Faster and smarter with CHIM studies

What makes CHIM studies so interesting?

Which characteristics does the immune system have before a patient is infected, and what changes occur during the incubation time? This can vary per patient. It is impossible to acquire information about this during research into ill patients. Furthermore, nobody knows at what exact time patients are infected nor in which dose the pathogen managed to penetrate. That is what makes CHIM studies interesting. Study subjects are deliberately exposed to a pathogen such as a bacteria, virus or parasite. This is usually with a low dose or a weakened form. If participants nevertheless become ill, then an effective therapy is available.

Fast and smart

CHIM studies are growing in popularity. Meta Roestenberg is Professor of Human Models for Vaccine Development at Leiden University Medical Center. ‘These studies are also interesting for pharmaceutical companies’, she says. ‘The study subject is administered a possibly effective vaccine or protective drug (prophylaxis), and then we check the effect after deliberate exposure to the pathogen. If the drug ultimately proves to have an insufficient effect, we no longer need to perform an expensive and time-consuming phase 3 study in which the vaccine or working drug is investigated in thousands of patients. CHIM is not a substitution for these large studies into the effectiveness. However, it is a tool to do things faster and smarter.’

CHIM studies into whooping cough and RSV

Dimitri Diavatopoulos, an immunologist at Radboudumc, investigates whooping cough. ‘For decades, infants have been vaccinated against this bacterial infection’, he says. ‘Nevertheless, the disease is occurring increasingly often, because although the vaccine combats the symptoms, it is less efficient at preventing someone from becoming infected. We are searching for a new vaccine that helps to combat the bacteria. If we are successful, then hopefully there will no longer be any whooping cough infections.’ He uses a CHIM for the research; adult study subjects are administered the whooping cough bacteria via the nasal mucosa. Diavatopoulos: ‘Due to ethical considerations, it is not possible to conduct such a study on children. CHIM does also have its limitations. It is a fit-for-purpose model.’

Louis Bont, Professor of Infectious diseases at University Medical Center Utrecht, has developed a possible drug against the respiratory syncytial virus (RSV). This is an influenza virus that kills 200,000 babies worldwide each year. A CHIM study will soon start, for which participants will not be admitted to a hospital but will quarantine at home. ‘That is comfortable for them’, he says, ‘and it saves us a lot of costs.’

Ethical frameworks of the WHO

Research in which healthy people are infected is controversial and has a fraught history. In the first half of the 20th-century, people in prisons and concentration camps were deliberately infected. Meta Roestenberg: ‘Nowadays, the ethical frameworks of CHIM studies receive a lot of attention. For example, the World Health Organisation (WHO) has a guideline for questions such as: how do you weigh up the risks against the importance of the research? Sometimes, that is clear: nobody would start a CHIM with HIV. However, there are also models in which the deliberations are complex or in which local societal influences play a role.’

Is there a role for CHIM studies in research into SARS-CoV-2?

An example of a model in which local societal influences play a role is the CHIM model for SARS-CoV-2. In the United States, CHIM studies are not being done, whereas they are being realised in the United Kingdom. On behalf of the Ministry of Health, Welfare and Sport, ZonMw appointed a committee of experts that assessed the utility and necessity of CHIM studies into SARS-CoV-2 for the Netherlands. Meta Roestenberg was the applicant for the study, and Dimitri Diavatopoulos and Louis Bont were members of the committee as was paediatrician Else Bijker from the University of Oxford. The report was submitted to the Ministry of Health, Welfare and Sport in September 2021.

Wait, debate and prepare now policy

Based on the report from the committee members, ZonMw advised a wait, debate and prepare now policy. ‘Young people can also become severely ill from the virus or develop Lung COVID. There is no effective treatment, and so no absolutely effective medicine is available’, says Else Bijker. If we prepare properly, then we will be able to start faster as soon as the need is sufficiently high.’

‘Is there fire damage or extinguishing damage?’

‘Sometimes, a CHIM is the only possibility to distinguish cause and effect’, says Louis Bont. For example, do people fall ill from SARS-CoV-2 or from the immune response to it? In a nutshell, are we talking about fire damage or extinguishing damage?’ He doubts whether a CHIM against SARS-CoV-2 should be started in a situation where there were few infections. If there are many infections, as is currently the case, then a different deliberation could be made.

‘A CHIM can lead to unexpected findings’

Dimitri Diavatopoulos would welcome a study into SARS-CoV-2. ‘A CHIM can lead to unexpected findings’, he says. ‘In the CHIM for whooping cough, we discovered that study subjects with antibodies in their nasal mucosa had not produced antibodies in their blood. Neither did they become infected after exposure to the bacteria; we did not find the bacteria in them at any of the check-ups. However, in study subjects without antibodies in the mucosa, we did find antibodies in the blood. We also found the bacteria in their nasal mucosa during the check-ups. We soon plan to start a similar CHIM study into pneumococci, a bacteria that can cause pneumonia. The role of the mucosa is very interesting.’

‘These are complex studies, and we have the expertise’

Meta Roestenberg is also a proponent of CHIM research into SARS-CoV-2 in the Netherlands. ‘A variant could emerge that is insensitive for the current vaccines’, she said at the time of the interview. ‘We would do well to be prepared for that.’ She believes the Netherlands – together with several other countries – is ideally suited for CHIM studies. ‘Our ethical committees and regulatory bodies are strong, and our labs satisfy the highest safety and quality requirements. These are complex studies, and we have the expertise. Try culturing a vial of viruses. That is anything but simple.’

See the summary of the advisory report (only in Dutch)

COVID-19 programme

Together with the commissioning bodies, policymakers, researchers, patients, professionals from the field, data professionals and international partners, ZonMw is working on current and future possibilities to contribute with research and knowledge to solutions that combat coronavirus and COVID-19 and their effects on society. The advisory report is one aspect of this.

Text: Riëtte Duynstee
Final editing: ZonMw