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The Oxford Vaccine Group, part of University of Oxford, gave 99 volunteers a drink laced with live Salmonella Typhi bacteria a month after vaccinating them. Between 40% and 50% of the volunteers for the trial were students, Healthcare professionals were allowed to take part if they were not in patient-facing jobs or if they were willing to take around 3-4 weeks off work to be infected.
A third had been vaccinated with Typbar-TCV, a new conjugate typhoid vaccine, a third with established vaccine Typhim Vi and the rest with meningitis vaccine Menveo, which does not protect against typhoid. Neither the volunteers nor the doctors carrying out the injections knew who was getting which vaccine.
The volunteers were monitored by staff during daily visits to its centre at Oxford’s Churchill Hospital, and had 24-hour access to advice. When they showed signs of contracting typhoid, or after 14 days, they received a course of antibiotics to cure them.
Oxford Vaccine Group is now analysing the data, with results to be announced during 2017.
Andrew Pollard, the group’s director of the university’s professor of paediatric infection and immunity, says this kind of ‘challenge’ trial using a small number of volunteers provides a faster alternative to large-scale trials in countries where the disease is prevalent.
“What we’ve done is set up a model which allows us to test the vaccine very rapidly and efficiently. Rather than waiting for people living in the affected areas of the world to develop infection through exposure to contaminated food or water to see if the vaccine protects them, we vaccinate our healthy volunteers and then deliberately infect them, to see whether the vaccine will protect them or not,” he says.
The trial cost around £1.5m, with funding from the Bill and Melinda Gates Foundation and the European Commission. The cost of a field trial could be tens of millions of pounds.
"Human challenge models are a highly effective way to evaluate the potential utility of new vaccines and help inform development strategies that will ultimately lead to improvements in human health,” says Duncan Steele, the Gates Foundation’s deputy director and strategic lead for enteric vaccines. “The Oxford study on new typhoid vaccines will play an important role in helping direct understanding of the performance of these new generation vaccines to reduce the spread of typhoid in some of the poorest regions of the world."
Prof Pollard says that challenge trials can allow several kinds of vaccine to be tested, to see which is most suitable for field trials. The technique is already used to test vaccines for malaria and influenza, with other investigators in Oxford involved in such trials, as well as dengue fever and shigella dysentery.
Other conjugate vaccines, which combine sugars from the surface of bacteria with proteins rather than using live bacteria, are already used to prevent meningitis and pneumonia. Prof Pollard says Typbar-TCV, which has already been approved for use in India, looks likely to provide longer-lasting and more effective immunity.
Between 20m and 25m people contract typhoid every year worldwide, with at least 200,000-250,000 people dying from it. A study by Oxford Vaccine Group in Kathmandu in Nepal found that 15% of children taken to a primary health centre during the typhoid season had the bacterium in their blood.
Between 40% and 50% of the volunteers for the trial were students, but those from health and science backgrounds working for Oxford’s NHS trusts and universities were also well-represented. Healthcare professionals were allowed to take part if they were not in patient-facing jobs or if they were willing to take around 3-4 weeks off work to be infected.
Volunteers were paid expenses and for their time, although the latter worked out at not much more than the minimum wage, with a maximum of £2,930. The group’s research found that altruism was the main reason for taking part.
Daniel Lammin swallowed the typhoid drink in May 2016 while studying social work at Ruskin College in Oxford; he now works for mental health charity Oxfordshire Mind. Saying that “this is going to sound very social worker,” he says he took part “to help participate in creating a vaccine that could save potentially millions of lives across Asia and Africa – I felt I wanted to be part of that”. Nevertheless, staff insisting on explaining the trial several times before letting him volunteer, to make sure he understood the risks.
A week after infecting himself, he found his temperature was slightly up. “I didn’t actually feel ill,” he says, but when reporting it he was told to visit the centre the next morning to start a course of antibiotics, as well as anti-bacterial and anti-nausea drugs. “Other than being a bit sweaty from having a high temperature, I lost a little bit of my appetite and had a couple of muscle aches,” he says. “I’ve felt worse from things that I haven’t had to take medicines to heal from.” The whole process “felt really safe” due to the high level of monitoring.