Respiratory viral infection promotes the awakening and outgrowth of dormant metastatic breast cancer cells in lungs (preprint)

Breast cancer is the second most common cancer globally. Most deaths from breast cancer are due to metastatic disease which often follows long periods of clinical dormancy1. Understanding the mechanisms that disrupt the quiescence of dormant disseminated cancer cells (DCC) is crucial for addressing metastatic progression. Infection with respiratory viruses (e.g. influenza or SARS-CoV-2) is common and triggers an inflammatory response locally and systemically2,3. Here we show that influenza virus infection leads to loss of the pro-dormancy mesenchymal phenotype in breast DCC in the lung, causing DCC proliferation within days of infection, and a greater than 100-fold expansion of carcinoma cells into metastatic lesions within two weeks. Such DCC phenotypic change and expansion is interleukin-6 (IL-6)-dependent. We further show that CD4 T cells are required for the maintenance of pulmonary metastatic burden post-influenza virus infection, in part through attenuation of CD8 cell responses in the lungs. Single-cell RNA-seq analyses reveal DCC-dependent impairment of T-cell activation in the lungs of infected mice. SARS-CoV-2 infected mice also showed increased breast DCC expansion in lungs post-infection. Expanding our findings to human observational data, we observed that cancer survivors contracting a SARS-CoV-2 infection have substantially increased risks of lung metastatic progression and cancer-related death compared to cancer survivors who did not. These discoveries underscore the significant impact of respiratory viral infections on the resurgence of metastatic cancer, offering novel insights into the interconnection between infectious diseases and cancer metastasis.

Strategic use of SARS-CoV-2 wastewater concentration data could enhance, but not replace, high-resolution community prevalence survey programmes (preprint)

Wastewater-based epidemiology (WBE) has been proposed as a tool for public health authorities to monitor community transmission of SARS-CoV-2 and other agents. Here, we review the utility of WBE for estimating SARS-CoV-2 prevalence using wastewater data from the Environmental Monitoring for Health Protection (EMHP) programme and prevalence data from the REal-time Assessment of Community Transmission-1 (REACT-1) study in England. Our analysis shows a temporally evolving relationship between wastewater and prevalence which limits the utility of WBE for estimating SARS-CoV-2 prevalence in high spatial resolution without a concurrent prevalence survey. We further characterise WBE for SARS-CoV-2 prevalence as i) vaccination-coverage-dependent and ii) variant-specific. Our work provides a gesopatial framework to map wastewater concentrations to public health boundaries, enabling public health authorities to interpret the relationship between wastewater and prevalence. We demonstrate that WBE can improve the cost efficiency and accuracy of community prevalence surveys which on their own may have incomplete geographic coverage or small sample sizes.

LONG-TERM PHYSICAL AND MENTAL HEALTH IMPACT OF COVID-19 ON ADULTS IN ENGLAND: FOLLOW UP OF A LARGE RANDOM COMMUNITY SAMPLE (preprint)

BackgroundThe COVID-19 pandemic is having a lasting impact on health and well-being. We compare current self-reported health, quality of life and symptom profiles for people with ongoing symptoms following COVID-19 to those who have never had COVID-19 or have recovered. MethodsA cohort study was established with participants from the REACT programme. A sample (N=800,000) of adults were contacted between August and December 2022 to complete a questionnaire about their current health and COVID-19 history. We used logistic regression to identify predictors of persistent symptoms lasting [≥]12 weeks following COVID-19. We fitted Accelerated Failure Time models to assess factors associated with rate of recovery from persistent symptoms. FindingsOverall, 276,840/800,000 (34.6%) of invited participants completed the questionnaire. Median duration of COVID-related symptoms (N=130,251) was 1.3 weeks (inter-quartile range 6 days to 2 weeks), with 7.5% and 5.2% reporting ongoing symptoms [≥]12 weeks and [≥]52 weeks respectively. Female sex, having [≥]1 comorbidity, more severe symptoms at time of COVID-19 and being infected when Wild-type variant was dominant were associated with higher probability of symptoms lasting [≥]12 weeks. Longer time to recovery in those with persistent symptoms was found for females, people with comorbidities, living in more deprived areas, current smokers and for Wild-type compared to later variants. Mental health and health-related quality of life were significantly worse among participants with ongoing persistent COVID-19 symptoms compared with those who had never had COVID-19 or had recovered. InterpretationAlthough COVID-19 is usually of short duration, some adults experience persistent and burdensome illness. FundingThis work is independent research funded by the National Institute for Health and Care Research (NIHR) (REACT Long COVID (REACT-LC) (COV-LT-0040)). This research is part of the Data and Connectivity National Core Study, led by Health Data Research UK in partnership with the Office for National Statistics and funded by UK Research and Innovation (UKRI) (MC_PC_20029). The views expressed in this publication are those of the author(s) and not necessarily those of NIHR or UKRI.

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

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.

Variant-specific symptoms of COVID-19 among 1,542,510 people in England (preprint)

Infection with SARS-CoV-2 virus is associated with a wide range of symptoms. The REal-time Assessment of Community Transmission -1 (REACT-1) study has been monitoring the spread and clinical manifestation of SARS-CoV-2 among random samples of the population in England from 1 May 2020 to 31 March 2022. We show changing symptom profiles associated with the different variants over that period, with lower reporting of loss of sense of smell and taste for Omicron compared to previous variants, and higher reporting of cold-like and influenza-like symptoms, controlling for vaccination status. Contrary to the perception that recent variants have become successively milder, Omicron BA.2 was associated with reporting more symptoms, with greater disruption to daily activities, than BA.1. With restrictions lifted and routine testing limited in many countries, monitoring the changing symptom profiles associated with SARS-CoV-2 infection and induced changes in daily activities will become increasingly important.

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

Summary 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’.

The Omicron SARS-CoV-2 epidemic in England during February 2022 (preprint)

Background: The third wave of COVID-19 in England peaked in January 2022 resulting from the rapid transmission of the Omicron variant. However, rates of hospitalisations and deaths were substantially lower than in the first and second waves Methods: In the REal-time Assessment of Community Transmission-1 (REACT-1) study we obtained data from a random sample of 94,950 participants with valid throat and nose swab results by RT-PCR during round 18 (8 February to 1 March 2022). Findings: We estimated a weighted mean SARS-CoV-2 prevalence of 2.88% (95% credible interval [CrI] 2.76-3.00), with a within-round reproduction number (R) overall of 0.94 (0.91-0.96). While within-round weighted prevalence fell among children (aged 5 to 17 years) and adults aged 18 to 54 years, we observed a level or increasing weighted prevalence among those aged 55 years and older with an R of 1.04 (1.00-1.09). Among 1,195 positive samples with sublineages determined, only one (0.1% [0.0-0.5]) corresponded to AY.39 Delta sublineage and the remainder were Omicron: N=390, 32.7% (30.0-35.4) were BA.1; N=473, 39.6% (36.8-42.5) were BA.1.1; and N=331, 27.7% (25.2-30.4) were BA.2. We estimated an R additive advantage for BA.2 (vs BA.1 or BA.1.1) of 0.40 (0.36-0.43). The highest proportion of BA.2 among positives was found in London. Interpretation: In February 2022, infection prevalence in England remained high with level or increasing rates of infection in older people and an uptick in hospitalisations. Ongoing surveillance of both survey and hospitalisations data is required. Funding: Department of Health and Social Care, England.

Post-peak dynamics of a national Omicron SARS-CoV-2 epidemic during January 2022 (preprint)

Background: Rapid transmission of the SARS-CoV-2 Omicron variant has led to the highest ever recorded case incidence levels in many countries around the world. Methods: The REal-time Assessment of Community Transmission-1 (REACT-1) study has been characterising the transmission of the SARS-CoV-2 virus using RT-PCR test results from self-administered throat and nose swabs from randomly-selected participants in England at ages 5 years and over, approximately monthly since May 2020. Round 17 data were collected between 5 and 20 January 2022 and provide data on the temporal, socio-demographic and geographical spread of the virus, viral loads and viral genome sequence data for positive swabs. Results: From 102,174 valid tests in round 17, weighted prevalence of swab positivity was 4.41% (95% credible interval [CrI], 4.25% to 4.56%), which is over three-fold higher than in December 2021 in England. Of 3,028 sequenced positive swabs, 2,393 lineages were determined and 2,374 (99.2%) were Omicron including 19 (0.80% of all Omicron lineages) cases of BA.2 sub-lineage and one BA.3 (0.04% of all Omicron) detected on 17 January 2022, and only 19 (0.79%) were Delta. The growth of the BA.2 Omicron sub-lineage against BA.1 and its sub-lineage BA.1.1 indicated a daily growth rate advantage of 0.14 (95% CrI, 0.03, 0.28) for BA.2, which corresponds to an additive R advantage of 0.46 (95% CrI, 0.10, 0.92). Within round 17, prevalence was decreasing overall (R=0.95, 95% CrI, 0.93, 0.97) but increasing in children aged 5 to 17 years (R=1.13, 95% CrI, 1.09, 1.18). Those 75 years and older had a swab-positivity prevalence of 2.46% (95% CI, 2.16%, 2.80%) reflecting a high level of infection among a highly vulnerable group. Among the 3,613 swab-positive individuals reporting whether or not they had had previous infection, 2,334 (64.6%) reported previous confirmed COVID-19. Of these, 64.4% reported a positive test from 1 to 30 days before their swab date. Risks of infection were increased among essential/key workers (other than healthcare or care home workers) with mutually adjusted Odds Ratio (OR) of 1.15 (95% CI, 1.05, 1.26), people living in large compared to single-person households (6+ household size OR 1.73; 95% CI, 1.44, 2.08), those living in urban vs rural areas (OR 1.24, 95% CI, 1.13, 1.35) and those living in the most vs least deprived areas (OR 1.34, 95% CI, 1.20, 1.49). Conclusions: We observed unprecedented levels of infection with SARS-CoV-2 in England in January 2022, an almost complete replacement of Delta by Omicron, and evidence for a growth advantage for BA.2 compared to BA.1. The increase in the prevalence of infection with Omicron among children (aged 5 to 17 years) during January 2022 could pose a risk to adults, despite the current trend for prevalence in adults to decline. (Funded by the Department of Health and Social Care in England.)

Rapid increase in Omicron infections in England during December 2021: REACT-1 study (preprint)

Background The highest-ever recorded numbers of daily severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections in England has been observed during December 2021 and have coincided with a rapid rise in the highly transmissible Omicron variant despite high levels of vaccination in the population. Although additional COVID-19 measures have been introduced in England and internationally to contain the epidemic, there remains uncertainty about the spread and severity of Omicron infections among the general population. Methods The REal-time Assessment of Community Transmission–1 (REACT-1) study has been monitoring the prevalence of SARS-CoV-2 infection in England since May 2020. REACT-1 obtains self-administered throat and nose swabs from a random sample of the population of England at ages 5 years and over. Swabs are tested for SARS-CoV-2 infection by reverse transcription polymerase chain reaction (RT-PCR) and samples testing positive are sent for viral genome sequencing. To date 16 rounds have been completed, each including ∼100,000 or more participants with data collected over a period of 2 to 3 weeks per month. Socio-demographic, lifestyle and clinical information (including previous history of COVID-19 and symptoms prior to swabbing) is collected by online or telephone questionnaire. Here we report results from round 14 (9-27 September 2021), round 15 (19 October - 05 November 2021) and round 16 (23 November - 14 December 2021) for a total of 297,728 participants with a valid RT-PCR test result, of whom 259,225 (87.1%) consented for linkage to their NHS records including detailed information on vaccination (vaccination status, date). We used these data to estimate community prevalence and trends by age and region, to evaluate vaccine effectiveness against infection in children ages 12 to 17 years, and effect of a third (booster) dose in adults, and to monitor the emergence of the Omicron variant in England. Results We observed a high overall prevalence of 1.41% (1.33%, 1.51%) in the community during round 16. We found strong evidence of an increase in prevalence during round 16 with an estimated reproduction number R of 1.13 (1.06, 1.09) for the whole of round 16 and 1.27 (1.14, 1.40) when restricting to observations from 1 December onwards. The reproduction number in those aged 18-54 years was estimated at 1.23 (1.14, 1.33) for the whole of round 16 and 1.41 (1.23, 1.61) from 1 December. Our data also provide strong evidence of a steep increase in prevalence in London with an estimated R of 1.62 (1.34, 1.93) from 1 December onwards and a daily prevalence reaching 6.07% (4.06%, 9.00%) on 14 December 2021. As of 1 to 11 December 2021, of the 275 lineages determined, 11 (4.0%) corresponded to the Omicron variant. The first Omicron infection was detected in London on 3 December, and subsequent infections mostly appeared in the South of England. The 11 Omicron cases were all aged 18 to 54 years, double-vaccinated (reflecting the large numbers of people who have received two doses of vaccine in this age group) but not boosted, 9 were men, 5 lived in London and 7 were symptomatic (5 with classic COVID-19 symptoms: loss or change of sense of smell or taste, fever, persistent cough), 2 were asymptomatic, and symptoms were unknown for 2 cases. The proportion of Omicron (vs Delta or Delta sub-lineages) was found to increase rapidly with a daily increase of 66.0% (32.7%, 127.3%) in the odds of Omicron (vs. Delta) infection, conditional on swab positivity. Highest prevalence of swab positivity by age was observed in (unvaccinated) children aged 5 to 11 years (4.74% [4.15%, 5.40%]) similar to the prevalence observed at these ages in round 15. In contrast, prevalence in children aged 12 to 17 years more than halved from 5.35% (4.78%, 5.99%) in round 15 to 2.31% (1.91%, 2.80%) in round 16. As of 14 December 2021, 76.6% children at ages 12 to 17 years had received at least one vaccine dose; we estimated that vaccine effectiveness against infection was 57.9% (44.1%, 68.3%) in this age group. In addition, the prevalence of swab positivity in adults aged 65 years and over fell by over 40% from 0.84% (0.72%, 0.99%) in round 15 to 0.48% (0.39%,0.59%) in round 16 and for those aged 75 years and over it fell by two-thirds from 0.63% (0.48%,0.82%) to 0.21% (0.13%,0.32%). At these ages a high proportion of participants (>90%) had received a third vaccine dose; we estimated that adults having received a third vaccine dose had a three- to four-fold lower risk of testing positive compared to those who had received two doses. Conclusion A large fall in swab positivity from round 15 to round 16 among 12 to 17 year olds, most of whom have been vaccinated, contrasts with the continuing high prevalence among 5 to 11 year olds who have largely not been vaccinated. Likewise there were large falls in swab positivity among people aged 65 years and over, the vast majority of whom have had a third (booster) vaccine dose; these results reinforce the importance of the vaccine and booster campaign. However, the rapidly increasing prevalence of SARS-CoV-2 infections in England during December 2021, coincident with the rapid rise of Omicron infections, may lead to renewed pressure on health services. Additional measures beyond vaccination may be needed to control the current wave of infections and prevent health services (in England and other countries) from being overwhelmed. Summary The unprecedented rise in SARS-CoV-2 infections is concurrent with rapid spread of the Omicron variant in England and globally. We analysed prevalence of SARS-CoV-2 and its dynamics in England from end of November to mid-December 2021 among almost 100,000 participants from the REACT-1 study. Prevalence was high during December 2021 with rapid growth nationally and in London, and of the proportion of infections due to Omicron. We observed a large fall in swab positivity among mostly vaccinated older children (12-17 years) compared with unvaccinated younger children (5-11 years), and in adults who received a third vs. two doses of vaccine. Our results reiterate the importance of vaccination and booster campaigns; however, additional measures may be needed to control the rapid growth of the Omicron variant.

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 (preprint)

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 round 15 final report: Increased breakthrough SARS-CoV-2 infections among adults who had received two doses of vaccine, but booster doses and first doses in children are providing important protection (preprint)

Background It has been nearly a year since the first vaccinations against SARS-CoV-2 were delivered in England. The third wave of COVID-19 in England began in May 2021 as the Delta variant began to outcompete and largely replace other strains. The REal-time Assessment of Community Transmission-1 (REACT-1) series of community surveys for SARS-CoV-2 infection has provided insights into transmission dynamics since May 2020. Round 15 of the REACT-1 study was carried out from 19 October to 5 November 2021. Methods We estimated prevalence of SARS-CoV2 infection and used multiple logistic regression to analyse associations between SARS-CoV-2 infection in England and demographic and other risk factors, based on RT-PCR results from self-administered throat and nose swabs in over 100,000 participants. We estimated (single-dose) vaccine effectiveness among children aged 12 to 17 years, and among adults compared swab-positivity in people who had received a third (booster) dose with those who had received two vaccine doses. We used splines to analyse time trends in swab-positivity. Results During mid-October to early-November 2021, weighted prevalence was 1.57% (1.48%, 1.66%) compared to 0.83% (0.76%, 0.89%) in September 2021 (round 14). Weighted prevalence increased between rounds 14 and 15 across most age groups (including older ages, 65 years and over) and regions, with average reproduction number across rounds of R=1.09 (1.08, 1.11). During round 15, there was a fall in prevalence from a maximum around 20-21 October, with an R of 0.76 (0.70, 0.83), reflecting falls in prevalence at ages 17 years and below and 18 to 54 years. School-aged children had the highest weighted prevalence of infection: 4.95% (4.39%, 5.58%) in those aged 5 to 12 years and 5.21% (4.61%, 5.87%) in those aged 13 to 17 years. In multiple logistic regression, age, sex, key worker status and presence of one or more children in the home were associated with swab positivity. There was evidence of heterogeneity between rounds in swab positivity rates among vaccinated individuals at ages 18 to 64 years, and differences in key demographic and other variables between vaccinated and unvaccinated adults at these ages. Vaccine effectiveness against infection in children was estimated to be 56.2% (41.3%, 67.4%) in rounds 13, 14 and 15 combined, adjusted for demographic factors, with a similar estimate obtained for round 15 only. Among adults we found that those who received a third dose of vaccine were less likely to test positive compared to those who received only two vaccine doses, with adjusted odds ratio (OR) =0.38 (0.26, 0.55). Discussion Swab-positivity was very high at the start of round 15, reaching a maximum around 20 to 21 October 2021, and then falling through late October with an uncertain trend in the last few days of data collection. The observational nature of survey data and the relatively small proportion of unvaccinated adults call into question the comparability of vaccinated and unvaccinated groups at this relatively late stage in the vaccination programme. However, third vaccine doses for eligible adults and the vaccination of children aged 12 years and over are associated with lower infection risk and, thus, remain a high priority (with possible extension to children aged 5-12 years). These should help reduce SARS-CoV-2 transmission during the winter period when healthcare demands typically rise.

REACT-1 round 15 interim report: High and rising prevalence of SARS-CoV-2 infection in England from end of September 2021 followed by a fall in late October 2021 (preprint)

Background: The third wave of COVID-19 in England coincided with the rapid spread of the Delta variant of SARS-CoV-2 from the end of May 2021. Case incidence data from the national testing programme (Pillar 2) in England may be affected by changes in testing behaviour and other biases. Community surveys may provide important contextual information to inform policy and the public health response. Methods: We estimated patterns of community prevalence of SARS-CoV-2 infection in England using RT-PCR swab-positivity, demographic and other risk factor data from round 15 (interim) of the REal-time Assessment of Community Transmission-1 (REACT-1) study (round 15a, carried out from 19 to 29 October 2021). We compared these findings with those from round 14 (9 to 27 September 2021). Results: During mid- to late-October 2021 (round 15a) weighted prevalence was 1.72% (1.61%, 1.84%) compared to 0.83% (0.76%, 0.89%) in September 2021 (round 14). The overall reproduction number (R) from round 14 to round 15a was 1.12 (1.11, 1.14) with increases in prevalence over this period (September to October) across age groups and regions except Yorkshire and The Humber. However, within round 15a (mid- to late-October) there was evidence of a fall in prevalence with R of 0.76 (0.65, 0.88). The highest weighted prevalence was observed among children aged 5 to 12 years at 5.85% (5.10%, 6.70%) and 13 to 17 years at 5.75% (5.02%, 6.57%). At regional level, there was an almost four-fold increase in weighted prevalence in South West from round 14 at 0.59% (0.43%,0.80%) to round 15a at 2.18% (1.84%, 2.58%), with highest smoothed prevalence at subregional level also found in South West in round 15a. Age, sex, key worker status, and presence of children in the home jointly contributed to the risk of swab-positivity. Among the 126 sequenced positive swabs obtained up until 23 October, all were Delta variant; 13 (10.3%) were identified as the AY.4.2 sub-lineage. Discussion: We observed the highest overall prevalence of swab-positivity seen in the REACT-1 study in England to date in round 15a (October 2021), with a two-fold rise in swab-positivity from round 14 (September 2021). Despite evidence of a fall in prevalence from mid- to late-October 2021, prevalence remains high, particularly in school-aged children, with evidence also of higher prevalence in households with one or more children. Thus, vaccination of children aged 12 and over remains a high priority (with possible extension to children aged 5-12) to help reduce within-household transmission and disruptions to education, as well as among adults, to lessen the risk of serious disease among those infected.

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 (preprint)

Background: England 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. Methods: In 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. Results: We 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, 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, 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. However, the prevalence was lower in those with one or two doses of vaccine than in unvaccinated individuals at 1.76% (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. Discussion: In 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 within 3 to 6 months 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.

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

Introduction Long 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. Methods Within 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. Results Among 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. Interpretation A 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.

Symptom reporting in over 1 million people: community detection of COVID-19 (preprint)

Summary Control of the SARS-CoV-2 epidemic requires rapid identification and isolation of infected individuals and their contacts. Community testing in England (Pillar 2) by polymerase chain reaction (PCR) is reserved for those reporting at least one of four ‘classic’ COVID-19 symptoms (loss or change of sense of smell, loss or change of sense of taste, fever, new continuous cough). 1 Detection of positive cases in the community might be improved by including additional symptoms and their combinations. We used data from the REal-time Assessment of Community Transmission-1 (REACT-1) study to investigate symptom profiles for PCR positivity at different ages. Among rounds 2–7 (June to December 2020), an age-stratified, variable selection approach stably selected chills (all ages), headache (5–17 years), appetite loss (18–54 and 55+ years) and muscle aches (18–54 years) as jointly and positively predictive of PCR positivity together with the classic four symptoms. Between round 7 (November to December 2020) and round 8 (January 2021) when new variant B.1.1.7 predominated, only loss or change of sense of smell (more predictive in round 7) and (borderline) new persistent cough (more predictive in round 8) differed between cases. At any level of PCR testing, triage based on the symptoms identified here would result in more cases detected than the current approach.