Human challenge studies in the study of infectious diseases
What can deliberately infecting healthy people tell us about infectious diseases? How is this useful for developing treatments, and how do we manage the risks?
Test, trace and isolate programmes across the UK are under pressure as COVID-19 cases rise in all age groups and demand for tests grows. Further pressure comes from people seeking tests because they have symptoms caused by other respiratory viruses but need a test in order to rule out COVID-19. The Scientific Advisory Group on Emergencies has described the impact of current test and tracing on the transmission of the virus as “marginal”. How does test and trace work and what are the current challenges limiting its effectiveness in reducing COVID-19 cases?
DOI: https://doi.org/10.58248/RR48
Test, trace and isolate (TTI) programmes in operation across the UK seek to find and break chains of transmission of the SARS-CoV-2 virus and limit the number of infections. The principles of test and trace are to ensure that anyone with symptoms of COVID-19 are tested quickly and any close contacts of positive cases are advised to isolate. This may then guide subsequent actions such as testing of contacts to bring the self-isolation period to an end. This is different to mass testing of a mostly uninfected population, which was part of the Prime Minister’s 9 September announcement on approaches to enable lifting restrictions on daily life. Different TTI programmes are in operation across the UK, but they are all based on the same public health principles.
In addition to testing people with COVID-19 symptoms, TTI programmes also target testing to specific groups who may be at higher risk from the consequences of an infection (such as care home residents) or because they are at higher risk of exposure due to the settings in which they work or spend time (such as healthcare workers in hospitals). Other testing is done to monitor where infections are occurring and how they spread. The UK testing programme is separated into different groups called pillars. This is discussed further down.
The tests used identify if someone has a current infection. High quality diagnostic tests using samples from nose and throat swabs are processed in laboratories across the UK. Antibody tests are used to see if someone has been infected previously and are used in programmes for a different purpose: to understand what proportion of people have been infected and to study the spread of the disease. You can read this article to find out more about the diagnostic tests used in TTI programmes in the UK.
The Scientific Advisory Group on Emergencies (SAGE) has been advising the UK Government since the pandemic began. According to SAGE, the most important features of test and trace are that as many people with the infection are rapidly tested and that their contacts are identified quickly so they can self-isolate, with testing for those who have symptoms. Self-isolation is one of the most effective social distancing measures to reduce transmission of the virus. The key features of a TTI programme are therefore rapid access to high quality tests, fast turnaround of results, rapid identification (and testing if required) of contacts, and the behavioural response of those people interacting with the programmes. You can read more about the behavioural aspects of TTI in this article.
SAGE and its expert sub-groups discussed testing early in the pandemic, but more detailed discussions of population level testing and contact tracing began in April with a discussion on the key features of an effective programme on 1 May. This discussion was taking place at a time when there were considerable uncertainties about how and where transmission occurs, the optimal point in the course of an infection to test, the number of infected but asymptomatic people who could transmit the virus, the extent and duration of any immunity, and the operational constraints that might enhance or limit TTI programmes’ capabilities (such as the availability of a contact tracing app, and diagnostic test quality and testing capacity).
SAGE used modelling studies to examine how different test and tracing strategies would affect the transmission of the virus in the population. One study calculated that viral transmission could be reduced by 26% if 80% of cases and contacts are identified, cases are tested quickly after symptoms start and if contacts isolate within 24 hours.
The features of the virus and people’s behaviour are very important. These include how long it takes someone to become ill if they are infected with the virus, how infectious they are before symptoms show and that about 28% of people who have the virus will not have any symptoms at all. This is particularly relevant to targeting frequent testing of people in high risk settings such as care homes and hospitals. The extent to which people and their contacts engage with test and trace and comply with self-isolation is very important. This is discussed in Test, Trace and Isolate: Behavioural aspects. The speed with which the system can break transmission chains is critical; the limits of effectiveness are determined by the length of time it takes for symptoms of the virus to appear in contacts. For SARS-CoV-2 this is 5–6 days. This means that unless an infected person and their contacts are identified quickly, the contacts may have been infectious for days and go on to transmit it to others.
SAGE used data about international TTI programmes and UK modelling studies to understand how elements of a programme might collectively have an impact on the transmission of the virus. For example, they looked at different outcomes related to how quickly contacts are traced (24, 48 and 72 hours). They found that the sooner that contacts isolate the better, and that any delay beyond 48–72 hours does little to reduce the overall viral transmission. SAGE also considered a report on TTI by the Royal Society’s DELVE (Data Evaluation and Learning for Viral Epidemics) group. The DELVE report summarised the key features as speed, compliance and coverage. They also noted that an integrated localised approach would become more important as the epidemic progresses, as local outbreaks would require tailored management.
As knowledge about the virus increased, SAGE reached a consensus on features of a TTI programme that would have a meaningful impact on the spread of the virus and also highlighted the risks of failure of TTI:
Each nation has its own TTI programme:
Data about the performance of TTI programmes are published but the level of detail and the parameters used to evaluate them vary across nations. Details about the performance of the NHS Test and Trace service in England are discussed below. Northern Ireland’s Public Health Agency publishes Coronavirus weekly and monthly bulletins. Public Health Scotland publishes weekly COVID-19 statistical reports and the Welsh Government publishes weekly statistics of Test, Trace and Protect. The NHS Test and Trace data include: how many people have been tested and how many tested positive; time to get a test result; how many people and how long it took for positive cases to be referred to test and trace; and how many close contacts were identified and reached.
Test eligibility criteria are similar across the four countries and are based on having symptoms consistent with COVID-19. People with a new continuous cough, a high temperature, and a loss of or change to the sense of taste or smell must self-isolate for at least 10 days and request a test. While several other symptoms are associated with COVID-19, research for SAGE shows that this group of symptoms are consistently the best predictors to use in test and trace.
The NHS website provides instructions on how to behave according to test results. In the case of a positive test, people will be contacted by the test and trace programme running in their country to provide details of their contacts. They will need to provide the name, telephone number and/or email address of anyone they have had close contact with in the 2 days prior to symptoms starting, as well as details of any place they visited. In England this stage is coordinated by PHE local health protection teams or by a centralised system (depending on the definition of cases, see below). In Wales, contact tracing is delivered by a number of partners, including Public Health Wales, local Health Boards and Local Authorities in Wales, and NHS Wales Informatics Service (NWIS). In Scotland people who had a positive test are contacted by local contact tracing teams or the National Contact Tracing Service, while in Northern Ireland by the Public Health Agency Contact Tracing Service.
On 24 September the NHS COVID-19 app was launched in England and Wales. The UK Government reports 16.5m downloads but there are no published data on uptake. The app has several features: it allows the tracing of contacts using Bluetooth technology, provides details on the Local COVID Alert Level, allows check-ins into venues such as restaurants or bars, monitors symptoms, helps with test ordering and keeps track of self-isolation times.
On 10 September the NHS Protect Scotland app was launched in Scotland and on 31 July the StopCOVID NI Proximity app was launched in Northern Ireland. They use the same technology as the NHS COVID-19 app; providing contact tracing and alerting, but none of the other features. Unlike the Scottish and English apps, the StopCOVID NI Proximity app is also available for young people, aged 11 to 15.
More details on apps for contact tracing can be found in Contact tracing apps for COVID-19: September update.
A recent Cochrane systematic review evaluated the impact of digital contact tracing technologies in epidemics. Data on the impact of COVID-19 contact tracing apps across the UK are not yet available.
Since the launch of the NHS COVID-19 app, several technical issues have been reported, including disappearing alerts of possible COVID-19 exposure. More recently, employees in different sectors, including banks, fuel firms, pharmaceutical companies and education, have been told to switch off the app at work.
The NHS Test and Trace service launched on 27 May. In September, the Health Foundation published ‘NHS Test and Trace: the journey so far’, a detailed analysis on how this service evolved and the challenges it is facing.
As shown in the flowchart above, the NHS Test and Trace programme is characterised by two components:
There are four testing pillars in England:
All positive cases, irrespective of pillar, must be reported to PHE, with cases from Pillars 1, 2 and 4 then transferred to NHS Test and Trace.
Laboratory capacity for each pillar has been widely discussed in the past few months. Analysis by the Nuffield Trust highlighted that around a third of laboratory capacity between 17–23 September was assigned to Pillar 3 testing, but only a fraction of that was used. Moreover, they pointed out a lack of transparency about capacity data, which are reported only at a UK level (rather than at a regional level), making evaluation difficult.
NHS Test and Trace statistics are published weekly. These describe aspects of the testing system (the overall number of people tested for SARS-CoV-2, the number of those testing positive, and the time needed for test results to become available) and contact tracing (numbers transferred to the contact tracing system and time taken to reach them, and close contacts identified and the time taken to reach them).
Key points explored in the following section (see Figure 2 below):
Since NHS Test and Trace launched, 8.3m people have been tested at least once. Two-thirds of these were through Pillar 2 swab tests. While the number of tests in Pillar 1 has been relatively stable since test and trace began in late May, the number of Pillar 2 tests has been rising sharply. There has been a steep rise in cases detected in both pillars since early September. According to the data collected between 1 and 7 October, when weekly swab testing capacity for Pillar 2 was 2.1m tests:
The total number of positive cases detected in the community by the NHS Test and Trace system is significantly less than the estimated number of cases in the community derived from the ONS COVID-19 infection survey and a surveillance study called REACT. This indicates that a large number of infected people may not be being picked up by TTI.
While 87.0% of Pillar 1 tests had a 24-hour turnaround, this was the case for only 14.8% of Pillar 2 tests. Mobile test units, regional and local test sites were faster (with a median of 26–29 hours) than home testing kits (median 75 hours) and satellite centres (median 63 hours). These values represent a minor decrease from the previous week for mobile test units, regional and local test sites, and an increase for home testing kits and satellites centres.
Following a positive test (either from Pillars 1, 2 or 4), 87,918 people were transferred to the contact tracing system between 1 and 7 October. Of those, 67,511 (76.8% of those transferred and 75.1% of all positive cases) were reached and asked to provide details of recent close contacts. According to the UK Government website, “the number of people transferred to NHS Test and Trace does not always align with the number of people testing positive due to the time taken for this data to be transferred and data not being de-duplicated”.
Among the cases reached by the contact tracing system:
Only 57,523 people (65.4% of transferred cases and 64% of all positive cases) provided contact details.
Of 216,627 people identified as recent close contacts, 189,698 (87.6%) were contacts of non-complex cases and 26,929 (12.4%) were complex. 109,345 of the non-complex contacts (57.6%) were reached and asked to self-isolate. This proportion has declined over the past 3 weeks. 41,851 non-complex contacts (22% of the non-complex contacts in total and 38.5% of those reached) were reached and advised to self-isolate within 24 hours of the case that reported them being transferred to the contact tracing system.
Almost all complex close contacts (97.7%; 26,316 contacts) were reached and asked to self-isolate. No data are available on the proportion on them reached in 24 hours.
The relaxation of restrictions, reopening of schools and increased transmission of SARS-CoV-2 and other respiratory viruses have led to an increase in test demand and a decrease in access to tests since early September. The North West and the North East experienced the highest case rate by the end of September.
In September, the Chair of NHS Test and Trace, Baroness Harding of Winscombe, told the House of Commons Science and Technology Committee that test demand was three to four times higher than test capacity.
To mitigate shortages in capacity, the UK Government published a test prioritisation list on 21 September:
There are several barriers for a TTI programme to work properly. Asymptomatic and pre-symptomatic transmission represent a challenge for any symptom-based TTI programme, such as those running in the UK. Studies have estimated that a third of infections are asymptomatic, and that asymptomatic cases are half as infectious as symptomatic cases. One modelling study (not peer-reviewed) concluded that TTI strategies are not likely to be sufficient to contain the natural spread of SARS-CoV-2 due to asymptomatic and pre-symptomatic transmission, missing contacts and/or imperfect isolation.
Delays at different stages of any TTI programme impact its effectiveness: a modelling study published in The Lancet found that minimising testing delay had the largest impact on reducing transmissions. In addition, SARS-CoV-2 test accuracyno diagnostic test is 100% accurate and this has a major role in the efficacy of a TTI programme. Some experts have suggested that poor test sensitivity could have a critical role in reducing the effectiveness of contact tracing and faster (and less sensitive) testing could exacerbate it.
Different strategies have been proposed to improve TTI programmes in the UK. Considering the role of asymptomatic cases, on 23 July the Royal Statistical Society recommended random visits to carry out swab tests in households with reported cases.
In a statement on 9 September the Prime Minister announced the ambition to increase England’s testing capacity to 500,000 tests per day by the end of October.
Some experts have called for better data collection, including the day of symptom-onset and the day of the end of isolation to better monitor cases. Others have suggested that when a TTI programme fails, then the only alternatives are nationwide blanket measures.
Contact tracing in NHS Test and Trace was initially managed centrally. This approach requires effective coordination between multiple government and health organisations operating at the national and local level. A report on general TTI programmes published by the Royal Society in May noted the importance of local approaches to manage outbreaks as the epidemic progresses. Integrating TTI with local surveillance is seen as particularly important since it offers more detailed information that can be used to understand local outbreaks. A decentralised approach to test and trace, under the control of local public health teams also enables actions to be better tailored to communities. This approach is routinely used to manage outbreaks of infectious diseases. On 10 August the contact tracing element of NHS Test and Trace was moved from central to local management, giving local councils’ public health teams more responsibility.
In May, the Royal Society DELVE initiative published a review of international approaches to Test, Trace, Isolate, focusing on Germany, South Korea, Taiwan, Singapore, New Zealand and Iceland to offer insights for the UK. Testing strategies, use of technology to support contact tracing and turn-around times were among the factors analysed.
The Scientific Pandemic Influenza Group on Behaviours (SPI-B) prepared a document on local lockdown measures to control outbreaks of COVID-19 that was considered by SAGE on 30 July. It illustrates COVID-19 monitoring across different countries. Germany is described as the country where monitoring and response has mostly occurred a regional level, while New Zealand had the most centralised approach.
Another study analysed different approaches to easing restrictions in Asia and Europe, highlighting how an effective TTI programme is at the core of any successful exit strategy for COVID-19 restrictions, together with knowledge of infection levels, community engagement, health system capacity and border control measures. A large divergence in government preparedness emerged as a concern among the authors of the study.
Experts often describe South Korea, Germany, Taiwan and Australia as examples to follow for the UK, given their investments in public health infrastructure, digital surveillance and ability to boost COVID-19 testing. One study (not-peer reviewed) directly compared TTI programmes in six countries (Germany, Ireland, Spain, South Africa, South Korea and the UK). It concluded that each has its own advantages and disadvantages and that openness and evaluation need to be a key part of any TTI programme.
Winter sees peak demand on the NHS as a range of seasonal viruses circulate, notably influenza. The risk of increased transmission of SARS-CoV-2 arises from people spending more time in closer contact indoors in spaces that are less well-ventilated than in warmer months and the likelihood that SARS-CoV-2 virus survives longer in cooler, drier air. One study that has not yet been peer reviewed has suggested that COVID-19 could be more severe when temperatures are lower. Estimating the impact of weather on outcomes is difficult, so further research is needed to understand how temperature and humidity affect transmission and disease.
SAGE has reported on wider winter challenges and the impact on test and trace since May. There is a seasonal surge of several respiratory viruses prevalent from early autumn through winter, many of which cause symptoms like those of COVID-19. This leads to increased demand as people seek tests to find out if they have COVID-19 or not. This has coincided with the lifting of a range of non-pharmaceutical interventions and an increase in viral transmission. The latest data show that the number of cases in all age groups have risen substantially since early September. The need for rapid diagnostic tests that can accurately discriminate between COVID-19 and other infections is a government priority and many such tests are in development.
On 20 July, the UK Government announced £3 billion of extra funding to support the NHS over the winter and new Guidance on containing and managing local coronavirus (COVID-19) outbreaks. Themes in local outbreak plans included local testing, contact tracing in complex settings and data integration. On 3 September the Government announced the opening of a new Lighthouse Lab to increase capacity and on 18 September it published the Adult social care: coronavirus (COVID-19) winter plan 2020 to 2021. The plan sets out COVID-19 testing actions for local authorities, NHS organisations and care providers, such as regular testing of people discharged from hospital to a care home, or regular testing of staff and residents.
At the end of September, the Welsh Government published the Winter Protection Plan. Increasing testing capacity and helping people to understand how and when to get a test are among the priorities for their Test, Trace and Protect strategy.
On 25 August, the Scottish Government announced the first of 11 walk-through testing sites planned to increase testing capacity ahead of the winter. On 29 September, it announced £1.1 billion of health and social care funding for the COVID-19 response and winter preparations.
On 6 October, the NI Government published its COVID-19 – Surge Planning Strategic Framework.
Mass testing of the population is a different approach to TTI. This is because mass testing is carried out at a population level or for a defined group in which most people are not infected. SAGE has published advice on how such mass testing could work, but highlights how it is distinct from TTI. However, any future mass screening programme needs to be fully integrated with TTI so that all infectious people are reported for contact tracing. Some experts are critical of a mass testing approach, especially considering the impact of false positives and false negatives at a national level.
A paper for SAGE, written on 21 September analysing the effectiveness and harms of different measures to minimise cases of COVID-19, was published on 12 October. It noted that the main approach since restrictions on daily life have lifted has been to use TTI and other measures to reduce viral transmission. While it is not possible to evaluate the contribution of each measure to overall reductions in transmission with any accuracy, based on the available data SAGE considers that the role of TTI is marginal. This results from low levels of engagement with TTI, testing delays and poor adherence to self-isolation requirements.
In its latest paper, SAGE highlights several knowledge gaps and recommends several research priorities. Further work is needed to improve backwards contact tracing and data linkage to enhance knowledge of transmission routes. It also recommends more detailed data collection on the environments and occupations where people are interacting so these can be linked to TTI.
12 March was the last day on which community testing for COVID-19 was conducted.
31 January: The first two UK cases of COVID-19 are announced by England’s Chief Medical Officer.
28 February: England’s Chief Medical Officer announces the first case of COVID-19 transmitted in the UK.
Scotland launches pilot Test, Trace and Protect programme in three health board areas.
16 March: SAGE advises that diagnostic testing needs to be urgently increased. PHE reports that testing is being scaled up to 10,000 per day – focused on intensive care units, hospital admissions and key workers and that commercial self-test options are being evaluated.
18 March: SAGE reports testing capacity is at 6,084 daily, with a goal to increase this to 25,000 as soon as possible. It also notes the importance of key worker (especially NHS staff) access to testing and to increase testing capacity.
23 March: SAGE reports NHS testing capacity at 5,000 per day, and states a need for a clear rationale for prioritising testing for patients and repeated testing for healthcare workers.
26 March: SAGE reiterates need to urgently ramp up testing of appropriate quality.
2 April: SAGE discusses the elements for a successful long-term testing strategy that involves high quality tests and a clear public communication strategy. Key points: a testing strategy should have target volumes for reporting infections in hospital patients, NHS staff, age stratified population surveys and wider communities. Quality of testing and communication of results is critical as this could potentially lead to unsafe behaviours or unsafe demands on workers by employers.
7 April: SAGE discusses a COVID-19 app and notes that linking it to viral test diagnosis is important, as well as integration with testing and contact tracing and the impact on testing demand.
9 April: SAGE highlights the need to anticipate future testing need when social interventions are lifted. The NHS estimates that it needs 8,000 patient tests per day and 6,000–7,000 staff tests per day. It notes that any future mass testing programme should consider impact on clinical management, including whether testing can anticipate future demand on NHS and on enabling people to return to work. It would also need to consider the relationship between testing and contact tracing, testing to support those shielding and behavioural consequences of mass testing.
16 April: SAGE discusses testing for contact tracing and notes that, even for low levels of infection, the testing capacity would need to be 100,000s of tests per day.
23 April: SAGE noted the need to understand what the current total testing capacity is and what infection level a test and trace programme could cope with.
30 April: SAGE discusses the principles for testing in a contact tracing system. Speed of results and test performance are identified as important factors to determine whether contacts should only isolate once the index case tests positive or as soon as symptoms are reported. A meeting dedicated to testing is agreed for 1 May.
1 May: SAGE agrees the key features needed from a test and trace programme. Ideally, testing should be rapid such that contacts of an index case are asked to isolate only on the basis of a positive test result for an index case. Adherence to isolation is critical. It discusses contact testing but there is insufficient evidence as to who best to do this. Contacts should be requested to self-isolate for 14 days. Backwards contact tracing should be incorporated into any test and trace strategy.
5 May: SAGE discusses the scale and role of test and trace in the context of changes to lifting restrictions.
7 May: SAGE considers a report by NERVTAG on how to define cases based on symptoms and discusses the importance of the public understanding of COVID-19 symptoms in the context of effective test and trace.
12 May: SAGE reiterates the importance of a putting a test, trace and isolate programme in place.
14 May: SAGE states that lifting any further social distancing measures should not be contemplated until test and trace is up and running. It discusses social bubbles and states that active contact tracing should be a precondition of introducing bubbles.
On 28 May NHS Test and Trace launches in England. Test, Trace and Protect launches in Northern Ireland. Test, Trace Isolate, Support launches in Scotland.
19 May: SAGE states that a test and trace programme is necessary before any further adjustments to social distancing measures are made and states key attributes. It also considers a report on TTI by the Royal Society DELVE group.
21 May: SAGE notes that if a test, trace and isolate programme starts working when there is high disease rates then it could rapidly become overwhelmed. SAGE discusses school openings under different test, trace and isolate scenarios. It highlighted the importance of scaling test and trace capability when the prevalence of other respiratory diseases that share COVID-19 symptoms increases.
On 1 June Test, Trace, Protect launches in Wales. On 30 July StopCOVID NI app launches in Northern Ireland.
4 June: SAGE reiterates the importance of test and trace to prevent a rising number of infections and the importance of capability to track and trace clusters of cases.
11 June: SAGE recommends backwards contact tracing as a way of identifying clusters.
On 10 September the Protect Scotland app launches in Scotland
20 August: SAGE discusses testing strategies that could enable early release from self-isolation and notes the factors that limit the effectiveness of test and trace.
27 August: SAGE states that test and trace coverage and speed must be optimised in order to isolate cases quickly.
On 24 September the NHS COVID-19 app launches in England and Wales.
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