An evaluation of the national testing response during the COVID-19 pandemic in England: a multistage mixed-methods study protocol.

INTRODUCTION: In 2020, the UK government established a large-scale testing programme to rapidly identify individuals in England who were infected with SARS-CoV-2 and had COVID-19. This comprised part of the UK government's COVID-19 response strategy, to protect those at risk of severe COVID-19 disease and death and to reduce the burden on the health system. To assess the success of this approach, the UK Health Security Agency (UKHSA) commissioned an independent evaluation of the activities delivered by the National Health System testing programme in England. The primary purpose of this evaluation will be to capture key learnings from the roll-out of testing to different target populations via various testing services between October 2020 and March 2022 and to use these insights to formulate recommendations for future pandemic preparedness strategy. In this protocol, we detail the rationale, approach and study design. METHODS AND ANALYSIS: The proposed study involves a stepwise mixed-methods approach, aligned with established methods for the evaluation of complex interventions in health, to retrospectively assess the combined impact of key asymptomatic and symptomatic testing services nationally. The research team will first develop a theory of change, formulated in collaboration with testing service stakeholders, to understand the causal pathways and intended and unintended outcomes of each testing service and explore contextual impacts on each testing service's intended outcomes. Insights gained will help identify indicators to evaluate how the combined aims of the testing programme were achieved, using a mixed-methods approach. ETHICS AND DISSEMINATION: The study protocol was granted ethics approval by the UKHSA Research Ethics and Governance Group (reference NR0347). All relevant ethics guidelines will be followed throughout. Findings arising from this evaluation will be used to inform lessons learnt and recommendations for UKHSA on appropriate pandemic preparedness testing programme designs; findings will also be disseminated in peer-reviewed journals, a publicly available report to be published online and at academic conferences. The final report of findings from the evaluation will be used as part of a portfolio of evidence produced for the independent COVID-19 government inquiry in the UK. TRANSPARENCY DECLARATION: The lead author (the manuscript's guarantor) affirms that the manuscript is an honest, accurate and transparent account of the study being reported; no important aspects of the study have been omitted, and any discrepancies from the study as planned have been explained.

Self-swabbing versus assisted swabbing for viral detection by qRT-PCR: the experience from SARS-CoV-2 based on a meta-analysis of six prospectively designed evaluations conducted in a UK setting.

PURPOSE: In April 2020, the UK Government implemented NHS Test and Trace to provide SARS-CoV-2 quantitative reverse transcription polymerase chain reaction (qRT-PCR) testing for the public, with nose-and-throat swabbing for samples performed by trained staff. Self-swabbing (SS) would allow rapid scale-up of testing capacity and access. Six studies were undertaken to determine whether SS was as effective for detecting SARS-CoV-2 as swabbing performed by trained staff. METHODS: Six prospective studies were conducted between April-October 2020, using six swab/media combinations. Differences between assisted swabbing (AS) and SS were evaluated for concordance, positivity, sensitivity, cycle threshold (Ct) values and void rates. Statistical analysis was performed using 95% confidence intervals (CIs), paired t-tests and model-based methods. RESULTS: Overall, 3,253 individuals were recruited (median age 37 years, 49% female), with 2,933 having valid paired qRT-PCR results. Pooled concordance rate was 98% (95% CI: 96%, 99%). Positivity rate differences for SS (8.1%) and AS (8.4%) and differences in pooled sensitivities between SS (86%; 95% CI: 78%, 92%) and AS (91%; 95% CI: 78%, 96%) were nonsignificant. Both types of swabbing led to pooled void rates below 2% and strongly correlated Ct values. Age, sex and previous swabbing experience did not have a significant impact on concordance or sensitivity. CONCLUSION: The UK adopted a policy to promote self-testing for SARS-CoV-2 based on data demonstrating equivalence of SS versus AS. Positive outcomes with SS are likely generalisable to testing for other respiratory pathogens, and we consider self-sampling and self-testing essential for future pandemic preparedness.

Nanopore sequencing of influenza A and B in Oxfordshire and the United Kingdom, 2022-23.

OBJECTIVES: We evaluated Nanopore sequencing for influenza surveillance. METHODS: Influenza A and B PCR-positive samples from hospital patients in Oxfordshire, UK, and a UK-wide population survey from winter 2022-23 underwent Nanopore sequencing following targeted rt-PCR amplification. RESULTS: From 941 infections, successful sequencing was achieved in 292/388 (75 %) available Oxfordshire samples: 231 (79 %) A/H3N2, 53 (18 %) A/H1N1, and 8 (3 %) B/Victoria and in 53/113 (47 %) UK-wide samples. Sequencing was more successful at lower Ct values. Most same-sample replicate sequences had identical haemagglutinin segments (124/141, 88 %); 36/39 (92 %) Illumina vs. Nanopore comparisons were identical, and 3 (8 %) differed by 1 variant. Comparison of Oxfordshire and UK-wide sequences showed frequent inter-regional transmission. Infections were closely-related to 2022-23 vaccine strains. Only one sample had a neuraminidase inhibitor resistance mutation. 849/941 (90 %) Oxfordshire infections were community-acquired. 63/88 (72 %) potentially healthcare-associated cases shared a hospital ward with ≥ 1 known infectious case. 33 epidemiologically-plausible transmission links had sequencing data for both source and recipient: 8 were within ≤ 5 SNPs, of these, 5 (63 %) involved potential sources that were also hospital-acquired. CONCLUSIONS: Nanopore influenza sequencing was reproducible and antiviral resistance rare. Inter-regional transmission was common; most infections were genomically similar. Hospital-acquired infections are likely an important source of nosocomial transmission and should be prioritised for infection prevention and control.

A self-controlled case series study to measure the risk of SARS-CoV-2 infection associated with attendance at sporting and cultural events: the UK Events Research Programme events.

BACKGROUND: In 2021, whilst societies were emerging from major social restrictions during the SARS-CoV-2 pandemic, the UK government instigated an Events Research Programme to examine the risk of COVID-19 transmission from attendance at cultural events and explore ways to enable people to attend a range of events whilst minimising risk of transmission. We aimed to measure any impact on risk of COVID-19 transmission from attendance at events held at or close to commercially viable capacity using routinely collected data. METHODS: Data were obtained on attendees at Phase 3 Events Research Programme events, for which some infection risk mitigation measures were in place (i.e. evidence of vaccination or a negative lateral flow test). Attendance data were linked with COVID-19 test result data from the UK Test and Trace system. Using a self-controlled case series design, we measured the within person incidence rate ratio for testing positive for COVID-19, comparing the rate in days 3 to 9 following event attendance (high risk period) with days 1 and 2 and 10-16 (baseline period). Rate ratios were adjusted for estimates of underlying regional COVID-19 prevalence to account for population level fluctuations in infection risk, and events were grouped into broadly similar types. RESULTS: From attendance data available for 188,851 attendees, 3357 people tested positive for COVID-19 during the observation period. After accounting for total testing trends over the period, incidence rate ratios and 95% confidence intervals for positive tests were 1.16 (0.53-2.57) for indoor seated events, 1.12 (0.95-1.30) for mainly outdoor seated events, 0.65 (0.51-0.83) for mainly outdoor partially seated events, and 1.70 (1.52-1.89) for mainly outdoor unseated multi-day events. CONCLUSIONS: For the majority of event types studied in the third phase of the UK Events Research Programme, we found no evidence of an increased risk of COVID-19 transmission associated with event attendance. However, we found a 70% increased risk of infection associated with attendance at mainly outdoor unseated multi-day events. We have also demonstrated a novel use for self-controlled case series methodology in monitoring infection risk associated with event attendance.

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.

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 the 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 the symptoms and influenza vaccination, using adjusted logistic and multinomial models. RESULTS: 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. CONCLUSIONS: 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.

Faster detection of asymptomatic COVID-19 cases among care home staff in England through the combination of SARS-CoV-2 testing technologies.

To detect SARS-CoV-2 amongst asymptomatic care home staff in England, a dual-technology weekly testing regime was introduced on 23 December 2020. A lateral flow device (LFD) and quantitative reverse transcription polymerase chain reaction (qRT-PCR) test were taken on the same day (day 0) and a midweek LFD test was taken three to four days later. We evaluated the effectiveness of using dual-technology to detect SARS-CoV-2 between December 2020 to April 2021. Viral concentrations derived from qRT-PCR were used to determine the probable stage of infection and likely level of infectiousness. Day 0 PCR detected 1,493 cases of COVID-19, of which 53% were in the early stages of infection with little to no risk of transmission. Day 0 LFD detected 83% of cases that were highly likely to be infectious. On average, LFD results were received 46.3 h earlier than PCR, enabling removal of likely infectious staff from the workplace quicker than by weekly PCR alone. Demonstrating the rapidity of LFDs to detect highly infectious cases could be combined with the ability of PCR to detect cases in the very early stages of infection. In practice, asymptomatic care home staff were removed from the workplace earlier, breaking potential chains of transmission.

Rapid antigen testing for SARS-CoV-2 by lateral flow assay: A field evaluation of self- and professional testing at UK community testing sites.

BACKGROUND: The advent of lateral flow devices (LFDs) for SARS-CoV-2 detection enabled widespread use of rapid self-tests during the pandemic. While self-testing using LFDs is now common, whether self-testing provides comparable performance to professional testing was a key question that remained important for pandemic planning. METHODS: Three prospective multi-centre studies were conducted to compare the performance of self- and professional testing using LFDs. Participants tested themselves or were tested by trained (professional) testers at community testing sites in the UK. Corresponding qRT-PCR test results served as reference standard. The performance of Innova, Orient Gene and SureScreen LFDs by users (self) and professional testers was assessed in terms of sensitivity, specificity, and kit failure (void) rates. Impact of age, sex and symptom status was analysed using logistic regression modelling. RESULTS: 16,617 participants provided paired tests, of which 15,418 were included in the analysis. Self-testing with Innova, Orient Gene or SureScreen LFDs achieved sensitivities of 50 %, 53 % or 72 %, respectively, compared to qRT-PCR. Self and professional LFD testing showed no statistically different sensitivity with respect to corresponding qRT-PCR testing. Specificity was consistently equal to or higher than 99 %. Sex and age had no or only marginal impact on LFD performance while sensitivity was significantly higher for symptomatic individuals. Sensitivity of LFDs increased strongly to up to 90 % with higher levels of viral RNA measured by qRT-PCR. CONCLUSIONS: Our results support SARS-CoV-2 self-testing with LFDs, especially for the detection of individuals whose qRT-PCR tests showed high viral concentrations.

Insights for precision oncology from the integration of genomic and clinical data of 13,880 tumors from the 100,000 Genomes Cancer Programme.

The Cancer Programme of the 100,000 Genomes Project was an initiative to provide whole-genome sequencing (WGS) for patients with cancer, evaluating opportunities for precision cancer care within the UK National Healthcare System (NHS). Genomics England, alongside NHS England, analyzed WGS data from 13,880 solid tumors spanning 33 cancer types, integrating genomic data with real-world treatment and outcome data, within a secure Research Environment. Incidence of somatic mutations in genes recommended for standard-of-care testing varied across cancer types. For instance, in glioblastoma multiforme, small variants were present in 94% of cases and copy number aberrations in at least one gene in 58% of cases, while sarcoma demonstrated the highest occurrence of actionable structural variants (13%). Homologous recombination deficiency was identified in 40% of high-grade serous ovarian cancer cases with 30% linked to pathogenic germline variants, highlighting the value of combined somatic and germline analysis. The linkage of WGS and longitudinal life course clinical data allowed the assessment of treatment outcomes for patients stratified according to pangenomic markers. Our findings demonstrate the utility of linking genomic and real-world clinical data to enable survival analysis to identify cancer genes that affect prognosis and advance our understanding of how cancer genomics impacts patient outcomes.

The effectiveness and efficiency of asymptomatic SARS-CoV-2 testing strategies for patient and healthcare workers within acute NHS hospitals during an omicron-like period.

BACKGROUND: Asymptomatic SARS-CoV-2 testing of hospitalised patients began in April-2020, with twice weekly healthcare worker (HCW) testing introduced in November-2020. Guidance recommending asymptomatic testing was withdrawn in August-2022. Assessing the impact of this decision from data alone is challenging due to concurrent changes in infection prevention and control practices, community transmission rates, and a reduction in ascertainment rate from reduced testing. Computational modelling is an effective tool for estimating the impact of this change. METHODS: Using a computational model of SARS-CoV-2 transmission in an English hospital we estimate the effectiveness of several asymptomatic testing strategies, namely; (1) Symptomatic testing of patients and HCWs, (2) testing of all patients on admission with/without repeat testing on days 3 and 5-7, and (3) symptomatic testing plus twice weekly asymptomatic HCW testing with 70% compliance. We estimate the number of patient and HCW infections, HCW absences, number of tests, and tests per case averted or absence avoided, with differing community prevalence rates over a 12-week period. RESULTS: Testing asymptomatic patients on admission reduces the rate of nosocomial SARS-CoV-2 infection by 8.1-21.5%. Additional testing at days 3 and 5-7 post admission does not significantly reduce infection rates. Twice weekly asymptomatic HCW testing can reduce the proportion of HCWs infected by 1.0-4.4% and monthly absences by 0.4-0.8%. Testing asymptomatic patients repeatedly requires up to 5.5 million patient tests over the period, and twice weekly asymptomatic HCW testing increases the total tests to almost 30 million. The most efficient patient testing strategy (in terms of tests required to prevent a single patient infection) was testing asymptomatic patients on admission across all prevalence levels. The least efficient was repeated testing of patients with twice weekly asymptomatic HCW testing in a low prevalence scenario, and in all other prevalence levels symptomatic patient testing with regular HCW testing was least efficient. CONCLUSIONS: Testing patients on admission can reduce the rate of nosocomial SARS-CoV-2 infection but there is little benefit of additional post-admission testing. Asymptomatic HCW testing has little incremental benefit for reducing patient cases at low prevalence but has a potential role at higher prevalence or with low community transmission. A full health-economic evaluation is required to determine the cost-effectiveness of these strategies.

COVID-19 risk mitigation in reopening mass cultural events: population-based observational study for the UK Events Research Programme in Liverpool City Region.

OBJECTIVES: To understand severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transmission risks, perceived risks and the feasibility of risk mitigations from experimental mass cultural events before coronavirus disease 2019 (COVID-19) restrictions were lifted. DESIGN: Prospective, population-wide observational study. SETTING: Four events (two nightclubs, an outdoor music festival and a business conference) open to Liverpool City Region UK residents, requiring a negative lateral flow test (LFT) within the 36 h before the event, but not requiring social distancing or face-coverings. PARTICIPANTS: A total of 12,256 individuals attending one or more events between 28 April and 2 May 2021. MAIN OUTCOME MEASURES: SARS-CoV-2 infections detected using audience self-swabbed (5-7 days post-event) polymerase chain reaction (PCR) tests, with viral genomic analysis of cases, plus linked National Health Service COVID-19 testing data. Audience experiences were gathered via questionnaires, focus groups and social media. Indoor CO2 concentrations were monitored. RESULTS: A total of 12 PCR-positive cases (likely 4 index, 8 primary or secondary), 10 from the nightclubs. Two further cases had positive LFTs but no PCR. A total of 11,896 (97.1%) participants with scanned tickets were matched to a negative pre-event LFT: 4972 (40.6%) returned a PCR within a week. CO2 concentrations showed areas for improving ventilation at the nightclubs. Population infection rates were low, yet with a concurrent outbreak of >50 linked cases around a local swimming pool without equivalent risk mitigations. Audience anxiety was low and enjoyment high. CONCLUSIONS: We observed minor SARS-CoV-2 transmission and low perceived risks around events when prevalence was low and risk mitigations prominent. Partnership between audiences, event organisers and public health services, supported by information systems with real-time linked data, can improve health security for mass cultural events.

Detection of SARS-CoV-2 BA.2.86 by lateral flow devices.

We evaluated the performance of 12 lateral flow devices by assessing their analytical sensitivity for SARS-CoV-2 variant BA.2.86. Kits from ACON, Orient Gene, Xiamen Biotime, Getein, and SureScreen detected variant BA.2.86 to sufficient sensitivity levels, comparable to those observed with previous Omicron variants. The stocks of lateral flow devices currently held by the UK government do not currently need changing for deployment for this variant.

Limited historical admixture between European wildcats and domestic cats.

Domestic cats were derived from the Near Eastern wildcat (Felis lybica), after which they dispersed with people into Europe. As they did so, it is possible that they interbred with the indigenous population of European wildcats (Felis silvestris). Gene flow between incoming domestic animals and closely related indigenous wild species has been previously demonstrated in other taxa, including pigs, sheep, goats, bees, chickens, and cattle. In the case of cats, a lack of nuclear, genome-wide data, particularly from Near Eastern wildcats, has made it difficult to either detect or quantify this possibility. To address these issues, we generated 75 ancient mitochondrial genomes, 14 ancient nuclear genomes, and 31 modern nuclear genomes from European and Near Eastern wildcats. Our results demonstrate that despite cohabitating for at least 2,000 years on the European mainland and in Britain, most modern domestic cats possessed less than 10% of their ancestry from European wildcats, and ancient European wildcats possessed little to no ancestry from domestic cats. The antiquity and strength of this reproductive isolation between introduced domestic cats and local wildcats was likely the result of behavioral and ecological differences. Intriguingly, this long-lasting reproductive isolation is currently being eroded in parts of the species' distribution as a result of anthropogenic activities.

PCR testing of traced contacts for SARS-CoV-2 in England, January to July 2021.

BackgroundThe NHS Test and Trace (NHSTT) programme was established in May 2020 in England to deliver SARS-CoV-2 testing and contact tracing in order to identify infected individuals and reduce COVID-19 spread. To further control transmission, people identified as contacts were asked to self-isolate for 10 days and test only if they became symptomatic. From March 2021, eligibility criteria for PCR testing expanded to include asymptomatic contacts of confirmed cases.AimTo analyse testing patterns of contacts before and after the change in testing guidance in England to assess the impact on PCR testing behaviour with respect to symptom status and contact type.MethodsTesting and contact tracing data were extracted from the national data systems and linked. Subsequently, descriptive statistical analysis was applied to identify trends in testing behaviour.ResultsBetween 1 January and 31 July 2021, over 5 million contacts were identified and reached by contact tracers; 42.3% took a PCR test around the time they were traced. Overall positivity rate was 44.3% and consistently higher in symptomatic (60-70%) than asymptomatic (around 20%, March-June) contacts. The proportion of tests taken by asymptomatic contacts increased over time, especially after the change in testing guidance. No link was observed between uptake of PCR tests and vaccination coverage. Fully vaccinated contacts showed lower positivity (23.8%) than those with one dose (37.2%) or unvaccinated (51.0%).ConclusionAlmost 1 million asymptomatic contacts were tested for SARS-CoV-2, identifying 214,056 positive cases, demonstrating the value of offering PCR testing to this group.

The evaluation of a multi-day testing approach with antigen lateral flow devices for people eligible for community-based COVID-19 treatments.

BACKGROUND: COVID-19 therapeutics including antiviral and monoclonal antibody treatments (hereafter 'COVID-19 treatments') require rapid administration to be effective. As part of the community-based antiviral and therapeutic treatment pathway for COVID-19 there has been a move from PCR testing in those eligible to a rapid antigen lateral flow testing regime. OBJECTIVES: To determine whether a multi-day lateral flow device (LFD) testing regime is a feasible alternative to PCR for diagnosing symptomatic patients eligible for COVID-19 treatments. An LFD regime might return a positive result more quickly than a PCR and hence expedite access to COVID-19 treatments. METHODS: A retrospective analysis was conducted of diagnostic testing for SARS-CoV-2 with a combination of PCR and LFDs of symptomatic patients eligible for COVID-19 treatments. LFD testing patterns were not assigned. Patients self-censored and the patterns were retro-fitted to the observed results. RESULTS: The LFD testing patterns offered high sensitivity, close to 92%; however, the false positive rate also increased, with most of the multi-day testing patterns having a false positive rate greater than 3%. The highest sensitivity was seen among patients who tested with LFD on the same day as PCR. CONCLUSIONS: There were multiple observed testing behaviours. We conclude that multi-day LFD testing for COVID-19 provides a feasible alternative to PCR to in eligible patients, allowing swift prescription of COVID-19 treatments in most cases. This approach requires acceptance of a trade-off for a small increase in false-positive and -negative results.

High attack rate in a large care home outbreak of SARS-CoV-2 BA.2.86, East of England, August 2023.

We investigated an outbreak of SARS-CoV-2 variant BA.2.86 in an East of England care home. We identified 45 infections (33 residents, 12 staff), among 38 residents and 66 staff. Twenty-nine of 43 PCR swabs were sequenced, all of which were variant BA.2.86. The attack rate among residents was 87%, 19 were symptomatic, and one was hospitalised. Twenty-four days after the outbreak started, no cases were still unwell. Among the 33 resident cases, 29 had been vaccinated 4 months earlier.

Swab pooling enables rapid expansion of high-throughput capacity for SARS-CoV-2 community testing.

BACKGROUND: The challenges of rapid upscaling of testing capacity were a major lesson from the COVID-19 pandemic response. The need for process adjustments in high-throughput testing laboratories made sample pooling a challenging option to implement. OBJECTIVE: This study aimed to evaluate whether pooling samples at source (swab pooling) was as effective as qRT-PCR testing of individuals in identifying cases of SARS-CoV-2 in real-world community testing conditions using the same high-throughput pipeline. METHODS: Two cohorts of 10 (Pool10: 1,030 participants and 103 pools) and 6 (Pool6: 1,284 participants and 214 pools) samples per pool were tested for concordance, sensitivity, specificity, and Ct value differences with individual testing as reference. RESULTS: Swab pooling allowed unmodified application of an existing high-throughput SARS-Cov-2 testing pipeline with only marginal loss of accuracy. For Pool10, concordance was 98.1% (95% Confidence interval: 93.3-99.8%), sensitivity was 95.7% (85.5-99.5%), and specificity was 100.0% (93.6-100.0%). For Pool6, concordance was 97.2% (94.0-99.0%), sensitivity was 97.5% (93.7-99.3%), and specificity was 96.4% (87.7-99.6%). Differences of outcomes measure between pool size were not significant. Most positive individual samples, which were not detected in pools, had very low viral concentration. If only individual samples with a viral concentration > 400 copies/ml (i.e. Ct value < 30) were considered positive, the overall sensitivity of pooling increased to 99.5%. CONCLUSION: The study demonstrated high sensitivity and specificity by swab pooling and the immediate capability of high-throughput laboratories to implement this method making it an option in planning of rapid upscaling of laboratory capacity for future pandemics.

Performance of antigen lateral flow devices in the UK during the alpha, delta, and omicron waves of the SARS-CoV-2 pandemic: a diagnostic and observational study.

BACKGROUND: Antigen lateral flow devices (LFDs) have been widely used to control SARS-CoV-2. We aimed to improve understanding of LFD performance with changes in variant infections, vaccination, viral load, and LFD use, and in the detection of infectious individuals. METHODS: In this diagnostic study, paired LFD and RT-PCR test results were prospectively collected from asymptomatic and symptomatic participants in the UK between Nov 4, 2020, and March 21, 2022, to support the National Health Service (NHS) England's Test and Trace programme. The LFDs evaluated were the Innova SARS-CoV-2 Antigen Rapid Qualitative Test, the Orient Gene Rapid Covid-19 (Antigen) Self-Test, and the Acon Flowflex SARS-CoV-2 Antigen Rapid Test (Self-Testing). Test results were collected across various community testing settings, including predeployment testing sites, routine testing centres, homes, schools, universities, workplaces, targeted community testing, and from health-care workers. We used multivariable logistic regression to analyse LFD sensitivity and specificity using RT-PCR as a reference standard, adjusting for viral load, LFD manufacturer, test setting, age, sex, test assistance, symptom status, vaccination status, and SARS-CoV-2 variant. National contact tracing data from NHS Test and Trace (Jan 1, 2021, to Jan 11, 2022) were used to estimate the proportion of transmitting index patients (with ≥1 RT-PCR-positive or LFD-positive contact) potentially detectable by LFDs (specifically Innova, as the most widely used LFD) with time, accounting for index viral load, variant, and symptom status. FINDINGS: We assessed 75 382 pairs of LFD and RT-PCR tests. Of these, 4131 (5·5%) were RT-PCR-positive. LFD sensitivity versus RT-PCR was 63·2% (95% CI 61·7-64·6) and specificity was 99·71% (95% CI 99·66-99·74). Increased viral load was independently associated with being LFD positive (adjusted odds ratio [aOR] 2·85 [95% CI 2·66-3·06] per 1 log10 copies per mL increase; p<0·0001). There was no evidence that LFD sensitivity differed for delta (B.1.617.2) infections versus alpha (B.1.1.7) or pre-alpha (B.1.177) infections (aOR 1·00 [0·69-1·45]; p=0·99), whereas omicron (BA.1 or BA.2) infections appeared more likely to be LFD positive (aOR 1·63 [1·02-2·59]; p=0·042). Sensitivity was higher in symptomatic participants (68·7% [95% CI 66·9-70·4]) than in asymptomatic participants (52·8% [50·1-55·4]). Among 347 374 unique index patients with probable onward transmission, 78·3% (95% CI 75·3-81·2) were estimated to have been detectable with LFDs (Innova), and this proportion was mostly stable with time and for successive variants. Overall, the estimated proportion of infectious index patients detectable by the Innova LFD was lower in asymptomatic patients (57·6% [53·6-61·9]) versus symptomatic patients (79·7% [76·7-82·5]). INTERPRETATION: LFDs remained able to detect most SARS-CoV-2 infections throughout vaccine roll-out and across different viral variants. LFDs can potentially detect most infections that transmit to others and reduce the risk of transmission. However, performance is lower in asymptomatic individuals than in symptomatic individuals. FUNDING: UK Health Security Agency, the UK Government Department of Health and Social Care, National Institute for Health Research (NIHR) Health Protection Research Unit in Healthcare Associated Infections and Antimicrobial Resistance, and the University of Oxford NIHR Biomedical Research Centre.

COVID-19: Third dose booster vaccine effectiveness against breakthrough coronavirus infection, hospitalisations and death in patients with cancer: A population-based study.

PURPOSE: People living with cancer and haematological malignancies are at an increased risk of hospitalisation and death following infection with acute respiratory syndrome coronavirus 2. Coronavirus third dose vaccine boosters are proposed to boost waning immune responses in immunocompromised individuals and increase coronavirus protection; however, their effectiveness has not yet been systematically evaluated. METHODS: This study is a population-scale real-world evaluation of the United Kingdom's third dose vaccine booster programme for cancer patients from 8th December 2020 to 7th December 2021. The cancer cohort comprises individuals from Public Health England's national cancer dataset, excluding individuals less than 18 years. A test-negative case-control design was used to assess the third dose booster vaccine effectiveness. Multivariable logistic regression models were fitted to compare risk in the cancer cohort relative to the general population. RESULTS: The cancer cohort comprised of 2,258,553 tests from 361,098 individuals. Third dose boosters were evaluated by reference to 87,039,743 polymerase chain reaction coronavirus tests. Vaccine effectiveness against breakthrough infections, symptomatic infections, coronavirus hospitalisation and death in cancer patients were 59.1%, 62.8%, 80.5% and 94.5%, respectively. Lower vaccine effectiveness was associated with a cancer diagnosis within 12 months, lymphoma, recent systemic anti-cancer therapy (SACT) or radiotherapy. Patients with lymphoma had low levels of protection from symptomatic disease. In spite of third dose boosters, following multivariable adjustment, individuals with cancer remain at an increased risk of coronavirus hospitalisation and death compared to the population control (OR 3.38, 3.01, respectively. p < 0.001 for both). CONCLUSIONS: Third dose boosters are effective for most individuals with cancer, increasing protection from coronavirus. However, their effectiveness is heterogenous and lower than the general population. Many patients with cancer will remain at the increased risk of coronavirus infections even after 3 doses. In the case of patients with lymphoma, there is a particularly strong disparity of vaccine effectiveness against breakthrough infection and severe disease. Breakthrough infections will disrupt cancer care and treatment with potentially adverse consequences on survival outcomes. The data support the role of vaccine boosters in preventing severe disease, and further pharmacological intervention to prevent transmission and aid viral clearance to limit the disruption of cancer care as the delivery of care continues to evolve during the coronavirus pandemic.

Vaccine effectiveness against COVID-19 breakthrough infections in patients with cancer (UKCCEP): a population-based test-negative case-control study.

BACKGROUND: People with cancer are at increased risk of hospitalisation and death following infection with SARS-CoV-2. Therefore, we aimed to conduct one of the first evaluations of vaccine effectiveness against breakthrough SARS-CoV-2 infections in patients with cancer at a population level. METHODS: In this population-based test-negative case-control study of the UK Coronavirus Cancer Evaluation Project (UKCCEP), we extracted data from the UKCCEP registry on all SARS-CoV-2 PCR test results (from the Second Generation Surveillance System), vaccination records (from the National Immunisation Management Service), patient demographics, and cancer records from England, UK, from Dec 8, 2020, to Oct 15, 2021. Adults (aged ≥18 years) with cancer in the UKCCEP registry were identified via Public Health England's Rapid Cancer Registration Dataset between Jan 1, 2018, and April 30, 2021, and comprised the cancer cohort. We constructed a control population cohort from adults with PCR tests in the UKCCEP registry who were not contained within the Rapid Cancer Registration Dataset. The coprimary endpoints were overall vaccine effectiveness against breakthrough infections after the second dose (positive PCR COVID-19 test) and vaccine effectiveness against breakthrough infections at 3-6 months after the second dose in the cancer cohort and control population. FINDINGS: The cancer cohort comprised 377 194 individuals, of whom 42 882 had breakthrough SARS-CoV-2 infections. The control population consisted of 28 010 955 individuals, of whom 5 748 708 had SARS-CoV-2 breakthrough infections. Overall vaccine effectiveness was 69·8% (95% CI 69·8-69·9) in the control population and 65·5% (65·1-65·9) in the cancer cohort. Vaccine effectiveness at 3-6 months was lower in the cancer cohort (47·0%, 46·3-47·6) than in the control population (61·4%, 61·4-61·5). INTERPRETATION: COVID-19 vaccination is effective for individuals with cancer, conferring varying levels of protection against breakthrough infections. However, vaccine effectiveness is lower in patients with cancer than in the general population. COVID-19 vaccination for patients with cancer should be used in conjunction with non-pharmacological strategies and community-based antiviral treatment programmes to reduce the risk that COVID-19 poses to patients with cancer. FUNDING: University of Oxford, University of Southampton, University of Birmingham, Department of Health and Social Care, and Blood Cancer UK.