Impact of vaccination on COVID-19-associated admissions to critical care in England: a population cohort study of linked data (preprint)

Introduction This study aims to explore the impact of COVID-19 vaccination on critical care by examining associations between vaccination and admission to critical care with COVID-19 during England's Delta wave, by age group, dose, and over time. Methods We used linked routinely-collected data to conduct a population cohort study of patients admitted to adult critical care in England for management of COVID-19 between 1 May and 15 December 2021. Included participants were the whole population of England aged 18 years or over (44.7 million), including 10,141 patients admitted to critical care with COVID-19. The intervention was vaccination with one, two, or a booster/three doses of any COVID-19 vaccine. Results Compared with unvaccinated patients, vaccinated patients were older (median 64 years for patients receiving two or more doses versus 50 years for unvaccinated), with higher levels of severe comorbidity (20.3% versus 3.9%) and immunocompromise (15.0% versus 2.3%). Compared with patients who were unvaccinated, those vaccinated with two doses had a relative risk reduction (RRR) of between 90.1% (patients aged 18-29, 95% CI, 86.8% to 92.7%) and 95.9% (patients aged 60-69, 95% CI, 95.5% to 96.2%). Waning was only observed for those aged 70+, for whom the RRR reduced from 97.3% (91.0% to 99.2%) to 86.7% (85.3% to 90.1%) between May and December but increased again to 98.3% (97.6% to 98.8%) with a booster/third dose. Conclusion Important demographic and clinical differences exist between vaccinated and unvaccinated patients admitted to critical care with COVID-19. While not a causal analysis, our findings are consistent with a substantial and sustained impact of vaccination on reducing admissions to critical care during England's Delta wave, with evidence of waning predominantly restricted to those aged 70+.

NEURO-COVAX: An Italian Population-Based Study of Neurological Complications After COVID-19 Vaccines (preprint)

Objective In this Italian population-based study, we aimed to evaluate neurological complications after first and/or second dose of COVID-19 vaccines and factors potentially associated with adverse effects.Methods Our study included adults aged-18 years and older, receiving two vaccine doses in vaccination Hub Novegro (Lombardy) between July 7–16 2021. NEURO-COVAX questionnaire was able to capture neurological events, onset and duration. Data digitized centrally by Lombardy-Region were used to match demographic/clinical characteristics and identify a vulnerable profile. Associations between vaccine-lines and development of complications were assessed.Results NEURO-COVAX-cohort included 19.108 vaccinated-people: 15.368 mRNA BNT162b2, 2077 mRNA-1273, 1651 ChAdOx1nCov-19 and 12 Ad26.COV2, subsequently excluded. About 31.3% of sample developed post-vaccination neurological complications, particularly ChAdOx1nCov-19. Vulnerable clinical profile emerged, over 40% of symptomatic people showed comorbidities in clinical history. Defining neurological risk profile, we found increased risk for ChAdOx1nCov-19 of tremor (OR:5.12, 95% CI:3.51–7.48), insomnia (OR:1.87, 95% CI:1.02–3.39); muscle spasms (OR:1.62, 95% CI:1.08–2.46) and headache (OR:1.49, 95% CI:0.96–1.57); for mRNA-1273 of parethesias (OR:2.37, 95% CI:1.48–3.79), vertigo (OR:1.68, 95% CI:1.20–2.35), diplopia (OR:1.55, 95% CI:0.67–3.57), daytime sleepiness (OR:1.28, 95% CI:0.98–1.67).Discussion This study estimates prevalence and risk of neurological complications associated to COVID-19 vaccines, improving vaccination guidelines and loading in future to personalized preventive medicine.

Uptake of Sotrovimab for prevention of severe COVID-19 and its safety in the community in England (preprint)

Sotrovimab is a neutralising monoclonal antibody (nMAB), currently administrated in England to treat extremely clinically vulnerable COVID-19 patients. Trials have shown it to have mild or moderate side effects, however safety in real-world settings has not been yet evaluated. We used national databases to investigate its uptake and safety in community patients across England. We used a cohort study to describe uptake and a self-controlled case series design to evaluate the risks of 49 pre-specified suspected adverse events in the 2-28 days post-treatment. Between December 11, 2021 and May 24, 2022, there were 172,860 COVID-19 patients eligible for treatment. Of the 22,815 people who received Sotrovimab, 21,487 (94.2%) had a positive SARS-CoV-2 test and 5,999 (26.3%) were not on the eligible list. Between treated and untreated eligible individuals, the mean age (54.6, SD: 16.1 vs 54.1, SD: 18.3) and sex distribution (women: 60.9% vs 58.1%; men: 38.9% vs 41.1%) were similar. There were marked variations in uptake between ethnic groups, which was higher amongst Indian (15.0%; 95%CI 13.8, 16.3), Other Asian (13.7%; 95%CI 11.9, 15.8), White (13.4%; 95%CI 13.3, 13.6), and Bangladeshi (11.4%; 95%CI 8.8, 14.6); and lower amongst Black Caribbean individuals (6.4%; 95%CI 5.4, 7.5) and Black Africans (4.7%; 95%CI 4.1, 5.4). We found no increased risk of any of the suspected adverse events in the overall period of 2-28 days post-treatment, but an increased risk of rheumatoid arthritis (IRR 3.08, 95% CI 1.44, 6.58) and of systematic lupus erythematosus (IRR 5.15, 95% CI 1.60, 16.60) in the 2-3 days post-treatment, when we narrowed the risk period. FundingNational Institute of Health Research (Grant reference 135561)

Risk of myocarditis following sequential COVID-19 vaccinations by age and sex (preprint)

ABSTRACT In an updated self-controlled case series analysis of 42,200,614 people aged 13 years or more, we evaluate the association between COVID-19 vaccination and myocarditis, stratified by age and sex, including 10,978,507 people receiving a third vaccine dose. Myocarditis risk was increased during 1-28 days following a third dose of BNT162b2 (IRR 2.02, 95%CI 1.40, 2.91). Associations were strongest in males younger than 40 years for all vaccine types with an additional 3 (95%CI 1, 5) and 12 (95% CI 1,17) events per million estimated in the 1-28 days following a first dose of BNT162b2 and mRNA-1273, respectively; 14 (95%CI 8, 17), 12 (95%CI 1, 7) and 101 (95%CI 95, 104) additional events following a second dose of ChAdOx1, BNT162b2 and mRNA-1273, respectively; and 13 (95%CI 7, 15) additional events following a third dose of BNT162b2, compared with 7 (95%CI 2, 11) additional events following COVID-19 infection. An association between COVID-19 infection and myocarditis was observed in all ages for both sexes but was substantially higher in those older than 40 years. These findings have important implications for public health and vaccination policy. Funding Health Data Research UK.

Analysis of severe outcomes associated with the SARS-CoV-2 Variant of Concern 202012/01 in England using ICNARC Case Mix Programme and QResearch databases (preprint)

ABSTRACT Background A new, more transmissible variant of SARS-CoV-2, variant of concern (VOC) 202012/01 or lineage B.1.1.7, has emerged in the UK. We estimate the risk of critical care admission, mortality in critical ill patients, and overall mortality associated with VOC B.1.1.7 compared with the original variant. We also compare clinical outcomes between these variants ‘ groups. Methods We linked a large primary care (QResearch), the national critical care (ICNARC CMP) and the COVID-19 testing (PHE) database and extracted two cohorts. The first was used to explore the association between VOC B.1.1.7 and critical care admission and 28-day mortality. The second to determine the risk of mortality in critically ill patients with VOC B.1.1.7 compared to those without. We used Royston-Parmar models adjusted for age, sex, region, other socio-demographics and comorbidities (asthma, COPD, type I and II, hypertension). We reported information on types and duration of organ supports for the two variants ‘ groups. Findings The first cohort included 198,420 patients. Of these, 80,494 had VOC B.1.1.7, 712 were critically ill and 630 died by 28 days. The second cohort included 3432 critically ill patients. Of these, 2019 had VOC B.1.1.7 and 822 died at the end of critical care. Using the first cohort, we estimated adjusted hazard ratios for critical care admission and mortality to be 1.99 (95% CI: 1.59, 2.49) and 1.59 (95% CI: 1.25-2.03) for VOC B.1.1.7 compared with the original variant group, respectively. The adjusted hazard ratio for mortality in critical care, estimated using the second cohort, was 0.93 (95% CI 0.76-1.15) for patients with VOC B.1.1.7, compared to those without. Interpretation VOC B.1.1.7 appears to be more severe. Patients with VOC B.1.1.7 are at increased risk of critical care admission and mortality compared with patients without. For patients receiving critical care, mortality appears independent of virus strain. RESEARCH IN CONTEXT Evidence before this study A new variant of the SARS-CoV-2 virus, variant of concern (VOC) 202012/01, or lineage B.1.1.7, was detected in England in September 2020. The characteristics and outcomes of patients infected with VOC B.1.1.7 are not yet known. VOC B.1.1.7 has been associated with increased transmissibility. Early analyses have suggested infection with VOC B.1.1.7 may be associated with a higher risk of mortality compared with infection with other virus variants, but these analyses had either limited ability to adjust for key confounding variables or did not consider critical care admission. The effects of VOC B.1.1.7 on severe COVID-19 outcomes remain unclear. Added value of this study This study found a 60% higher risk of 28-day mortality associated with infection with VOC B.1.1.7 in patients tested in the community in comparison with the original variant, when adjusted for key confounding variables. The risk of critical care admission for those with VOC B.1.1.7 is double the risk associated with the original variant. For patients receiving critical care, the infecting variant is not associated with the risk of mortality at the end of critical care. Implications of all the available evidence The higher mortality and rate of critical care admission associated with VOC B.1.1.7, combined with its known increased transmissibility, are likely to put health care systems under further stress. These effects may be mitigated by the ongoing vaccination programme.

Influenza, Shingles and Pneumococcal Vaccine Uptake, Offer and Refusal in Adult Populations at High-Risk for COVID-19: A UK Population-Based Cohort Study (preprint)

Background: As COVID-19 vaccination programs are being rolled out globally, we studied the ethnic, deprivation, household size and comorbidity ‘patterning’ of existing vaccination programs in populations at high-risk for COVID-19, to inform risk-stratified vaccination strategies and mitigate health inequalities. Methods: A population-level cohort study of UK adults aged 65 years or older, using a large primary care database. We used multivariable logistic regression to assess uptake of influenza, pneumococcal and shingles vaccination across ethnic groups, deprivation quintile, household size, and comorbidities, computing odds ratios (OR) adjusted for age, sex, demographics, body mass index and smoking. Offers and refusals of each vaccination type were analysed in those not receiving them. Findings: The cohort comprised 2,054,463 patients from 1,318 general practices. 1,452,014 (70.7%) patients received influenza vaccine, 1,391,228 (67.7%) received pneumococcal vaccine, and 690,783 (53.4%) received shingles vaccine. Compared to Whites, influenza vaccination uptake was lower in Pakistani (adjusted odds ratio (OR) 0.82; 99% confidence interval: 0.74-0.90), Black Caribbean (OR 0.46; 0.43-0.48), Black African (OR 0.63; 0.58-0.68), Chinese (OR 0.70; 0.64-0.76) and ‘Other ethnic group’ (OR 0.65; 0.63-0.69). The Black Caribbean group had higher vaccination refusal than the White group for influenza vaccination (OR 1.17; 1.05-1.30). Vaccination uptake was lower among the more deprived and those living in household sizes above 3 or more persons, with some significant interactions between ethnicity and comorbidities. Uptake of all three vaccines was higher in those with asthma, COPD, type 2 diabetes, hypertension and learning disability, whilst lower in those with dementia. Interpretation: Whilst uptake and refusal of influenza, shingles and pneumococcal vaccination are patterned by ethnicity, deprivation, household size and comorbidities, vaccination offer is mostly patterned by comorbidities. This information can inform national policies to ensure equitable implementation of COVID-19 vaccination programs to avoid exacerbating health inequalities.Funding Statement: This project was funded by the Medical Research Council (Grant Ref: MR/V027778/1).Declaration of Interests: PST reports previous consultation with AstraZeneca and Duke-NUS outside the submitted work. KK is a Member of the Scientific Advisory Group for Emergencies (SAGE), Member of Independent SAGE, Director of the University of Leicester Centre for Black Minority Health and Trustee of the south Asian Health Foundation. JHC is a member of several SAGE committees and chair of the risk stratification subgroup of the NERVTAG. She is unpaid director of QResearch and founder and former medical director of ClinRisk Ltd (outside the submitted work). MP, AKC, HDM, DS, TAR, FZ, BRS, SJG, CC, CG have no interests to declare.