Epidemiological impact of a large number of incorrect negative SARS-CoV-2 test results in South West England during September and October 2021

BackgroundIn England, free testing for COVID-19 was widely available from early in the pandemic until 1 April 2022. Based on apparent differences in the rate of positive PCR tests at a single laboratory compared to the rest of the laboratory network, we hypothesised that a substantial number of UK PCR tests processed during September and October 2021 may have been incorrectly reported as negative, compared with the rest of the laboratory network. We investigate the epidemiological impact of this incident. MethodsWe estimate the additional number of COVID-19 cases that would have been reported had the sensitivity of the laboratory test procedure not dropped for the period 2 September to 12 October. In addition, by making comparisons between the most affected local areas and comparator populations, we estimate the number of additional infections, cases, hospitalisations and deaths that could have occurred as a result of increased transmission due to the misclassification of tests. ResultsWe estimate that around 39,000 tests may have been incorrectly classified during this period and, as a direct result of this incident, the most affected areas in the South West could have experienced between 6,000 and 34,000 additional reportable cases, with a central estimate of around 24,000 additional reportable cases. Using modelled relationships between key variables, we estimate that this central estimate could have translated to approximately 55,000 additional infections, which means that each incorrect negative test likely led to just over two additional infections. In those same geographical areas, our results also suggest an increased number of admissions and deaths. ConclusionThe incident is likely to have had a measurable impact on cases and infections in the affected areas in the South West of England.

Quantifying changes in the IFR and IHR over 23 months of the SARS-CoV-2 pandemic in England

BackgroundThe relationship between prevalence of infection and severe outcomes such as hospitalisation and death changed over the course of the COVID-19 pandemic. The REal-time Assessment of Community Transmission-1 (REACT-1) study estimated swab positivity in England approximately monthly from May 2020 to 31 March 2022. This period covers widespread circulation of the original strain, the emergence of the Alpha, Delta and Omicron variants and the rollout of Englands mass vaccination campaign. MethodsHere, we explore this changing relationship between prevalence of swab positivity and the infection fatality rate (IFR) and infection hospitalisation rate (IHR) over 23 months of the pandemic in England, using publicly available data for the daily number of deaths and hospitalisations, REACT-1 swab positivity data, time-delay models and Bayesian P-spline models. We analyse data for all age groups together, as well as in two sub-groups: those aged 65 and over and those aged 64 and under. ResultsDuring 2020, we estimated the IFR to be 0.67% and the IHR to be 2.6%. By late-2021/early-2022 the IFR and IHR had both decreased to 0.097% and 0.76% respectively. Continuous estimates of the IFR and IHR of the virus were observed to increase during the periods of Alpha and Deltas emergence. During periods of vaccination rollout, and the emergence of the Omicron variant, the IFR and IHR of the virus decreased. During 2020, we estimated a time-lag of 19 days between hospitalisation and swab positivity, and 26 days between deaths and swab positivity. By late-2021/early-2022 these time-lags had decreased to 7 days for hospitalisations, and 18 days for deaths. ConclusionEven though many populations have high levels of immunity to SARS-CoV-2 from vaccination and natural infection, waning of immunity and variant emergence will continue to be an upwards pressure on IHR and IFR. As investments in community surveillance are scaled back, alternative methods should be developed to accurately track the ever changing relationship between infection, hospitalisation and death.

Validity of self-testing at home with rapid SARS-CoV-2 antibody detection by lateral flow immunoassay

BackgroundSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibody lateral flow immunoassays (LFIA) can be carried out in the home and have been used as an affordable and practical approach to large-scale antibody prevalence studies. However, assay performance differs from that of high-throughput laboratory-based assays which can be highly sensitive. We explore LFIA performance under field conditions compared to laboratory-based ELISA and assess the potential of LFIAs to identify people who lack functional antibodies following infection or vaccination. MethodsField evaluation of a self-administered LFIA test (Fortress, NI) among 3758 participants from the REal-time Assessment of Community Transmission-2 (REACT-2) study in England selected based on vaccination history and previous LFIA result to ensure a range of antibody titres. In July 2021, participants performed, at home, a self-administered LFIA on finger-prick blood, reported and submitted a photograph of the result, and provided a self-collected capillary blood sample (Tasso-SST) for serological assessment of IgG antibodies to the spike protein using the Roche Elecsys(R) Anti-SARS-CoV-2 assay. We compared the self-administered and reported LFIA result to the quantitative Roche assay and checked the reading of the LFIA result with an automated image analysis (ALFA). In a subsample of 250 participants, we compared the results to live virus neutralisation. ResultsAlmost all participants (3593/3758, 95.6%) had been vaccinated or reported prior infection, with most having received one (862, 22.9%) or two (2430, 64.7%) COVID-19 vaccine doses. Overall, 2777/3758 (73.9%) were positive on self-reported LFIA, 2811/3457 (81.3%) positive by LFIA when ALFA-reported, and 3622/3758 (96.4%) positive on Roche anti-S (using the manufacturer reference standard threshold for positivity of 0.8 U ml-1). Live virus neutralisation was detected in 169 of 250 randomly selected samples (67.6%); 133/169 were positive with self-reported LFIA (sensitivity 78.7%; 95% CI 71.8, 84.6), 142/155 (91.6%; 86.1, 95.5) with ALFA, and 169 (100%; 97.8, 100.0) with Roche anti-S. There were 81 samples with no detectable virus neutralisation; 47/81 were negative with self-reported LFIA (specificity 58.0%; 95% CI 46.5, 68.9), 34/75 (45.3%; 33.8, 57.3) with ALFA, and 0/81 (0%; 0.0, 4.5) with Roche anti-S. All 250 samples remained positive with Roche anti-S when the threshold was increased to 1000U ml-1. ConclusionsSelf-administered LFIA can provide insights into population patterns of infection and vaccine response, and sensitivity can be improved with automated reading of the result. The LFIA is less sensitive than a quantitative antibody test, but the positivity in LFIA correlates better than the quantitative ELISA with virus neutralisation.

Trends in SARS-CoV-2 infection prevalence during England's roadmap out of lockdown, January to July 2021

BackgroundFollowing rapidly rising COVID-19 case numbers, England entered a national lockdown on 6 January 2021, with staged relaxations of restrictions from 8 March 2021 onwards. AimWe characterise how the lockdown and subsequent easing of restrictions affected trends in SARS-CoV-2 infection prevalence. MethodsOn average, risk of infection is proportional to infection prevalence. The REal-time Assessment of Community Transmission-1 (REACT-1) study is a repeat cross-sectional study of over 98,000 people every round (rounds approximately monthly) that estimates infection prevalence in England. We used Bayesian P-splines to estimate prevalence and the time-varying reproduction number (Rt) nationally, regionally and by age group from round 8 (beginning 6 January 2021) to round 13 (ending 12 July 2021) of REACT-1. As a comparator, a separate segmented-exponential model was used to quantify the impact on Rt of each relaxation of restrictions. ResultsFollowing an initial plateau of 1.54% until mid-January, infection prevalence decreased until 13 May when it reached a minimum of 0.09%, before increasing until the end of the study to 0.76%. Following the first easing of restrictions, which included schools reopening, the reproduction number Rt increased by 82% (55%, 108%), but then decreased by 61% (82%, 53%) at the second easing of restrictions, which was timed to match the Easter school holidays. Following further relaxations of restrictions, the observed Rt increased steadily, though the increase due to these restrictions being relaxed was masked by the effects of vaccination and the rapid rise of Delta. There was a high degree of synchrony in the temporal patterns of prevalence between regions and age groups. ConclusionHigh-resolution prevalence data fitted to P-splines allowed us to show that the lockdown was highly effective at reducing risk of infection with school holidays/closures playing a significant part.

The new normal? Dynamics and scale of the SARS-CoV-2 variant Omicron epidemic in England

The SARS-CoV-2 pandemic has been characterised by the regular emergence of genomic variants which have led to substantial changes in the epidemiology of the virus. With natural and vaccine-induced population immunity at high levels, evolutionary pressure favours variants better able to evade SARS-CoV-2 neutralising antibodies. The Omicron variant was first detected in late November 2021 and exhibited a high degree of immune evasion, leading to increased infection rates in many countries. However, estimates of the magnitude of the Omicron wave have relied mainly on routine testing data, which are prone to several biases. Here we infer the dynamics of the Omicron wave in England using PCR testing and genomic sequencing obtained by the REal-time Assessment of Community Transmission-1 (REACT-1) study, a series of cross-sectional surveys testing random samples of the population of England. We estimate an initial peak in national Omicron prevalence of 6.89% (5.34%, 10.61%) during January 2022, followed by a resurgence in SARS-CoV-2 infections in England during February-March 2022 as the more transmissible Omicron sub-lineage, BA.2 replaced BA.1 and BA.1.1. Assuming the emergence of further distinct genomic variants, intermittent epidemics of similar magnitude as the Omicron wave may become the new normal.

Consistent Pattern of Epidemic Slowing Across Many Geographies Led to Longer, Flatter Initial Waves of the COVID-19 Pandemic

To define appropriate planning scenarios for future pandemics of respiratory pathogens, it is important to understand the initial transmission dynamics of COVID-19 during 2020. Here, we fit an age-stratified compartmental model with a flexible underlying transmission term to daily COVID-19 death data from states in the contiguous U.S. and to national and sub-national data from around the world. The daily death data of the first months of the COVID-19 pandemic was categorized into one of four main types: "spring single-peak profile", "summer single-peak profile", "spring/summer two-peak profile" and "broad with shoulder profile". We estimated a reproduction number R as a function of calendar time tc and as a function of time since the first death reported in that population (local pandemic time, tp). Contrary to the multiple categories and range of magnitudes in death incidence profiles, the R(tp) profiles were much more homogeneous. We find that in both the contiguous U.S. and globally, the initial value of both R(tc) and R(tp) was substantial: at or above two. However, during the early months, pandemic time R(tp) decreased exponentially to a value that hovered around one. This decrease was accompanied by a reduction in the variance of R(tp). For calendar time R(tc), the decrease in magnitude was slower and non-exponential, with a smaller reduction in variance. Intriguingly, similar trends of exponential decrease and reduced variance were not observed in raw death data. Our findings suggest that the combination of specific government responses and spontaneous changes in behaviour ensured that transmissibility dropped, rather than remaining constant, during the initial phases of a pandemic. Future pandemic planning scenarios should be based on models that assume similar decreases in transmissibility, which lead to longer epidemics with lower peaks when compared with models based on constant transmissibility. Author summaryIn planning for a future novel respiratory pandemic, or the next variant of SARS-Cov-2, it is important to characterize and understand the observed epidemic patterns during the first months of the COVID-19 outbreak. Here, we describe COVID-19 epidemic patterns observed in the U.S. and globally in terms of patterns of the basic reproduction number, R(t), using an age-stratified compartmental model. We find that daily death data of the first months of the COVID-19 pandemic can be classified into one of four types: "spring single-peak profile", "summer single-peak profile", "spring/summer two-peak profile" and "broad with shoulder profile". Using the concept of local pandemic time, tp, we show a consistent pattern on four continents of an initial large magnitude and variance in reproductive number R(tp) that decreases monotonically and hovers around one for many days, regardless of specific intervention measures imposed by local authorities and without an accompanying decrease in daily death prevalence. We attribute this to significant behavior changes in populations in response to the perceived risk of COVID-19.

SARS-CoV-2 lineage dynamics in England from September to November 2021: high diversity of Delta sub-lineages and increased transmissibility of AY.4.2

Since the emergence of SARS-CoV-2, evolutionary pressure has driven large increases in the transmissibility of the virus. However, with increasing levels of immunity through vaccination and natural infection the evolutionary pressure will switch towards immune escape. Here we present phylogenetic relationships and lineage dynamics within England (a country with high levels of immunity), as inferred from a random community sample of individuals who provided a self-administered throat and nose swab for rt-PCR testing as part of the REal-time Assessment of Community Transmission-1 (REACT-1) study. From 9 to 27 September 2021 (round 14) and 19 October to 5 November 2021 (round 15), all lineages sequenced within REACT-1 were Delta or a Delta sub-lineage with 44 unique lineages identified. The proportion of the original Delta variant (B.1.617.2) was found to be increasing between September and November 2021, which may reflect an increasing number of sub-lineages which have yet to be identified. The proportion of B.1.617.2 was greatest in London, which was further identified as a region with an increased level of genetic diversity. The Delta sub-lineage AY.4.2 was found to be robustly increasing in proportion, with a reproduction number 15% (8%, 23%) greater than its parent and most prevalent lineage, AY.4. Both AY.4.2 and AY.4 were found to be geographically clustered in September but this was no longer the case by late October/early November, with only the lineage AY.6 exhibiting clustering towards the South of England. Though no difference in the viral load based on cycle threshold (Ct) values was identified, a lower proportion of those infected with AY.4.2 had symptoms for which testing is usually recommend (loss or change of sense of taste, loss or change of sense of smell, new persistent cough, fever), compared to AY.4 (p = 0.026). The evolutionary rate of SARS-CoV-2, as measured by the mutation rate, was found to be slowing down during the study period, with AY.4.2 further found to have a reduced mutation rate relative to AY.4. As SARS-CoV-2 moves towards endemicity and new variants emerge, genomic data obtained from random community samples can augment routine surveillance data without the potential biases introduced due to higher sampling rates of symptomatic individuals.

REACT-1 study round 14: High and increasing prevalence of SARS-CoV-2 infection among school-aged children during September 2021 and vaccine effectiveness against infection in England

BackgroundEngland experienced a third wave of the COVID-19 epidemic from end May 2021 coinciding with the rapid spread of Delta variant. Since then, the population eligible for vaccination against COVID-19 has been extended to include all 12-15-year-olds, and a booster programme has been initiated among adults aged 50 years and over, health care and care home workers, and immunocompromised people. Meanwhile, schoolchildren have returned to school often with few COVID-19-related precautions in place. MethodsIn the REal-time Assessment of Community Transmission-1 (REACT-1) study, throat and nose swabs were sent to non-overlapping random samples of the population aged 5 years and over in England. We analysed prevalence of SARS-CoV-2 using reverse transcription-polymerase chain reaction (RT-PCR) swab-positivity data from REACT-1 round 14 (between 9 and 27 September 2021). We combined results for round 14 with round 13 (between 24 June and 12 July 2021) and estimated vaccine effectiveness and prevalence of swab-positivity among double-vaccinated individuals. Unlike all previous rounds, in round 14, we switched from dry swabs transported by courier on a cold chain to wet swabs using saline. Also, at random, 50% of swabs (not chilled until they reached the depot) were transported by courier and 50% were sent through the priority COVID-19 postal service. ResultsWe observed stable or rising prevalence (with an R of 1.03 (0.94, 1.14) overall) during round 14 with a weighted prevalence of 0.83% (0.76%, 0.89%). The highest weighted prevalence was found in children aged 5 to 12 years at 2.32% (1.96%, 2.73%) and 13 to 17 years at 2.55% (2.11%, 3.08%). All positive virus samples analysed correspond to the Delta variant or sub-lineages of Delta with one instance of the E484K escape mutation detected. The epidemic was growing in those aged 17 years and under with an R of 1.18 (1.03, 1.34), but decreasing in those aged 18 to 54 years with an R of 0.81 (0.68, 0.97). For all participants and all vaccines combined, at ages 18 to 64 years, vaccine effectiveness against infection (rounds 13 and 14 combined) was estimated to be 62.8% (49.3%, 72.7%) after two doses compared to unvaccinated people when adjusted for round, age, sex, index of multiple deprivation, region and ethnicity; the adjusted estimate was 44.8% (22.5%, 60.7%) for AstraZeneca and 71.3% (56.6%, 81.0%) for Pfizer-BioNTech, and for all vaccines combined it was 66.4% (49.6%, 77.6%) against symptomatic infection (one or more of 26 surveyed symptoms in month prior). Across rounds 13 and 14, at ages 18 years and over, weighted prevalence of swab-positivity was 0.55% (0.50%, 0.61%) for those who received their second dose 3-6 months before their swab compared to 0.35% (0.31%, 0.40%) for those whose second dose was within 3 months of their swab, while weighted prevalence among unvaccinated individuals was1.76% (1.60%, 1.95%). In round 14, age group, region, key worker status, and household size jointly contributed to the risk of higher prevalence of swab-positivity. DiscussionIn September 2021 infections were increasing exponentially in the 5-to-17-year age group coinciding with the start of the autumn school term in England. Relatively few schoolchildren aged 5 to 17 years have been vaccinated in the UK though single doses are now being offered to those aged 12 years and over. In adults, the higher prevalence of swab-positivity following two doses of vaccine from 3 to 6 months compared to within 3 months of second dose supports the use of a booster vaccine. It is important that the vaccination programme maintains high coverage and reaches children and unvaccinated or partially vaccinated adults to reduce transmission and associated disruptions to work and education.

Exponential growth, high prevalence of SARS-CoV-2 and vaccine effectiveness associated with Delta variant in England during May to July 2021

BackgroundThe prevalence of SARS-CoV-2 infection continues to drive rates of illness and hospitalisations despite high levels of vaccination, with the proportion of cases caused by the Delta lineage increasing in many populations. As vaccination programs roll out globally and social distancing is relaxed, future SARS-CoV-2 trends are uncertain. MethodsWe analysed prevalence trends and their drivers using reverse transcription-polymerase chain reaction (RT-PCR) swab-positivity data from round 12 (between 20 May and 7 June 2021) and round 13 (between 24 June and 12 July 2021) of the REal-time Assessment of Community Transmission-1 (REACT-1) study, with swabs sent to non-overlapping random samples of the population ages 5 years and over in England. ResultsWe observed sustained exponential growth with an average doubling time in round 13 of 25 days (lower Credible Interval of 15 days) and an increase in average prevalence from 0.15% (0.12%, 0.18%) in round 12 to 0.63% (0.57%, 0.18%) in round 13. The rapid growth across and within rounds appears to have been driven by complete replacement of Alpha variant by Delta, and by the high prevalence in younger less-vaccinated age groups, with a nine-fold increase between rounds 12 and 13 among those aged 13 to 17 years. Prevalence among those who reported being unvaccinated was three-fold higher than those who reported being fully vaccinated. However, in round 13, 44% of infections occurred in fully vaccinated individuals, reflecting imperfect vaccine effectiveness against infection despite high overall levels of vaccination. Using self-reported vaccination status, we estimated adjusted vaccine effectiveness against infection in round 13 of 49% (22%, 67%) among participants aged 18 to 64 years, which rose to 58% (33%, 73%) when considering only strong positives (Cycle threshold [Ct] values < 27); also, we estimated adjusted vaccine effectiveness against symptomatic infection of 59% (23%, 78%), with any one of three common COVID-19 symptoms reported in the month prior to swabbing. Sex (round 13 only), ethnicity, household size and local levels of deprivation jointly contributed to the risk of higher prevalence of swab-positivity. DiscussionFrom end May to beginning July 2021 in England, where there has been a highly successful vaccination campaign with high vaccine uptake, infections were increasing exponentially driven by the Delta variant and high infection prevalence among younger, unvaccinated individuals despite double vaccination continuing to effectively reduce transmission. Although slower growth or declining prevalence may be observed during the summer in the northern hemisphere, increased mixing during the autumn in the presence of the Delta variant may lead to renewed growth, even at high levels of vaccination.

Characterising the persistence of RT-PCR positivity and incidence in a community survey of SARS-CoV-2

BackgroundCommunity surveys of SARS-CoV-2 RT-PCR swab-positivity provide prevalence estimates largely unaffected by biases from who presents for routine case testing. The REal-time Assessment of Community Transmission-1 (REACT-1) has estimated swab-positivity approximately monthly since May 2020 in England from RT-PCR testing of self-administered throat and nose swabs in random non-overlapping cross-sectional community samples. Estimating infection incidence from swab-positivity requires an understanding of the persistence of RT-PCR swab positivity in the community. MethodsDuring round 8 of REACT-1 from 6 January to 22 January 2021, of the 2,282 participants who tested RT-PCR positive, we recruited 896 (39%) from whom we collected up to two additional swabs for RT-PCR approximately 6 and 9 days after the initial swab. We estimated sensitivity and duration of positivity using an exponential model of positivity decay, for all participants and for subsets by initial N-gene cycle threshold (Ct) value, symptom status, lineage and age. Estimates of infection incidence were obtained for the entire duration of the REACT-1 study using P-splines. ResultsWe estimated the overall sensitivity of REACT-1 to detect virus on a single swab as 0.79 (0.77, 0.81) and median duration of positivity following a positive test as 9.7 (8.9, 10.6) days. We found greater median duration of positivity where there was a low N-gene Ct value, in those exhibiting symptoms, or for infection with the Alpha variant. The estimated proportion of positive individuals detected on first swab, P0, was found to be higher for those with an initially low N-gene Ct value and those who were pre-symptomatic. When compared to swab-positivity, estimates of infection incidence over the duration of REACT-1 included sharper features with evident transient increases around the time of key changes in social distancing measures. DiscussionHome self-swabbing for RT-PCR based on a single swab, as implemented in REACT-1, has high overall sensitivity. However, participants time-since-infection, symptom status and viral lineage affect the probability of detection and the duration of positivity. These results validate previous efforts to estimate incidence of SARS-CoV-2 from swab-positivity data, and provide a reliable means to obtain community infection estimates to inform policy response.

Global predictions of short- to medium-term COVID-19 transmission trends : a retrospective assessment

BackgroundAs of July 2021, more than 180,000,000 cases of COVID-19 have been reported across the world, with more than 4 million deaths. Mathematical modelling and forecasting efforts have been widely used to inform policy-making and to create situational awareness. Methods and FindingsFrom 8th March to 29th November 2020, we produced weekly estimates of SARS-CoV-2 transmissibility and forecasts of deaths due to COVID-19 for countries with evidence of sustained transmission. The estimates and forecasts were based on an ensemble model comprising of three models that were calibrated using only the reported number of COVID-19 cases and deaths in each country. We also developed a novel heuristic to combine weekly estimates of transmissibility and potential changes in population immunity due to infection to produce forecasts over a 4-week horizon. We evaluated the robustness of the forecasts using relative error, coverage probability, and comparisons with null models. ConclusionsDuring the 39-week period covered by this study, we produced short- and medium-term forecasts for 81 countries. Both the short- and medium-term forecasts captured well the epidemic trajectory across different waves of COVID-19 infections with small relative errors over the forecast horizon. The model was well calibrated with 56.3% and 45.6% of the observations lying in the 50% Credible Interval in 1-week and 4-week ahead forecasts respectively. We could accurately characterise the overall phase of the epidemic up to 4-weeks ahead in 84.9% of country-days. The medium-term forecasts can be used in conjunction with the short-term forecasts of COVID-19 mortality as a useful planning tool as countries continue to relax stringent public health measures that were implemented to contain the pandemic.

Increasing SARS-CoV-2 antibody prevalence in England at the start of the second wave: REACT-2 Round 4 cross-sectional study in 160,000 adults

BackgroundREACT-2 Study 5 is a population survey of the prevalence of SARS-CoV-2 antibodies in the community in England. MethodsWe contacted a random sample of the population by sending a letter to named individuals aged 18 or over from the NHS GP registrations list. We then sent respondents a lateral flow immunoassay (LFIA) kit for SARS-CoV-2 antibody self-testing and asked them to perform the test at home and complete a questionnaire, including reporting of their test result. Overall, 161,537 adults completed questionnaires and self-administered LFIA tests for IgG against SARS-CoV-2 between 27 October and 10 November 2020. ResultsThe overall adjusted and weighted prevalence was 5.6% (95% CI 5.4-5.7). This was an increase from 4.4% (4.3-4.5) in round 3 (September), a relative increase of 26.9% (24.0-29.9).The largest increase by age was in the 18 to 24 year old age group, which increased (adjusted and weighted) from 6.7% (6.3-7.2) to 9.9% (9.3-10.4), and in students, (adjusted, unweighted) from 5.9% (4.8-7.1) to 12.1% (10.8-13.5). Prevalence increased most in Yorkshire and The Humber, from 3.4% (3.0-3.8) to 6.3% (5.9-6.8) and the North West from 4.5% (4.2-4.9) to 7.7% (7.2-8.1). In contrast, the prevalence in London was stable, at 9.5% (9.0-9.9) and 9.5% (9.1-10.0) in rounds 3 and 4 respectively. We found the highest prevalence in people of Bangladeshi 15.1% (10.9-20.5), Pakistani 13.9% (11.2-17.2) and African 13.5% (10.7-16.8) ethnicity, and lowest in those of white British ethnicity at 4.2% (4.0-4.3). InterpretationThe second wave of infection in England is apparent in increasing antibody prevalence, particularly in younger people, students, and in the Northern Regions. By late October a large proportion of the population remained susceptible to SARS-CoV-2 infection in England based on naturally acquired immunity from the first and early second wave.

Vaccine uptake and SARS-CoV-2 antibody prevalence among 207,337 adults during May 2021 in England: REACT-2 study

BackgroundThe programme to vaccinate adults in England has been rapidly implemented since it began in December 2020. The community prevalence of SARS-CoV-2 anti-spike protein antibodies provides an estimate of total cumulative response to natural infection and vaccination. We describe the distribution of SARS-CoV-2 IgG antibodies in adults in England in May 2021 at a time when approximately 7 in 10 adults had received at least one dose of vaccine. MethodsSixth round of REACT-2 (REal-time Assessment of Community Transmission-2), a cross-sectional random community survey of adults in England, from 12 to 25 May 2021; 207,337 participants completed questionnaires and self-administered a lateral flow immunoassay test producing a positive or negative result. ResultsVaccine coverage with one or more doses, weighted to the adult population in England, was 72.9% (95% confidence interval 72.7-73.0), varying by age from 25.1% (24.5-25.6) of those aged 18 to 24 years, to 99.2% (99.1-99.3) of those 75 years and older. In adjusted models, odds of vaccination were lower in men (odds ratio [OR] 0.89 [0.85-0.94]) than women, and in people of Black (0.41 [0.34-0.49]) compared to white ethnicity. There was higher vaccine coverage in the least deprived and highest income households. People who reported a history of COVID-19 were less likely to be vaccinated (OR 0.61 [0.55-0.67]). There was high coverage among health workers (OR 9.84 [8.79-11.02] and care workers (OR 4.17 [3.20-5.43]) compared to non-key workers, but lower in hospitality and retail workers (OR 0.73 [0.64-0.82] and 0.77 [0.70-0.85] respectively) after adjusting for age and key covariates. The prevalence of antibodies (weighted to the adult population of England and adjusted for test characteristics) was 61.1% (95% CI 60.9-61.4), up from 6.6% (5.4-5.7) in round 4 (27 October to 10 November 2020) and 13.9% (13.7-14.1) in round 5 (26 January to 8 February 2021). Prevalence (adjusted and weighted) increased with age, from 35.8% (35.1-36.5) in those aged 18 to 24 years, to 95.3% (94.6-95.9) in people 75 and over. Antibodies were 30% less likely to be detected in men than women (adjusted OR 0.69, 0.68-0.70), and were higher in people of Asian (OR 1.67 [1.58-1.77]), Black (1.55 [1.41-1.69]), mixed 1.17 [1.06-1.29] and other (1.37 [1.23-1.51]) ethnicities compared with white ethnicity. Workers in hospitality (OR 0.69 [0.63-0.74]) and retail (0.71 [0.67-0.75]) were less likely to have antibodies. Following two doses of Pfizer-BioNTech vaccine, antibody positivity (adjusted for test performance) was 100% (100-100) at all ages except 80 years and older when it was 97.8% (95.9-99.6). For AstraZeneca positivity was over 90% up to age 69, and then 89.2% (88.5-89.9) in 70-79 year olds and 83.6% (78.5-88.3) in those aged 80 and over. Following a single dose of Pfizer-BioNTech positivity ranged from 100.0% (91.1-100.0) in those aged 18-29 to 32.2% (18.2-51.1) in those aged 70-79 years. For AstraZeneca this was 72.2% (68.5-75.9) in the youngest and 46.2% (40.0-52.7) in the oldest age group. DiscussionThe successful roll out of the vaccination programme in England has led to a high proportion of individuals having detectable antibodies, particularly in older age groups and those who have had two doses of vaccine. This is likely to be associated with high levels of protection from severe disease, and possibly from infection. Nonetheless, there remain some key groups with a lower prevalence of antibody, notably unvaccinated younger people, certain minority ethnic groups, those living in deprived areas and workers in some public facing employment. Obtaining improved rates of vaccination in these groups is essential to achieving high levels of protection against the virus through population immunity. FundingDepartment of Health and Social Care in England.

SARS-CoV-2 Antibody Lateral Flow Assay for antibody prevalence studies following vaccine roll out: a Diagnostic Accuracy Study

BackgroundLateral flow immunoassays (LFIAs) have the potential to deliver affordable, large scale antibody testing and provide rapid results without the support of central laboratories. As part of the development of the REACT programme extensive evaluation of LFIA performance was undertaken with individuals following natural infection. Here we assess the performance of the selected LFIA to detect antibody responses in individuals who have received at least one dose of SARS-CoV-2 vaccine. MethodsThis is a prospective diagnostic accuracy study. SettingSampling was carried out at renal outpatient clinic and healthcare worker testing sites at Imperial College London NHS Trust. Laboratory analyses were performed across Imperial College London sites and university facilities. ParticipantsTwo cohorts of patients were recruited; the first was a cohort of 108 renal transplant patients attending clinic following SARS-CoV-2 vaccine booster, the second cohort comprised 40 healthcare workers attending for first SARS-CoV-2 vaccination, and 21 day follow up. A total of 186 paired samples were collected. InterventionsDuring the participants visit, capillary blood samples were analysed on LFIA device, while paired venous sampling was sent for serological assessment of antibodies to the spike protein (anti-S) antibodies. Anti-S IgG were detected using the Abbott Architect SARS-CoV-2 IgG Quant II CMIA. Main outcome measuresThe accuracy of Fortress LFIA in detecting IgG antibodies to SARS-CoV-2 compared to anti-spike protein detection on Abbott Assay. ResultsUsing the threshold value for positivity on serological testing of [≥]7.10 BAU/ml, the overall performance of the test produces an estimate of sensitivity of 91.94% (95% CI 85.67% to 96.06%) and specificity of 93.55% (95% CI 84.30% to 98.21%) using the Abbott assay as reference standard. ConclusionsFortress LFIA performs well in the detection of antibody responses for intended purpose of population level surveys, but does not meet criteria for individual testing.

REACT-1 round 13 interim report: acceleration of SARS-CoV-2 Delta epidemic in the community in England during late June and early July 2021

BackgroundDespite high levels of vaccination in the adult population, cases of COVID-19 have risen exponentially in England since the start of May 2021 driven by the Delta variant. However, with far fewer hospitalisations and deaths per case during the recent growth in cases compared with 2020, it is intended that all remaining social distancing legislation in England will be removed from 19 July 2021. MethodsWe report interim results from round 13 of the REal-time Assessment of Community Transmission-1 (REACT-1) study in which a cross-sectional sample of the population of England was asked to provide a throat and nose swab for RT-PCR and to answer a questionnaire. Data collection for this report (round 13 interim) was from 24 June to 5 July 2021. ResultsIn round 13 interim, we found 237 positives from 47,729 swabs giving a weighted prevalence of 0.59% (0.51%, 0.68%) which was approximately four-fold higher compared with round 12 at 0.15% (0.12%, 0.18%). This resulted from continued exponential growth in prevalence with an average doubling time of 15 (13, 17) days between round 12 and round 13. However, during the recent period of round 13 interim only, we observed a shorter doubling time of 6.1 (4.0, 12) days with a corresponding R number of 1.87 (1.40, 2.45). There were substantial increases in all age groups under the age of 75 years, and especially at younger ages, with the highest prevalence in 13 to 17 year olds at 1.33% (0.97%, 1.82%) and in 18 to 24 years olds at 1.40% (0.89%, 2.18%). Infections have increased in all regions with the largest increase in London where prevalence increased more than eight-fold from 0.13% (0.08%, 0.20%) in round 12 to 1.08% (0.79%, 1.47%) in round 13 interim. Overall, prevalence was over 3 times higher in the unvaccinated compared with those reporting two doses of vaccine in both round 12 and round 13 interim, although there was a similar proportional increase in prevalence in vaccinated and unvaccinated individuals between the two rounds. DiscussionWe are entering a critical period with a number of important competing processes: continued vaccination rollout to the whole adult population in England, increased natural immunity through infection, reduced social mixing of children during school holidays, increased proportion of mixing occurring outdoors during summer, the intended full opening of hospitality and entertainment and cessation of mandated social distancing and mask wearing. Surveillance programmes are essential during this next phase of the epidemic to provide clear evidence to the government and the public on the levels and trends in prevalence of infections and their relationship to vaccine coverage, hospitalisations, deaths and Long COVID.

Persistent symptoms following SARS-CoV-2 infection in a random community sample of 508,707 people

BackgroundLong COVID, describing the long-term sequelae after SARS-CoV-2 infection, remains a poorly defined syndrome. There is uncertainty about its predisposing factors and the extent of the resultant public health burden, with estimates of prevalence and duration varying widely. MethodsWithin rounds 3-5 of the REACT-2 study, 508,707 people in the community in England were asked about a prior history of COVID-19 and the presence and duration of 29 different symptoms. We used uni-and multivariable models to identify predictors of persistence of symptoms (12 weeks or more). We estimated the prevalence of symptom persistence at 12 weeks, and used unsupervised learning to cluster individuals by symptoms experienced. FindingsAmong the 508,707 participants, the weighted prevalence of self-reported COVID-19 was 19.2% (95% CI: 19.1,19.3). 37.7% of 76,155 symptomatic people post COVID-19 experienced at least one symptom, while 14.8% experienced three or more symptoms, lasting 12 weeks or more. This gives a weighted population prevalence of persistent symptoms of 5.75% (5.68, 5.81) for one and 2.22% (2.1, 2.26) for three or more symptoms. Almost a third of people (8,771/28,713 [30.5%]) with at least one symptom lasting 12 weeks or more reported having had severe COVID-19 symptoms ("significant effect on my daily life") at the time of their illness, giving a weighted prevalence overall for this group of 1.72% (1.69,1.76). The prevalence of persistent symptoms was higher in women than men (OR: 1.51 [1.46,1.55]) and, conditional on reporting symptoms, risk of persistent symptoms increased linearly with age by 3.5 percentage points per decade of life. Obesity, smoking or vaping, hospitalisation, and deprivation were also associated with a higher probability of persistent symptoms, while Asian ethnicity was associated with a lower probability. Two stable clusters were identified based on symptoms that persisted for 12 weeks or more: in the largest cluster, tiredness predominated, while in the second there was a high prevalence of respiratory and related symptoms. InterpretationA substantial proportion of people with symptomatic COVID-19 go on to have persistent symptoms for 12 weeks or more, which is age-dependent. Clinicians need to be aware of the differing manifestations of Long COVID which may require tailored therapeutic approaches. Managing the long-term sequelae of SARS-CoV-2 infection in the population will remain a major challenge for health services in the next stage of the pandemic. FundingThe study was funded by the Department of Health and Social Care in England. Research in contextO_ST_ABSEvidence before this studyC_ST_ABSRecent systematic reviews have documented the wide range of symptoms and reported prevalence of persistent symptoms following COVID-19. A dynamic review of Long COVID studies (NIHR Evidence) in March 2021 summarised the literature on the prevalence of persistent symptoms after acute COVID19, and reported that most studies (14) were of hospitalised patients, with higher prevalence of persistent symptoms compared with two community-based studies. There was limited evidence from community studies beyond 12 weeks. Another systematic review reported a median of over 70% of people with symptoms lasting at least 60 days. A review of risk factors for Long COVID found consistent evidence for an increased risk amongst women and those with high body mass index (BMI) but inconsistent findings on the role of age and little evidence concerning risks among different socioeconomic or ethnic groups which are often not well captured in routine healthcare records. Long COVID is increasingly recognised as heterogenous, likely underpinned by differing biological mechanisms, but there is not yet consensus on defining subtypes of the condition. Added value of this studyThis community-based study of over half a million people was designed to be representative of the adult population of England. A random sample of adults ages 18 years and above registered with a GP were invited irrespective of previous access to services for COVID-19, providing an estimate of population prevalence that was representative of the whole population. The findings show substantial declines in symptom prevalence over the first 12 weeks following Covid-19, reported by nearly one fifth of respondents, of whom over a third remained symptomatic at 12 weeks and beyond, with little evidence for decline thereafter. Risk factors identified for persistent symptoms (12 weeks or more) suggestive of Long COVID confirm some previous findings - an increased risk in women, obese and overweight individuals and those hospitalised for COVID-19, with strong evidence for an increasing risk with age. Additional evidence was found for an increased risk in those with lower income, smoking or vaping and healthcare or care home workers. A lower risk was found in those of Asian ethnicity. Clustering identified two distinct groups of individuals with different symptom profiles at 12 weeks, highlighting the heterogeneity of clinical presentation. The smaller cluster had higher prevalence of respiratory and related symptoms, while for those in the larger cluster tiredness was the dominant symptom, with lower prevalence of organ-specific symptoms. Implications of available evidenceThere is a high prevalence of persistent symptoms beyond 12 weeks after acute COVID-19, with little evidence of decline thereafter. This highlights the needs for greater support for patients, both through specialised services and, for those from low-income settings, financial support. The understanding that there are distinct clusters of persistent symptoms, the most common of which is dominated by fatigue, is important for the recognition and clinical management of the condition outside of specialised services.

Acceptability, usability and performance of lateral flow immunoassay tests for SARS-CoV-2 antibodies: REACT-2 study of self-testing in non-healthcare key workers

BackgroundSeroprevalence studies in key worker populations are essential to understand the epidemiology of SARS-CoV-2. Various technologies, including laboratory assays and point-of-care self-tests, are available for antibody testing. The interpretation of seroprevalence studies requires comparative data on the performance of antibody tests. MethodsIn June 2020, current and former members of the UK Police forces and Fire service performed a self-test lateral flow immunoassay (LFIA) and provided a saliva sample, nasopharyngeal swab, venous blood samples for Abbott ELISA and had a nurse performed LFIA. We present the prevalence of PCR positivity and antibodies to SARS-CoV-2 in this cohort following the first wave of infection in England; the acceptability and usability of self-test LFIAs (defined as use of the LFIA kit and provision of a valid result, respectively); and determine the sensitivity and specificity of LFIAs compared to laboratory ELISAs. ResultsIn this cohort of non-healthcare key workers, 7.4% (396/5,348; 95% CI, 6.7-8.1) were antibody positive. Seroprevalence was 8.9% (6.9-11.4) in those under 40 years, 11.5% (8.8-15.0) in those of non-white British ethnicity and 7.8% (7.1-8.7) in those currently working. The self-test LFIA had an acceptability of 97.7% and a usability of 90.0%. There was substantial agreement between within-participant LFIA results (kappa 0.80; 0.77-0.83). The LFIAs (self-test and nurse-performed) had a similar performance: compared to ELISA, sensitivity was 82.1% (77.7-86.0) self-test and 76.4% (71.9-80.5) nurse-performed with specificity of 97.8% (97.3-98.2) and 98.5% (98.1-98.8) respectively. ConclusionA greater proportion of the non-healthcare key worker cohort showed evidence of previous infection with SARS-CoV-2 than the general population at 6.0% (5.8-6.1) following the first wave in England. The high acceptability and usability reported by participants and the similar performance of self-test and nurse-performed LFIAs indicate that the self-test LFIA is fit for purpose for home-testing in occupational and community prevalence studies.

REACT-1 round 12 report: resurgence of SARS-CoV-2 infections in England associated with increased frequency of the Delta variant

BackgroundEngland entered a third national lockdown from 6 January 2021 due to the COVID-19 pandemic. Despite a successful vaccine rollout during the first half of 2021, cases and hospitalisations have started to increase since the end of May as the SARS-CoV-2 Delta (B.1.617.2) variant increases in frequency. The final step of relaxation of COVID-19 restrictions in England has been delayed from 21 June to 19 July 2021. MethodsThe REal-time Assessment of Community Transmision-1 (REACT-1) study measures the prevalence of swab-positivity among random samples of the population of England. Round 12 of REACT-1 obtained self-administered swab collections from participants from 20 May 2021 to 7 June 2021; results are compared with those for round 11, in which swabs were collected from 15 April to 3 May 2021. ResultsBetween rounds 11 and 12, national prevalence increased from 0.10% (0.08%, 0.13%) to 0.15% (0.12%, 0.18%). During round 12, we detected exponential growth with a doubling time of 11 (7.1, 23) days and an R number of 1.44 (1.20, 1.73). The highest prevalence was found in the North West at 0.26% (0.16%, 0.41%) compared to 0.05% (0.02%, 0.12%) in the South West. In the North West, the locations of positive samples suggested a cluster in Greater Manchester and the east Lancashire area. Prevalence in those aged 5-49 was 2.5 times higher at 0.20% (0.16%, 0.26%) compared with those aged 50 years and above at 0.08% (0.06%, 0.11%). At the beginning of February 2021, the link between infection rates and hospitalisations and deaths started to weaken, although in late April 2021, infection rates and hospital admissions started to reconverge. When split by age, the weakened link between infection rates and hospitalisations at ages 65 years and above was maintained, while the trends converged below the age of 65 years. The majority of the infections in the younger group occurred in the unvaccinated population or those without a stated vaccine history. We observed the rapid replacement of the Alpha (B.1.1.7) variant of SARS-CoV-2 with the Delta variant during the period covered by rounds 11 and 12 of the study. DiscussionThe extent to which exponential growth continues, or slows down as a consequence of the continued rapid roll-out of the vaccination programme, including to young adults, requires close monitoring. Data on community prevalence are vital to track the course of the epidemic and inform ongoing decisions about the timing of further lifting of restrictions in England.

REACT-1 round 11 report: low prevalence of SARS-CoV-2 infection in the community prior to the third step of the English roadmap out of lockdown

BackgroundNational epidemic dynamics of SARS-CoV-2 infections are being driven by: the degree of recent indoor mixing (both social and workplace), vaccine coverage, intrinsic properties of the circulating lineages, and prior history of infection (via natural immunity). In England, infections, hospitalisations and deaths fell during the first two steps of the "roadmap" for exiting the third national lockdown. The third step of the roadmap in England takes place on 17 May 2021. MethodsWe report the most recent findings on community infections from the REal-time Assessment of Community Transmission-1 (REACT-1) study in which a swab is obtained from a representative cross-sectional sample of the population in England and tested using PCR. Round 11 of REACT-1 commenced self-administered swab-collection on 15 April 2021 and completed collections on 3 May 2021. We compare the results of REACT-1 round 11 to round 10, in which swabs were collected from 11 to 30 March 2021. ResultsBetween rounds 10 and 11, prevalence of swab-positivity dropped by 50% in England from 0.20% (0.17%, 0.23%) to 0.10% (0.08%, 0.13%), with a corresponding R estimate of 0.90 (0.87, 0.94). Rates of swab-positivity fell in the 55 to 64 year old group from 0.17% (0.12%, 0.25%) in round 10 to 0.06% (0.04%, 0.11%) in round 11. Prevalence in round 11 was higher in the 25 to 34 year old group at 0.21% (0.12%, 0.38%) than in the 55 to 64 year olds and also higher in participants of Asian ethnicity at 0.31% (0.16%, 0.60%) compared with white participants at 0.09% (0.07%, 0.11%). Based on sequence data for positive samples for which a lineage could be identified, we estimate that 92.3% (75.9%, 97.9%, n=24) of infections were from the B.1.1.7 lineage compared to 7.7% (2.1%, 24.1%, n=2) from the B.1.617.2 lineage. Both samples from the B.1.617.2 lineage were detected in London from participants not reporting travel in the previous two weeks. Also, allowing for suitable lag periods, the prior close alignment between prevalence of infections and hospitalisations and deaths nationally has diverged. DiscussionWe observed marked reductions in prevalence from March to April and early May 2021 in England reflecting the success of the vaccination programme and despite easing of restrictions during lockdown. However, there is potential upwards pressure on prevalence from the further easing of lockdown regulations and presence of the B.1.617.2 lineage. If prevalence rises in the coming weeks, policy-makers will need to assess the possible impact on hospitalisations and deaths. In addition, consideration should be given to other health and economic impacts if increased levels of community transmission occur.

SARS-CoV-2 lineage dynamics in England from January to March 2021 inferred from representative community samples

Genomic surveillance for SARS-CoV-2 lineages informs our understanding of possible future changes in transmissibility and vaccine efficacy. However, small changes in the frequency of one lineage over another are often difficult to interpret because surveillance samples are obtained from a variety of sources. Here, we describe lineage dynamics and phylogenetic relationships using sequences obtained from a random community sample who provided a throat and nose swab for rt-PCR during the first three months of 2021 as part of the REal-time Assessment of Community Transmission-1 (REACT-1) study. Overall, diversity decreased during the first quarter of 2021, with the B.1.1.7 lineage (first identified in Kent) predominant, driven by a 0.3 unit higher reproduction number over the prior wild type. During January, positive samples were more likely B.1.1.7 in younger and middle-aged adults (aged 18 to 54) than in other age groups. Although individuals infected with the B.1.1.7 lineage were no more likely to report one or more classic COVID-19 symptoms compared to those infected with wild type, they were more likely to be antibody positive 6 weeks after infection. Viral load was higher in B.1.1.7 infection as measured by cycle threshold (Ct) values, but did not account for the increased rate of testing positive for antibodies. The presence of infections with non-imported B.1.351 lineage (first identified in South Africa) during January, but not during February or March, suggests initial establishment in the community followed by fade-out. However, this occurred during a period of stringent social distancing and targeted public health interventions and does not immediately imply similar lineages could not become established in the future. Sequence data from representative community surveys such as REACT-1 can augment routine genomic surveillance.