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?
There is very good evidence that children who have COVID-19 are much less likely to develop severe symptoms and much less likely to die from the disease than people in older age groups. There is good evidence that children under 13 years old are less susceptible to developing clinical disease (this means having recognisable signs and symptoms) than adults. It is not yet clear whether this is also the case for older children. There is some research indicating that children aged 13 years and under may be less susceptible to infection than adults, but the confidence in this evidence is low. There is insufficient research to say whether this is the case for older children. There is some evidence to suggest that children transmit the virus less than adults, but more research is needed to reduce uncertainty. Pregnant women are not more likely to contract the virus. Transmission of the virus from mothers to babies is low. Some babies born to COVID-19 positive mothers will develop an infection; these babies are not at increased risk of severe disease.
This article discusses the latest evidence describing how COVID-19 affects children, and the role that children have in the transmission of the virus in the population. This is a complex interplay between how susceptible children are, how infectious they are, the proportion of children in a population, and how they mix with other age groups. This is relevant to implementing policies that seek to limit transmission by children.
Children of all ages, including newborns, can be infected by the SARS-CoV-2 virus. There is some evidence suggesting that younger children are less susceptible to infection than adults. It is not clear whether older children differ in their susceptibility to infection compared with adults. In the earliest stages of the outbreak, epidemiological studies of disease clusters reported that severe infections were more common in adults than children. It was not possible at that early stage to know whether children were less likely to catch the virus, or be less likely to have symptoms, or both, and how they might be involved in transmission. The World Health Organization’s (WHO) report of the WHO-China joint mission on COVID-19, which was published in late February, confirmed the emerging pattern that children accounted for a very small proportion (2.4%) of all reported cases at that time. In its meetings with Chinese officials and experts, the WHO team was also told that there were no known cases where transmission was from a child to an adult. Subsequent studies in multiple countries involving larger samples of people of all ages consistently show that children under the age of 18 account for less than 2% of all infections detected. As the pandemic has progressed, researchers have examined how the virus affects children; these studies are used to inform clinical practice and policy-making.
The data so far show that the likelihood of being infected and developing clinical disease follows an age gradient, where the risk of being infected increases with age.
Initial studies looked at the various characteristics of people who had tested positive for COVID-19, including age and sex. A study of the first 7,755 confirmed cases in South Korea reported 75 cases in 0 to 9 year olds, and 405 cases in 10 to 19 year olds. There were no deaths in either group.
Another approach is to test whole communities or a large sample of people who are representative of the whole population. This is an important method since it will also detect people who test positive but are asymptomatic. A study in Vo, Italy analysed how lockdown impacted transmission in the community. Of the 234 children aged 0 to 10 years tested, none were found to be positive for the virus. Some of these children were living with family members infected with the virus. A much larger population screening study in Iceland tested 9,199 people representing 6% of the population. The study was split into two main parts:
Children under 10 years old were less likely to test positive than other age groups, and the percentage infected increased with age. For the targeted testing group, 6.7% of under 10s tested positive compared with 13.7% for all people over 10 years old. For the general testing, no children under 10 tested positive, compared with 0.8% of those over 10 years old.
A Spanish study commissioned by the Ministry of Health (that has not been peer reviewed) looked for COVID-19 antibodies in a large population sample of 60,897 people between 27 April and 11 May. The sample was representative of the overall population. It found that overall, 5.0% of the sample had antibodies against SARS-CoV-2, with no differences between males and females. The percentage of children who had antibodies against SARS-CoV-2 also shows an age gradient:
A similar age gradient is also seen in mortality data for COVID-19, with very few deaths in children. UK data are discussed below.
There is some data showing that there are more cases in male children than females; this is also the case for adults. There are no clear answers yet as to why this is the case, but scientists have speculated that this is likely to reflect a combination of biological mechanisms and behavioural differences (the latter particularly for adults). Females tend to have a more effective immune response making them more resilient to infectious disease. This is thought to derive from the large number of immune genes on the X chromosome (females have two X chromosomes).
The UK has paediatric surveillance programmes for COVID-19. In the UK, daily updates are published on the Government’s COVID-19 data dashboard – these data detail cases by age group but not deaths by age group. These data are collected by Public Health England, which publishes a detailed weekly bulletin about COVID-19, with equivalent releases produced by agencies in the rest of the UK (Northern Ireland, Scotland, Wales). Data from Public Health England shows the age gradient for confirmed cases for both sexes.
The Office for National Statistics publishes data on COVID-19 mortality in England and Wales. There are difference in how deaths are reported between these agencies. The Government data dashboard reports the deaths of people who had tested positive but not all deaths recorded will have been officially registered at that point. The ONS data reports registered deaths where COVID-19 is mentioned on the death certificate.
Provisional ONS data on COVID-19 deaths are published weekly since the first UK COVID-19 deaths were registered in early March. The latest data published on 19 May with data up to week ending 8 May reports that since the pandemic began there have been:
As of 5pm on 21 May the Government data dashboard reports the total number of deaths for all age groups in the UK at 36,393.
The ONS published some early results from a pilot study that seeks to find out how many people in England have COVID-19 infections. Testing of 10,705 people in the community (excluding care homes and hospitals) took place between 27 April and 10 May. People took their own nose and throat swab samples. Based on that data, ONS calculated that between those dates, an estimated 0.27% of England’s population would test positive. The data also showed that there was no difference in the proportion of people who tested positive in any age group but there was a wide range of uncertainty for the figure for each age group. It reported data on children by including them in the age range 2 to 19 years, rather than in several age cohorts from 0–18 years as other studies have done. The pilot will go on to include 25,000 people, with a view to a larger study over the next 12 months across the UK. The larger studies will reduce the uncertainty associated with these estimates. Self-swabbing of the nose and throat is difficult and could impair the sensitivity of the test, making it more likely that positive results are underestimated. Conducting this type of survey with an antibody test in a much larger number of people would improve the quality of the data and give a better estimate of COVID-19 prevalence. This is because an antibody test gives information about whether an individual has been infected since the beginning of the pandemic, rather than whether someone is infected with live virus at a single point in time as this study does.
Children tend to experience milder symptoms than adults or have no symptoms at all (asymptomatic). The pattern of symptoms also differs, for example, children are less likely to have a fever, cough and shortness of breath than adults, but are more likely to experience gastrointestinal symptoms and vomiting. Children usually recover within 1 to 2 weeks. A detailed review article on the characteristics of COVID-19 in children outlines the results from numerous international studies about how the disease affects this age group.
Very few children develop severe disease. The risk of a child dying from COVID-19 is extremely low, with a current estimate of mortality of 0.01%. This means one in every 10,000 cases.
In early April, reports emerged of critically ill children (some of whom were COVID-19 positive) who had symptoms characteristic of a rare toxic shock syndrome that can arise from bacterial infections and symptoms of another condition called atypical Kawasaki disease. The WHO has published a scientific brief on this topic and, as with its other work to drive a harmonised international approach to COVID-19 research and clinical guidance, is coordinating clinical data collection to inform medical practice. The UK’s Paediatric Intensive Care Society states that serious illness as a result of COVID-19 is a very rare event in children. It has developed clinical guidance for health professionals and primary care doctors have been alerted to how this condition presents in children.
There are limited data on whether children with underlying medical conditions are at greater risk. Five studies looking at paediatric cases have indicated that having a weakened immune system does not significantly increase the risk of developing severe disease. However, researchers expect that children with cardio-vascular or respiratory disease, or who are immunosuppressed as a result of medical treatment (such as for some cancers) may be more vulnerable. This is reflected in some research data that looked at whether children admitted to hospital with COVID-19 had other medical problems. Studies in Italy, China and the US have found that more children with other health problems were hospitalised, although this wasn’t necessarily linked to having more serious disease, apart from in infants aged under 12 months.
There are no data yet on whether children from black and minority ethnic groups are at increased risk from COVID-19.
Understanding the role that children play in transmitting the virus is of significant policy relevance, since measures can be taken to limit the opportunities for transmission to take place between children and adults – notably closing childcare and educational settings. This information is also critical in designing population immunisation programmes; although a COVID-19 vaccine is not expected for at least 12 to 18 months at the earliest if a successful vaccine candidate(s) is found. For example, children in the UK are immunised against seasonal influenza, which in addition to protecting the children themselves, also confers protection to the wider population because children readily transmit influenza virus in the community.
The extent to which children transmit the virus is not yet fully understood and is complicated by the fact that there are asymptomatic cases. Data from research in community clusters and larger studies that test population samples, such as those carried out in South Korea and Iceland, report fewer cases in children than adults, suggesting that children may be less likely to get the disease.
Studies of early clusters of disease in families and in small groups showed that children were not the source of infection in those groups. For example, in a study of a disease cluster in the French Alps, a 9-year-old child with symptoms had made a large number of contacts during a trip to the Alps and then at three different schools. Of the 169 tested contacts, only one person tested positive.
Asymptomatic and pre-symptomatic transmission of the virus have been reported and there is also some evidence that those who have symptoms are more likely to transmit the virus than those who are asymptomatic. A study in the Netherlands reported that children have a minor role in transmission and that the virus is primarily spread between people of similar age. They also found that it is less common for adults to infect children, but when this does happen it tends to be within a household.
An Australian study looked at all COVID-19 cases reported in primary and high schools in New South Wales between March and mid-April and reported preliminary findings with data up to 21 April. 18 individuals (9 pupils and 9 staff) were identified as COVID-19 cases in 15 schools (10 high schools and 5 primaries). Close contacts of these cases included 735 pupils and 128 staff. There were no cases in any staff members as a result from contact with the infected school pupils. Two children were identified as having had COVID-19 and it is highly likely, but not certain, that they contracted the virus from the infected school contacts. A limitation of this study is that not all participants were tested for the virus.
A review of all the relevant research so far on transmission by children will be published as a pre-print next week (this means that it has not yet been reviewed by other scientists). This has been carried out by a group of scientists led by University College London. From analysing research studies that undertook contact tracing, the authors conclude, based on the evidence so far, that children are 56% less likely to become infected than adults. This is in line with a modelling study published as a pre-print in early May, which concluded that under 20-year-olds were approximately 50% less susceptible to infection than older age groups. On analysis of wider population level studies, the authors conclude that while it is possible that children may play a limited role in transmission, the evidence for this to date is weak. The reviewers highlight that many studies that seek to answer this question have limitations in terms of study design or quality, which make it difficult to draw conclusions with certainty.
The research so far is indicative that children may not play a significant role in spreading COVID-19, in contrast with other respiratory viruses such as influenza. More evidence from high quality large scale serosurveillance studies (that look at SARS-CoV-2 antibodies in a population) are needed to quantify the risk of transmission of the virus from children and how this differs from adults. Many such studies are underway.
There is some research on whether pregnant women are at greater risk from COVID-19 and if they pass the virus to their babies during pregnancy, birth and breastfeeding.
Research shows that pregnant women have the same COVID-19 risk factors as the general population, notably age, existing health problems including diabetes, asthma, high blood pressure, being overweight or obese. Being in a black or minority ethnic group is also a confounding risk for pregnant women. There is no evidence of an increased risk of miscarriage.
The UK has a real-time surveillance program of pregnant women who test positive for COVID-19. This allows them to be tracked throughout pregnancy and birth. The largest study on outcomes for pregnant women and their babies was reported in a UK study by the University of Oxford (not yet peer reviewed) using data from the surveillance program. The researchers analysed data from 427 pregnant women hospitalised with COVID-19. As with other research, most women were hospitalised in the later stages of pregnancy. One in 20 infants (12 infants in total) tested positive for COVID-19, of which half had a positive test immediately after birth. There have been other reports of infants testing positive for IgM antibodies to the virus in umbilical blood shortly after birth (IgM antibodies are made by the body first in response to an infection and do not cross the placenta). No virus was detected in these babies in subsequent testing and they did not have any symptoms. It is not yet possible to rule out whether the virus is passed to infants during pregnancy. Several studies have shown that maternal IgG antibodies against COVID-19 cross the placenta.
There is no evidence from the Oxford study, or other studies, to indicate that babies who test positive for COVID-19 are at increased risk of severe disease.
A recently published study examined the breastmilk from two mothers with COVID-19. Their milk was tested for evidence of the genetic material from SARS-CoV-2 daily. The milk from one mother tested positive for 4 consecutive days. This coincided with mild COVID-19 symptoms in her infant, who also tested positive for the virus. However, it was not possible to conclude that the infant was infected through breastfeeding.
The Royal College of Paediatrics and Child Health has published an evidence summary of various aspects of COVID-19 and children which is updated regularly.
COVID-19 in Children, UK Research and Innovation
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