Abstract
This cohort study of adults in England evaluates the association of sociodemographic and clinical risk factors with death from COVID-19 among individuals who completed primary vaccination and received a messenger RNA (mRNA) booster.
Introduction
With the emergence of the Omicron variant, it has become critical to identify risk factors associated with COVID-19 death in individuals who have completed primary vaccination and received a messenger RNA (mRNA) booster dose. Existing evidence is based on people who have received 1 or 2 doses of a COVID-19 vaccine and were infected by the Alpha or Delta variant.1,2,3 Understanding which groups are at increased risk of COVID-19 death after receiving a booster is crucial for the prioritization of further booster doses and access to COVID-19 therapeutics.
Methods
We used data from the Office for National Statistics Public Health Data Asset, a population-level linked data set combining the 2011 Census of England and Wales and electronic health records covering 80% of the population of England (eMethods in the Supplement). Ethics approval was obtained from the National Statistician’s Data Ethics Advisory Committee and reporting follows the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guideline for cohort studies. Our study population included those aged 18 to 100 years living in England who had completed both doses of their primary vaccination schedule and had received their mRNA booster 14 days or more prior to December 31, 2021.
Our outcome of interest was time to death involving COVID-19 (ie, International Statistical Classification of Diseases and Related Health Problems, Tenth Revision codes U071 and U072 recorded on death certificate) occurring between January 1 and March 16, 2022. Cox regression modeling (R version 3.5.1 [R Project for Statistical Computing]) was used to estimate the hazard ratio (HR) and 95% CIs of death involving COVID-19 in 2-tailed tests for a range of sociodemographic characteristics (sex, age, ethnicity, and measures of socioeconomic position) and clinical risk factors (based on the conditions identified in the QCovid risk model [eTable in the Supplement]).1 Data on ethnicity from the 2011 Census used the selected categories identified by ONS, which were aggregated to the UK Government Statistical Service harmonized standard. Non–COVID-19 deaths were censored. Models were adjusted for time since booster dose as of December 31, 2021, and region.
Results
In the 19 473 570 individuals in our cohort (8 801 865 men [45.2%]; mean [SD] age, 60.8 [16] years; 17 918 962 [92.0%] White individuals), there were 4781 (0.02%) deaths involving COVID-19 and 58 020 (0.3%) deaths from other causes. The median (IQR) age of those who died of COVID-19 was 85 (78-99) years (mean, 83.3 years) (Table).
Table. Characteristics of the Study Population and Deaths.
| Variable | Individuals, No. (%) | COVID-19 deaths, No. (%) |
|---|---|---|
| Deaths | 62 801 (0.3%) | 4781 (0.02) |
| Mean (SD) age, y | 60.8 (16) | 83.3 (9.8) |
| Sex | ||
| Men | 8 801 865 (45.2) | 2664 (55.7) |
| Women | 10 671 705 (54.8) | 2117 (44.3) |
| Mean (SD) time since booster dose, d | 48 (24) | 66.2 (21.8) |
| Race and ethnicity | ||
| Bangladeshi and Pakistani | 223 712 (1.1) | 35 (0.7) |
| Black | 275 350 (1.4) | 37 (0.8) |
| Chinese | 87 800 (0.5) | 10 (0.2) |
| Indian | 495 847 (2.5) | 95 (2.0) |
| White | 17 918 962 (92.0) | 4566 (95.5) |
| Mixed | 170 114 (0.9) | 11 (0.2) |
| Other | 301 785 (1.5) | 27 (0.6) |
| IMD | ||
| 1 (most deprived) | 2 671 942 (13.7) | 900 (18.8) |
| 2 | 3 384 141 (17.4) | 898 (18.9) |
| 3 | 4 103 685 (21.1) | 1011 (21.1) |
| 4 | 4 520 346 (23.2) | 980 (20.5) |
| 5 (least deprived) | 4 793 456 (24.6) | 992 (20.7) |
| Key worker status | 12 781 562 (65.6) | 3252 (68.0) |
| Disability (limited a lot) | 1 307 789 (6.7) | 1176 (24.6) |
| Education: degree | 6 015 501 (30.9) | 757 (15.8) |
| Asthma | 1 340 726 (6.9) | 288 (6.0) |
| Atrial fibrillation | 649 076 (3.3) | 771 (16.1) |
| Cancer of blood or bone marrow | 134 668 (0.7) | 266 (5.6) |
| Chronic kidney disease | 728 667 (3.7) | 874 (18.3) |
| COPD | 681 708 (3.5) | 708 (14.8) |
| Congenital heart problem | 28 187 (0.1) | <10a |
| Coronary heart disease | 685 197 (3.5) | 572 (12.0) |
| Other rare chronic respiratory disorders (cystic fibrosis bronchiectasis or alveolitis) | 116 912 (0.6) | 113 (2.4) |
| Dementia | 243 656 (1.3) | 1025 (21.4) |
| Epilepsy | 117 859 (0.6) | 55 (1.2) |
| Heart failure | 323 642 (1.7) | 616 (12.9) |
| Learning disability or Down syndrome | 129 057 (0.7) | 34 (0.7) |
| Liver cirrhosis | 40 134 (0.2) | 30 (0.6) |
| Lung or oral cancer | 36 752 (0.2) | 50 (1.0) |
| Motor neurone disease, multiple sclerosis, myasthenia, or Huntington disease | 11 735 (0.1) | 13 (0.3) |
| Parkinson disease | 67 801 (0.3) | 139 (2.9) |
| Peripheral vascular disease | 121 872 (0.6) | 120 (2.5) |
| Pulmonary hypertension or fibrosis | 38 487 (0.2) | 110 (2.3) |
| Prior fracture (hip, wrist, spine, or humerus) | 14 338 (0.1) | 18 (0.4) |
| Rheumatoid arthritis or SLE | 193 386 (1.0) | 154 (3.2) |
| SCID | 6094 (0.03) | 10 (0.2) |
| Sickle cell or severe combined immunodeficiency syndrome | 1624 (0.01) | <10a |
| Stroke or TIA | 372 933 (1.9) | 410 (8.6) |
| Thrombosis or pulmonary embolus | 1819 (<.01) | <10a |
| Schizophrenia | 107 154 (0.6) | 33 (0.7) |
| Type 1 diabetes | 232 298 (1.2) | 87 (1.8) |
| Type 2 diabetes | 1 538 173 (7.9) | 798 (16.7) |
| BMI | ||
| Morbidly obese | 399 690 (2.1) | 70 (1.5) |
| Overweight | 3 680 341 (18.9) | 880 (18.4) |
| Ideal | 3 178 187 (16.3) | 986 (20.6) |
| Underweight | 138 729 (0.7) | 145 (3.0) |
| Obese | 2 541 104 (13.0) | 491 (10.3) |
| Missing | 9 535 519 (49.0) | 2209 (46.2) |
| Care home resident | 105 589 (0.5) | 478 (10.0) |
| Region | ||
| West Midlands | 2 080 092 (10.7) | 568 (11.9) |
| London | 2 117 506 (10.9) | 442 (9.2) |
| Yorkshire and Humber | 2 011 985 (10.3) | 551 (11.5) |
| North West | 2 549 572 (13.1) | 683 (14.3) |
| East Midlands | 1 822 155 (9.4) | 467 (9.8) |
| South East | 3 361 853 (17.3) | 737 (15.4) |
| South West | 2 211 007 (11.4) | 454 (9.5) |
| North East | 999 584 (5.1) | 331 (6.9) |
| East of England | 2 319 816 (11.9) | 548 (11.5) |
Abbreviations: BMI, body mass index (calculated as weight in kilograms divided by height in meters squared); COPD, chronic obstructive pulmonary disease; IMD, index of multiple deprivation; SCID, severe combined immunodeficiency; SLE, systemic lupus erythematosus; TIA, transient ischemic attack.
Results capped at 10 cases to preserve patient anonymity.
Age was the most important characteristic associated with the risk of postbooster COVID-19 death (Figure, panel A), with an HR of 31.3 (95% CI, 26.1-37.6) for an 80-year-old individual compared with a 50-year-old. Women were at lower risk than men (HR, 0.52; 95% CI, 0.49-0.55). Living in a care home or in a socioeconomically deprived area were also associated with increased risk of COVID-19 death (Figure, panel B). There was no association between the risk of COVID-19 death and ethnicity, except for those of Indian background, who were at slightly elevated risk compared with White individuals.
Figure. Risk Factors for Death From COVID-19 After Receiving a Booster.
Hazard ratios (HRs) were calculated with a Cox regression model. In panel A, the reference for HRs are men with healthy body mass index (BMI, which is calculated as weight in kilograms divided by height in meters squared) in index of multiple deprivation (IMD) quintile 1 for 50 days since last booster. In panels B and C, the dashed lines illustrate an HR of 1. Prior fracture includes fractures of the hip, wrist, spine, or humerus.
COPD indicates chronic obstructive pulmonary disease; SCID, severe combined immunodeficiency; SLE, systemic lupus erythematosus; TIA, transient ischemic attack.
Most of the QCovid risk groups were associated with an increased HR of postbooster breakthrough death, except for congenital heart disease, asthma, and prior fracture (Figure, panel C). Risk was particularly elevated for people with severe combined immunodeficiency (HR, 6.2; 95% CI, 3.3-11.5). There were several conditions associated with HRs of greater than 3, including cancer of blood or bone marrow and dementia.
Discussion
This study identified subpopulations that remain at increased risk of COVID-19 fatality after receiving their booster vaccine during the Omicron wave. Age remained the factor most associated with the risk of death, and men were at higher risk than women. The association with ethnicity was unclear and differed from previous studies, but this is likely to be due largely to the pronounced differences in vaccination uptake between ethnic groups in previous studies.4 Limitations of our study were that we only included data for the population living in England who were enumerated in the 2011 Census of England and Wales. The association between the QCovid risk groups and the risk of death were stronger in people who had received a booster and were infected by the Omicron variant compared with evidence from the Alpha and Delta period in doubly vaccinated individuals.1,2,3 The subpopulations with the highest risk should be considered a priority for COVID-19 therapeutics and further booster doses.5,6
eMethods.
eTable. Sociodemographic Characteristics and Clinical Risk Factors
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Associated Data
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Supplementary Materials
eMethods.
eTable. Sociodemographic Characteristics and Clinical Risk Factors