Challenges in estimating waning effectiveness of two doses of BNT162b2 and ChAdOx1 COVID-19 vaccines beyond six months: an OpenSAFELY cohort study using linked electronic health records (preprint)

Quantifying the waning effectiveness of second COVID-19 vaccination beyond six months and against the omicron variant is important for scheduling subsequent doses. With the approval of NHS England, we estimated effectiveness up to one year after second dose, but found that bias in such estimates may be substantial.

Therapeutic potential of IL6R blockade for the treatment of sepsis and sepsis-related death: Findings from a Mendelian randomisation study (preprint)

Introduction Sepsis is characterised by dysregulated, life-threatening immune responses, which are thought to be driven by cytokines such as interleukin-6 (IL-6). Genetic variants in IL6R known to downregulate IL-6 signalling are associated with improved COVID-19 outcomes, a finding later confirmed in randomised trials of IL-6 receptor antagonists (IL6RA). We hypothesised that blockade of IL6R could also improve outcomes in sepsis. Methods We performed a Mendelian randomisation analysis using single nucleotide polymorphisms (SNPs) in and near IL6R to evaluate the likely causal effects of IL6R blockade on sepsis, sepsis severity, other infections, and COVID-19. We weighted SNPs by their effect on CRP and combined results across them in inverse variance weighted meta-analysis, proxying the effect of IL6RA. Our outcomes were measured in UK Biobank, FinnGen, the COVID-19 Host Genetics Initiative (HGI), and the GenOSept and GainS consortium. We performed several sensitivity analyses to test assumptions of our methods, including utilising variants around CRP in a similar analysis. Results In the UK Biobank cohort (N=485,825, including 11,643 with sepsis), IL6R blockade was associated with a decreased risk of sepsis (OR=0.80; 95% CI 0.66-0.96, per unit of natural log transformed CRP decrease). The size of this effect increased with severity, with larger effects on 28-day sepsis mortality (OR=0.74; 95% CI 0.38-0.70); critical care admission with sepsis (OR=0.48, 95% CI 0.30-0.78) and critical care death with sepsis (OR=0.37, 95% CI 0.14 - 0.98) Similar associations were seen with severe respiratory infection: OR for pneumonia in critical care 0.69 (95% CI 0.49 - 0.97) and for sepsis survival in critical care (OR=0.22; 95% CI 0.04- 1.31) in the GainS and GenOSept consortium. We also confirm the previously reported protective effect of IL6R blockade on severe COVID-19 (OR=0.69, 95% 0.57 - 0.84) in the COVID-19 HGI, which was of similar magnitude to that seen in sepsis. Sensitivity analyses did not alter our primary results. Conclusions IL6R blockade is causally associated with reduced incidence of sepsis, sepsis related critical care admission, and sepsis related mortality. These effects are comparable in size to the effect seen in severe COVID-19, where IL-6 receptor antagonists were shown to improve survival. This data suggests a randomised trial of IL-6 receptor antagonists in sepsis should be considered.

Effectiveness of BNT162b2 booster doses in England: an observational study in OpenSAFELY-TPP (preprint)

Background The UK COVID-19 vaccination programme delivered its first "booster" doses in September 2021, initially in groups at high risk of severe disease then across the adult population. The BNT162b2 Pfizer-BioNTech vaccine was used initially, with Moderna mRNA-1273 subsequently also used. Methods We used the OpenSAFELY-TPP database, covering 40% of English primary care practices and linked to national coronavirus surveillance, hospital episodes, and death registry data, to estimate the effectiveness of boosting with BNT162b2 compared with no boosting in eligible adults who had received two primary course vaccine doses between 16 September and 16 December 2021 when the Delta variant of SARS-CoV-2 was dominant. Follow up was for up to 10 weeks. Each booster recipient was matched with an unboosted control on factors relating to booster priority status and prior immunisation. Additional factors were adjusted for in Cox models estimating hazard ratios (HRs). Outcomes were positive SARS-CoV-2 test, COVID-19 hospitalisation, COVID-19 death and non-COVID-9 death. Booster vaccine effectiveness was defined as 1-HR. Results Among 4,352,417 BNT162b2 booster recipients matched with unboosted controls, estimated effectiveness of a booster dose compared with two doses only was 50.7% (95% CI 50.1-51.3) for positive SARS-CoV-2 test, 80.1% (78.3-81.8) for COVID-19 hospitalisation, 88.5% (85.0-91.1) for COVID-19 death, and 80.3% (79.0-81.5) for non-COVID-19 death. Estimated effectiveness was similar among those who had received a BNT162b2 or ChAdOx1-S two-dose primary vaccination course, but effectiveness against severe COVID-19 was slightly lower in those classified as clinically extremely vulnerable (76.3% (73.1-79.1) for COVID-19 hospitalisation, and 85.1% (79.6-89.1) for COVID-19 death). Estimated effectiveness against each outcome was lower in those aged 18-65 years than in those aged 65 and over. Conclusion Our findings are consistent with strong protection of BNT162b2 boosting against positive SARS-CoV-2 test, COVID-19 hospitalisation, and COVID-19 death.

Comparative effectiveness of ChAdOx1 versus BNT162b2 COVID-19 vaccines in Health and Social Care workers in England: a cohort study using OpenSAFELY (preprint)

Background: The UK COVID-19 vaccination programme delivered both the BNT162b2 mRNA (Pfizer-BioNTech) and the ChAdOx1 (Oxford-AstraZeneca) vaccines during overlapping periods, providing a rare opportunity to emulate a trial that directly compares both vaccines using routinely-collected NHS data. Frontline Health and Social Care workers comprise a useful population to assess comparative effectiveness due to early vaccine eligibility and relatively high post-vaccination transmission risk due to occupational exposure. Methods: With the approval of NHS England we used the OpenSAFELY-TPP database, covering 40% of GP practices in England and linked to national coronavirus surveillance, hospital episodes, and death registry data, to compare the effectiveness of ChAdOx1 versus BNT162b2 in 1/3 million health and social care workers vaccinated between 4 January and 28 February 2021. Recipients were followed-up for 20 weeks. Second-dose effects were estimated under an intention-to-treat strategy. Primary outcomes were recorded SARS-CoV-2 infection, COVID-19-related accident and emergency attendance, and COVID-19-related hospital admission. Results: The cumulative incidence of each outcome was similar for both vaccines during the first 20 weeks post-vaccination. The cumulative incidence of recorded SARS-CoV-2 infection 6 weeks after vaccination with BNT162b2 was 19.2 per 1000 people (95%CI 18.6 to 19.7) and with ChAdOx1 was 18.9 (95%CI 17.6 to 20.3), representing a difference of -0.24 per 1000 people (95%CI -1.71 to 1.22). The difference in the cumulative incidence of COVID-19 accident and emergency attendance at 6 weeks was 0.01 per 1000 people (95%CI -0.27 to 0.28). For COVID-19 hospital admission, this difference was 0.03 per 1000 people (95%CI -0.22 to 0.27). Conclusion: In this cohort of healthcare workers where we would not anticipate vaccine type to be related to health status, we found no substantial differences in the incidence of SARS-CoV-2 infection or COVID-19 disease up to 20 weeks after vaccination. Incidence dropped sharply after 3-4 weeks and there were very few COVID-19 hospital attendance and admission events after this period. This is in line with expected onset of vaccine-induced immunity, and suggests strong protection against COVID-19 disease for both vaccines.

Collider bias undermines our understanding of COVID-19 disease risk and severity (preprint)

Observational data on COVID-19 including hypothesised risk factors for infection and progression are accruing rapidly, often from non-random sampling such as hospital admissions, targeted testing or voluntary participation. Here, we highlight the challenge of interpreting observational evidence from such samples of the population, which may be affected by collider bias. We illustrate these issues using data from the UK Biobank in which individuals tested for COVID-19 are highly selected for a wide range of genetic, behavioural, cardiovascular, demographic, and anthropometric traits. We discuss the sampling mechanisms that leave aetiological studies of COVID-19 infection and progression particularly susceptible to collider bias. We also describe several tools and strategies that could help mitigate the effects of collider bias in extant studies of COVID-19 and make available a web app for performing sensitivity analyses. While bias due to non-random sampling should be explored in existing studies, the optimal way to mitigate the problem is to use appropriate sampling strategies at the study design stage.