Can we save lives by deliberately infecting people?

 In early March 2021, in the middle of the COVID-19 pandemic a surprising-sounding experiment was taking place. Researchers at Imperial College London and Oxford University in partnership with hVIVO 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 10^th Century China, deliberately inoculating healthy people with smallpox to make them immune to the disease. This practice continued into the 18^th 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 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 hypothesized 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.

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 informed consent. The volunteers were told about the risk to themselves of participation. Sadly, later in the 20^th century, some human infection studies entered a darker chapter where this consent was not sought, such as experimentation on prisoners in Nazi Germany and Imperial Japan.

Informed consent is the bedrock upon which all modern research involving volunteers is built, and infection studies are not exempt from that. The landscape of human infection studies has changed dramatically since the middle of the 20^th 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 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.

One of the ways in which deliberate human infection studies are most beneficial is in the testing of vaccines. Vaccines are tested in the same way as any drug, the first studies involve a small number of participants who 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, phase III, studies are often very large, the Pfizer COVID trial had 43,548 participants and Moderna 30,420. One of the reasons for these large numbers of participants is the uncertain nature of infection. Even during a pandemic, most people will not be exposed to the infectious agent (particularly if other measures, such as stay at home and social distancing are in place). This means that to get to statistically meaningful numbers to compare infection rates with and without the vaccine, you need more subjects. Infectious challenge studies can get around this, 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 till they had clinical symptoms before treating with antibiotics. Again, pausing to think of the volunteers – knowing that you are likely to get a bout of diarrhoea and going ahead 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 group tested whether 2 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.

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 parasites live in snails 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 infection study, this looks to address both the development of vaccines and improve our understanding about infection. In the earliest results from the study, it was seen that volunteers who had not had COVID 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 2 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.