In the middle of the pandemic, scientists intentionally infected healthy volunteers with SARS-CoV-2, the virus that causes COVID-19. John Tregoning, Reader in Respiratory Infections at the Department of Infectious Disease, explains why these experiments, and the volunteers who take part in them, are critical to modern medicine.
In early March 2021, in the middle of the COVID-19 pandemic, a surprising-sounding set of experiments were taking place. Researchers at Imperial College London (and separately at the University of Oxford) were deliberately infecting healthy volunteers with SARS-CoV-2. This was in fact the latest in a long line of controlled human infection studies – where volunteers are deliberately infected with an infectious pathogen under extremely controlled conditions.
Deliberate human infection for health benefit goes back a long way – the earliest evidence of infection for beneficial use is 10th Century China, deliberately inoculating healthy people with smallpox to make them immune to the disease. This practice continued into the 18th century, when an English doctor, Thomas Dimsdale, deliberately infected Catherine the Great and her son with a very low dose of smallpox virus to protect them against the disease.
This idea of infecting people deliberately to protect them from disease led to Edward Jenner’s famous studies inventing the first ever vaccine. Jenner hypothesised that you didn’t need to use material derived from smallpox to be protected, you could use material from a related virus, cowpox. He proved this worked using a human challenge study; he vaccinated James Phipps (his gardener’s son) with cowpox then deliberately exposed him to smallpox repeatedly, showing that the vaccine worked and Phipps was immune to smallpox.
Deliberate infection
The practice of deliberate infection for scientific benefit really took off after the demonstration by Pasteur, Koch and others that microbes cause disease. In the early 1900’s, Walter Reed, the American public health pioneer, was trying to understand where yellow fever came from – he had a suspicion that it came from mosquitos. This was important because identifying the source could alter behaviour and reduce the incidence. To test his hypothesis, Reed recruited 11 volunteers to be bitten by mosquitos that had previously bitten a yellow fever patient; two of the volunteers contracted yellow fever, strongly supporting his idea. One important development in Reed’s infection studies was the concept of ‘informed consent’. The volunteers were informed about the risk to themselves of participation, before they gave their consent to take part. Sadly, later in the 20th century, some human infection studies entered a darker chapter, with the horrific experimentation on prisoners in Nazi Germany and Imperial Japan without their consent.
Informed consent is the bedrock upon which all modern research involving volunteers is built, and it is crucial for infection studies. The landscape of human infection studies has changed dramatically since the middle of the 20th century; now, ensuring the health and safety of participants is of paramount importance and trials are carefully designed to minimise any potential risks. Studies are only performed following extensive ethical review by an external body, for example all human infection studies carried out at Imperial College London have ethical approval from the UK Health Research Authority. There is ongoing debate about whether infection studies can ever be ethical, in terms of deliberately exposing someone to the risk of harm; even in the context of minimising the risk. However, there are many benefits to the studies and when volunteers understand the risk and choose to participate for the greater good, they can achieve important things.
Vaccines
One of the ways in which deliberate human infection studies (or ‘challenge studies’) are most beneficial is in the testing of vaccines. Vaccines are tested in the same way as any drug and the first studies involve a small number of participants who receive a dose of vaccine and are closely monitored to check first and foremost whether the vaccines are safe. These early studies (called Phase I clinical trials) can also inform about whether the vaccine is making an immune response. However, in order to demonstrate that the vaccine can prevent disease, much larger studies are needed. These studies (phase III) are often very large, because you can’t be sure how many of your vaccinated volunteers will then be exposed to the infectious agent. This means that you need huge numbers of subjects to get to statistically meaningful numbers to compare infection rates with and without a vaccine.
Infectious challenge studies can help to overcome this barrier, especially when the pathogen being tested is rare. One example of this is typhoid, a bacterial infection that causes diarrhoea in approximately 10-20 million people a year, mostly in low- and middle-income countries. A research team in Oxford gave volunteers a typhoid infection and tracked them untill they had clinical symptoms before treating them with antibiotics. Again, pausing to think of the volunteers – knowing that you are likely to get a bout of diarrhoea and going ahead with it anyway, for other people’s benefit, takes a special mindset.
Indeed, without volunteers, modern medicine would falter, so we all owe a large debt of thanks to these selfless individuals. Having shown it was possible to infect people in a controlled way, the Oxford group tested whether two new vaccines could reduce disease. They showed that whilst 77% of the volunteers without a vaccine developed typhoid, only 35% of the vaccinated volunteers did. Deliberate infection studies have also been used to support the rollout of vaccines for cholera, malaria and shigella.
Measuring antibodies
Another important benefit of deliberate human infection studies is in understanding how specific viruses cause disease and how we can be protected against them. The Common Cold Unit was a British research centre operating on Salisbury plain between 1946 and 1989. It set out to understand respiratory infections; being somewhat isolated it was able to look at transmission of colds, by infecting one volunteer and then housing them together with other uninfected volunteers. It also provided us with important information about the levels of immunity required to protect against influenza. By measuring antibodies in the blood of people before they were infected it was possible to identify a threshold above which infection was unlikely to occur; this threshold is still in use for the development of influenza vaccines.
Some diseases have more challenges than others in setting up the infections. Whilst respiratory viruses can be grown and dripped into the nose, other infections get into our bodies through a third organism, called a vector. In the case of schistosomiasis (sometimes called bilharzia), the disease-causing parasites live in snails (the vector) before infecting people. To help develop drugs and vaccines for this neglected tropical disease, researchers have had to learn snail husbandry!
Returning to the coronavirus human challenge studies, these look to address both the development of vaccines and improve our understanding about infection. In the earliest results from the Imperial-led study, the team showed symptoms start to develop very fast, on average about two days after contact with the virus. The infection first appears in the throat; infectious virus peaks about five days into infection and, at that stage, is significantly more abundant in the nose than the throat. It was seen that volunteers who had not had COVID-19 before could be infected with an extremely low dose of the virus, which might help to explain why SARS-CoV-2 is so infectious. It can also inform more generally about the behaviour of respiratory viruses. These studies are now progressing to help in the design and testing of the next generation of vaccines and drugs.
As we have seen in the last two years, infections can be extraordinarily disruptive. Studying how they behave, why we get infected and how to prevent this is extremely important – when performed safely and ethically, human infection studies are an important part of our toolkit.
John Tregoning is Reader in Respiratory Infections at the Department of Infectious Disease and has studied the immune responses to vaccination and respiratory infection for over 20 years.