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?
An infected person produces respiratory droplets when talking, coughing and sneezing. These are responsible for the transmission of virus between people. Droplets can travel up to 2m, with finer aerosols containing smaller viral particles travelling even further. Numerous complex and interacting factors influence how they move and settle onto surfaces, and how infectious they are. The further away a person is, the fewer droplets they will be exposed to and so their risk of being infected with the virus reduces. The advice on 2 m distancing is a risk assessment based on relative not absolute risk; 2 m does not represent zero risk. Measures to mitigate the increased risk of reducing physical distancing include ventilation, physical barriers (screens and face coverings), reduced building occupancy and enhanced cleaning. These will vary according to the context. The wider range of social distancing practices will need to be maintained to contain viral transmission even if the 2 m advice changes. Social distancing and other public health measures are likely to be needed long-term, until a vaccine or more effective treatments for COVID-19 are available. There are numerous knowledge gaps about SARS-CoV-2 transmission; research to address them will inform policy-making.
DOI: https://doi.org/10.58248/RR32
In March 2020, the UK Government recommended several measures as part of an approach termed social distancing. This refers to several behaviours that reduce virus transmission chains, including limiting social contacts, practising respiratory hygiene and, more recently, wearing face coverings. An essential part of reducing the risk of transmission of COVID-19 was that people must maintain a 2 m gap between each other. This practice is now commonly understood and referred to as social distancing. The advised distance results from an assessment of the relative risk of transmission of virus between people and is not an absolute measure of safety.
The Prime Minister referred to the importance of this advice explicitly in a statement on 22 March. This advice is also prominent in government advice for working safely during the pandemic, with specific guidance for businesses on how this could be managed, such as putting up signs, marking out areas and creating one-way routes. Additional advice was outlined to offer protection in cases where a 2 m distance cannot be maintained. This includes the use of physical devices such as barriers or screens, alongside other approaches to reduce the number of people in a given area. In early June, the Government recommended the use of face coverings, with subsequent announcements that these are obligatory on public transport and in hospitals. The importance of practising social distancing by observing the 2 m gap is reinforced through public health messaging.
The recommended distance between people varies internationally. For example, the German Government advises 1.5 m and the French Government advises 1 m.
There is increasing debate about whether the 2 m social distancing limit should be reduced in the UK. This is largely in the context of re-opening various sectors as lockdown measures are relaxed, in order to maximise the capacity within physical settings such as business premises, cultural venues, public buildings and schools. This article summarises the latest research on the transmission of the SARS-CoV-2 virus and how this has informed advice on social distancing, and options for changing the rule as the incidence of disease decreases.
On 23 June, the Prime Minister announced that from 4 July, the new advice is that where it is possible to keep 2 m apart, people should do so. If it is not possible then the distance may be reduced to 1 m plus, provided that other measures to mitigate any additional risk are taken. This advice applies only to England. The devolved governments have not amended their social distancing advice.
Transmission of virus between people depends on the quantity and viability of the virus, the duration and mode of exposure (for example coughing or speaking), multiple interacting and complex environmental factors, and the orientation to, and distance from, the source. The source can be a person or a contaminated surface.
The novel coronavirus SARS-CoV-2 that causes COVID-19 measures 0.06–0.14 µm in diameter. This is about 600 times smaller than the width of an average human hair. It is spread through two main routes:
Respiratory droplets (5–10 µm) are generated when someone coughs or sneezes. If someone is in close contact (within 1 m) then they are at risk of being exposed to droplets through the mouth, nose and eyes. Droplets may be carried over a distance of 1–2 m, with smaller droplets carrying further.
Contact with the virus by touching contaminated surfaces. Transmission can occur if someone then touches their mouth, nose or eyes.
There is ongoing research to see if SARS-CoV-2 transmission is airborne. Airborne transmission refers to viral particles smaller than 5 µm. These particles can remain in the air for long periods and can be transmitted over larger distances than larger droplets. Some early experimental studies have reported that small amounts of viral particles can be detected in the air, but it is not yet clear whether such particles could cause infections. A precautionary approach has been taken in medical and dental settings where aerosol–generating procedures are used that create fine particles, with staff required to don appropriate personal protective equipment (PPE) to minimise risk.
Contact transmission of SARS-CoV-2 is better understood than the airborne route and thought to be an important mode of transmission. Transmission depends on the amount of virus on a surface; transfer to the hands and face and then to mucous membranes such as the eyes, nose and mouth; and the quality and frequency of hand hygiene practices.
Normal activities, such as breathing, talking, singing, coughing and sneezing, produce droplets and fine aerosols that can contain respiratory viruses. Understanding how they move and contribute to transmission between people is essential for assessing the risks and designing strategies to mitigate these. These risks will vary according to the context.
The movement of droplets and aerosols of all sizes is partly determined by their characteristics, which may contain varying amounts of substances such as fats, proteins and salts. It is also influenced by interacting environmental factors including air flow, temperature and humidity, whether inside or outdoors. The movement of air indoors is a dynamic process, in response to the movement of people, opening and closing of doors and windows, furniture layouts and ventilation systems.
Because SARS-CoV-2 is a new virus there is limited evidence so far on the exact nature of the production and transmission of aerosols that contain it and their potential to cause infections in others. However, assumptions can be made from data about other respiratory viruses and these have been used to inform policy-making. Studying and modelling the movement and deposition of respiratory droplets and aerosols is complex, but several studies have characterised them in different settings. Large droplets are likely to be deposited on surfaces within 1–2 m and so the transmission route would be directly onto another person’s face or via touching contaminated surfaces. Aerosols produced by coughing can form plumes that can travel several metres, even indoors. Research on SARS-CoV-2 is advancing rapidly, with some relevant studies published. One found that the virus can remain in aerosol form for at least three hours, and others have characterised the extent of viral contamination in hospital rooms even with cleaning procedures in place, for example a study carried out in a Wuhan hospital.
The evidence so far indicates that deposition of SARS-CoV-2 virus from aerosols is a transmission route, in addition to physical contact with droplets or by touching contaminated surfaces. The relative importance of the three transmission routes is not yet clear but it is likely to vary depending on the setting and the source person carrying the infection. For aerosols, most of the risk arises from the potential that aerosols containing the virus will be inhaled but there is some risk from the deposition of virus in aerosols on surfaces. There is little evidence so far on how much virus is present in exhaled breath, and how this differs between people and by severity of disease. Exposure to the virus also depends on the quantity of virus-containing aerosols generated and how they dissipate in the air, whether indoors or outside. There are little data as yet on what constitutes an infectious dose of virus and if this differs between contact transmission and inhalation.
The Scientific Advisory Group for Emergencies (SAGE) provides scientific advice about COVID-19 to the UK Government to inform policy-making. It has discussed the details of viral transmission several times, with the latest scientific evidence considered on each occasion. This has resulted in a range of public health measures to break viral transmission chains, including maintaining 2 m distance between people.
SAGE considered a scientific report on environmental dispersion of SARS-CoV-2 at a meeting on 14 April. This report outlined how the movement of viral particles is determined by numerous interacting environmental conditions, such as temperature, humidity, movement and ventilation. It also discussed emerging evidence of the likelihood that most transmission takes place indoors and the uncertainties about the transfer and viability of virus. The report also highlighted the importance and complexities of developing models that can inform how risk can be quantified in different circumstances and the potential impacts of a range of mitigation measures. It also outlined that indoor environments are likely to be riskier and that controlling exposure to aerosols indoors can be done with well-designed ventilation, using air cleaning technologies, and by limiting the number of people inside. The report highlights that there is some evidence suggesting that wearing a surgical face mask, or other face coverings, offers a small reduction in transmission of virus.
A sub-group of experts, the Environmental and Modelling Group for SAGE published an overview of the evidence on environmental factors influencing transmission on 28 April, updated on 2 May. This evidence summary was discussed at a SAGE meeting on 29 April. The purpose of the paper was to assess the risks associated with transmission from droplet, airborne and contact routes, taking into account the time spent in an environment, the distance from and the nature of the source. Overall, the risk of transmission decreases as the distance from the source increases. The risk increases as the duration of exposure to the source increases. The SAGE report uses these examples to illustrate the different elements that contribute to the overall relative risk:
SAGE continues to note the critical importance of all public health measures, especially hand hygiene. It continues to consider the development of new measures, for example endorsing disinfection technologies and approaches to minimise transmission on public transport, and the risks associated with lifting multiple containment measures too quickly.
The effectiveness of the 2 m rule was discussed in a SAGE report on 28 April. It is based on a tolerable reduction in risk from the transmission of droplets and aerosols. The SAGE report also suggested that measures could be put in place such that the 2 m distance could be reduced in some circumstances. Adequate ventilation is important, especially in enclosed spaces where there are lots of people. Other additive measures could also mitigate any increased risk of reducing the 2 m rule or where this is difficult to maintain. These include installing physical structures to create barriers or to divert air flow, additional cleaning and increased hand hygiene, walking or standing back-to-back or side-by-side rather than being face-to-face or behind others, and wearing a face mask or covering in crowded, enclosed spaces. Other approaches include limiting the circle of people with whom one interacts using social bubbles and reducing the time periods for activities. Short duration closer contacts to people outdoors are likely to present minimal risk. It is unlikely that aerosol particles persist in the air for more than 30 minutes in areas with good ventilation.
A review of multiple studies published in The Lancet concluded that there is sufficient evidence to support reducing the physical distancing advice to 1 m, as this is associated with a large reduction in infection risk. It notes that 2 m is likely to be more effective. A key limitation of this review is that all the studies it analysed were subject to biases in different ways and some studies were based on other coronaviruses, such as MERS-CoV and SARS-CoV. Some of the statistical methods used by the authors have been critiqued by other scientists. The quality of some of the individual studies included in the review have also been criticised.
As the prevalence of community infections decreases, as indicated by the Office for National Statistics COVID-19 survey and other national data, so does the overall risk of transmission. Therefore, it might be considered proportionate to reduce the distancing advice in line with lower levels of community infection.
The scientific advice overall is that 2 m remains safer than 1 m but that additional mitigating measures could be used to offset the increase in risk. However, there are uncertainties associated with how this risk varies in different circumstances. A consideration in developing public health messages is that having one simple rule is easier to understand and follow than having flexible rules that apply under different circumstances. The simplicity of the 2 m advice for everyone is thought to be an important factor in its success.
Characterising the risks associated with the specific circumstances of different environments is essential in order to develop plans for minimising risk so that venues can re-open in a safe way. Scientists advising Government are developing tools with which to assess the risks associated with different environments and activities taking place within them.
More detailed data on viral survival on surfaces indoors and outdoors is important in order to develop cleaning protocols and inform risk assessments for public and workplace settings. Research data suggest that, while the virus could persist on surface for 72 hours, there is a substantial reduction after 48 hours – this is a practical precautionary value used by Public Health England. Better data will also inform how design and the choice of materials used in the environment could be valuable, especially for high frequency contact objects such as door handles, since SARS-CoV-2 persists on different materials for varying amounts of time.
Monitoring environments and occupations linked to certain environmental conditions is seen as essential in targeting appropriate mitigation measures to minimise the risk of transmission. Data on occupational exposure outside health and care settings is emerging. This is exemplified by several outbreaks of COVID-19 linked to meat processing plants in the US, Germany, Australia, Wales, England and France. It is not yet clear to what extent this occupational group’s risk differs than others, but working in close proximity on production lines, shouting in a noisy environment, inadequate hand hygiene and inadequate and improper use of PPE are all possible contributing factors. These facilities are also cold, humid and artificially lit, factors that are conducive to viral survival. Socio-economic factors are also relevant; workers sharing overcrowded accommodation and communal transport were thought to be an additional causative factor for an outbreak in one plant in Germany. An academic review published in June has examined which settings linked to clusters of COVID-19. Meat processing plants are just one of many indoor environments that merit close monitoring as lockdown restrictions are lifted.
Re-opening schools to all pupils is seen as critical, not only for children’s education but also to protect their mental health, and to enable working parents to return to normal working patterns. Children are affected differently by COVID-19 than adults and have a different role in transmission, so measures to change social distancing in schools may differ from environments which only have adults.
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