SARS-CoV-2, influenza A/B and respiratory syncytial virus positivity and association with influenza-like illness and self-reported symptoms, over the 2022/23 winter season in the UK: a longitudinal surveillance cohort (preprint)

Background Syndromic surveillance often relies on patients presenting to healthcare. Community cohorts, although more challenging to recruit, could provide additional population-wide insights, particularly with SARS-CoV-2 co-circulating with other respiratory viruses. Methods We estimated positivity and incidence of SARS-CoV-2, influenza A/B, and RSV, and trends in self-reported symptoms including influenza-like illness (ILI), over the 2022/23 winter season in a broadly representative UK community cohort (COVID-19 Infection Survey), using negative-binomial generalised additive models. We estimated associations between test positivity and each of symptoms and influenza vaccination, using adjusted logistic and multinomial models. Findings Swabs taken at 32,937/1,352,979 (2.4%) assessments tested positive for SARS-CoV-2, 181/14,939 (1.2%) for RSV and 130/14,939 (0.9%) for influenza A/B, varying by age over time. Positivity and incidence peaks were earliest for RSV, then influenza A/B, then SARS-CoV-2, and were highest for RSV in the youngest and for SARS-CoV-2 in the oldest age-groups. Many test-positives did not report key symptoms: middle-aged participants were generally more symptomatic than older or younger participants, but still only ~25% reported ILI-WHO and ~60% ILI-ECDC. Most symptomatic participants did not test positive for any of the three viruses. Influenza A/B-positivity was lower in participants reporting influenza vaccination in the current and previous seasons (odds ratio=0.55 (95% CI 0.32,0.95)) versus neither season. Interpretation Symptom profiles varied little by aetiology, making distinguishing SARS-CoV-2, influenza and RSV using symptoms challenging. Most symptoms were not explained by these viruses, indicating the importance of other pathogens in syndromic surveillance. Influenza vaccination was associated with lower rates of community influenza test positivity. Funding UK Health Security Agency, Department of Health and Social Care, National Institute for Health Research.

Risk of SARS-CoV-2 reinfection during multiple Omicron variant waves in the UK general population (preprint)

SARS-CoV-2 reinfections increased substantially after Omicron variants emerged. Large-scale community-based comparisons across multiple Omicron waves of reinfection characteristics, risk factors, and protection afforded by previous infection and vaccination, are limited, especially after widespread national testing stopped. We studied 245,895 adults >=18y in the UK's national COVID-19 Infection Survey with at least one infection (identified from positive swab tests done within the study, linked from national testing programmes, or self-reported by participants, up to their last study assessment). We quantified the risk of reinfection in multiple infection waves, including those driven by BA.1, BA.2, BA.4/5, and most recently BQ.1/CH.1.1/XBB.1.5 variants, in which most reinfections occurred. Reinfections had higher cycle threshold (Ct) values (lower viral load) and lower percentages self-reporting symptoms compared with first infections. Across multiple Omicron waves, protection against reinfection was significantly higher in those previously infected with more recent than earlier variants, even at the same time from previous infection. Protection against Omicron reinfections decreased over time from the most recent infection if this was the previous or penultimate variant (generally within the preceding year), but did not change or even slightly increased over time if this was with an even earlier variant (generally >1 year previously). Those 14-180 days after receiving their most recent vaccination had a lower risk of reinfection with all Omicron variants except BA.2 than those >180 days from their most recent vaccination. Reinfection risk was independently higher in those aged 30-45 years, and with either low or high Ct values in their most recent previous infection. Overall, the risk of Omicron reinfection is high, but with lower severity than first infections; reinfection risk is likely driven as much by viral evolution as waning immunity.

Employment outcomes of people with Long Covid symptoms: community-based cohort study (preprint)

Background: Evidence on the long-term employment consequences of SARS-CoV-2 infection is lacking. We used data from a large, community-based sample in the UK to estimate associations between Long Covid and subsequent employment outcomes. Methods: This was an observational, longitudinal study using a pre-post design. We included UK COVID-19 Infection Survey participants who completed questionnaires on Long Covid from 3 February 2021 to 30 September 2022 when they were aged 16 to 64 years and not in full-time education. We used conditional logit modelling to explore the time-varying relationship between Long Covid status [≥]12 weeks after a first test-confirmed SARS-CoV-2 infection (reference: pre-infection) and labour market inactivity (neither working nor looking for work) or workplace absence lasting [≥]4 weeks. Results: Of 206,299 included participants (mean age 45 years, 54% female, 92% white), 15% were ever inactive in the labour market and 10% were ever long-term absent during follow-up. Compared with pre-infection, inactivity was higher in participants reporting Long Covid 30 to <40 weeks (adjusted odds ratio (aOR): 1.45; 95% CI: 1.17 to 1.81) or 40 to <52 weeks (1.34; 1.05 to 1.72) post-infection. Compared with pre-infection, reporting Long Covid was also associated with increased odds of long-term absence 18 to <24 weeks (1.40; 1.04 to 1.90) and 24 to <30 weeks (1.45; 1.03 to 2.04) post-infection, but not beyond 30 weeks. Combining with official statistics on Long Covid prevalence, our estimates translate to 27,000 (95% CI: 6,000 to 47,000) working-age adults in the UK being inactive because of their Long Covid symptoms in July 2022. Conclusions: Long Covid is likely to have contributed to reduced levels of participation in the UK labour market, though it is unlikely to be the sole driver. Further research is required to quantify the contribution of other factors, such as indirect health effects of the pandemic.

Improving the representativeness of UKs national COVID-19 Infection Survey through spatio-temporal regression and post-stratification (preprint)

Population-representative estimates of SARS-CoV-2 infection prevalence and antibody levels in specific geographic areas at different time points are needed to optimise policy responses. However, even population-wide surveys are potentially impacted by biases arising from differences in participation rates across key groups. Here, we use spatio-temporal regression and post-stratification models to UKs national COVID-19 Infection Survey (CIS) to obtain representative estimates of PCR positivity (6,496,052 tests) and antibody prevalence (1,941,333 tests) for different regions, ages and ethnicities (7-December-2020 to 4-May-2022). Not accounting for vaccination status through post-stratification led to small underestimation of PCR positivity, but more substantial overestimations of antibody levels in the population (up to 21%), particularly in groups with low vaccine uptake in the general population. There was marked variation in the relative contribution of different areas and age-groups to each wave. Future analyses of infectious disease surveys should take into account major drivers of outcomes of interest that may also influence participation, with vaccination being an important factor to consider.

Correlates of protection against SARS-CoV-2 Omicron variant and anti-spike antibody responses after a third/booster vaccination or breakthrough infection in the UK general population (preprint)

Following primary SARS-CoV-2 vaccination, understanding the relative extent of protection against SARS-CoV-2 infection from boosters or from breakthrough infections (i.e. infection in the context of previous vaccination) has important implications for vaccine policy. In this study, we investigated correlates of protection against Omicron BA.4/5 infections and anti-spike IgG antibody trajectories after a third/booster vaccination or breakthrough infection following second vaccination in 154,149 adults [≥]18y from the United Kingdom general population. We found that higher anti-spike IgG antibody levels were associated with increased protection against Omicron BA.4/5 infection and that breakthrough infections were associated with higher levels of protection at any given antibody level than booster vaccinations. Breakthrough infections generated similar antibody levels to third/booster vaccinations, and the subsequent declines in antibody levels were similar to or slightly slower than those after third/booster vaccinations. Taken together our findings show that breakthrough infection provides longer lasting protection against further infections than booster vaccinations. For example, considering antibody levels associated with 67% protection against infection, a third/booster vaccination did not provide long-lasting protection, while a Delta/Omicron BA.1 breakthrough infection could provide 5-10 months of protection against Omicron BA.4/5 reinfection. 50-60% of the vaccinated UK population with a breakthrough infection would still be protected by the end of 2022, compared to <15% of the triple-vaccinated UK population without previous infection. Although there are societal impacts and risks to some individuals associated with ongoing transmission, breakthrough infection could be an efficient immune-boosting mechanism for subgroups of the population, including younger healthy adults, who have low risks of adverse consequences from infection.

Detecting changes in population trends in infection surveillance using community SARS-CoV-2 prevalence as an exemplar (preprint)

BackgroundMonitoring infection trends is vital to informing public health strategy. Detecting and quantifying changes in growth rates can inform policymakers rationale for implementing or continuing interventions aimed at reducing impact. Substantial changes in SARS-CoV-2 prevalence with emergence of variants provides opportunity to investigate different methods to do this. MethodsWe included PCR results from all participants in the UKs COVID-19 Infection Survey between 1 August 2020-30 June 2022. Change-points for growth rates were identified using iterative sequential regression (ISR) and second derivatives of generalised additive models (GAMs). Consistency between methods and timeliness of detection were compared. FindingsOf 8,799,079 visits, 147,278 (1{middle dot}7%) were PCR-positive. Over the time period, change-points associated with emergence of major variants were estimated to occur a median 4 days earlier (IQR 0-8) in GAMs versus ISR, with only 2/48 change-points identified by only one method. Estimating recent change-points using successive data periods, four change-points (4/96) identified by GAMs were not found when adding later data or by ISR; 77% (74/96) of change-points identified by successive GAMs were identified by ISR. Change-points were detected 3-5 weeks after they occurred in both methods but could be detected earlier within specific subgroups. InterpretationChange-points in growth rates of SARS-CoV-2 can be detected in near real-time using ISR and second derivatives of GAMs. To increase certainty about changes in epidemic trajectories both methods could be run in parallel. Running either method in near real-time on different infection surveillance data streams could provide timely warnings of changing underlying epidemiology. FundingUK Health Security Agency, Department of Health and Social Care (UK), Welsh Government, Department of Health (on behalf of the Northern Ireland Government), Scottish Government, National Institute for Health Research.

Efficacy of ultra-short, response-guided sofosbuvir and daclatasvir therapy for Hepatitis C: a single arm mechanistic pilot study (preprint)

ABSTRACT Background WHO has called for research into predictive factors for selecting persons who could be successfully treated with shorter durations of direct acting antiviral (DAA) therapy for Hepatitis C. We evaluated early virological response as a means of shortening treatment and explored host, viral and pharmacokinetic contributors to treatment outcome. Methods Duration of sofosbuvir and daclatasvir (SOF/DCV) was determined according to day 2 (D2) virologic response for HCV genotype (gt) 1- or 6-infected adults in Vietnam with mild liver disease. Participants received 4 or 8 weeks treatment according to whether D2 HCV RNA was above or below 500 IU/ml (standard duration is 12 weeks). Primary endpoint was sustained virological response (SVR12). Those failing therapy were retreated with 12 weeks SOF/DCV. Host IFNL4 genotype and viral sequencing was performed at baseline, with repeat viral sequencing if virological rebound was observed. Levels of SOF, its inactive metabolite GS-331007 and DCV were measured on day 0 and 28. Results Of 52 adults enrolled, 34 received 4 weeks SOF/DCV, 17 got 8 weeks and one withdrew. SVR12 was achieved in 21/34 (62%) treated for 4 weeks, and 17/17 (100%) treated for 8 weeks. Overall 38/51 (75%) were cured with first-line treatment (mean duration 37 days). Despite a high prevalence of putative NS5A-inhibitor resistance associated substitutions (RAS), all first-line treatment failures cured after retreatment (13/13). We found no evidence treatment failure was associated with host IFNL4 genotype, viral subtype, baseline RAS or DCV levels. SOF metabolite levels were higher in those failing 4-week therapy. Conclusions Shortened SOF/DCV therapy, with retreatment if needed, reduces DAA use while maintaining high cure rates. D2 virologic response alone does not adequately predict SVR12 with 4 weeks treatment. Funding Funded by the Medical Research Council (grant MR/P025064/1) and The Global Challenges Research Fund (Wellcome Trust Grant 206/296/Z/17/Z).) Clinical trial number ISRCTN17100273

Antibiotic Review Kit for Hospitals (ARK-Hospital): a stepped wedge cluster randomised controlled trial (preprint)

Background Strategies to reduce antibiotic overuse in hospitals depend on clinicians taking decisions to stop unnecessary antibiotics. There is a lack of evidence on how support clinicians do this effectively. We evaluated a multifaceted behaviour change intervention (ARK) which aims to reduce antibiotic consumption in hospitals by increasing decisions to stop antibiotics at clinical review. Methods We performed a stepped-wedge, hospital-level, cluster-randomised controlled trial using computer-generated sequence randomisation of 39 acute hospitals to 7 calendar-time blocks (12/February/2018–01/July/2019). Co-primary outcomes were monthly antibiotic defined-daily-doses (DDD) per acute/medical admission (organisation-level, superiority) and all-cause 30-day mortality (patient-level, non-inferiority, margin 5%). Clusters were eligible if they admitted non-elective medical patients, could identify an intervention “champion” and provide pre-intervention data from February/2016. Sites were followed up for a minimum of 14 months. Intervention effects were assessed using interrupted time series analyses in each cluster. Overall effects were derived through random-effects meta-analysis, using meta-regression to assess heterogeneity in effects across prespecified factors. Trial registration was ISRCTN12674243 . Findings Adjusted estimates showed a year-on-year reduction in antibiotic consumption (−4.8%, 95%CI: -9.1%,-0.2%, p=0.042) following the ARK intervention. Among 7,160,421 acute/medical admissions, we observed a -2.7% (95%CI: -5.7%,+0.3%, p=0.079) immediate and +3.0% (95%CI: - 0.1%,+6.2%, p=0.060) sustained change in adjusted 30-day mortality. This mortality trend was not related to the magnitude of antibiotic reduction achieved (Spearman’s ρ=0.011, p=0.949). Whilst 90-day mortality odds appeared to increase over time (+3.9%, 95%CI:+0.5%,+7.4%, p=0.023), this was not observed among admissions before COVID-19 onset (+3.2%, 95%CI:-1.5%,+8.2%, p=0.182). Length of hospital stay was unaffected. Interpretation The weak, inconsistent effects of the intervention on mortality are likely to be explained by the COVID-19 pandemic onset during the post-implementation phase. We conclude that the ARK-intervention resulted in sustained, safe reductions in hospital antibiotic use. Funding NIHR Programme Grants for Applied Research, RP-PG-0514-20015. Research in context Evidence before this study Acutely ill patients often need to receive antibiotics before full diagnostic information is available. Consequently, reducing overuse of antibiotics in hospitals requires clinicians to review and where appropriate, stop unnecessary antibiotic prescriptions. Evidence-based tools to support clinicians stop unnecessary antibiotics do not exist. We searched PubMed, with no language or date restrictions, on 31/January/2022 for clinical studies focused on improving antibiotic use for hospitalised adults using the terms “anti-bacterial agents therapeutic use” AND “antibiotic stewardship”. Among the 427 studies found, the great majority were uncontrolled evaluations of different approaches to education, decision support and feedback. These included one before-after study, which found no impact of unsupported clinician-led prescription review. Three small, hospital-level cluster-randomised trials were identified. One evaluated different approaches to feedback, one compared different hospital specialties and one found intense feedback to be effective. All were small and none considered clinical outcomes or sustainability. There is a need for research to deliver proven interventions ready for implementation into practice. Added value of this study We evaluated a multifaceted “Antibiotic Review Kit” (ARK) intervention to support prescribers to appropriately stop antibiotics at clinical review. ARK comprises a prescription decision-aid supported by a brief online training tool, guidance on implementation (including regular data collection and feedback) and a patient information leaflet. We found that the intervention was associated with a sustained reduction in hospital-level antibiotic use overall and of oral and narrow-spectrum antibiotics specifically. Weak trends were observed for 30-day mortality in opposite directions for immediate and sustained impact. Although there was a sustained increase in 90-day mortality after the intervention, this was only seen when analyses included patients admitted after the start of the COVID-19 pandemic. Taken together we conclude that these mortality effects are unrelated to the intervention. Implications of all available evidence The ARK intervention is safe and effective in reducing antibiotic use among adult medical hospital admissions. The tools used are now freely available for adoption into practice.

Disparities in SARS-CoV-2 case rates by ethnicity, religion, measures of socio-economic position, English proficiency, and self-reported disability: cohort study of 39 million people in England during the Alpha and Delta waves (preprint)

Objective To examine socio-demographic disparities in SARS-CoV-2 case rates during the second (Alpha) and third (Delta) waves of the COVID-19 pandemic. Design Retrospective, population-based cohort study. Setting Resident population of England. Participants 39,006,194 people aged 10 years and over who were enumerated at the 2011 Census, registered with the National Health Service (NHS) and alive on 1 September 2020. Main outcome measures Testing positive for SARS-CoV-2 during the second wave (1 September 2020 to 22 May 2021) or third wave (23 May to 10 December 2021) of the pandemic. We calculated age-standardised case rates by socio-demographic characteristics and used logistic regression models to estimate adjusted odds ratios (ORs). Results During the study period, 5,767,584 individuals tested positive for SARS-CoV-2. In the second wave, the fully-adjusted odds of having a positive test, relative to the White British group, were highest for the Bangladeshi (OR: 1.88, 95% CI 1.86 to 1.90) and Pakistani (1.81, 1.79 to 1.82) ethnic groups. Relative to the Christian group, Muslim and Sikh religious groups had fully-adjusted ORs of 1.58 (1.57 to 1.59) and 1.74 (1.72 to 1.76), respectively. Greater area deprivation, disadvantaged socio-economic position, living in a care home and low English language proficiency were also associated with higher odds of having a positive test. However, the disparities between groups varied over time. Being Christian, White British, non-disabled, and from a more advantaged socio-economic position were all associated with increased odds of testing positive during the third wave. Conclusion There are large socio-demographic disparities on SARS-CoV-2 cases which have varied between different waves of the pandemic. Research is now urgently needed to understand why these disparities exist to inform policy interventions in future waves or pandemics. What is already known on this topic People with pre-existing health conditions or disability, ethnic minority groups, the elderly, some religious groups, people with low socio-economic status, and those living in deprived areas have been disproportionately affected by the COVID-19 pandemic in terms of risk of infection and adverse outcomes. What this study adds Using linked data on 39 million people in England, we found that during the second wave, COVID-19 case rates were highest among the Bangladeshi and Pakistani ethnic groups, the Muslim religious group, individuals from deprived areas and of low socio-economic position; during the third wave, being Christian, White British, non-disabled, and from a more advantaged socio-economic position were all associated with increased odds of receiving a positive test Adjusting for geographical factors, socio-demographic characteristics, and pre-pandemic health status explained some, but not all, of the excess risk When stratifying the dataset by broad age groups, the odds of receiving a positive test remained higher among the Bangladeshi and Pakistani ethnic groups aged 65 years and over during the third wave, which may partly explain the continued elevated mortality rates in these groups

Risk of COVID-19 related deaths for SARS-CoV-2 Omicron (B.1.1.529) compared with Delta (B.1.617.2) (preprint)

Objective To assess the risk of death involving COVID-19 following infection from Omicron (B.1.1.539/BA.1) relative to Delta (B.1.617.2). Design Retrospective cohort study. Setting England, UK, 1 December 2021 to 25 January 2022. Participants 1,035,163 people aged 18-100 years who tested positive for SARS-CoV-2 in the national surveillance programme, and had an infection identified as either Omicron- or Delta compatible. Main outcome measures Death involving COVID-19 as identified from death certification records. The exposure of interest was the SARS-CoV-2 variant identified from NHS Test and Trace PCR positive tests taken in the community (pillar 2) and analysed by Lighthouse laboratories. Cause-specific Cox proportional hazard regression models were adjusted for sex, age, vaccination status, previous infection, calendar time, ethnicity, Index of Multiple Deprivation rank, household deprivation, university degree, keyworker status, country of birth, main language, region, disability, and comorbidities. Additionally, we tested for interactions between variant and sex, age, vaccination status and comorbidities. Results The risk of death involving COVID-19 was 67% lower for Omicron compared to Delta and the reduction in the risk of death involving COVID-19 for Omicron compared to Delta was more pronounced in males than in females and in people under 70 years old than in people aged 70 years or over. Regardless of age, reduction of the risk of death from Omicron relative to Delta more was more pronounced in people who had received a booster than in those having received only two doses. Conclusions Our results support early work showing the relative reduction in severity of Omicron compared to Delta in terms of hospitalisation and extends this research to assess COVID-19 mortality. Our work also highlights the importance of the vaccination booster campaign, where the reduction in risk of death involving COVID-19 is most pronounced in individuals who had received a booster. What is already known on this topic The Omicron variant, which refers to the whole lineage (BA.1, BA.2, BA.3) had already been shown to be more transmissible than the Delta variant, but there is emerging evidence suggests that the risk of hospitalisation and risk of death within 28 days after a SARS-COV-2 test is lower. However, with a highly transmissible infection and high levels of population testing, definition of death within 28 days is more likely to be susceptible to misclassification bias due to asymptomatic or co-incidental infection. There is no study so far comparing the risk of COVID-19 death as identified from death certification records, with the cause of death assessed by the physician who attended the patient in the last illness. What this study adds Using data from a large cohort of COVID-19 infections that occurred in December 2021, we examined the difference in the risk COVID-19 death, as identified from death certification records, between the Delta and Omicron BA.1 variant. Our study shows that risk of death involving COVID-19 was reduced by 67% following infection with the Omicron BA.1 variant relative to the Delta variant after adjusting for a wide range of potential confounders, including vaccination status and comorbidities. Importantly, we found that the relative risk of COVID-19 mortality following Omicron versus Delta infection varied by age and sex, with lower relative risk in younger individuals and for males than females. The reduction in risk of death involving COVID-19 was also most pronounced in individuals who had received a booster.

Risk of Long Covid in people infected with SARS-CoV-2 after two doses of a COVID-19 vaccine: community-based, matched cohort study (preprint)

Background: It is unclear whether receiving two COVID-19 vaccinations before SARS-CoV-2 infection reduces the risk of developing Long Covid symptoms. We examined whether the likelihood of symptoms 12 weeks after infection differed by vaccination status. Methods: We included COVID-19 Infection Survey participants aged 18-69 years who tested positive for SARS-CoV-2 between 26 April 2020 and 30 November 2021; we excluded participants who, before their first test-confirmed infection, had suspected COVID-19 or Long Covid symptoms, or were single-vaccinated. Participants who were double-vaccinated [≥]14 days before infection were 1:1 propensity-score matched, based on socio-demographic characteristics and time from infection to follow-up for Long Covid, to those unvaccinated at time of infection. We estimated adjusted odds ratios (aOR) of Long Covid symptoms [≥]12 weeks post-infection, comparing double-vaccinated with unvaccinated (reference group) participants. Results: The study sample comprised 3,090 double-vaccinated participants (mean age 49 years, 54% female, 92% white, median follow-up from infection 96 days) and matched control participants. Long Covid symptoms were reported by 294 double-vaccinated participants (prevalence 9.5%) compared with 452 unvaccinated participants (14.6%), corresponding to an aOR for Long Covid symptoms of 0.59 (95% CI: 0.50 to 0.69). There was no evidence of heterogeneity by adenovirus vector versus messenger ribonucleic acid vaccines (p=0.25). Conclusions: COVID-19 vaccination is associated with reduced risk of Long Covid, emphasising the need for public health initiatives to increase population-level vaccine uptake. Longer follow-up is needed, as is the assessment of further vaccine doses and the Omicron variant.

Changes in the trajectory of Long Covid symptoms following COVID-19 vaccination: community-based cohort study (preprint)

ObjectiveTo estimate associations between COVID-19 vaccination and Long Covid symptoms in adults who were infected with SARS-CoV-2 prior to vaccination. DesignObservational cohort study using individual-level interrupted time series analysis. SettingRandom sample from the community population of the UK. Participants28,356 COVID-19 Infection Survey participants (mean age 46 years, 56% female, 89% white) aged 18 to 69 years who received at least their first vaccination after test-confirmed infection. Main outcome measuresPresence of long Covid symptoms at least 12 weeks after infection over the follow-up period 3 February to 5 September 2021. ResultsMedian follow-up was 141 days from first vaccination (among all participants) and 67 days from second vaccination (84% of participants). First vaccination was associated with an initial 12.8% decrease (95% confidence interval: -18.6% to -6.6%) in the odds of Long Covid, but increasing by 0.3% (-0.6% to +1.2%) per week after the first dose. Second vaccination was associated with an 8.8% decrease (-14.1% to -3.1%) in the odds of Long Covid, with the odds subsequently decreasing by 0.8% (-1.2% to -0.4%) per week. There was no statistical evidence of heterogeneity in associations between vaccination and Long Covid by socio-demographic characteristics, health status, whether hospitalised with acute COVID-19, vaccine type (adenovirus vector or mRNA), or duration from infection to vaccination. ConclusionsThe likelihood of Long Covid symptoms reduced after COVID-19 vaccination, and the improvement was sustained over the follow-up period after the second dose. Vaccination may contribute to a reduction in the population health burden of Long Covid, though longer follow-up time is needed. Summary boxWhat is already known on this topic O_LICOVID-19 vaccines are effective at reducing rates of SARS-CoV-2 infection, transmission, hospitalisation, and death C_LIO_LIThe incidence of Long Covid may be reduced if infected after vaccination, but the relationship between vaccination and pre-existing long COVID symptoms is unclear, as published studies are generally small and with self-selected participants C_LI What this study adds O_LIThe likelihood of Long Covid symptoms reduced after COVID-19 vaccination, and the improvement was sustained over the follow-up period after the second dose C_LIO_LIThere was no evidence of differences in this relationship by socio-demographic characteristics, health-related factors, vaccine type, or duration from infection to vaccination C_LIO_LIAlthough causality cannot be inferred from this observational evidence, vaccination may contribute to a reduction in the population health burden of Long Covid; further research is needed to understand the biological mechanisms that may ultimately contribute to the development of therapeutics for Long Covid C_LI

The challenge of limited vaccine supplies: impact of prior infection on anti-spike IgG antibody trajectories after a single COVID-19 vaccination (preprint)

Given high SARS-CoV-2 incidence, coupled with slow and inequitable vaccine roll-out, there is an urgent need for evidence to underpin optimum vaccine deployment, aiming to maximise global population immunity at speed. We evaluate whether a single vaccination in previously infected individuals generates similar initial and subsequent antibody responses to two vaccinations in those without prior infection. We compared anti-spike IgG antibody responses after a single dose of ChAdOx1, BNT162b2, or mRNA-1273 SARS-CoV-2 vaccines in the COVID-19 Infection Survey in the UK general population. In 100,849 adults who received at least one vaccination, 13,404 (13.3%) had serological and/or PCR evidence of prior infection. Prior infection significantly boosted antibody responses for all three vaccines, producing a higher peak level and longer half-life, and a response comparable to those without prior infection receiving two vaccinations. In those with prior infection, median time above the positivity threshold was estimated to last for >1 year after the first dose. Single-dose vaccination targeted to those previously infected may provide protection in populations with high rates of previous infection faced with limited vaccine supply, as an interim measure while vaccine campaigns are scaled up.

Impact of the COVID-19 pandemic on community antibiotic prescribing and stewardship: a qualitative interview study with general practitioners in England (preprint)

The COVID-19 pandemic has had a profound impact on the delivery of primary care services. We aimed to identify general practitioners (GPs) perceptions and experiences of how the COVID-19 pandemic influenced antibiotic prescribing and antimicrobial stewardship (AMS) in general practice in England. Twenty-four semi-structured interviews were conducted with 18 GPs at two time-points: autumn 2020 (14 interviews) and spring 2021 (10 interviews). Interviews were audio-recorded, transcribed and analysed thematically, taking a longitudinal approach. Participants reported a lower threshold for antibiotic prescribing (and fewer consultations) for respiratory infections and COVID-19 symptoms early in the pandemic, then returning to more usual (pre-pandemic) prescribing. They perceived less impact on antibiotic prescribing for urinary and skin infections. Participants perceived the changing ways of working and consulting (e.g., proportions of remote and in-person consultations), and the changing patient presentations and GP workload as influencing the fluctuations in antibiotic prescribing. This was compounded by decreased engagement with, and priority of, AMS due to COVID-19-related urgent priorities. Re-engagement with AMS is needed, e.g., through reviving antibiotic prescribing feedback and targets/incentives. While the pandemic disrupted the usual ways of working, it also produced opportunities, e.g., for re-organising ways of managing infections and AMS in the future.

COVID-19 vaccination, risk-compensatory behaviours, and social contacts in four countries in the UK (preprint)

The physiological effects of vaccination against SARS-CoV-2 (COVID-19) are well documented, yet the behavioural effects are largely unknown. Risk compensation suggests that gains in personal safety, as a result of vaccination, are offset by increases in risky behaviour, such as socialising, commuting and working outside the home. This is potentially problematic because transmission of SARS-CoV-2 is driven by contacts, which could be amplified by vaccine-related risk compensation behaviours. Here, we show that social behaviours were overall unrelated to personal vaccination, but - adjusting for variation in mitigation policies - were responsive to the level of vaccination in the wider population: individuals in the UK were risk compensating when rates of vaccination were rising. This effect was observed across four nations of the UK, each of which varied policies autonomously.

The impact of SARS-CoV-2 vaccination on Alpha and Delta variant transmission (preprint)

BackgroundPre-Delta, vaccination reduced SARS-CoV-2 transmission from individuals infected despite vaccination, potentially via reducing viral loads. While vaccination still lowers the risk of infection, similar viral loads in vaccinated and unvaccinated individuals infected with Delta question how much vaccination prevents transmission. MethodsWe performed a retrospective observational cohort study of adult contacts of SARS-CoV-2-infected adult index cases using English contact testing data. We used multivariable Poisson regression to investigate associations between transmission and index case and contact vaccination, and how these vary with Alpha and Delta variants (classified using S-gene detection/calendar trends) and time since second vaccination. Results54,667/146,243(37.4%) PCR-tested contacts of 108,498 index cases were PCR-positive. Two doses of BNT162b2 or ChAdOx1 vaccines in Alpha index cases were independently associated with reduced PCR-positivity in contacts (aRR, adjusted rate ratio vs. unvaccinated=0.32[95%CI 0.21-0.48] and 0.48[0.30-0.78] respectively). The Delta variant attenuated vaccine-associated reductions in transmission: two BNT162b2 doses reduced Delta transmission (aRR=0.50[0.39-0.65]), more than ChAdOx1 (aRR=0.76[0.70-0.82]). Variation in Ct values (indicative of viral load) explained 7-23% of vaccine-associated transmission reductions. Transmission reductions declined over time post-second vaccination, for Delta reaching similar levels to unvaccinated individuals by 12 weeks for ChAdOx1 and attenuating substantially for BNT162b2. Protection in contacts also declined in the 3 months post-second vaccination. ConclusionsVaccination reduces transmission of Delta, but by less than the Alpha variant. The impact of vaccination decreased over time. Factors other than PCR Ct values at diagnosis are important in understanding vaccine-associated transmission reductions. Booster vaccinations may help control transmission together with preventing infections.

Symptoms and SARS-CoV-2 positivity in the general population in the UK (preprint)

BackgroundSeveral community-based studies have assessed the ability of different symptoms to identify COVID-19 infections, but few have compared symptoms over time (reflecting SARS-CoV-2 variants) and by vaccination status. MethodsUsing data and samples collected by the COVID-19 Infection Survey at regular visits to representative households across the UK, we compared symptoms in new PCR-positives and comparator test-negative controls. ResultsFrom 26/4/2020-7/8/2021, 27,869 SARS-CoV-2 PCR-positive episodes occurred in 27,692 participants (median 42 years (IQR 22-58)); 13,427 (48%) self-reported symptoms ("symptomatic positive episodes"). The comparator group comprised 3,806,692 test-negative visits (457,215 participants); 130,612 (3%) self-reported symptoms ("symptomatic negative visit"). Reporting of any symptoms in positive episodes varied over calendar time, reflecting changes in prevalence of variants, incidental changes (e.g. seasonal pathogens, schools re-opening) and vaccination roll-out. There was a small increase in sore throat reporting in symptomatic positive episodes and negative visits from April-2021. After May-2021 when Delta emerged there were substantial increases in headache and fever in positives, but not in negatives. Although specific symptom reporting in symptomatic positive episodes vs. negative visits varied by age, sex, and ethnicity, only small improvements in symptom-based infection detection were obtained; e.g. adding fatigue/weakness or all eight symptoms to the classic four symptoms (cough, fever, loss of taste/smell) increased sensitivity from 74% to 81% to 90% but tests per positive from 4.6 to 5.3 to 8.7. ConclusionsWhilst SARS-CoV-2-associated symptoms vary by variant, vaccination status and demographics, differences are modest and do not warrant large-scale changes to targeted testing approaches given resource implications. SummaryWithin the COVID-19 Infection Survey, recruiting representative households across the UK general population, SARS-CoV-2-associated symptoms varied by viral variant, vaccination status and demographics. However, differences are modest and do not currently warrant large-scale changes to targeted testing approaches.

Sociodemographic inequality in COVID-19 vaccination coverage amongst elderly adults in England: a national linked data study (preprint)

Objective: To examine inequalities in COVID-19 vaccination rates amongst elderly adults in England Design: Cohort study Setting: People living in private households and communal establishments in England Participants: 6,829,643 adults aged 70 years or above (mean 78.7 years, 55.2% female) who were alive on 15 March 2021. Main outcome measures: Having received the first dose of a vaccine against COVID-19 by 15 March 2021. We calculated vaccination rates and estimated unadjusted and adjusted odds ratios using logistic regression models. Results: By 15 March 2021, 93.2% of people living in England aged 70 years and over had received at least one dose of a COVID-19 vaccine. While vaccination rates differed across all factors considered apart from sex, the greatest disparities were seen between ethnic and religious groups. The lowest rates were in people of Black African and Black Caribbean ethnic backgrounds, where only 67.2% and 73.9% had received a vaccine, with adjusted odds of not being vaccinated at 5.01 (95% CI 4.86 - 5.16) and 4.85 (4.75 - 4.96) times greater than the White British group. The proportion of individuals self-identifying as Muslim and Buddhist who had received a vaccine was 79.1% and 84.1%, respectively. Older age, greater area deprivation, less advantaged socio-economic position (proxied by living in a rented home), being disabled and living either alone or in a multi-generational household were also associated with higher odds of not having received the vaccine. Conclusion: People disproportionately affected seem most hesitant to COVID-19 vaccinations. Policy Interventions to improve these disparities are urgently needed.

Impact of vaccination on SARS-CoV-2 cases in the community: a population-based study using the UK COVID-19 Infection Survey (preprint)

Objectives: To assess the effectiveness of COVID-19 vaccination in preventing SARS-CoV-2 infection in the community. Design: Prospective cohort study. Setting: The UK population-representative longitudinal COVID-19 Infection Survey. Participants: 373,402 participants aged [≥]16 years contributing 1,610,562 RT-PCR results from nose and throat swabs between 1 December 2020 and 3 April 2021. Main outcome measures: New RT-PCR-positive episodes for SARS-CoV-2 overall, by self-reported symptoms, by cycle threshold (Ct) value (<30 versus [≥]30), and by gene positivity (compatible with the B.1.1.7 variant versus not). Results: Odds of new SARS-CoV-2 infection were reduced 65% (95% CI 60 to 70%; P<0.001) in those [≥]21 days since first vaccination with no second dose versus unvaccinated individuals without evidence of prior infection (RT-PCR or antibody). In those vaccinated, the largest reduction in odds was seen post second dose (70%, 95% CI 62 to 77%; P<0.001).There was no evidence that these benefits varied between Oxford-AstraZeneca and Pfizer-BioNTech vaccines (P>0.9).There was no evidence of a difference in odds of new SARS-CoV-2 infection for individuals having received two vaccine doses and with evidence of prior infection but not vaccinated (P=0.89). Vaccination had a greater impact on reducing SARS-CoV-2 infections with evidence of high viral shedding Ct<30 (88% reduction after two doses; 95% CI 80 to 93%; P<0.001) and with self-reported symptoms (90% reduction after two doses; 95% CI 82 to 94%; P<0.001); effects were similar for different gene positivity patterns. Conclusion: Vaccination with a single dose of Oxford-AstraZeneca or Pfizer-BioNTech vaccines, or two doses of Pfizer-BioNTech, significantly reduced new SARS-CoV-2 infections in this large community surveillance study. Greater reductions in symptomatic infections and/or infections with a higher viral burden are reflected in reduced rates of hospitalisations/deaths, but highlight the potential for limited ongoing transmission from asymptomatic infections in vaccinated individuals. Registration: The study is registered with the ISRCTN Registry, ISRCTN21086382.

Increased infections, but not viral burden, with a new SARS-CoV-2 variant (preprint)

BackgroundA new variant of SARS-CoV-2, B.1.1.7/VOC202012/01, was identified in the UK in December-2020. Direct estimates of its potential to enhance transmission are limited. MethodsNose and throat swabs from 28-September-2020 to 2-January-2021 in the UKs nationally representative surveillance study were tested by RT-PCR for three genes (N, S and ORF1ab). Those positive only on ORF1ab+N, S-gene target failures (SGTF), are compatible with B.1.1.7/VOC202012/01. We investigated cycle threshold (Ct) values (a proxy for viral load), percentage of positives, population positivity and growth rates in SGTF vs non-SGTF positives. Results15,166(0.98%) of 1,553,687 swabs were PCR-positive, 8,545(56%) with three genes detected and 3,531(23%) SGTF. SGTF comprised an increasing, and triple-gene positives a decreasing, percentage of infections from late-November in most UK regions/countries, e.g. from 15% to 38% to 81% over 1.5 months in London. SGTF Ct values correspondingly declined substantially to similar levels to triple-gene positives. Population-level SGTF positivity remained low (<0.25%) in all regions/countries until late-November, when marked increases with and without self-reported symptoms occurred in southern England (to 1.5-3%), despite stable rates of non-SGTF cases. SGTF positivity rates increased on average 6% more rapidly than rates of non-SGTF positives (95% CI 4-9%) supporting addition rather than replacement with B.1.1.7/VOC202012/01. Excess growth rates for SGTF vs non-SGTF positives were similar in those up to high school age (5% (1-8%)) and older individuals (6% (4-9%)). ConclusionsDirect population-representative estimates show that the B.1.1.7/VOC202012/01 SARS-CoV-2 variant leads to higher infection rates, but does not seem particularly adapted to any age group.