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

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

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

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

Diversity of symptom phenotypes in SARS-CoV-2 community infections observed in multiple large datasets (preprint)

Through the use of cutting-edge unsupervised classification techniques from statistics and machine learning, we characterise symptom phenotypes among symptomatic SARS-CoV-2 PCR-positive community cases. We first analyse each dataset in isolation and across age bands, before using methods that allow us to compare multiple datasets. While we observe separation due to the total number of symptoms experienced by cases, we also see a separation of symptoms into gastrointestinal, respiratory and other types, and different symptom co-occurrence patterns at the extremes of age. In this way, we are able to demonstrate the deep structure of symptoms of COVID-19 without usual biases due to study design. This is expected to have implications for the identification and management of community SARS-CoV-2 cases and could be further applied to symptom-based management of other diseases and syndromes.

Impact of Delta on viral burden and vaccine effectiveness against new SARS-CoV-2 infections in the UK (preprint)

The effectiveness of BNT162b2, ChAdOx1, and mRNA-1273 vaccines against new SARS-CoV-2 infections requires continuous re-evaluation, given the increasingly dominant Delta variant. We investigated the effectiveness of the vaccines in a large community-based survey of randomly selected households across the UK. We found that the effectiveness of BNT162b2 and ChAd0x1 against any infections (new PCR positives) and infections with symptoms or high viral burden is reduced with the Delta variant. A single dose of the mRNA-1273 vaccine had similar or greater effectiveness compared to a single dose of BNT162b2 or ChAdOx1. Effectiveness of two doses remains at least as great as protection afforded by prior natural infection. The dynamics of immunity following second doses differed significantly between BNT162b2 and ChAdOx1, with greater initial effectiveness against new PCR-positives but faster declines in protection against high viral burden and symptomatic infection with BNT162b2. There was no evidence that effectiveness varied by dosing interval, but protection was higher among those vaccinated following a prior infection and younger adults. With Delta, infections occurring following two vaccinations had similar peak viral burden to those in unvaccinated individuals. SARS-CoV-2 vaccination still reduces new infections, but effectiveness and attenuation of peak viral burden are reduced with Delta.

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

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

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

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

Community prevalence of SARS-CoV-2 in England during April to September 2020: Results from the ONS Coronavirus Infection Survey (preprint)

Background: Decisions regarding the continued need for control measures to contain the spread of SARS-CoV-2 rely on accurate and up-to-date information about the number of people and risk factors for testing positive. Existing surveillance systems are not based on population samples and are generally not longitudinal in design. Methods: From 26 April to 19 September2020, 514,794 samples from 123,497 individuals were collected from individuals aged 2 years and over from a representative sample of private households from England. Participants completed a questionnaire and nose and throat swab were taken. The percentage of individuals testing positive for SARS-CoV-2 RNA was estimated over time using dynamic multilevel regression and post-stratification, to account for potential residual non-representativeness. Potential changes in risk factors for testing positive over time were also evaluated using multilevel regression models. Findings: Between 26 April and 19 September 2020, in total, results were available from 514,794 samples from 123,497 individuals, of which 489 were positive overall from 398 individuals. The percentage of people testing positive for SARS-CoV-2 changed substantially over time, with an initial decrease between end of April and June, followed by low levels during the summer, before marked increases end of August and September 2020. Having a patient-facing role and working outside your home were important risk factors for testing positive in the first period but not (yet) in the second period of increased positivity rates, and age (young adults) being an important driver of the second period of increased positivity rates. A substantial proportion of infections were in individuals not reporting symptoms (53%-70%, dependent on calendar time). Interpretation: Important risk factors for testing positive varied substantially between the initial and second periods of higher positivity rates, and a substantial proportion of infections were in individuals not reporting symptoms, indicating that continued monitoring for SARS-CoV-2 in the community will be important for managing the epidemic moving forwards.

Viral load in community SARS-CoV-2 cases varies widely and temporally (preprint)

Background: Information on COVID-19 in representative community surveillance is limited, particularly regarding cycle threshold (Ct) values (a proxy for SARS-CoV-2 viral load) and symptoms. Methods: We included all positive nose and throat swabs between 26 April-11 October 2020 from the UK national COVID-19 Infection Survey, tested by RT-PCR for the N, S and ORF1ab genes. We investigated predictors of median Ct value using quantile regression. Results: 1892(0.22%) of 843,851 results were positive, 1362(72%), 185(10%) and 345(18%) for 3, 2 or 1 genes respectively. Ct for different genes were strongly correlated (rho=0.99) with overall median Ct 26.2 (IQR 19.7-31.1; range 10.3-37.6), corresponding to ~2,500 dC/ml (IQR 80-240,000). Ct values were independently lower in those reporting symptoms, with more genes detected, and in first (vs. subsequent) positives per-participant, with no evidence of independent effects of sex, ethnicity, age, deprivation or other test characteristics (p>0.20). Whilst single-gene positives without reported symptoms almost invariably had Ct>30, triple-gene positives without reported symptoms had widely varying Ct. Incorporating pre-test probability and Ct values, 1547(82%) and 112(6%) positives had higher or lower supporting evidence for genuine infection. Ct values, symptomatic percentages and supporting evidence changed over time. With lower positivity in the summer, there were proportionally more lower evidence positives, and higher evidence positives had higher Ct values (p<0.0001), suggesting lower viral burden. Declines in mean/median Ct values were apparent throughout August and preceded increases in positivity rates. Conclusions: Community SARS-CoV-2 infections show marked variation in viral load. Ct values could be a useful epidemiological early-warning indicator.