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1.
Preprint in English | medRxiv | ID: ppmedrxiv-22276154

ABSTRACT

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.

2.
Preprint in English | medRxiv | ID: ppmedrxiv-22275908

ABSTRACT

Targeted vaccination policies can have a significant impact on the number of infections and deaths in an epidemic. However, optimising such policies is complicated and the resultant solution may be difficult to explain to policy-makers and to the public. The key novelty of this paper is a derivation of the leading order optimal vaccination policy under multi-group SIR (Susceptible-Infected-Recovered) dynamics in two different cases. Firstly, it considers the case of a small vulnerable subgroup in a population and shows that (in the asymptotic limit) it is optimal to vaccinate this group first, regardless of the properties of the other groups. Then, it considers the case of a small vaccine supply and transforms the optimal vaccination problem into a simple knapsack problem by linearising the final size equations. Both of these cases are then explored further through numerical examples which show that these solutions are also directly useful for realistic parameter values. Moreover, the findings of this paper give some general principles for optimal vaccination policies which will help policy-makers and the public to understand the reasoning behind optimal vaccination programs in more generic cases. Author summaryThe COVID-19 pandemic has illustrated the importance of vaccination programs in preventing infections and deaths from an epidemic. A common feature of vaccination programs across the world has been a prioritisation of different groups within each countrys population, particularly those who are more vulnerable to the disease. Finding the best priority order is crucial, but may be complicated and difficult to justify to policy-makers and the public. In this paper, we consider two extreme cases where the best prioritisation order can be mathematically derived. Firstly, we consider the case of a population with a very small, very vulnerable group and show that this group should always be vaccinated first. Then, we consider the case of a small supply of vaccines and derive an equation which gives the best prioritisation order. Understanding these extreme cases is important, as it highlights general principles of optimal policies which will be useful when understanding the solution in more complicated settings.

3.
Preprint in English | medRxiv | ID: ppmedrxiv-22275900

ABSTRACT

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.

4.
PLoS Computational Biology ; 18(4), 2022.
Article in English | ProQuest Central | ID: covidwho-1842903

ABSTRACT

We find that epidemic resurgence, defined as an upswing in the effective reproduction number (R) of the contagion from subcritical to supercritical values, is fundamentally difficult to detect in real time. Inherent latencies in pathogen transmission, coupled with smaller and intrinsically noisier case incidence across periods of subcritical spread, mean that resurgence cannot be reliably detected without significant delays of the order of the generation time of the disease, even when case reporting is perfect. In contrast, epidemic suppression (where R falls from supercritical to subcritical values) may be ascertained 5–10 times faster due to the naturally larger incidence at which control actions are generally applied. We prove that these innate limits on detecting resurgence only worsen when spatial or demographic heterogeneities are incorporated. Consequently, we argue that resurgence is more effectively handled proactively, potentially at the expense of false alarms. Timely responses to recrudescent infections or emerging variants of concern are more likely to be possible when policy is informed by a greater quality and diversity of surveillance data than by further optimisation of the statistical models used to process routine outbreak data.

5.
Preprint in English | medRxiv | ID: ppmedrxiv-22275368

ABSTRACT

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.

6.
Preprint in English | medRxiv | ID: ppmedrxiv-22275147

ABSTRACT

Reliably estimating the dynamics of transmissible diseases from noisy surveillance data is an enduring problem in modern epidemiology. Key parameters, such as the time-varying reproduction number, Rt at time t, are often inferred from incident time series, with the aim of informing policymakers on the growth rate of outbreaks or testing hypotheses about the effectiveness of public health interventions. However, the reliability of these inferences depends critically on reporting errors and latencies innate to those time series. While studies have proposed corrections for these issues, methodology for formally assessing how these noise sources degrade Rt estimate quality is lacking. By adapting Fisher information and experimental design theory, we develop an analytical framework to quantify the uncertainty induced by under-reporting and delays in reporting infections. This yields a novel metric, defined by the geometric means of reporting and cumulative delay probabilities, for ranking surveillance data informativeness. We apply this metric to two primary data sources for inferring Rt: epidemic case and death curves. We show that the assumption of death curves as more reliable, commonly made for acute infectious diseases such as COVID-19 and influenza, is not obvious and possibly untrue in many settings. Our framework clarifies and quantifies how actionable information about pathogen transmissibility is lost due to surveillance limitations.

7.
Preprint in English | medRxiv | ID: ppmedrxiv-22275015

ABSTRACT

It is widely acknowledged that vaccinating at maximal effort in the face of an ongoing epidemic is the best strategy to minimise infections and deaths from the disease. Despite this, no one has proved that this is guaranteed to be true if the disease follows multi-group SIR (Susceptible-Infected-Recovered) dynamics. This paper provides a novel proof of this principle for the existing SIR framework, showing that the total number of deaths or infections from an epidemic is decreasing in vaccination effort. Furthermore, it presents a novel model for vaccination which assumes that vaccines are distributed randomly to the unvaccinated population and suggests, using COVID-19 data, that this more accurately captures vaccination dynamics than the model commonly found in the literature. However, as the novel model provides a strictly larger set of possible vaccination policies, the results presented in this paper hold for both models. HighlightsO_LIIt is proved that it is optimal to vaccinate at maximal effort C_LIO_LIA novel model of vaccination is explored with COVID-19 vaccine data C_LIO_LIResults are presented which hold for both the novel and classical vaccination models. C_LI

8.
Preprint in English | medRxiv | ID: ppmedrxiv-22273042

ABSTRACT

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.

9.
Preprint in English | medRxiv | ID: ppmedrxiv-22272177

ABSTRACT

BackgroundThe 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 MethodsIn 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). FindingsWe 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{middle dot}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. InterpretationIn 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. FundingDepartment of Health and Social Care, England. O_TEXTBOXResearch in contextO_ST_ABSEvidence before this studyC_ST_ABSA search of PubMed using title or abstract terms ("Omicron" or "BA.1" or "BA.2") and "prevalence" without language or other restrictions, identified 51 results (with no duplicates). All 51 results were evaluated, with 18 deemed relevant. One study focused on Omicron case rates in South Africa during the early stage after the discovery of the new variant (November 2021), one described genomic surveillance of SARS-CoV-2 in the USA (June - December 2021), one analysed clinical outcomes based on health records (January - December 2021), one described the results of whole-genome sequencing of SARS-CoV-2 samples collected in North Africa (March - December 2021), and one was from a previous REACT survey round (November - December 2021). The others focused on the mutation distribution of Omicron, disease severity, immune response, vaccine effectiveness, and prevalence in animal hosts. Added value of this studyWe analysed data from throat and nose swabs collected at home by a randomly selected sample of residents of England, aged 5 years and older, obtained during round 18 (8 February to 1 March 2022) of the REal-time Assessment of Community Transmission-1 (REACT-1) study. We estimated a weighted prevalence of SARS-CoV-2 of 2.88% (95% CrI 2.76-3.00) in England in February 2022, which was substantially lower than that estimated in January 2022 (4.41% [4.25-4.56]). The within-round dynamics differed by age group with weighted prevalence falling among children (aged 5 to 17 years) with an R of 0.79 (0.74-0.84) and adults aged 18 to 54 years with an R of 0.92 (0.89-0.96), in contrast to the level or increasing weighted prevalence among those aged 55 years and older with an R of 1.04 (1.00-1.09). Exponential models estimated a daily growth rate advantage of 0.12 (0.11-0.13) in the odds of BA.2 (vs BA.1 or BA.1.1) corresponding to an R additive advantage of 0.40 (0.36-0.43). Implications of all the available evidenceRandom community surveys of SARS-CoV-2 provide robust insights into transmission dynamics and identify groups at heightened risk of infection based on estimates of population prevalence that are unbiased by test-seeking behaviour or availability of tests. In England, replacement by BA.2 of other Omicron sublineages, the level or increasing rates of infection in older people and the uptick in hospitalisations in England toward the end of February 2022 require ongoing surveillance, both to monitor the levels of current (and future) SARS-CoV-2 variants and the risks of severe disease. C_TEXTBOX

10.
Preprint in English | medRxiv | ID: ppmedrxiv-22270365

ABSTRACT

BackgroundRapid transmission of the SARS-CoV-2 Omicron variant has led to the highest ever recorded case incidence levels in many countries around the world. MethodsThe 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. ResultsFrom 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). ConclusionsWe 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.)

11.
Preprint in English | medRxiv | ID: ppmedrxiv-21268252

ABSTRACT

BackgroundThe 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. MethodsThe 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. ResultsWe 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. ConclusionA 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. SummaryThe 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.

12.
Preprint in English | medRxiv | ID: ppmedrxiv-21267925

ABSTRACT

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.

13.
Preprint in English | medRxiv | ID: ppmedrxiv-21267806

ABSTRACT

BackgroundIt 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. MethodsWe 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. ResultsDuring 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). DiscussionSwab-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.

14.
Preprint in English | medRxiv | ID: ppmedrxiv-21265877

ABSTRACT

BackgroundThe 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. MethodsWe 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). ResultsDuring 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. DiscussionWe 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.

15.
Preprint in English | medRxiv | ID: ppmedrxiv-21264965

ABSTRACT

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.

16.
Preprint in English | medRxiv | ID: ppmedrxiv-21261987

ABSTRACT

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.

17.
Preprint in English | medRxiv | ID: ppmedrxiv-21260912

ABSTRACT

BackgroundPhase III trials have estimated COVID-19 vaccine efficacy (VE) against symptomatic and asymptomatic infection. We explore the direction and magnitude of potential biases in these estimates and their implications for vaccine protection against infection and against disease in breakthrough infections. MethodsWe developed a mathematical model that accounts for natural and vaccine-induced immunity, changes in serostatus and imperfect sensitivity and specificity of tests for infection and antibodies. We estimated expected biases in VE against symptomatic, asymptomatic and any SARS-CoV-2 infections and against disease following infection for a range of vaccine characteristics and measurement approaches, and the likely overall biases for published trial results that included asymptomatic infections. ResultsVE against asymptomatic infection measured by PCR or serology is expected to be low or negative for vaccines that prevent disease but not infection. VE against any infection is overestimated when asymptomatic infections are less likely to be detected than symptomatic infections and the vaccine protects against symptom development. A competing bias towards underestimation arises for estimates based on tests with imperfect specificity, especially when testing is performed frequently. Our model indicates considerable uncertainty in Oxford-AstraZeneca ChAdOx1 and Janssen Ad26.COV2.S VE against any infection, with slightly higher than published, bias-adjusted values of 59.0% (95% uncertainty interval [UI] 38.4 to 77.1) and 70.9% (95% UI 49.8 to 80.7) respectively. ConclusionMultiple biases are likely to influence COVID-19 VE estimates, potentially explaining the observed difference between ChAdOx1 and Ad26.COV2.S vaccines. These biases should be considered when interpreting both efficacy and effectiveness study results.

18.
Preprint in English | medRxiv | ID: ppmedrxiv-21260746

ABSTRACT

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.

19.
Preprint in English | medRxiv | ID: ppmedrxiv-21260926

ABSTRACT

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.

20.
Preprint in English | medRxiv | ID: ppmedrxiv-21260497

ABSTRACT

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.

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