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.

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.

Time-varying risk of death after SARS-CoV-2 infection in Swedish long-term care facility residents: a matched cohort study.

OBJECTIVES: To evaluate whether SARS-CoV-2 infection in residents of long-term care (LTC) facilities is associated with higher mortality after the acute phase of infection, and to estimate survival in uninfected residents. DESIGN: Extended follow-up of a previous, propensity score-matched, retrospective cohort study based on the Swedish Senior Alert register. SETTING: LTC facilities in Sweden. PARTICIPANTS: n=3604 LTC residents with documented SARS-CoV-2 until 15 September 2020 matched to 3604 uninfected controls using time-dependent propensity scores on age, sex, health status, comorbidities, prescription medications, geographical region and Senior Alert registration time. In a secondary analysis (n=3731 in each group), geographical region and Senior Alert registration time were not matched for in order to increase the follow-up time in controls and allow for an estimation of median survival. PRIMARY OUTCOME MEASURES: All-cause mortality until 24 October 2020, tracked using the National Cause of Death Register. RESULTS: Median age was 87 years and 65% were women. Excess mortality peaked at 5 days after documented SARS-CoV-2-infection (HR 21.5, 95% CI 15.9 to 29.2), after which excess mortality decreased. From the second month onwards, mortality rate became lower in infected residents than controls. The HR for death during days 61-210 of follow-up was 0.76 (95% CI 0.62 to 0.93). The median survival of uninfected controls was 1.6 years, which was much lower than the national life expectancy in Sweden at age 87 (5.05 years in men, 6.07 years in women). CONCLUSIONS: The risk of death after SARS-CoV-2 infection in LTC residents peaked after 5 days and decreased after 2 months, probably because the frailest residents died during the acute phase, leaving healthier residents remaining. The limited life expectancy in this population suggests that LTC resident status should be accounted for when estimating years of life lost due to COVID-19.

Effectiveness of a fourth dose of mRNA COVID-19 vaccine against all-cause mortality in long-term care facility residents and in the oldest old: A nationwide, retrospective cohort study in Sweden.

Background: The effect of a fourth dose of COVID-19 vaccine on the risk of death in the oldest and frailest individuals is unknown. Methods: Two matched cohorts were formed using Swedish nationwide registers. In the first, residents of long-term care facilities (LTCFs) given a fourth dose of an mRNA vaccine from 1 January 2022 onwards were matched 1:1 on birth year and county of residence to residents given at least a third dose (N = 24,524). In the second, all individuals aged ≥80 years given a fourth dose were matched 1:1 to individuals given at least a third dose (N = 394,104). Cox regression models were used to estimate hazard ratios for all-cause mortality in fourth-dose recipients as compared with in third-dose recipients, with relative vaccine effectiveness (VE) estimated as 1 minus the hazard ratio. Findings: From 7 days after baseline and onwards, there were 1119 deaths in the LTCF cohort during a median follow-up of 77 days and a maximum follow-up of 126 days. During days 7 to 60, the VE of the fourth dose was 39% (95% CI, 29-48), which declined to 27% (95% CI, -2-48) during days 61 to 126. In the cohort of all individuals aged ≥80 years, there were 5753 deaths during a median follow-up of 73 days and a maximum follow-up of 143 days. During days 7 to 60, the VE of the fourth dose was 71% (95% CI, 69-72), which declined to 54% (95% CI, 48-60) during days 61 to 143. The VE of the fourth dose seemed stronger when it was compared to third-dose recipients where at least four months had passed since vaccination (P < 0·001 for interaction). Interpretation: As compared with a third dose, a fourth dose of an mRNA COVID-19 vaccine, administered during the Omicron era, was associated with reduced risk of death from all causes in residents of LTCFs and in the oldest old during the first two months, after which the protection became slightly lower. These findings suggest that a fourth dose may prevent premature mortality in the oldest and frailest even after the emergence of the Omicron variant, although the timing of vaccination seems to be important with respect to the slight waning observed after two months. Funding: There was no funding source for this study.

Risk of SARS-CoV-2 reinfection and COVID-19 hospitalisation in individuals with natural and hybrid immunity: a retrospective, total population cohort study in Sweden.

BACKGROUND: Real-world evidence supporting vaccination against COVID-19 in individuals who have recovered from a previous SARS-CoV-2 infection is sparse. We aimed to investigate the long-term protection from a previous infection (natural immunity) and whether natural immunity plus vaccination (hybrid immunity) was associated with additional protection. METHODS: In this retrospective cohort study, we formed three cohorts using Swedish nationwide registers managed by the Public Health Agency of Sweden, the National Board of Health and Welfare, and Statistics Sweden. Cohort 1 included unvaccinated individuals with natural immunity matched pairwise on birth year and sex to unvaccinated individuals without natural immunity at baseline. Cohort 2 and cohort 3 included individuals vaccinated with one dose (one-dose hybrid immunity) or two doses (two-dose hybrid immunity) of a COVID-19 vaccine, respectively, after a previous infection, matched pairwise on birth year and sex to individuals with natural immunity at baseline. Outcomes of this study were documented SARS-CoV-2 infection from March 20, 2020, until Oct 4, 2021, and inpatient hospitalisation with COVID-19 as main diagnosis from March 30, 2020, until Sept 5, 2021. FINDINGS: Cohort 1 was comprised of 2 039 106 individuals, cohort 2 of 962 318 individuals, and cohort 3 of 567 810 individuals. During a mean follow-up of 164 days (SD 100), 34 090 individuals with natural immunity in cohort 1 were registered as having had a SARS-CoV-2 reinfection compared with 99 168 infections in non-immune individuals; the numbers of hospitalisations were 3195 and 1976, respectively. After the first 3 months, natural immunity was associated with a 95% lower risk of SARS-CoV-2 infection (adjusted hazard ratio [aHR] 0·05 [95% CI 0·05-0·05] p<0·001) and an 87% (0·13 [0·11-0·16]; p<0·001) lower risk of COVID-19 hospitalisation for up to 20 months of follow-up. During a mean follow-up of 52 days (SD 38) in cohort 2, 639 individuals with one-dose hybrid immunity were registered with a SARS-CoV-2 reinfection, compared with 1662 individuals with natural immunity (numbers of hospitalisations were eight and 113, respectively). One-dose hybrid immunity was associated with a 58% lower risk of SARS-CoV-2 reinfection (aHR 0·42 [95% CI 0·38-0·47]; p<0·001) than natural immunity up to the first 2 months, with evidence of attenuation thereafter up to 9 months (p<0·001) of follow-up. During a mean follow-up of 66 days (SD 53) in cohort 3, 438 individuals with two-dose hybrid immunity were registered as having had a SARS-CoV-2 reinfection, compared with 808 individuals with natural immunity (numbers of hospitalisations were six and 40, respectively). Two-dose hybrid immunity was associated with a 66% lower risk of SARS-CoV-2 reinfection (aHR 0·34 [95% CI 0·31-0·39]; p<0·001) than natural immunity, with no significant attenuation up to 9 months (p=0·07). To prevent one reinfection in the natural immunity cohort during follow-up, 767 individuals needed to be vaccinated with two doses. Both one-dose (HR adjusted for age and baseline date 0·06 [95% CI 0·03-0·12]; p<0·001) and two-dose (HR adjusted for age and baseline date 0·10 [0·04-0·22]; p<0·001) hybrid immunity were associated with a lower risk of COVID-19 hospitalisation than natural immunity. INTERPRETATION: The risk of SARS-CoV-2 reinfection and COVID-19 hospitalisation in individuals who have survived and recovered from a previous infection remained low for up to 20 months. Vaccination seemed to further decrease the risk of both outcomes for up to 9 months, although the differences in absolute numbers, especially in hospitalisations, were small. These findings suggest that if passports are used for societal restrictions, they should acknowledge either a previous infection or vaccination as proof of immunity, as opposed to vaccination only. FUNDING: None.

Risk of infection, hospitalisation, and death up to 9 months after a second dose of COVID-19 vaccine: a retrospective, total population cohort study in Sweden.

BACKGROUND: Vaccine effectiveness against COVID-19 beyond 6 months remains incompletely understood. We aimed to investigate the effectiveness of COVID-19 vaccination against the risk of infection, hospitalisation, and death during the first 9 months after vaccination for the total population of Sweden. METHODS: This retrospective, total population cohort study was done using data from Swedish nationwide registers. The cohort comprised all individuals vaccinated with two doses of ChAdOx1 nCoV-19, mRNA-1273, or BNT162b2, and matched unvaccinated individuals, with data on vaccinations and infections updated until Oct 4, 2021. Two outcomes were evaluated. The first was SARS-CoV-2 infection of any severity from Jan 12 to Oct 4, 2021. The second was severe COVID-19, defined as hospitalisation for COVID-19 or all-cause 30-day mortality after confirmed infection, from March 15 to Sept 28, 2021. FINDINGS: Between Dec 28, 2020, and Oct 4, 2021, 842 974 individuals were fully vaccinated (two doses), and were matched (1:1) to an equal number of unvaccinated individuals (total study cohort n=1 685 948). For the outcome SARS-CoV-2 infection of any severity, the vaccine effectiveness of BNT162b2 waned progressively over time, from 92% (95% CI 92 to 93; p<0·001) at 15-30 days, to 47% (39 to 55; p<0·001) at 121-180 days, and to 23% (-2 to 41; p=0·07) from day 211 onwards. Waning was slightly slower for mRNA-1273, with a vaccine effectiveness of 96% (94 to 97; p<0·001) at 15-30 days and 59% (18 to 79; p=0·012) from day 181 onwards. Waning was also slightly slower for heterologous ChAdOx1 nCoV-19 plus an mRNA vaccine, for which vaccine effectiveness was 89% (79 to 94; p<0·001) at 15-30 days and 66% (41 to 80; p<0·001) from day 121 onwards. By contrast, vaccine effectiveness for homologous ChAdOx1 nCoV-19 vaccine was 68% (52 to 79; p<0·001) at 15-30 days, with no detectable effectiveness from day 121 onwards (-19% [-98 to 28]; p=0·49). For the outcome of severe COVID-19, vaccine effectiveness waned from 89% (82 to 93; p<0·001) at 15-30 days to 64% (44 to 77; p<0·001) from day 121 onwards. Overall, there was some evidence for lower vaccine effectiveness in men than in women and in older individuals than in younger individuals. INTERPRETATION: We found progressively waning vaccine effectiveness against SARS-CoV-2 infection of any severity across all subgroups, but the rate of waning differed according to vaccine type. With respect to severe COVID-19, vaccine effectiveness seemed to be better maintained, although some waning became evident after 4 months. The results strengthen the evidence-based rationale for administration of a third vaccine dose as a booster. FUNDING: None.

Effectiveness of heterologous ChAdOx1 nCoV-19 and mRNA prime-boost vaccination against symptomatic Covid-19 infection in Sweden: A nationwide cohort study.

BACKGROUND: The effectiveness of heterologous prime-boost Coronavirus disease 2019 (Covid-19) vaccination is currently unknown. METHODS: From individuals vaccinated with two doses against Covid-19 in Sweden until July 5, 2021 (N=3,445,061), we formed a study cohort including 94,569 individuals that had received heterologous ChAdOx1 nCoV-19 / BNT162b2 prime-boost vaccination, 16,402 individuals that received heterologous ChAdOx1 nCoV-19 / mRNA-1273 prime-boost vaccination, and 430,100 individuals that received homologous ChAdOx1 nCoV-19 / ChAdOx1 nCoV-19 prime-boost vaccination. In addition, 180,716 individuals were selected who were unvaccinated at the date of vaccination in the corresponding case. Unvaccinated individuals were censored at first dose of any vaccine. Baseline was the date of the second dose of any vaccine, with the same date in the corresponding unvaccinated individual. The outcome included incident symptomatic Covid-19 infection occurring >14 days after baseline. FINDINGS: During a mean follow-up time of 76 (range 1-183) days, symptomatic Covid-19 infection was confirmed in 187 individuals with heterologous vaccine schedules (incidence rate: 2.0/100,000 person-days) and in 306 individuals from the unvaccinated control group (incidence rate: 7.1/100,000 person-days). The adjusted vaccine effectiveness was 67% (95% CI, 59-73, P<0.001) for heterologous ChAdOx1 nCoV-19 / BNT162b2 prime-boost vaccination, and 79% (95% CI, 62-88, P<0.001) for heterologous ChAdOx1 nCoV-19 / mRNA-1273 prime-boost vaccination. When combined and analysed together, the two heterologous vaccine schedules had an effectiveness of 68% (95% CI, 61-74, P<0.001) which was significantly greater (Pinteraction<0.001) than the 50% effectiveness for homologous ChAdOx1 nCoV-19 / ChAdOx1 nCoV-19 (95% CI, 41-58, P<0.001). INTERPRETATION: The findings of this study suggest that the use of heterologous ChAdOx1 nCoV-19 and mRNA prime-boost vaccination is an effective alternative to increase population immunity against Covid-19, including against the Delta variant which dominated the confirmed cases during the study period. These findings could have important implications for vaccination strategies and logistics, and consequently in the battle against the Covid-19 pandemic.

Association Between Risk of COVID-19 Infection in Nonimmune Individuals and COVID-19 Immunity in Their Family Members.

Importance: The association between COVID-19 immunity within families and the risk of infection in nonimmune family members is unknown. Objective: To investigate the association between risk of COVID-19 in nonimmune individuals and the number of their family members with known immunity acquired from a previous COVID-19 infection or full vaccination (2 vaccine doses). Design, Setting, and Participants: In this cohort study of data from nationwide registries in Sweden, all individuals who acquired immunity from either previous COVID-19 infection or full vaccination until May 26, 2021, were considered for inclusion. Each person with immunity was matched 1:1 to an individual without immunity from an identified cohort of individuals with families comprising 2 to 5 members. Exposures: Number of immune family members in each family on April 14, 2021 (index date), who acquired immunity from a previous COVID-19 infection or full vaccination (2 doses of the mRNA-1273, BNT162b2 mRNA, or ChAdOx1 nCoV-19 vaccine). Main Outcomes and Measures: Incident COVID-19 infection in nonimmune family members from April 15 to May 26, 2021. Results: A total of 1 789 728 individuals from 814 806 families were included in the analysis. Each family comprised 2 to 5 family members, with a mean (SD) age at baseline of 51.3 (19.5) years. During a mean (range) follow-up time of 26.3 (1-40) days, 88 797 of 1 549 989 (5.7%) nonimmune family members (mean [SD] age, 51.6 [17.7] years; 790 276 men [51.0%]) were diagnosed with COVID-19. There was an inverse dose-response association between the number of immune members in each family and the risk of incident COVID-19 infection in nonimmune family members. Nonimmune families with 1 immune family member had a 45% to 61% lower risk of contracting COVID-19 (hazard ratio [HR], 0.39-0.55; 95% CI, 0.37-0.61, P < .001). The risk reduction increased to 75% to 86% in families with 2 immune family members (HR, 0.14-0.25; 95% CI, 0.11-0.27; P < .001), 91% to 94% with 3 immune family members (HR, 0.06-0.09; 95% CI, 0.04-0.10; P < .001), and 97% with 4 immune family members (HR, 0.03; 95% CI, 0.02-0.05; P < .001). The results were similar for the outcome of COVID-19 infection that was severe enough to warrant a hospital stay. Conclusions and Relevance: In this cohort study, family members without immunity had a 45% to 97% lower risk of contracting COVID-19 as the number of immune family members increased. Vaccination is a key strategy for decreasing the transmission of the virus within families.

Excess Mortality After COVID-19 in Swedish Long-Term Care Facilities.

OBJECTIVE: To compare 30-day mortality in long-term care facility (LTCF) residents with and without COVID-19 and to investigate the impact of 31 potential risk factors for mortality in COVID-19 cases. DESIGN: Retrospective cohort study. SETTING AND PARTICIPANTS: All residents of LTCFs registered in Senior Alert, a Swedish national database of health examinations in older adults, during 2019-2020. METHODS: We selected residents with confirmed COVID-19 until September 15, 2020, along with time-dependent propensity score-matched controls without COVID-19. Exposures were COVID-19, age, sex, comorbidities, medications, and other patient characteristics. The outcome was all-cause 30-day mortality. RESULTS: A total of 3731 residents (median age 87 years, 64.5% female) with COVID-19 were matched to 3731 controls without COVID-19. Thirty-day mortality was 39.9% in COVID-19 cases and 5.7% in controls [relative risk 7.05, 95% confidence interval (CI) 6.10-8.14]. In COVID-19 cases, the odds ratio (OR) for 30-day mortality was 2.44 (95% CI 1.57-3.81) in cases aged 80-84 years, 2.99 (95% CI 1.93-4.65) in cases aged 85-89 years, and 3.28 (95% CI 2.11-5.10) in cases aged ≥90 years, as compared with cases aged <70 years. Other risk factors for mortality among COVID-19 cases included male sex (OR, 2.60, 95% CI 2.22-3.05), neuropsychological conditions (OR, 2.18; 95% CI 1.76-2.71), impaired walking ability (OR, 1.45, 95% CI 1.17-1.78), urinary and bowel incontinence (OR 1.51, 95% CI 1.22-1.85), diabetes (OR 1.36, 95% CI 1.14-1.62), chronic kidney disease (OR 1.37, 95% CI 1.11-1.68) and previous pneumonia (OR 1.57, 95% CI 1.32-1.85). Nutritional factors, cardiovascular diseases, and antihypertensive medications were not significantly associated with mortality. CONCLUSIONS AND IMPLICATIONS: In Swedish LTCFs, COVID-19 was associated with a large excess in mortality after controlling for an extensive number of risk factors. Beyond older age and male sex, several prevalent clinical risk factors independently contributed to higher mortality. These findings suggest that reducing transmission of COVID-19 in LTCFs will likely prevent a considerable number of deaths.

Risk factors for COVID-19 diagnosis, hospitalization, and subsequent all-cause mortality in Sweden: a nationwide study.

We conducted a nationwide, registry-based study to investigate the importance of 34 potential risk factors for coronavirus disease 2019 (COVID-19) diagnosis, hospitalization (with or without intensive care unit [ICU] admission), and subsequent all-cause mortality. The study population comprised all COVID-19 cases confirmed in Sweden by mid-September 2020 (68,575 non-hospitalized, 2494 ICU hospitalized, and 13,589 non-ICU hospitalized) and 434,081 randomly sampled general-population controls. Older age was the strongest risk factor for hospitalization, although the odds of ICU hospitalization decreased after 60-69 years and, after controlling for other risk factors, the odds of non-ICU hospitalization showed no trend after 40-49 years. Residence in a long-term care facility was associated with non-ICU hospitalization. Male sex and the presence of at least one investigated comorbidity or prescription medication were associated with both ICU and non-ICU hospitalization. Three comorbidities associated with both ICU and non-ICU hospitalization were asthma, hypertension, and Down syndrome. History of cancer was not associated with COVID-19 hospitalization, but cancer in the past year was associated with non-ICU hospitalization, after controlling for other risk factors. Cardiovascular disease was weakly associated with non-ICU hospitalization for COVID-19, but not with ICU hospitalization, after adjustment for other risk factors. Excess mortality was observed in both hospitalized and non-hospitalized COVID-19 cases. These results confirm that severe COVID-19 is related to age, sex, and comorbidity in general. The study provides new evidence that hypertension, asthma, Down syndrome, and residence in a long-term care facility are associated with severe COVID-19.