3 doses (Fig 1). In a first set of analyses, named the safety analysis, all diagnoses set during hospitalisation were evaluated in all individuals given at least 1 dose of vaccine during follow-up (N = 645,355) as compared to individuals never vaccinated during follow-up (N = 186,918). In a second set of analyses, VE against COVID-19 hospitalisation was evaluated by comparing individuals given at least 2 doses of vaccine (N = 501,945) to individuals never vaccinated during follow-up (N = 157,979), excluding all individuals with a previous documented SARS-CoV-2 infection (Fig 1). Data on individuals vaccinated against COVID-19 and data on documented SARS-CoV-2 infections were collected from the Swedish Vaccination Register and the SmiNet register, respectively. Both these registers are managed by the Public Health Agency of Sweden and all healthcare providers in Sweden were obliged to report to these registers according to law [10,11].

Fig 1. Description of the study cohort.

Fig 1

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Outcomes

In the safety analysis, based on all diagnoses set in the cohort during inpatient hospital stay until 5 June 2022, results are presented for all-cause hospitalisation and for 30 different diagnoses. The 30 specific diagnoses were selected based on their incidence and general interest given previous reports of links between certain diagnoses and COVID-19 mRNA vaccination [4,12,13]. Only the first diagnosis was evaluated for each individual, and individuals with this diagnosis at baseline were therefore excluded from the prospective analyses.

In the VE analysis, the primary outcome was a main diagnosis of COVID-19 (thus, “due to” COVID-19 rather than “with” COVID-19), set during inpatient hospital stay from 1 January 2022 until 5 June 2022. The secondary outcome was documented SARS-CoV-2 infection of any severity from the SmiNet register, from 1 January 2022 until 28 February 2022, in line with the changes made to testing guidelines in Sweden. For these 2 outcomes, only cases that occurred 7 days after the second dose of vaccine and onwards were counted to ensure the full effect of vaccination. The start of 1 January was selected on the basis that the omicron variant was first documented in Sweden on 29 November 2021 [14], and by early January 2022, it represented >90% of sequenced cases (S1 Table).

Data on all diagnoses used in this study were obtained from the National Patient Register [15] using 10th revision International Classification of Disease codes, starting from 1 January 2016 earliest until 5 June 2022 latest. The definition and diagnostic codes for all diagnoses considered in the safety analysis and for the analysis of risk factors for COVID-19 hospitalisation are shown in Table 1. The positive predictive value for diagnoses set within the National Patient Register differs but has generally been found to be between 85% and 95%, although sensitivity is often lower [15]. Finally, data on death due to COVID-19 or influenza, defined as death within 30 days after the diagnosis, were obtained from the National Cause of Death Register [16].

Table 1. Baseline characteristics of the individuals at date of the first dose of vaccine and in never vaccinated individuals.

Vaccinated with ≥1 dose (N = 645,355) Never vaccinated (N = 186,918) p
Age, years (standard deviation) 15.4 (1.9) 14.8 (2.0) < 0.001
Female sex 318,983 (49.4) 85,798 (45.9) < 0.001
Born in Sweden 567,298 (87.9) 139,213 (74.5) < 0.001
Mean baseline date 10 October 2021 10 October 2021 < 0.001
Previous SARS-CoV-2 infection 91,934 (14.2) 20,896 (11.2) < 0.001
Previous diagnoses (ICD-10 code)
    Any diagnosis 25,686 (4.0) 7,515 (4.0) < 0.001
    Gastroenteritis (A09) 125 (0.019) 37 (0.020) 0.32
    Sepsis (A41) 45 (0.007) 17 (0.009) 0.54
    Erysipelas (A46) 25 (0.004) 9 (0.005) 0.93
    Bacterial infection unspecified (A49) 21 (0.003) 8 (0.004) 0.29
    Mononucleosis (B27) 224 (0.034) 38 (0.020) < 0.001
    Virus infection, unspecified (B34) 114 (0.018) 34 (0.018) 0.59
Chronic lymphocytic leukemia (C91) 30 (0.005) 13 (0.007) 0.07
    Iron deficiency anemia (D50) 93 (0.014) 40 (0.021) 0.16
    Thrombocytopenia (D69) 44 (0.007) 14 (0.007) 0.19
    Agranulocytosis (D70) 24 (0.004) 8 (0.004) 0.93
    Alcohol dependency (F10) 975 (0.15) 313 (0.17) 0.48
    Depressive episode (F32) 881 (0.14) 211 (0.11) < 0.001
    Anxiety state, unspecified (F41) 586 (0.09) 185 (0.10) 0.38
    Allergy or anaphylactic shock (T78) 177 (0.027) 58 (0.031) 0.35
    Anorexia nervosa (F50) 571 (0.088) 107 (0.092) < 0.001
    Epilepsy (G40) 318 (0.049) 113 (0.060) 0.004
    Otitis media (H66) 22 (0.003) 7 (0.004) 0.11
    Myocarditis (I40) 50 (0.008) 19 (0.010) 0.75
    Pericarditis (I30) 26 (0.004) 10 (0.005) 0.62
    Sinusitis (J01) 39 (0.006) 17 (0.009) 0.13
    Tonsillitis (J03) 166 (0.026) 38 (0.020) 0.67
    Chronic tonsillitis (J35) 208 (0.032) 58 (0.031) 0.58
    Upper respiratory infection (J06) 64 (0.010) 18 (0.010) 0.87
    Pneumonia (J15 and J18) 151 (0.023) 40 (0.021) 0.65
    Peritonsillar abscess (J36) 118 (0.018) 37 (0.020) 0.82
    Appendicitis (K35) 2,071 (0.32) 544 (0.29) < 0.001
    Crohn’s disease (K50) 107 (0.017) 39 (0.021) 0.15
    Cutaneous abscess (L02) 72 (0.011) 29 (0.016) 0.09
    Nephritis (N10) 252 (0.039) 53 (0.028) 0.10
    Traumatic brain injury (S06) 1,212 (0.19) 293 (0.16) < 0.001
Combined diagnoses
    Cerebral palsy/development disorders (G80, F73, F82, F84, Q02) 23,093 (3.6) 8,307 (4.4) < 0.001
    Selected infections (A49, J03, J15, J18, J35) 21,208 (3.3) 7,158 (3.8) < 0.001
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All data are shown as number (percentage) unless stated otherwise.

All previous diagnoses were main diagnoses set during inpatient hospital stay from 1 January 2020 earliest until 5 June 2022 latest as obtained from the National Patient Register, with the exception of the diagnoses listed under “combined diagnoses,” for which diagnoses set from 1 January 2016 and later was used and including secondary outpatient care.

Statistical analysis

In the safety analysis, diagnoses were evaluated before and after the first dose of vaccine in 645,355 individuals given at least 1 dose of vaccine and in 186,918 controls who were unvaccinated during the follow-up time. The baseline date in vaccinated individuals was the date of vaccination with the first dose. In the controls, a baseline date was randomly assigned based on the mean baseline date and standard deviation among the vaccinated individuals (10 October 2021 ± 54 days). Student t tests and chi-squared tests were used to compare the prevalence of different variables at baseline. To estimate hazard ratios (HRs) for all-cause hospitalisation and for the 30 different diagnoses during follow-up, Cox regression models were used. Individuals were censored on the date of the diagnosis of interest, death, or end of follow-up (5 June 2022), whichever came first.

In the VE analysis, the proportional hazards assumption was not met; hence, logistic regression was used to estimate odds ratios (ORs) for the primary outcome of COVID-19 hospitalisation (from 1 January 2022 until 5 June 2022), and for the secondary outcome of a SARS-CoV-2 infection (from 1 January 2022 until 28 February 2022). The ORs obtained were used to estimate VE as 1 minus the OR × 100. In all analyses, the first model was unadjusted and the second model was adjusted for baseline date, age, sex, and whether the individual was born in Sweden or not. Data underlying these covariates were retrieved from Statistics Sweden [17]. To investigate whether VE differed by the covariates, interaction analyses were performed using product terms created by multiplying the variable coding for vaccination status at baseline (vaccinated/unvaccinated) by each respective covariate, which was added to the logistic regression model. Given that the interaction term was statistically significant (p < 0.05) for the baseline date, VE was also estimated in subgroups according to this covariate. The number needed to vaccinate (NNV) with 2 doses to prevent 1 case of COVID-19 hospitalisation during follow-up was estimated as the inverse of the absolute risk difference between the groups (vaccinated/unvaccinated).

Finally, a sensitivity analysis using a negative control outcome was conducted to explore the potential risk of bias due to unmeasured confounding [18]. Here, a logistic regression model was performed, comparing individuals given at least 2 doses of COVID-19 mRNA vaccine compared to never vaccinated individuals concerning the outcome of hospitalisation due to influenza from 1 January 2022 until 5 June 2022. All analyses were performed in SPSS v29.0 for Mac (IBM, Armonk, New York, USA), and Stata v16.1 for Mac (Statcorp, College Station, Texas, USA). A two-sided p-value < 0.05 or ORs/HRs with 95% confidence intervals (CIs) not crossing one were considered statistically significant.

Results

The total cohort comprised 832,273 adolescents born 2003 to 2009 (age 11.3 to 19.2 years), of whom 645,355 received at least 1 dose of COVID-19 mRNA vaccine and 186,918 never vaccinated individuals (controls). Almost 90% of the vaccinated individuals received BNT162b2 as a first dose, while the remaining received mRNA-1273. Baseline characteristics are shown in Table 1. Individuals that were never vaccinated were slightly younger, more often of male sex and born outside of Sweden, and less often diagnosed with a previous SARS-CoV-2 infection before baseline (p < 0.001 for all). Concerning other diagnoses at baseline, differences between the groups were marginal (Table 1).

Serious adverse events after a first dose of vaccine

In the safety analysis (N = 832,273), there were a total of 19,580 all-cause hospitalisations among 14,266 individuals during follow-up. In vaccinated individuals, 1.69% (N = 10,906) were hospitalised at least once, compared to 1.80% (N = 3,360) in those never vaccinated (HR; 0.84, 95% CI [0.81, 0.88], p < 0.001; Table 2). There were marginal differences between the 2 groups in the 30 selected diagnoses (Table 2), although statistically significant associations in favour of vaccination were observed with respect to the risk of sepsis, thrombocytopenia, alcohol dependency, peritonsillar abscess, and Crohn’s disease (p < 0.05 for all). None of the other associations were statistically significant after adjustment.

Table 2. Risk of hospitalisation for any cause and for 30 selected diagnoses in vaccinated individuals vaccinated compared to never vaccinated individuals.

Vaccinated with ≥1 one dose (N = 645,355) Never vaccinated (N = 186,918) Unadjusted analyses Adjusted analyses
Outcome Number of cases (IR) Number of cases (IR) HR [95% CI] p HR [95% CI] p
All-cause hospitalisation 10,906 (71.9) 3,360 (76.5) 0.94 (0.91, 0.98) 0.003 0.84 (0.81, 0.88) < 0.001
Hospitalisation for selected diagnosis (ICD-10 code)
    Gastroenteritis (A09) 58 (0.38) 20 (0.45) 0.85 (0.51, 1.42) 0.54 0.99 (0.56, 1.66) 0.89
    Sepsis (A41) 5 (0.03) 7 (0.16) 0.20 (0.06, 0.64) 0.006 0.17 (0.05, 0.56) 0.003
    Erysipelas (A46) 8 (0.05) 2 (0.05) 1.28 (0.27, 6.15) 0.76 0.99 (0.18, 5.41) 0.99
    Bacterial infection unspecified (A49) 11 (0.07) 3 (0.07) 1.05 (0.29, 3.76) 0.94 0.83 (0.23, 3.05) 0.78
    Mononucleosis (B27) 115 (0.76) 26 (0.59) 1.27 (0.83, 1.95) 0.27 0.78 (0.50, 1.21) 0.26
    Virus infection, unspecified (B34) 42 (0.28) 7 (0.16) 1.74 (0.78, 3.86) 0.18 1.52 (0.67, 3.43) 0.32
    Chronic lymphocytic leukemia (C91) 4 (0.03) 4 (0.09) 0.29 (0.07, 1.16) 0.08 0.36 (0.08, 1.50) 0.16
    Iron deficiency anemia (D50) 38 (0.25) 14 (0.32) 0.79 (0.43, 1.46) 0.45 0.88 (0.47, 1.66) 0.70
    Thrombocytopenia (D69) 8 (0.05) 10 (0.23) 0.18 (0.10, 0.65) 0.004 0.21 (0.08, 0.58) 0.002
    Agranulocytosis (D70) 1 (0.007) 1 (0.02) - - -
    Alcohol dependency (F10) 409 (2.69) 123 (2.80) 0.97 (0.79, 1.18) 0.74 0.75 (0.61, 0.93) 0.008
    Depressive episode (F32) 363 (2.39) 102 (2.32) 1.03 (0.83, 1.29) 0.77 0.88 (0.70, 1.11) 0.28
    Anxiety state, unspecified (F41) 341 (2.25) 75 (1.70) 1.40 (1.09, 1.80) 0.009 0.92 (0.71, 1.19) 0.51
    Allergy or anaphylactic shock (T78) 64 (0.42) 23 (0.52) 0.81 (0.50, 1.30) 0.38 0.70 (0.43, 1.15) 0.16
    Anorexia nervosa (F50) 197 (1.30) 47 (1.07) 1.21 (0.88, 1.67) 0.23 1.08 (0.78, 1.50) 0.64
    Epilepsy (G40) 82 (0.54) 33 (0.75) 0.72 (0.48, 1.08) 0.12 0.89 (0.57, 1.41) 0.63
    Otitis media (H66) 7 (0.05) 3 (0.07) 0.67 (0.17, 2.60) 0.57 0.70 (0.16, 2.97) 0.63
    Myocarditis (I40) 86 (0.57) 19 (0.43) 1.31 (0.80, 2.15) 0.29 0.99 (0.60, 165) 0.98
    Pericarditis (I30) 21 (0.14) 3 (0.07) 2.00 (0.60, 6.73) 0.26 0.88 (0.26, 3.02) 0.84
    Sinusitis (J01) 15 (0.10) 10 (0.23) 0.43 (0.19, 0.96) 0.04 0.64 (0.26, 1.58) 0.33
    Tonsillitis (J03) 90 (0.59) 11 (0.25) 2.34 (1.25, 4.38) 0.008 1.51 (0.80, 2.86) 0.21
    Chronic tonsillitis (J35) 94 (0.59) 18 (0.41) 1.53 (0.92, 2.53) 0.10 1.15 (0.68, 1.93) 0.60
    Upper respiratory infection (J06) 24 (0.16) 4 (0.09) 1.76 (0.61, 5.10) 0.30 1.72 (0.56, 5.27) 0.35
    Pneumonia (J15 and J18) 68 (0.45) 16 (0.36) 1.26 (0.73, 2.17) 0.41 1.47 (0.82, 2.64) 0.20
    Peritonsillar abscess (J36) 52 (0.34) 17 (0.39) 0.90 (0.52, 1.97) 0.72 0.56 (0.32, 0.98) 0.04
    Appendicitis (K35) 665 (4.38) 174 (3.96) 1.11 (0.94, 1.32) 0.21 1.04 (0.87, 1.23) 0.69
    Crohn’s disease (K50) 24 (0.16) 14 (0.32) 0.49 (0.26, 0.96) 0.04 0.46 (0.23, 0.92) 0.03
    Cutaneous abscess (L02) 10 (0.07) 5 (0.11) 0.58 (0.20, 1.69) 0.32 0.59 (0.20, 1.69) 0.35
    Nephritis (N10) 105 (0.69) 18 (0.41) 1.69 (1.02, 2.79) 0.04 1.22 (0.73, 2.03) 0.45
    Traumatic brain injury (S06) 307 (2.02) 83 (1.89) 1.08 (0.84, 1.37) 0.56 1.09 (0.85, 1.41) 0.50
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CI, confidence interval; HR, hazard ratio. IR = incidence rates per 1 million person-days of follow-up. Adjusted analyses were adjusted for age, sex, baseline date, and whether the individual was born in Sweden.

Vaccine effectiveness against COVID-19 hospitalisation

In the analysis of VE against COVID-19 hospitalisation, 501,945 individuals vaccinated with 2 doses and 157,979 never vaccinated controls were included. Between 1 January 2022 and 5 June 2022, a total of 47 individuals (7 per 100,000) were hospitalised due to COVID-19. Of these, 21 cases were among those vaccinated with 2 doses (0.004%), and 26 among unvaccinated (0.016%), resulting in a VE of 76% (95% CI [57, 87], p < 0.001) (Table 3). The NNV with 2 doses to prevent 1 case of COVID-19 hospitalisation was 8,147. For those with a second dose of vaccine earlier than 15 November, the VE was 69% (95% CI [29, 87], p = 0.006), compared to 87% (95% CI [66, 95], p < 0.001) for those with a second dose of vaccine 15 November 2021 and later (p = 0.03 for interaction). When comparing individuals vaccinated with 3 doses (N = 41,225) compared to those vaccinated with 2 doses (N = 413,544), only 12 individuals in total (2.6 per 100,000 individuals) were hospitalised due to COVID-19 during follow-up (VE; 13%, 95% CI [−354, 84], p = 0.86). There were no deaths within 30 days of hospitalisation among the 261 individuals hospitalised due to COVID-19 in the total cohort (832,273) since the beginning of the pandemic in January 2020.

Table 3. VE against COVID-19 hospitalisation from 7 days onwards after a second dose of vaccine as compared to never vaccinated individuals from 1 January 2022 until 5 June 2022, and by time since vaccination and subgroups.

Vaccinated with 2 doses Never vaccinated Unadjusted analyses Adjusted analyses
Number of cases (%) Number of cases (%) VE [95% CI] p VE [95% CI] p
Total cohort (N = 659,924)a 21 (0.004%) 26 (0.016%) 75 (55, 86) < 0.001 76 (57, 87) < 0.001
Subgroups
Baseline date < 15 Nov 2021 (N = 287,871)b 15 (0.007%) 14 (0.018%) 61 (19, 81) 0.01 69 (29, 87) 0.006
Baseline date > 14 Nov 2021 (N = 372,053)c 6 (0.002%) 12 (0.015%) 86 (63, 95) < 0.001 87 (66, 95) < 0.001
Previously diagnosed with selected infections (N = 21,981)d 4 (0.025%) 11 (0.187%) 87 (58, 96) < 0.001 88 (58, 96) < 0.001
Previously diagnosed with development disorders (N = 25,832)e 6 (0.032%) 9 (0.124%) 74 (27, 91) 0.01 72 (20, 91) 0.02
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CI, confidence interval; VE, vaccine effectiveness.

Adjusted models were adjusted for age, baseline date, sex, and whether the individual was born in Sweden.

aOf which 501,945 were vaccinated and 157,979 never vaccinated.

bOf which 210,747 were vaccinated and 77,124 never vaccinated.

cOf which 291,198 were vaccinated and 87,187 never vaccinated.

dOf which 16,083 were vaccinated and 5,898 never vaccinated.

eOf which 18,553 were vaccinated and 7,279 never vaccinated.

Risk factors for COVID-19 hospitalisation and vaccine effectiveness by subgroups

Of the 47 individuals hospitalised due to COVID-19 in the VE analysis, 28 (60%) had previously been hospitalised for another condition, compared to 66,483 (10%) of the individuals in the rest of the cohort. In addition, of those hospitalised, 15 (32%) had previously been diagnosed with an infection (bacterial infection, tonsillitis, and pneumonia), compared to 21,966 (3.3%) in the rest of the cohort, equal to an adjusted OR for COVID-19 hospitalisation of 14.3 (95% CI [7.7, 26.6], p < 0.001). The VE in this risk group was similar (VE; 88%, 95% CI [58, 96], p < 0.001), as in the total cohort, but with a slightly lower vaccination uptake (73.2% versus 76.2%). In addition, 15 (32%) of the individuals hospitalised due to COVID-19 had previously been diagnosed with cerebral palsy and/or different development disorders, compared to 25,817 individuals (3.9%) in the rest of the cohort, resulting in an adjusted OR for COVID-19 hospitalisation of 12.7 (95% CI [6.8, 23.8], p < 0.001). Again, VE in this subgroup was similar as in the total cohort (VE; 72%, 95% CI [20, 91], p = 0.02), but with a slightly lower vaccination coverage (71.7% versus 76.4%). The NNV with 2 doses to prevent 1 case of COVID-19 hospitalisation in the subgroup of individuals previously diagnosed with infections or development disorders (N = 46,521) was 1,007.

Vaccine effectiveness against SARS-CoV-2 infection

The VE against SARS-CoV-2 infection of any severity was estimated among 488,441 individuals vaccinated with 2 doses compared to 153,882 never vaccinated controls. Between 1 January 2022 and 28 February 2022, there were 72,627 cases of confirmed SARS-CoV-2 infections. The VE varied by time since the last dose (p < 0.001; Table 4), with marginal VE in the total cohort (VE; 4%, 95% CI [3,4], p < 0.001), a low VE for individuals with a second dose no earlier than 1 November 2021 (VE; 27%, 95% CI [25, 29], p < 0.001), and a moderate VE for individuals with a second dose no earlier than 1 January 2022 (VE; 51%, 95% CI, [48, 55], p < 0.001).

Table 4. VE against SARS-CoV-2 infection of any severity from 7 days onwards after a second dose of vaccine as compared to never vaccinated individuals from 1 January 2022 until 28 February 2022, and by baseline date.

Vaccinated with 2 doses Never vaccinated Unadjusted analyses Adjusted analyses
Number of cases (%) Number of cases (%) VE [95% CI] p VE [95% CI] p
Total cohort (N = 642,323)a 55,101 (11.3%) 17,530 (11.4%) 1 (−1, 3) 0.23 4 (3, 4) < 0.001
Subgroups by baseline date
    ≥1 September 2021 (N = 611,401)b 51,497 (11.0%) 16,037 (11.3%) 3 (2, 5) < 0.001 12 (10, 13) < 0.001
    ≥1 October 2021 (N = 477,924)c 32,613 (9.2%) 13,655 (11.0%) 18 (17, 20) < 0.001 17 (15, 19) < 0.001
    ≥1 November 2021 (N = 402,682)d 27,213 (8.8%) 9,743 (10.5%) 18 (16, 20) < 0.001 27 (25, 29) < 0.001
    ≥1 December 2021 (N = 241,350)e 12,547 (6.8%) 5,288 (9.1%) 27 (24, 29) < 0.001 41 (39, 43) < 0.001
    ≥1 January 2022 (N = 105,630)f 2,087 (2.6%) 1,279 (4.8%) 47 (43, 50) < 0.001 51 (48, 55) < 0.001
Open in a new tab

CI, confidence interval; VE, vaccine effectiveness.

Adjusted models were adjusted for age, baseline date, sex, and whether the individual was born in Sweden.

aOf which 488,441 were vaccinated and 153,882 never vaccinated.

bOf which 469,627 were vaccinated and 141,774 never vaccinated.

cOf which 354,304 were vaccinated and 123,620 never vaccinated.

dOf which 309,804 were vaccinated and 92,878 never vaccinated.

eOf which 183,462 were vaccinated and 57,888 never vaccinated.

fOf which 79,161 were vaccinated and 26,469 never vaccinated.

Sensitivity analysis

The risk of hospitalisation due to influenza was evaluated in 600,721 individuals given at least 2 doses of COVID-19 vaccine compared to in 186,894 never vaccinated individuals. Between 1 January 2022 and 5 June 2022, a total of 47 individuals (6 per 100,000) were hospitalised due to influenza. The results showed that individuals vaccinated with 2 doses of vaccine did not experience a lower risk of hospitalisation due to influenza as compared to never vaccinated individuals (VE; −10%, 95% CI [−133, 48], p = 0.81), thus indicating an absence of important unmeasured confounding. Of the 117 individuals in the total cohort hospitalised for influenza since the start of the COVID-19 pandemic in January 2020, 1 individual died within 30 days of hospitalisation.

Discussion

In this nationwide study of more than 0.8 million Swedish adolescents, vaccination with at least 1 dose of monovalent COVID-19 mRNA vaccine was not associated an increased risk of hospitalisation for any cause, and vaccination with 2 doses was associated with lower risk of COVID-19 hospitalisation during an omicron-predominant period. However, the absolute risk of COVID-hospitalisation was extremely low, except in subgroups of adolescents that had previously been diagnosed with infections, cerebral palsy, or other development disorders.

Evidence on the safety and effectiveness of COVID-19 mRNA vaccination in adolescents during the omicron-predominant period is limited. In this study, vaccination was not associated with an increased risk of hospitalisation from any cause, or for any of the 30 selected diagnoses. This suggests that COVID-19 vaccination in adolescents is safe. These findings add to, and extend upon, those from a nationwide study in Scotland, reporting no association between vaccination and increased risk of hospital stay for 17 different diagnoses among adolescents [5]. The present study also estimated that 2 doses of mRNA vaccine had about 76% effectiveness against hospitalisation due to COVID-19. Similar estimates were reported in 2 case–control studies of adolescents conducted in the US and Brazil during an omicron-predominant period, where VE against COVID-19 hospitalisation or death was about 80% [6,7]. However, given their design, these studies were unable to determine how common severe COVID-19 is. Therefore, the very low absolute risk of severe disease observed in the present cohort study is an important finding for decision-making concerning the need for COVID-19 vaccination in adolescents. Overall, only 47 individuals, or 7 in 100,000, were hospitalised due to COVID-19 during a period of 5 months, and none of all adolescents hospitalised due to COVID-19 since the start of the pandemic died within 30 days of hospitalisation. Based on this very low risk of severe COVID-19 in the total cohort, the NNV with 2 doses to prevent 1 case during follow-up was more than 8,000. Interestingly, the absolute risk of being hospitalised due to COVID-19 and influenza was similar, despite that the infection pressure from SARS-CoV-2 during follow-up was more than 100 times higher than that of influenza [19].

Given the above, it is important to evaluate whether certain groups of adolescents are at higher risk of severe COVID-19, and if so, whether vaccination is associated with similar protection among these individuals. This study identified 2 different clusters of diagnoses that increased the risk of COVID-19 hospitalisation more than 10-fold. The first included previous infections (bacterial infection, tonsillitis, and pneumonia), and the second included cerebral palsy and other developmental disorders. An encouraging finding was that the VE in these subgroups was similar to that in the total cohort, and consequently, the NNV to prevent 1 case of COVID-19 hospitalisation was about 1,000 individuals. It is therefore of concern that vaccination coverage in these risk groups was somewhat lower compared to in the total cohort. Although we are unable to determine the underlying causes for this observation, factors such as recurrent infections interfering with the administration of the vaccine, and fear of adverse events, may have contributed. Taken together, these findings suggest that vaccination of adolescents during the omicron era should primarily be targeting those at high risk of severe disease, such as those with previous infections and development disorders.

Concerning the outcome of SARS-CoV-2 infection of any severity, the results indicated that VE from primary vaccination wanes within a few months, similar to observations made in a few other countries [7–9]. However, there is a lack of data exploring whether booster doses reduce the risk of severe COVID-19 as compared to primary vaccination [20]. The results for this comparison in the present study showed that COVID-19 hospitalisations during follow-up were once again extremely rare, implying that administration of booster doses to the general population of adolescents may not be warranted at the current stage of the pandemic. Based on these findings, it is of interest that the US and several countries in Europe are recommending booster doses to adolescents during the omicron era [21,22].

The present study has limitations that should be considered. Because of the observational design, conclusions based on the associations found should be made with caution. For example, despite that VE changed marginally before and after adjustment for covariates, there may be other factors that could have influenced the estimates. However, for the analysis of serious adverse events, we evaluated all diagnoses set during hospital stay both before and after the first dose of vaccine, thereby increasing the chance of detecting selection bias that could interfere with the results. In addition, the sensitivity analysis wherein influenza was used as a negative control outcome supported the lack of important confounding. Moreover, because COVID-19 hospitalisation in this population was very rare, it was not possible to estimate the VE of a first booster dose in this cohort with any form of precision. Finally, another limitation is that even though we excluded all individuals with documented prior SARS-CoV-2 infection, the estimates of VE could be underestimated if some of the individuals in the unvaccinated control group had acquired immunity from a prior SARS-CoV-2 infection that was either asymptomatic or undocumented. Strengths of this study include that all the registers used to obtain the data used in the present study have nationwide coverage with virtually zero loss to follow-up. Finally, the study cohort was based on the total population of Swedish adolescents, including 0.8 million individuals aged 11 to 19 years, which increases the possibility to generalise the findings to other countries with similar population structures.

In summary, monovalent COVID-19 mRNA vaccination was not associated with an increased risk for hospitalisation of any cause in adolescents, suggesting that they are safe to use. While vaccination was associated with a reduced risk of COVID-19 hospitalisation during the omicron era, the absolute risk among the general population of adolescents was extremely low. In contrast, in a large proportion of adolescents hospitalised due to COVID-19, certain risk factors were present, and the effectiveness of vaccination in these individuals was similar to in the total cohort. These results indicate that certain vulnerable subgroups of adolescents, rather than adolescents in general, should be prioritised for vaccination.

Supporting information

S1 STROBE Checklist. STROBE Checklist.

(DOCX)

Click here for additional data file. (34.7KB, docx)
S1 Table. Type of SARS-CoV-2 genotypes based on whole genome sequencing in Sweden during the follow-up period of the present study (week 1–22, 2022).

Data publicly available at the Public Health Agency of Sweden (https://www.folkhalsomyndigheten.se/smittskydd-beredskap/utbrott/aktuellautbrott/covid-19/statistik-och-analyser/sars-cov-2-virusvarianter-av-sarskild-betydelse/).

(PDF)

Click here for additional data file. (138.4KB, pdf)

Abbreviations

CI

confidence interval

COVID-19

Coronavirus Disease 2019

HR

hazard ratio

NNV

number needed to vaccinate

OR

odds ratio

SARS-CoV-2

Severe Acute Respiratory Syndrome Coronavirus 2

VE

vaccine effectiveness

Data Availability

The data underlying the findings of the present study were used under ethical approval and are publicly unavailable according to regulations under Swedish law. Researchers who are interested in obtaining the data can contact Statistics Sweden via mikrodata@scb.se (https://www.scb.se/en/services/ordering-data-and-statistics/ordering-microdata/), National Board of Health and Welfare via registerservice@socialstyrelsen.se (https://bestalladata.socialstyrelsen.se), and Public Health Agency of Sweden via info@folkhalsomyndigheten.se (https://www.folkhalsomyndigheten.se/the-public-health-agency-of-sweden/, and https://www.folkhalsomyndigheten.se/smittskydd-beredskap/utbrott/aktuellautbrott/covid-19/statistik-och-analyser/sars-cov-2-virusvarianter-av-sarskild-betydelse/).

Funding Statement

The author(s) received no specific funding for this work.

References

Decision Letter 0

Philippa Dodd

19 Oct 2022

Dear Dr Nordström,

Thank you for submitting your manuscript entitled "Safety and effectiveness of COVID-19 mRNA vaccination and risk factors for hospitalisation caused by the omicron variant in 0.8 million adolescents: A nationwide cohort study in Sweden" for consideration by PLOS Medicine.

Your manuscript has now been evaluated by the PLOS Medicine editorial staff as well as by an academic editor with relevant expertise and I am writing to let you know that we would like to send your submission out for external peer review.

However, before we can send your manuscript to reviewers, we need you to complete your submission by providing the metadata that is required for full assessment. To this end, please login to Editorial Manager where you will find the paper in the 'Submissions Needing Revisions' folder on your homepage. Please click 'Revise Submission' from the Action Links and complete all additional questions in the submission questionnaire.

Please re-submit your manuscript within two working days, i.e. by Oct 21 2022 11:59PM.

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Feel free to email us at plosmedicine@plos.org if you have any queries relating to your submission.

Kind regards,

Philippa Dodd, MBBS MRCP PhD

Senior Editor

PLOS Medicine

Decision Letter 1

Philippa Dodd

7 Dec 2022

Dear Dr. Nordström,

Thank you very much for submitting your manuscript "Safety and effectiveness of COVID-19 mRNA vaccination and risk factors for hospitalisation caused by the omicron variant in 0.8 million adolescents: A nationwide cohort study in Sweden" (PMEDICINE-D-22-03429R1) for consideration at PLOS Medicine.

Your paper was evaluated by a senior editor and discussed among all the editors here. It was also discussed with an academic editor with relevant expertise, and sent to independent reviewers, including a statistical reviewer. The reviews are appended at the bottom of this email and any accompanying reviewer attachments can be seen via the link below:

[LINK]

In light of these reviews, I am afraid that we will not be able to accept the manuscript for publication in the journal in its current form, but we would like to consider a revised version that addresses the reviewers' and editors' comments. Obviously we cannot make any decision about publication until we have seen the revised manuscript and your response, and we plan to seek re-review by one or more of the reviewers.

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PLOS Medicine

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Requests from the editors:

GENERAL

Please respond to all editor and reviewer comments detailed below, in full

Please ensure that the study is reported according to the STROBE guideline, and include the completed STROBE checklist as Supporting Information. Please add the following statement, or similar, to the Methods: "This study is reported as per the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guideline (S1 Checklist)."

The STROBE guideline can be found here: http://www.equator-network.org/reporting-guidelines/strobe/

When completing the checklist, please use section and paragraph numbers, rather than page numbers.

DATA AVAILABILITY STATEMENT

Thank you for including a Data Availability Statement (DAS) which requires revision. For each data source used in your study:

a) If the data are freely or publicly available, note this and state the location of the data: within the paper, in Supporting Information files, or in a public repository (include the DOI or accession number).

b) If the data are owned by a third party but freely available upon request, please note this and state the owner of the data set and contact information for data requests (web or email address). Note that a study author cannot be the contact person for the data.

c) If the data are not freely available, please describe briefly the ethical, legal, or contractual restriction that prevents you from sharing it. Please also include an appropriate contact (web or email address) for inquiries (again, this cannot be a study author).

COMMENTS FROM THE ACADEMIC EDITOR

It would be of value, if the authors explain why they prefer to select matched controls and thereafter adjust for the matching variables - instead of running the full cohort with adjustments. Less risk of introducing bias in the latter alternative. Further, I would like to underline reviewer #3’s request to, if possible, include more potential confounders from available registers.

ABSTRACT

Abstract Background:

Please ensure that the final sentence clearly states the study question

Line 44: Please include a summary of the adverse events referred to

Abstract methods and findings:

Line 49-50: when reporting statistical information suggest placing a colon after OR instead of a comma, placing CIs within square parentheses and using lower case p, as follows: (OR: 12.0, 95% CI [6.4, 22.6], p<0.001) to improve accessibility to the reader. Please check and amend throughout the manuscript. The use of commas between upper and lower limits adds clarity over the use of hyphens where negative values are reported

Please include any important dependent variables that are adjusted for in the analyses

In the last sentence of the Abstract Methods and Findings section, please describe the main limitation(s) of the study's methodology.

Abstract conclusions:

Line 60: suggest general population of adolescents perhaps? Or something similar

AUTHOR SUMMARY

Thank you for including an author summary

Please change the first sub-heading to “Why was this study done?”

Line 80: starting at “In addition...” suggest this is a separate bullet point

Line 96 onwards: suggest “Clear risk factors for COVID-19 hospitalisation included infections and different developmental disorders, resulting in over a tenfold increased risk of hospitalisation. Vaccine effectiveness among these individuals was similar as in the rest of the cohort.” – I think it might help to elaborate a little on the infections that you mention – what kind? Perhaps would be helpful to broaden the definition in the abstract also

Line 103: as above suggest “general population of adolescents” or something similar. Suggest removing the word “Therefore” and beginning with “Administration…” as a separate bulleted point

Line 105: suggest an individually bulleted point for this statement, which is of significant importance

METHODS and RESULTS

Did your study have a prospective protocol or analysis plan? Please state this (either way) early in the Methods section.

a) If a prospective analysis plan (from your funding proposal, IRB or other ethics committee submission, study protocol, or other planning document written before analyzing the data) was used in designing the study, please include the relevant prospectively written document with your revised manuscript as a Supporting Information file to be published alongside your study, and cite it in the Methods section. A legend for this file should be included at the end of your manuscript.

b) If no such document exists, please make sure that the Methods section transparently describes when analyses were planned, and when/why any data-driven changes to analyses took place.

c) In either case, changes in the analysis-- including those made in response to peer review comments-- should be identified as such in the Methods section of the paper, with rationale.

For all observational studies, we ask that authors ensure the following has been clearly indicated in the manuscript text:

(1) the specific hypotheses you intended to test,

(2) the analytical methods by which you planned to test them,

(3) the analyses you actually performed, and

(4) when reported analyses differ from those that were planned, transparent explanations for differences that affect the reliability of the study's results. If a reported analysis was performed based on an interesting but unanticipated pattern in the data, please be clear that the analysis was data-driven.

Line 194: “….as per when the guidelines for testing in Sweden had changed.” Suggest instead “…in-line with the changes made to testing guidelines in Sweden” or something similar

Please remove “role of the funding source” from the end of the methods section (line 244)

Line 254 onwards: where you report p-values please also report 95% CIs

Line 271: as for the abstract please revise the presentation of statistical information 75% (95% CI [54-86], p<0.001). Please revise throughout to ensure consistency and clarity

Line 306: (VE, 4%, 95% CI, 2-6, 307 P<0.001) perhaps a semicolon following VE? And parentheses and commas for CIs as previously detailed

Line 315: “…with no detectable VE (VE, -6%, 95% CI, -51-119, P=0.88)” is confusing to me, please check and revise accordingly. Please also see reviewer #3 comments.

We agree with the academic editor and the reviewer #3 that adjustment for additional covariates would be beneficial. Please include if possible, if not, please clearly state the reason why.

FIGURES

Line 521 details “Figure legends” but I cannot see any legends in my version of the manuscript or that nay are required, please remove.

Figure 1 – please ensure that all numerical values presented are identical to those in the manuscript text

TABLES

Table 2: Please also present the unadjusted analyses for comparison. As for the adjusted analyses please report 95% CIs and p-values

Table 3 and 4: please also report p-values where you report 95% CIs for adjusted and unadjusted analyses

DISCUSSION

Please remove the sub-heading “conclusions “ such that the discussion reads as single piece of continuous prose ending in the one paragraph conclusion.

Please remove declaration statements from the end of the discussion (line 405, 408, 411) and include only in the submission form when you re-submit your manuscript

REFERENCES

In text reference call outs should be placed within square brackets preceding punctuation as follows: Line 128 – “alleviated their restrictions [1].” As opposed to “alleviated their restrictions.[1]”

Please also remove spaces between citations where more than one study is cited i.e. [1,2,3,4] as opposed to [1, 2, 3, 4]

In the reference list please include up to but no more than 6 author names followed by et al where more than 6 authors contribute to a study

Please use the "Vancouver" style for reference formatting, and see our website for other reference guidelines https://journals.plos.org/plosmedicine/s/submission-guidelines#loc-references

Journal name abbreviations should be those found in the National Center for Biotechnology Information (NCBI) databases.

Comments from the reviewers:

Reviewer #1:

This paper describes the vaccine effectiveness and safety of mRNA COVID-19 vaccines among adolescents in Sweden during Omicron predominance, which is an important and timely topic. VE estimates against hospitalization for adolescents during Omicron predominance are needed, and thus the paper adds important evidence. The paper will be improved by additional explanation of methods and, if possible, inclusion of myocarditis as a specific safety outcome. My specific comments are below:

Specific comments:

1. The authors need to further explain the infection eligibility in the cohort. I don't understand the purpose of this eligibility and matching criteria nor if it was used for an analysis. The authors need to better explain that. This is described as a cohort study, in which case there should not be any selection based on the outcome (SARS-COV-2 infection or hospitalization).

2. The overall conclusion that adolescents may not need COVID-19 vaccination is based on low absolute risk of hospitalization, but this doesn't account for long-COVID or risk of MIS-C, which should be discussed. Additionally, the VE was 75% for hospitalization, meaning that there was a 75% risk reduction in hospitalization for adolescents after 2 doses of vaccination.

3. Also, the outcome of all-cause hospitalization for safety is important. Can the authors potentially also examine myocarditis/pericarditis for a safety outcome? If they cannot, they should mention myocarditis/pericarditis in the discussion.

4. Given that bivalent mRNA vaccines are now in use in multiple countries, the authors need to clearly specify in the title and abstract that these data reflect monovalent mRNA vaccines.

5. Abstract: The sentence regarding vaccine safety should specify that it is all-cause hospitalizations and that vaccinated in that sentence means ≥1 mRNA COVID-19 vaccine dose (which is different from the VE definition).

b. Abstract: Specify what previous infections are risk factors for COVID-19 hospitalizations. Do you mean prior COVID-19 infection as that would be counterintuitive? If this means prior infections, please specify of what and how this is measured.

c. Abstract conclusion regarding safety states "COVID-19 mRNA vaccination was not associated with an increased risk of any serious adverse event in adolescents" but only data on SAEs associated with hospitalization were presented in the abstract. The conclusion should reflect the data presented.

6. Summary: regarding this conclusion: "In contrast, individuals with a high risk for severe COVID-19 should be prioritised for vaccination."

a. It might be helpful to state here whether these individuals with a high risk for severe COVID-19 should be prioritized for primary series, additional doses, or both (likely both).

7. The introduction should include a summary of Sweden's COVID-19 vaccine recommendations for adolescents, so that non-Swedish readers can interpret these data in the context of Sweden's recommendations.

8. Introduction: Lines 134-135: This sentence implies that the data are inconsistent with myocarditis after COVID-19 vaccine. At this point, the data are fairly clear that there is a rare risk of myocarditis/pericarditis after COVID-19 vaccines (https://www.cdc.gov/vaccines/covid-19/clinical-considerations/myocarditis.html), and the risk is highest in adolescent males (half the population in this study). This sentence should be amended to clarify this point.

9. Introduction: Lines 137-139: Please specify the variant period for this 80% VE against hospitalization from prior studies.

10. Methods: Lines 164-165: I found this section a bit hard to follow. Were vaccinated adolescents matched to unvaccinated adolescents regardless of infection status? Similarly were adolescents with infection matched to those without regardless of vaccination status? Can you clarify?

11. Lines 244-245: Role of the funding source: This might be better stated as "no external funding was used for this study," as presumably the authors did this as part of their employment (meaning their time was funded by their employers) and the data likely is funded by Sweden's public health system.

12. Figure 1:

a. It would be helpful to specifically state how many adolescents were excluded with known prior SARS-CoV-2 infection.

b. It would be also helpful in the paper to specify what the hospitalization rate was among adolescents with any known prior SARS-CoV-2 infection is, as these adolescents would presumably be at lower risk of hospitalization. Given that in some countries (such as the US), the majority of people in this age group now have had prior COVID-19 infection, this question is of direct public health relevance.

13. Table 1: It is unclear what the previous ICD-10 diagnoses are from: any previous diagnosis listed in their medical records? Or it is only from a hospitalization? Is this lifetime or over a certain time frame? All that needs to be specified.

14. Results lines 270-275: Please include a median and IQR for times (days if possible) since vaccination. Given that we know that mRNA VE wanes over time in general, but may be more preserved for more severe outcomes, particularly among younger people (like adolescents), any additional data that can be included to allow us to understand whether these data had any suggestion of waning would be very helpful.

15. Results lines 276-277: Please include the percent of adolescents with 3 doses who were hospitalized (i.e. 12/41,225 = 0.029%). This percent appears to be higher than for controls (and 2-dose recipients). Is there a reason for this? What was the booster recommendation? How many days had it been since the booster dose?

16. Results lines 283-285: Among those previously hospitalized for another condition, during what time frame were they hospitalized (over their lifetime versus during a specific timeframe)?

17. Results 285-289: What kind of infection? More specificity on how you defined these ICD codes included in infection needs to be included. What other buckets of previous diagnoses were examined? That is unclear to me. I presume that this is a marker for being higher risk for hospitalization with infections, but do we know why that is? Are these kids with other underlying conditions, such as asthma, technology dependence, immunosuppression, etc?

18. Results: was there overlap between the group previously diagnosed with infection and those with CP or developmental delay?

19. Table 2: How were these 30 diagnostic groups defined? Were they from a list of pre-specified potential COVID risk factors or some other list (like complex chronic conditions of childhood) that has been shown to affect risk of hospitalization or death? That needs to be defined.

20. Table 3: Please include the first date of vaccine eligibility for these adolescents and if possible, median and IQR for days since vaccination.

21. Table 4: Please include the first date of vaccine eligibility for these adolescents (I am guessing it is September 1, 2021) and if possible, median and IQR for days since vaccination.

22. Discussion: Also, what was the infection-induced immunity seroprevalence in Sweden during this time, especially during adolescents? That would helpful add this (or anything known about this) to the discussion to put these results into context.

Reviewer #2: Alex McConnachie, Statistical Review

Nordstrom et al report on a nationwide, retrospective cohort study, looking at the association between COVID-19 mRNA vaccination, and subsequent adverse events and COVID-19 hospitalisations and infections during the omicron wave. This review considers the statistical aspects of the paper.

In short, these are very good. The population, exposures, and outcomes are clearly described. The statistical methods are well described and appropriate. A negative control analysis is also included.

A couple of minor points.

Was the PH assumption checked in the Cox models?

Line 278: I find hyphens don't work in confidence intervals where the values can be negative.

Reviewer #3: Nordström et al. safety of covid-19 vaccination, omicron.

Very important study.

my main objection to this study is that vaccination depends heavily on underlying factors (health seeking behaviour, underlying diseases/comorbidity, perhaps smoking, level of education etc etc), that either a heavily adjusted model or a propensity score model would have been better for this study.

Voluntary/"Elective" vaccinations (e.g. influenza) are often linked to "healthy behaviour" (influenza vaccinations typically protect against death all-year round, even when influenza is not around). if that is the case with covid.19 vaccination, then that would lead to a lower risk of hospitalisation for most things, including covid-19 (the so called vaccine efficiency) in this study.

Abstract, I am particularly happy to see that the authors present absolute risks/numbers needed to treat. I fully agree that needing to vaccinate >9000 teenagers to save 1 hospital admission for covid-19 (with 0 mortality during the Omicron period), argues against general vaccination in this age group.

Research summary; what did the researchers do and fin, please clarify that individuals were followed for 6 months. (study period), to say you followed them until June 2022 says rather little.

I do not understand the statement that covid-19 vaccination was not associated with risk of "any diagnoses" (??), you mean of any covid-19 diagnoses? or any hospital admission??

the safety analysis is important. However, I am surprised the authors did not specifically look at myocarditis/pericarditis since that is where the worry has been, and they even mention these potential adverse events in the research summary of earlier research.

Ethics approval. While informed consent is often waived in register-based studies that is usually not because of their retrospective study design but because of their register-based nature, that already collected data are used, and that the study is simply not feasible/possible if informed consent was required. So the authors may consider removing the argument why informed consent was waived.

Did really Statistics Sweden identify the exposed? That is usually the job of the National Board of Health and Welfare (or perhaps the Public Health Agency). Matching is however done by Statistics Sweden.

Control selection. there is of course a risk that individuals who chose not to vaccinate themselves did so because they were sure they had had covid-19 (even if not documented), and that would lead to a lower risk of covid-19 among the unexposed (thereby underestimating any protective effect of vaccination) how did the authors tackle this?

I like the dummy analyses with influenza as the outcome.

However, I still feel that any vaccination analysis should be adjusted for additional co-variates. I understand that such covariates may not have been available up until "vaccination date" since there is a lag of reporting some data, but perhaps adjust for covariates up until Dec 31, 2021 in your analyses?

in the results you state that controls were less often diagnosed with a previous SARS-COV2 infection, but was not such infection an exclusion criteria for control eligibility??

Sensitivity analysis, how can the VE 95%CI for influensa be -51 to 119, if the Vaccine efficiency was -6% (should be in the middle of the 95%CI, and if that is percent, how an it exceed 100%)?

Table 1. the codes for infections by no means cover all infections, only a small proportion.

a) please clarify that ("selected infections"),

b) add to the table legends what infections were included.

F10 is alcohol dependency, it is "acute alcohol intoxication", typically a young person with binge drinking Friday or Saturday night who ends up in the emergency department.

If you include Crohn's disease (K50) it is strange that you have not included the more common ulcerative colitis (K51)

Minor Table 1. incorrect spelling of "sinusitis"

Any attachments provided with reviews can be seen via the following link:

[LINK]

Decision Letter 2

Philippa Dodd

23 Jan 2023

Dear Dr. Nordström,

Thank you very much for re-submitting your manuscript "Safety and effectiveness of monovalent COVID-19 mRNA vaccination and risk factors for hospitalisation caused by the omicron variant in 0.8 million adolescents: A nationwide cohort study in Sweden" (PMEDICINE-D-22-03429R2) for review by PLOS Medicine.

I have discussed the paper with my colleagues and the academic editor and it was also seen again by xxx reviewers. I am pleased to say that provided the remaining editorial and production issues are dealt with we are planning to accept the paper for publication in the journal.

The remaining issues that need to be addressed are listed at the end of this email. Any accompanying reviewer attachments can be seen via the link below. Please take these into account before resubmitting your manuscript:

[LINK]

***Please note while forming your response, if your article is accepted, you may have the opportunity to make the peer review history publicly available. The record will include editor decision letters (with reviews) and your responses to reviewer comments. If eligible, we will contact you to opt in or out.***

In revising the manuscript for further consideration here, please ensure you address the specific points made by each reviewer and the editors. In your rebuttal letter you should indicate your response to the reviewers' and editors' comments and the changes you have made in the manuscript. Please submit a clean version of the paper as the main article file. A version with changes marked must also be uploaded as a marked up manuscript file.

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Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript.

Please note, when your manuscript is accepted, an uncorrected proof of your manuscript will be published online ahead of the final version, unless you've already opted out via the online submission form. If, for any reason, you do not want an earlier version of your manuscript published online or are unsure if you have already indicated as such, please let the journal staff know immediately at plosmedicine@plos.org.

If you have any questions in the meantime, please contact me or the journal staff on plosmedicine@plos.org.  

We look forward to receiving the revised manuscript by Jan 30 2023 11:59PM.   

Sincerely,

Philippa Dodd, MBBS MRCP PhD

Senior Editor 

PLOS Medicine

plosmedicine.org

------------------------------------------------------------

Requests from Editors:

GENERAL

Thank you for your detailed and considerate responses to previous editor and reviewer comments. Please respond to further outstanding comments as detailed below

STATISTICAL REPORTING

p values should be reported with a lowercase p. Please amend throughout including tables and figures where relevant

DATA AVAILABILITY STATEMENT

Thank you for updating your statement. Please upload this revised statement into the masncuript submission form when you re-submit your manuscript

AUTHOR SUMMARY

What did the researchers do and find – “There were certain strong risk factors….” Suggest instead, “There were specific risk factors for COVID-19 hospitalization including…”

What do these findings mean – point 2 starting “In contrast…” – suggest making this a separate bulleted point

ABSTRACT

Methods and findings section - “Strong risk factors for …” suggest alternative to the word strong perhaps “Predominant”

METHODS

Final paragraph – please ensure that (95%) CI has been defined at first use – I couldn’t see that it had but apologies if I have missed it

RESULTS

Please report p values using a lowercase p. Please check and amend throughout

DISCUSSION

Page 2, paragraph 1, final line: “… be targeting risk groups…” suggest “at risk” or “high risk” or something similar

SOCIAL MEDIA

To help us extend the reach of your research, please provide any Twitter handle(s) that would be appropriate to tag, including your own, your coauthors’, your institution, funder, or lab. Please respond to this email with any handles you wish to be included when we tweet this paper.

Comments from Reviewers:

Reviewer #2: Alex McConnachie, Statistical Review

I had very little to criticise in my original review, and the comments I had have been dealt with. I have no further comments.

Reviewer #3: Congratulations on a nice paper.¨

I especially appreciated the use of a negative control outcome: influenza.

Any attachments provided with reviews can be seen via the following link:

[LINK]

Decision Letter 3

Philippa Dodd

30 Jan 2023

Dear Dr Nordström, 

On behalf of my colleagues and the Academic Editor, Professor Lars Persson, I am pleased to inform you that we have agreed to publish your manuscript "Safety and effectiveness of monovalent COVID-19 mRNA vaccination and risk factors for hospitalisation caused by the omicron variant in 0.8 million adolescents: A nationwide cohort study in Sweden" (PMEDICINE-D-22-03429R3) in PLOS Medicine.

Prior to publication we require that you make the following final corrections:

1) Please ensure that the following statement regarding your data availability is uploaded into the appropriate section of the manuscript submission form (I could only see the previous version of your statement):

“The data underlying the findings of the present study were used under ethical approval and are publicly unavailable according to regulations under Swedish law. Researchers who are interested in obtaining the data can contact Statistics Sweden via mikrodata@scb.se (https://www.scb.se/en/services/ordering-data-and-statistics/ordering-microdata/), National Board of Health and Welfare via registerservice@socialstyrelsen.se (https://bestalladata.socialstyrelsen.se), and Public Health Agency of Sweden via info@folkhalsomyndigheten.se (https://www.folkhalsomyndigheten.se/the-public-healthagency-of-sweden/)”

2) Author Summary:

Thank you for your response and for noting my mistake! My apologies, I was meaning to refer to the “What did the researchers do and find?” section. The 2nd bullet point, where the sentence starts “In contrast…” please make this the 3rd of 4 bullet points.

3) Please ensure that your Twitter handles, as detailed to us below, are uploaded into the appropriate section of the manuscript submission form:

“Uppsala University (@UU_University and @uppsalauni) and Umeå University (@UmeaUniversity and @umeauniversitet).”

Before your manuscript can be formally accepted you will need to complete some formatting changes, which you will receive in a follow up email. Please be aware that it may take several days for you to receive this email; during this time no action is required by you. Once you have received these formatting requests, please note that your manuscript will not be scheduled for publication until you have made the required changes.

In the meantime, please log into Editorial Manager at http://www.editorialmanager.com/pmedicine/, click the "Update My Information" link at the top of the page, and update your user information to ensure an efficient production process. 

PRESS

We frequently collaborate with press offices. If your institution or institutions have a press office, please notify them about your upcoming paper at this point, to enable them to help maximise its impact. If the press office is planning to promote your findings, we would be grateful if they could coordinate with medicinepress@plos.org. If you have not yet opted out of the early version process, we ask that you notify us immediately of any press plans so that we may do so on your behalf.

We also ask that you take this opportunity to read our Embargo Policy regarding the discussion, promotion and media coverage of work that is yet to be published by PLOS. As your manuscript is not yet published, it is bound by the conditions of our Embargo Policy. Please be aware that this policy is in place both to ensure that any press coverage of your article is fully substantiated and to provide a direct link between such coverage and the published work. For full details of our Embargo Policy, please visit http://www.plos.org/about/media-inquiries/embargo-policy/.

To enhance the reproducibility of your results, we recommend that you deposit your laboratory protocols in protocols.io, where a protocol can be assigned its own identifier (DOI) such that it can be cited independently in the future. Additionally, PLOS ONE offers an option to publish peer-reviewed clinical study protocols. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols

Thank you again for submitting to PLOS Medicine, it has been a pleasure handling your manuscript. We look forward to publishing your paper. 

Best wishes,

Pippa

Philippa Dodd, MBBS MRCP PhD 

PLOS Medicine

Associated Data

    This section collects any data citations, data availability statements, or supplementary materials included in this article.

    Supplementary Materials

    S1 STROBE Checklist. STROBE Checklist.

    (DOCX)

    Click here for additional data file. (34.7KB, docx)
    S1 Table. Type of SARS-CoV-2 genotypes based on whole genome sequencing in Sweden during the follow-up period of the present study (week 1–22, 2022).

    Data publicly available at the Public Health Agency of Sweden (https://www.folkhalsomyndigheten.se/smittskydd-beredskap/utbrott/aktuellautbrott/covid-19/statistik-och-analyser/sars-cov-2-virusvarianter-av-sarskild-betydelse/).

    (PDF)

    Click here for additional data file. (138.4KB, pdf)
    Attachment

    Submitted filename: Authors responses 221225.docx

    Click here for additional data file. (65.3KB, docx)
    Attachment

    Submitted filename: Authors respones 230126.docx

    Click here for additional data file. (24.5KB, docx)

    Data Availability Statement

    The data underlying the findings of the present study were used under ethical approval and are publicly unavailable according to regulations under Swedish law. Researchers who are interested in obtaining the data can contact Statistics Sweden via mikrodata@scb.se (https://www.scb.se/en/services/ordering-data-and-statistics/ordering-microdata/), National Board of Health and Welfare via registerservice@socialstyrelsen.se (https://bestalladata.socialstyrelsen.se), and Public Health Agency of Sweden via info@folkhalsomyndigheten.se (https://www.folkhalsomyndigheten.se/the-public-health-agency-of-sweden/, and https://www.folkhalsomyndigheten.se/smittskydd-beredskap/utbrott/aktuellautbrott/covid-19/statistik-och-analyser/sars-cov-2-virusvarianter-av-sarskild-betydelse/).

    Articles from PLOS Medicine are provided here courtesy of PLOS

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