Infecting people on purpose:
The power of human challenge studies in tackling infectious disease

While malaria has been eradicated in several countries around the world, the mosquito-borne disease continues to be a pervasive threat in sub-Saharan Africa, claiming the lives of over half a million people each year. Most are children under five years of age. 

"The continent is being held back by a disease that can be treated and prevented. To do nothing is criminal," says Professor Faith Osier, Co-Director of Imperial’s Institute of Infection and Chair of Immunology and Vaccinology in the Faculty of Natural Sciences. 

A passionate advocate for Africa, its science and scientists, Professor Osier is on a mission to make malaria history through vaccination.

"I’ve been working on malaria for around 30 years, trying to understand how people become immune", she says.

Brought up in Nairobi, Kenya, Professor Osier first witnessed the devastating effects of malaria when working in paediatrics as a junior doctor in a rural district hospital.

"I was seeing firsthand the destructive impact it was having in my country."

It was here where Professor Osier’s drive to understand the mechanisms of immunity against malaria was ignited. 

"The children that I was treating on the ward every day were getting the disease very badly and developing severe complications afterwards, or sometimes even losing their lives. In contrast, their parents who were bringing them to hospital – who lived in the same house and were getting bitten by the same mosquitoes – were not getting ill", she explains. 

"It became obvious that their immune systems had somehow learnt to counter the infection. That’s how I became interested in understanding immunity because if you can understand that, then you can design a vaccine that can do the same thing but not take as long as naturally acquired immunity."

In an effort to design better vaccines, a team from the KEMRI-Wellcome Trust Research Program in Kilifi, Kenya, where Professor Osier previously worked, led the Controlled Human Malaria Infection in Semi-Immune Kenyan Adults (CHMI-SIKA) study. It involved purposely infecting semi-immune adult volunteers (those who had previously been naturally infected multiple times) from Kenya with malaria. 

"What's been absolutely magical about this human challenge study is that we’ve been able to show that this concept of ‘immunity in the community’ is really true", she says. 

"We saw from our experiment that when you infect volunteers who’ve had malaria many times before, their immune systems simply gobble it up and it doesn’t touch them at all. They don’t get sick. 

"But the next step was to unravel what was going on at a molecular level in order to inform the design of better vaccines."

The study revealed that the principle behind most vaccines – generating antibodies that bind to the infectious pathogen and fight it off – is only part of the story for malaria infection. Instead, antibodies that effectively ‘recruit’ other parts of the immune system were found to provide enhanced protection against malaria infection. 

As a result of their findings, the international research team has identified a possible way to produce these antibodies and is now creating experimental vaccines on various platforms to find the most effective one. 

Reflecting on her own experiences of malaria and what motivates her work, Professor Osier states: “As a mother, when you’re repeatedly faced with parents who’ve lost a child and have experienced that kind of devastation, you begin to understand what a huge impact it has on human life. 

"I believe that every life has value and the potential to achieve something great. Unfortunately, a lot of that potential is wasted because so many people succumb to this disease.

"So, when we intervene and prevent disease, we do good for humanity."

"Salmonellosis is a disease with an 'image problem'," states Dr Malick Gibani, Clinical Lecturer in the Department of Infectious Disease at Imperial.

"Somewhere in the region of 15 to 30 per cent of children infected with invasive non-typhoidal Salmonella die, and there aren't many illnesses like this where around a third of people die."

Despite being one of the leading causes of bloodstream infections in sub-Saharan Africa, invasive non-typhoidal Salmonella (iNTS) is poorly understood. But Dr Gibani hopes to change that.  

"Malaria, COVID-19, and influenza are all illnesses that have a high profile. They don’t take a huge amount of explaining to healthy volunteers. But when it comes to NTS, it’s not typically something that people have heard about," he says.  

"From an advocacy perspective, this is something that we’ve spent quite a lot of time thinking about because we’re trying to convince decision-makers and stakeholders that iNTS is something that we critically need to invest in."

NTS is the name given to a group of bacteria that typically cause foodborne illness. Most people experience diarrhoea and fever and recover over the course of a few days. These infections are usually linked to contaminated food or water and differ from typhoid fever, which is caused by another, specific type of salmonella.  

In some instances, these bacteria cross the gut and enter the bloodstream to cause a much more severe form of the disease – called invasive disease. This is almost always seen in medically vulnerable populations (infants, the elderly and immune-compromised patients), where iNTS can be life-threatening and can result in serious complications such as septicaemia and kidney failure.  

"To a certain extent, this is a geographically restricted disease where we see the highest burden of the disease in sub-Saharan Africa," Dr Gibani explains.  

"It’s predominantly seen in young children who are malnourished or immuno-compromised. There is a particularly strong association with other infections like malaria and in some cases, advanced HIV infection.

"It’s definitely a neglected disease but I think it's something where we can find an effective solution for, like a vaccine."

That’s why, as part of the Challenge Non-Typhoidal Salmonella (CHANTS) study, Dr Gibani and his team are working with Imperial College Healthcare NHS Trust to run and develop a human challenge model that can be used to test and accelerate vaccines for NTS – a world first.  

Known as a ‘dose-escalation’ study, CHANTS aims to determine the lowest possible dose of bacteria needed for volunteers to meet the criteria for diagnosis. Once the optimal dose is established and the model is proven safe, it can be replicated in future to test different vaccines. 

"The fact that this study is even happening at all is a major achievement. There’s already a lot of interest in the data that we're generating, both from key stakeholders in the regulatory space and vaccine stakeholders," he says.  

Having taken place across 2024, Dr Gibani is keen to translate the research findings into real-world practice and decision-making.  

"We want to build partnerships with vaccine developers so that we can use the model to accelerate potential candidates and get vaccines into the arms of people who need it the most."

Indeed, one key partner that Dr Gibani’s group is working closely with is GSK Vaccines Institute for Global Health (GVGH) to study antibody responses to Salmonella. They develop and research vaccines aimed at preventing and treating infectious diseases that disproportionately affect people in LMICs, with a particular focus on diseases with antimicrobial resistance (AMR) potential.  

“Salmonella has been included as a priority pathogen in the World Health Organization’s updated Bacterial Priority Pathogens List – a list of drug-resistant bacteria most threatening to human health,” he explains.  

“Waiting any longer to tackle this global health threat is therefore not an option. iNTS demands the research and development community’s immediate attention.”  

Dr Gibani and his team hope to develop further challenge models and identify ‘correlates of protection’ for iNTS. These are specific measurable signs in the body, like antibodies or immune responses, that indicate someone is protected from a disease. Researchers use these markers in vaccine development to understand if a vaccine is effective in providing immunity without waiting for actual infections to occur.

As someone who is fascinated by the transmission routes of respiratory viruses like influenza, it’s perhaps unsurprising that Professor Wendy Barclay has spearheaded efforts to apply this knowledge to COVID-19.

"What does it take for a virus to jump across from animals into humans? And then what does it take once it's in a human to become airborne? That’s what I’m really interested in," says Professor Barclay, Head of Imperial’s Department of Infectious Disease.  

During the height of the COVID-19 pandemic, she worked extensively with Imperial colleagues like Professor Chris Chiu, Dr Anika Singanayam and Dr Jie Zhou to provide granular insights into how people infected with COVID-19 spread the virus to their immediate surroundings. 

Harnessing her expertise in molecular virology, she facilitated the onerous process of creating a lab-grown SARS-CoV-2 strain that could be used to inoculate volunteers in the world’s first human challenge study for COVID-19.  

“At the time, it was the height of the pandemic and with it being a new virus, nobody really knew how to properly grow it in a lab. We therefore had to do lots of sequencing to check the virus wasn’t changing as we propagated in the cultured cells”, she explains.  

“We then had to work out how much virus to use because nobody knew when you caught COVID how many virus particles actually infected a person.  

“The safety of our volunteers was paramount, so we decided to go in with an incredibly low dose, and we hit it spot on because half of the volunteers got infected and half of them didn't.  

“In virology that's the perfect number because you get some people in whom you can study the virus growing intently, while from an immunology point of view, you've also got some people whose immune system is doing something for them to stop them getting infected, therefore allowing you to directly compare the groups.” 

Dr Anika Singanayam, who served as Principal Investigator of the study, echoes Professor Barclay’s sentiments about the value of this type of study design: "We could take samples from the same person frequently and longitudinally, allowing us to understand things in a lot more detail. For example, when people were emitting the most virus in relation to their symptoms, and how much virus we could detect from a swab of their nose and throat. These sorts of things are difficult to look at through other study designs, or through natural infection studies."

One of the major insights gleaned from the research was that the nose is a significant route for infected people shedding virus into the air and environment. This highlighted the need to reinforce public health messaging around proper face mask use, hand washing and surface cleaning.  

Looking ahead, Professor Barclay is keen to see human challenge studies move towards a ‘controlled transmission model’ for airborne viruses.  

“To understand the transmission of a virus, you need two people, not one. So, what I’d like to do next is move towards a transmission model where you've got a ‘donor’ and a ‘sentinel’. The donor is the person who you know is infected and the sentinel is like the canary in the coal mine, who may or may not get infected depending on whether the donor is breathing out lots of infectious virus.  

“Nobody's ever done this successfully in a human challenge model before, but I think that's what we need next. Because when the next outbreak comes, I honestly think that will be key to controlling an outbreak – understanding how you can stop a person transmitting to somebody else.”